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Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (EDNRB) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was en- hanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway.

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Language：English   Publishing type：Research paper (scientific journal)  

We aimed to identify the target antigens for combined central and peripheral demyelination (CCPD).
METHODS:
We screened target antigens by immunohistochemistry and immunoblotting using peripheral nerve tissues to identify target antigens recognized by serum antibodies from selected CCPD and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) cases. We then measured the level of antibody to the relevant antigen in 7 patients with CCPD, 16 patients with CIDP, 20 patients with multiple sclerosis, 20 patients with Guillain-Barré syndrome, 21 patients with other neuropathies, and 23 healthy controls (HC) by ELISA and cell-based assays using HEK293 cells.
RESULTS:
At the initial screening, sera from 2 patients with CCPD showed cross-like binding to sciatic nerve sections at fixed intervals, with nearly perfect colocalization with neurofascin immunostaining at the node and paranode. ELISA with recombinant neurofascin revealed significantly higher mean optical density values in the CCPD group than in other disease groups and HC. Anti-neurofascin antibody positivity rates were 86% in patients with CCPD, 10% in patients with multiple sclerosis, 25% in patients with CIDP, 15% in patients with Guillain-Barré syndrome, and 0% in patients with other neuropathies and HC. The cell-based assay detected serum anti-neurofascin antibody in 5 of 7 patients with CCPD; all others were negative. CSF samples examined from 2 patients with CCPD were both positive. In anti-neurofascin antibody-positive CCPD patients, including those with a limited response to corticosteroids, IV immunoglobulin or plasma exchange alleviated the symptoms.
CONCLUSION:
Anti-neurofascin antibody is frequently present in patients with CCPD. Recognition of this antibody may be important, because patients with CCPD who are antibody positive respond well to IV immunoglobulin or plasma exchange.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Brain, Behavior, and Immunity  

Multiple system atrophy (MSA) is a severe α-synucleinopathy facilitated by glial reactions; the cerebellar variant (MSA-C) preferentially involves olivopontocerebellar fibres with conspicuous demyelination. A lack of aggressive models that preferentially involve olivopontocerebellar tracts in adulthood has hindered our understanding of the mechanisms of demyelination and neuroaxonal loss, and thus the development of effective treatments for MSA. We therefore aimed to develop a rapidly progressive mouse model that recaptures MSA-C pathology. We crossed Plp1-tTA and tetO-SNCA*A53T mice to generate Plp1-tTA::tetO-SNCA*A53T bi-transgenic mice, in which human A53T α-synuclein-a mutant protein with enhanced aggregability-was specifically produced in the oligodendrocytes of adult mice using Tet-Off regulation. These bi-transgenic mice expressed mutant α-synuclein from 8 weeks of age, when doxycycline was removed from the diet. All bi-transgenic mice presented rapidly progressive motor deterioration, with wide-based ataxic gait around 22 weeks of age and death around 30 weeks of age. They also had prominent demyelination in the brainstem/cerebellum. Double immunostaining demonstrated that myelin basic protein was markedly decreased in areas in which SM132, an axonal marker, was relatively preserved. Demyelinating lesions exhibited marked ionised calcium-binding adaptor molecule 1-, arginase-1-, and toll-like receptor 2-positive microglial reactivity and glial fibrillary acidic protein-positive astrocytic reactivity. Microarray analysis revealed a strong inflammatory response and cytokine/chemokine production in bi-transgenic mice. Neuronal nuclei-positive neuronal loss and patchy microtubule-associated protein 2-positive dendritic loss became prominent at 30 weeks of age. However, a perceived decrease in tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta in bi-transgenic mice compared with wild-type mice was not significant, even at 30 weeks of age. Wild-type, Plp1-tTA, and tetO-SNCA*A53T mice developed neither motor deficits nor demyelination. In bi-transgenic mice, double immunostaining revealed human α-synuclein accumulation in neurite outgrowth inhibitor A (Nogo-A)-positive oligodendrocytes beginning at 9 weeks of age; its expression was further increased at 10 to 12 weeks, and these increased levels were maintained at 12, 24, and 30 weeks. In an α-synuclein-proximity ligation assay, α-synuclein oligomers first appeared in brainstem oligodendrocytes as early as 9 weeks of age; they then spread to astrocytes, neuropil, and neurons at 12 and 16 weeks of age. α-Synuclein oligomers in the brainstem neuropil were most abundant at 16 weeks of age and decreased thereafter; however, those in Purkinje cells successively increased until 30 weeks of age. Double immunostaining revealed the presence of phosphorylated α-synuclein in Nogo-A-positive oligodendrocytes in the brainstem/cerebellum as early as 9 weeks of age. In quantitative assessments, phosphorylated α-synuclein gradually and successively accumulated at 12, 24, and 30 weeks in bi-transgenic mice. By contrast, no phosphorylated α-synuclein was detected in wild-type, tetO-SNCA*A53T, or Plp1-tTA mice at any age examined. Pronounced demyelination and tubulin polymerisation, promoting protein-positive oligodendrocytic loss, was closely associated with phosphorylated α-synuclein aggregates at 24 and 30 weeks of age. Early inhibition of mutant α-synuclein expression by doxycycline diet at 23 weeks led to fully recovered demyelination; inhibition at 27 weeks led to persistent demyelination with glial reactions, despite resolving phosphorylated α-synuclein aggregates. In conclusion, our bi-transgenic mice exhibited progressively increasing demyelination and neuroaxonal loss in the brainstem/cerebellum, with rapidly progressive motor deterioration in adulthood. These mice showed marked microglial and astrocytic reactions with inflammation that was closely associated with phosphorylated α-synuclein aggregates. These features closely mimic human MSA-C pathology. Notably, our model is the first to suggest that α-synuclein oligomers may spread from oligodendrocytes to neurons in transgenic mice with human α-synuclein expression in oligodendrocytes. This model of MSA is therefore particularly useful for elucidating the in vivo mechanisms of α-synuclein spreading from glia to neurons, and for developing therapies that target glial reactions and/or α-synuclein oligomer spreading and aggregate formation in MSA.

DOI： 10.1016/j.bbi.2024.07.004

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：The Lancet Neurology  

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system that can lead to severe disability from muscle weakness and sensory disturbances. Around a third of patients do not respond to currently available treatments, and many patients with a partial response have residual neurological impairment, highlighting the need for effective alternatives. Efgartigimod alfa, a human IgG1 antibody Fc fragment, has demonstrated efficacy and safety in patients with generalised myasthenia gravis. We evaluated the safety, tolerability, and efficacy of subcutaneous efgartigimod PH20 in adults with CIDP. METHODS: ADHERE, a multistage, double-blind, placebo-controlled trial, enrolled participants with CIDP from 146 clinical sites from Asia-Pacific, Europe, and North America. Participants with evidence of clinically meaningful deterioration entered an open-label phase of weekly 1000 mg subcutaneous efgartigimod PH20 for no longer than 12 weeks (stage A). Those with confirmed evidence of clinical improvement (ECI; treatment responders) entered a randomised-withdrawal phase of 1000 mg subcutaneous efgartigimod PH20 weekly treatment versus placebo for a maximum of 48 weeks (stage B). Participants were randomised (1:1) through interactive response technology and stratified by their adjusted Inflammatory Neuropathy Cause and Treatment (aINCAT) score change during stage A and their most recent CIDP medication within 6 months before screening. Investigators, the clinical research organisation, and participants were masked to the treatment. The primary endpoint in stage A, evaluated in the stage A safety population, was confirmed ECI (≥1 points aINCAT decrease, ≥4 points [centile metric] Inflammatory Rasch-built Overall Disability Scale increase, or ≥8 kPa grip strength increase after four injections and two consecutive visits). The primary endpoint in stage B, evaluated in the modified intention-to-treat population, was the risk of relapse (time to first aINCAT increase of ≥1 points). ADHERE is registered with ClinicalTrials.gov (NCT04281472) and EudraCT (2019-003076-39) and is completed. FINDINGS: Between April 15, 2020, and May 11, 2023, 629 participants were screened; 322 (114 female, 208 male) entered stage A, of whom 214 (66%, 95% CI 61·0-71·6) had confirmed ECI. In stage B, 221 participants were randomised (79 female, 142 male; 111 to subcutaneous efgartigimod PH20, 110 to placebo). Subcutaneous efgartigimod PH20 significantly reduced the risk of relapse versus placebo (hazard ratio 0·39 [95% CI 0·25-0·61]; p<0·0001). 31 (27·9% [19·6-36·3]) participants given subcutaneous efgartigimod PH20 had a relapse versus 59 (53·6% [44·3-63·0]) given placebo. In stage A, treatment-emergent adverse events (TEAEs) occurred in 204 (63%) participants and serious TEAEs in 21 (7%). In stage B, TEAEs occurred in 71 (64%) participants on subcutaneous efgartigimod PH20 and 62 (56%) participants on placebo, and serious TEAEs in six (5%) on subcutaneous efgartigimod PH20 and six (5%) on placebo. Three deaths occurred: two in stage A (one non-related and one unlikely related to treatment) and one in stage B (placebo group). INTERPRETATION: ADHERE showed the efficacy of subcutaneous efgartigimod PH20 in reducing the risk of relapse versus placebo in people with CIDP who responded to treatment. Further studies are needed to provide data on the longer-term effects of efgartigimod alfa and how it compares with currently available treatment options. FUNDING: argenx.

DOI： 10.1016/S1474-4422(24)00309-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Diabetologia  

AIMS/HYPOTHESIS: Diabetic retinopathy is characterised by neuroinflammation that drives neuronal and vascular degenerative pathology, which in many individuals can lead to retinal ischaemia and neovascularisation. Infiltrating macrophages and activated retina-resident microglia have been implicated in the progression of diabetic retinopathy, although the distinct roles of these immune cells remain ill-defined. Our aim was to clarify the distinct roles of macrophages/microglia in the pathogenesis of proliferative ischaemic retinopathies. METHODS: Murine oxygen-induced retinopathy is commonly used as a model of ischaemia-induced proliferative diabetic retinopathy (PDR). We evaluated the phenotype macrophages/microglia by immunostaining, quantitative real-time RT-PCR (qRT-PCR), flow cytometry and scRNA-seq analysis. In clinical imaging studies of diabetic retinopathy, we used optical coherence tomography (OCT) and OCT angiography. RESULTS: Immunostaining, qRT-PCR and flow cytometry showed expression levels of M1-like macrophages/microglia markers (CD80, CD68 and nitric oxide synthase 2) and M2-like macrophages/microglia markers (CD206, CD163 and macrophage scavenger receptor 1) were upregulated in areas of retinal ischaemia and around neo-vessels, respectively. scRNA-seq analysis of the ischaemic retina revealed distinct ischaemia-related clusters of macrophages/microglia that express M1 markers as well as C-C chemokine receptor 2. Inhibition of Rho-kinase (ROCK) suppressed CCL2 expression and reduced CCR2-positive M1-like macrophages/microglia in areas of ischaemia. Furthermore, the area of retinal ischaemia was reduced by suppressing blood macrophage infiltration not only by ROCK inhibitor and monocyte chemoattractant protein-1 antibody but also by GdCl3. Clinical imaging studies of diabetic retinopathy using OCT indicated potential involvement of macrophages/microglia represented by hyperreflective foci in areas of reduced perfusion. CONCLUSIONS/INTERPRETATION: These results collectively indicated that heterotypic macrophages/microglia differentially contribute to retinal ischaemia and neovascularisation in retinal vascular diseases including diabetic retinopathy. This adds important new information that could provide a basis for a more targeted, cell-specific therapeutic approach to prevent progression to sight-threatening PDR.

DOI： 10.1007/s00125-024-06215-3

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Publisher：Neurology and Clinical Neuroscience  

Objective: To elucidate the roles of microglia and macrophages in neuroinflammation and their dual impact on the progression of neurological diseases. Background: Microglia and macrophages are integral components of the central and peripheral nervous systems, where they play important roles in maintaining homeostasis, influencing disease progression, and facilitating repair mechanisms. Methods: The review integrates recent advancements in single-cell RNA sequencing that highlight the extensive heterogeneity of microglia and macrophages, which helps in understanding their wide-ranging roles in different neurological conditions. Results: The analysis reveals that microglia and macrophages have a dual nature, capable of both exacerbating and mitigating disease processes across various conditions, including Alzheimer’s disease, multiple sclerosis, stroke, peripheral nerve disorders, and brain tumors. Conclusion: Modulating the activity of microglia and macrophages offers a promising avenue for therapeutic interventions in neurological disorders. There is a critical need for further research to fully leverage their therapeutic potential in targeting neuroinflammation to enhance patient outcomes.

DOI： 10.1111/ncn3.12829

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Language：English   Publisher：(一社)日本神経学会  

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neuropathology  

The hypothalamus is the region of the brain that integrates the neuroendocrine system and whole-body metabolism. Patients with Alzheimer's disease (AD) have been reported to exhibit pathological changes in the hypothalamus, such as neurofibrillary tangles (NFTs) and amyloid plaques (APs). However, few studies have investigated whether hypothalamic AD pathology is associated with clinical factors. We investigated the association between AD-related pathological changes in the hypothalamus and clinical pictures using autopsied brain samples obtained from deceased residents of a Japanese community. A total of 85 autopsied brain samples were semi-quantitatively analyzed for AD pathology, including NFTs and APs. Our histopathological studies showed that several hypothalamic nuclei, such as the tuberomammillary nucleus (TBM) and lateral hypothalamic area (LHA), are vulnerable to AD pathologies. NFTs are observed in various neuropathological states, including normal cognitive cases, whereas APs are predominantly observed in AD. Regarding the association between hypothalamic AD pathologies and clinical factors, the degree of APs in the TBM and LHA was associated with a lower body mass index while alive, after adjusting for sex and age at death. However, we found no significant association between hypothalamic AD pathology and the prevalence of hypertension, diabetes, or dyslipidemia. Our study showed that a lower BMI, which is a poor prognostic factor of AD, might be associated with hypothalamic AP pathology and highlighted new insights regarding the disruption of the brain-whole body axis in AD.

DOI： 10.1111/neup.12974

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Publisher：医歯薬出版  

DOI： 10.32118/cr033020142

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

<p>We describe a 44-year-old man with a complaint of atonic seizures of the left upper limb, followed by generalized seizures. Brain MRI showed isolated juxtacortical white matter T₂ hyperintensity with gadolinium (Gd) enhancement of the adjacent cortical gray matter and subcortical white matter in the right frontal convexity. Treatment with levetiracetam was effective for seizure suppression, and he had no other neurological abnormalities. Human leukocyte antigen typing revealed B54 and Cw1, which indicated the possibility of neuro-Sweet disease. However, a general examination, which included vital signs and eye and skin findings, was normal. A cerebrospinal fluid test showed a mild elevation in protein levels without pleocytosis and a normal range of interleukin-6. Electroencephalography showed intermittent slow waves without epileptic discharge in the bilateral temporal lobes. We detected subtle flow voids in the pia mater of the left frontal lobe, which suggested cerebrovascular disease, and specifically, the possibility of dural arteriovenous fistulas. Computed tomography angiography showed abnormally dilated perimedullary veins in the left frontal lobe. Cerebral angiography confirmed the existence of four dural arteriovenous fistulas, which included two retrograde leptomeningeal venous drainages in the right frontal cortical veins supplied by the anterior branch of the right middle meningeal artery. The other dural arteriovenous fistulas were retrograde leptomeningeal venous drainages in the left frontal cortical veins supplied by the anterior and posterior convexity branches of the left middle meningeal artery. The patient underwent successful endovascular embolization of all dural arteriovenous fistulas with Onyx injection. A follow-up MRI showed gradual improvement of the T₂ hyperintensity and Gd enhancement. He remained seizure-free for 2 years following endovascular embolization.</p>

DOI： 10.5692/clinicalneurol.cn-001947

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Language：Japanese   Publisher：The Pharmaceutical Society of Japan  

<p>難病中の難病である筋萎縮性側索硬化症の病態解明と治療法開発を目指し、著者らは全く新たな観点=脊髄前角細胞から末梢へ伸びる末梢神経軸索を「導管」に見立て、運ばれてくる異常蛋白の除去機構を疾患モデルを用いて検討した。その結果、マクロファージは確かに異常蛋白のクリアランスに寄与しており、これらのマクロファージ除去により脊髄前角細胞の脱落が促進した。末梢神経軸索輸送を介した異常蛋白の運搬除去に、マクロファージが重要な役割を果たしていることが明らかとなった。</p>

DOI： 10.14894/faruawpsj.60.5_409

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Language：English   Publisher：International Journal of Molecular Sciences  

Connexins (Cxs) form gap junctions through homotypic/heterotypic oligomerization. Cxs are initially synthesized in the endoplasmic reticulum, then assembled as hexamers in the Golgi apparatus before being integrated into the cell membrane as hemichannels. These hemichannels remain closed until they combine to create gap junctions, directly connecting neighboring cells. Changes in the intracellular or extracellular environment are believed to trigger the opening of hemichannels, creating a passage between the inside and outside of the cell. The size of the channel pore depends on the Cx isoform and cellular context-specific effects such as posttranslational modifications. Hemichannels allow various bioactive molecules, under ~1 kDa, to move in and out of the host cell in the direction of the electrochemical gradient. In this review, we explore the fundamental roles of Cxs and their clinical implications in various neurological dysfunctions, including hereditary diseases, ischemic brain disorders, degenerative conditions, demyelinating disorders, and psychiatric illnesses. The influence of Cxs on the pathomechanisms of different neurological disorders varies depending on the circumstances. Hemichannels are hypothesized to contribute to proinflammatory effects by releasing ATP, adenosine, glutamate, and other bioactive molecules, leading to neuroglial inflammation. Modulating Cxs’ hemichannels has emerged as a promising therapeutic approach.

DOI： 10.3390/ijms242316879

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Transplantation Proceedings  

Autoimmune encephalitis after liver transplantation (LT) is a rare disorder. This is because patients are usually in an immunosuppressed state after LT. Here, we report a rare case of autoantibody-negative autoimmune-encephalitis-induced coma after living-donor (LD) LT. A 45-year-old woman who underwent LDLT for primary biliary cholangitis (PBC) was brought to our hospital with the chief complaint of cognitive deficiency and an episode of memory loss. Physical examination, laboratory tests, and cerebrospinal fluid analysis revealed no significant findings. However, diffusion-weighted magnetic resonance imaging showed hyperintensity in the bilateral hippocampus. No autoantibodies associated with autoimmune encephalitis were detected. The diagnosis of antibody-negative autoimmune encephalitis was made on the basis of low immunosuppressive drug levels in the blood (indicative of poor adherence) and the presence of PBC as the autoimmune disease. The patient regained consciousness after intravenous methylprednisolone pulse therapy and plasma exchange. This case highlights that when examining patients with impaired consciousness after LDLT, it is important to consider autoimmune encephalitis as a potential diagnosis.

DOI： 10.1016/j.transproceed.2023.07.005

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Brain Pathology  

The pathological hallmark of multiple system atrophy (MSA) is aberrant accumulation of phosphorylated α-synuclein in oligodendrocytes, forming glial cytoplasmic inclusions (GCIs). Extensive demyelination occurs particularly in the olivopontocerebellar and striatonigral pathways, but its precise mechanism remains elusive. Glial connexins (Cxs), which form gap junction channels between astrocytes and oligodendrocytes, play critical roles in myelin maintenance, and have not been studied in MSA. Therefore, we immunohistochemically investigated glial Cx changes in the cerebellar afferent fibers in 15 autopsied patients with MSA. We classified demyelinating lesions into three stages based on Klüver-Barrera staining: early (Stage I), intermediate (Stage II), and late (Stage III) stages showing subtle, moderate, and severe myelin reduction, respectively. Myelin-associated glycoprotein, but not myelin oligodendrocyte glycoprotein, was preferentially decreased in Stage I, suggesting distal oligodendrogliopathy type demyelination. Accumulation of phosphorylated α-synuclein in oligodendrocytes was frequently seen in Stage I but less frequently observed in Stages II and III. Tubulin polymerization-promoting protein (TPPP/p25α)-positive oligodendrocytes were preserved in Stage I but successively decreased in Stages II and III. Even at Stage I, Cx32 was nearly absent from myelin, despite the relative preservation of other nodal proteins, such as neurofascin, claudin-11/oligodendrocyte-specific protein, and contactin-associated protein 1, which successively decreased in the later stages. Cx32 was re-distributed in the oligodendrocyte cytoplasm and co-localized with GCIs. Cx47 gradually decreased at the oligodendrocyte surface in a stage-dependent manner but was not co-localized with GCIs. Astrocytic Cx43 was down-regulated in Stage I but up-regulated in Stages II and III, reflecting astrogliosis. Cx43/Cx47 gap junctions significantly decreased from Stage I to III. Activated microglia/macrophages and T cells infiltrated in Stage I rather than Stages II and III. Therefore, early and extensive alterations of glial Cxs, particularly Cx32 loss, occur in MSA and may accelerate distal oligodendrogliopathy type demyelination and nodal/paranodal dysfunction through disruption of inter-glial communication.

DOI： 10.1111/bpa.13131

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：eClinicalMedicine  

Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients.

Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol.

Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]).

Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo.

Funding: Japan Agency for Medical Research and Development.

Keywords: COQ2; Clinical trial; Disease-modifying therapy; Multiple system atrophy; Ubiquinol.

DOI： 10.1016/j.eclinm.2023.101920

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurology: Neuroimmunology and NeuroInflammation  

BACKGROUND AND OBJECTIVES: The objective of this study was to discover novel nodal autoantibodies in chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: We screened for autoantibodies that bind to mouse sciatic nerves and dorsal root ganglia (DRG) using indirect immunofluorescence (IFA) assays with sera from 113 patients with CIDP seronegative for anti-neurofascin 155 and anticontactin-1 antibodies and 127 controls. Western blotting, IFA assays using HEK293T cells transfected with relevant antigen expression plasmids, and cell-based RNA interference assays were used to identify target antigens. Krox20 and Periaxin expression, both of which independently control peripheral nerve myelination, was assessed by quantitative real-time PCR after application of patient and control sera to Schwann cells. RESULTS: Sera from 4 patients with CIDP, but not control sera, selectively bound to the nodal regions of sciatic nerves and DRG satellite glia (p = 0.048). The main immunoglobulin G (IgG) subtype was IgG4. IgG from these 4 patients stained a 60-kDa band on Western blots of mouse DRG and sciatic nerve lysates. These features indicated leucine-rich repeat LGI family member 4 (LGI4) as a candidate antigen. A commercial anti-LGI4 antibody and IgG from all 4 seropositive patients with CIDP showed the same immunostaining patterns of DRG and cultured rat Schwann cells and bound to the 60-kDa protein in Western blots of LGI4 overexpression lysates. IgG from 3 seropositive patients, but none from controls, bound to cells cotransfected with plasmids containing LGI4 and a disintegrin and metalloprotease domain-containing protein 22 (ADAM22), an LGI4 receptor. In cultured rat Schwann and human melanoma cells constitutively expressing LGI4, LGI4 siRNA effectively downregulated LGI4 and reduced patients' IgG binding compared with scrambled siRNA. Application of serum from a positive patient to Schwann cells expressing ADAM22 significantly reduced the expression of Krox20, but not Periaxin. Anti-LGI4 antibody-positive patients had a relatively old age at onset (mean age 58 years), motor weakness, deep and superficial sensory impairment with Romberg sign, and extremely high levels of CSF protein. Three patients showed subacute CIDP onset resembling Guillain-Barré syndrome. DISCUSSION: IgG4 anti-LGI4 antibodies are found in some elderly patients with CIDP who present subacute sensory impairment and motor weakness and are worth measuring, particularly in patients with symptoms resembling Guillain-Barré syndrome.

DOI： 10.1212/NXI.0000000000200081

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Multiple Sclerosis and Related Disorders  

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), smoking is a known risk factor for disease susceptibility and disability progression. However, its impact on the efficacy of oral disease-modifying drugs (DMDs) is unclear. Therefore, we initiated a single-center, retrospective, observational study to investigate the relationship between smoking and disease activity in RRMS patients under oral DMDs. METHODS: We retrospectively enrolled RRMS patients who initiated oral DMDs (fingolimod or dimethyl fumarate) at our hospital between January 2012 and December 2019. Clinical data and smoking status at oral DMD initiation were collected up to December 2020. We conducted survival analyses for relapse and any disease activity, defined as relapse or MRI disease activity, among patients with distinct smoking statuses. RESULTS: We enrolled 103 RRMS patients under oral DMDs including 19 (18.4%) current smokers at baseline. Proportions of relapses and any disease activity during follow-up were higher in current smokers (relapse: p = 0.040, any disease activity: p = 0.004) and time from initiating oral DMDs to relapse was shorter in current smokers (log-rank test: p = 0.011; Cox proportional hazard analysis: hazard ratio (HR) 2.72 [95% confidence interval (CI) 1.22-6.09], p = 0.015) than in non-smokers. Time from initiating oral DMDs to any disease activity was also shorter in current smokers (log-rank test: p = 0.016; Cox proportional hazard analysis: HR 2.18 [95% CI 1.14-4.19], p = 0.019) than in non-smokers. The survival curves for relapse and any disease activity were not different between the former smoker and never-smoker groups. Multivariate survival analysis showed current smoking was an independent risk factor for relapse or any disease activity after adjusting for covariates (relapse: HR 2.54 [95% CI 1.06-6.10], p = 0.037; any disease activity: HR 3.47 [95% CI 1.27-9.50], p = 0.015). CONCLUSION: Smoking was a risk factor for disease activity in RRMS patients under oral DMD treatment. RRMS patients should be advised to stop smoking even after the initiation of DMDs.

DOI： 10.1016/j.msard.2023.104513

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY  

Chromosomally integrated human herpesvirus 6 (ciHHV6) is a condition where HHV6-DNA is integrated into the host germline genome. ciHHV6 can be misdiagnosed as active HHV6 infection. We report a 30-year-old woman presenting with psychological symptoms without a history of immunodeficiency. She had an ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid (CSF) with HHV6-DNA in the serum and CSF. The final diagnosis was anti-NMDAR encephalitis and ciHHV6 because laparoscopic oophorectomy and immunotherapy ameliorated her symptoms and HHV6-DNA was detected in her oral mucosa cells. This case suggests the need to assess whether HHV6-DNA is related to infection or ciHHV6 when HHV6-DNA is detected in the CSF of patients with encephalitis.

DOI： 10.1111/ncn3.12681

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Language：English   Publisher：(一社)日本神経学会  

脳脊髄液(CSF)で抗NMDA受容体(NMDAR)抗体とヒトヘルペスウイルス6(HHV6)-DNA陽性を示し、抗NMDAR脳炎および染色体に組み込まれたHHV6(ciHHV6)と最終診断された1例について報告した。症例は30歳女性で、Day0に亜急性の情動不安と錯乱状態を呈し頭痛を伴い、Day39に自宅の二階から飛び降りた。救急搬送されたが妄想が認められたため精神病院に移送され、移送先の医療施設で自己免疫性脳炎が疑われたことから、Day67に見当識障害、幻視、被害妄想、妄想気分、情緒不安定、激越を伴った状態で当院に移送された。CSFには軽度の髄液細胞増加、高タンパク血症、抗NMDAR抗体が検出され、血清とCSFからはHHV6-DNA陽性が示されたが、他のヘルペスウイルスDNAは陰性であった。脳波では突発活動を伴わないdiffuse background slowingが検出され、脳MRI検査では正常所見であったが、HHV6脳炎と抗NMDAR脳炎を疑い、抗ウイルス薬投与とメチルプレドニゾロン静注後に、静注免疫グロブリンが投与された。Day82に左卵巣腫瘍に対し腹腔鏡下卵巣摘出術を行い、血漿交換を行ったところ症状は改善され、CSF中細胞数とタンパク質も正常値に低下し、脳波も正常化した。しかし、6週間のガンシクロビル投与後も血清/CSFともにHHV6-DNA陽性、口腔粘膜細胞もHHV6-DNA陽性で、ガンシクロビル投与を中止したが、症状の増悪はみられなかった。以上の所見から、本例は抗NMDAR脳炎とciHHV6と最終診断された。

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：日本末梢神経学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

症例は初診時48歳の男性.緩徐進行性の複視を主訴に当科を受診した.家族歴はなく,エドロホニウムテストは陰性だった.血液検査で乳酸とピルビン酸値の上昇を認め,ミトコンドリア病を疑い,上腕二頭筋を生検したが筋病理,遺伝子検査とも異常は認められなかった.患者は後日,複視に対し眼筋縫縮術を施行された.その際に得られた組織で,ミトコンドリア遺伝子の多重欠失を認め,慢性進行性外眼筋麻痺の診断に至った.本例は上腕二頭筋組織に異常を認めず,外眼筋組織で遺伝子異常を認め,診断に至った.ミトコンドリア病では,ミトコンドリア遺伝子異常の組織特異性が指摘されており,生検を施行する際には罹患筋を選択することが望ましい.(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J01550&link_issn=&doc_id=20221220320006&doc_link_id=10.5692%2Fclinicalneurol.cn-001798&url=https%3A%2F%2Fdoi.org%2F10.5692%2Fclinicalneurol.cn-001798&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publisher：Wiley  

Chromosomally integrated human herpesvirus 6 (ciHHV6) is a condition where HHV6- DNA is integrated into the host germline genome. ciHHV6 can be misdiagnosed as active HHV6 infection. We report a 30-year-old woman presenting with psychological symptoms without a history of immunodeficiency. She had an ovarian teratoma and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies in the cerebrospinal fluid (CSF) with HHV6-DNA in the serum and CSF. The final diagnosis was anti-NMDAR encephalitis and ciHHV6 because laparoscopic oophorectomy and immunotherapy ameliorated her symptoms and HHV6-DNA was detected in her oral mucosa cells. This case suggests the need to assess whether HHV6-DNA is related to infection or ciHHV6 when HHV6-DNA is detected in the CSF of patients with encephalitis.

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：Japanese   Publisher：(一社)日本神経免疫学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neurology  

A 51-year-old woman presented with apraxia of eyelid opening, followed by slowly progressive masked facies, tongue tremor, dysphagia, neck and upper extremity rigidity, and bradykinesia 6 months after lumboperitoneal shunt placement for hydrocephalus after subarachnoid hemorrhage. An MRI examination of the brain showed midbrain compression, brainstem displacement inferiorly, and cistern effacement, consistent with infratentorial hypotension. 123I-ioflupane SPECT imaging showed reduced striatal dopamine transporter binding bilaterally. All symptoms and findings ameliorated after increasing shunt pressure (Figures 1 and 2 and Video 1). UPDRS Part III score improved from 24 to 5. Intracranial hypotension with midbrain sagging can cause reversible parkinsonism1,2 when displacement shear forces impair the nigrostriatal dopamine pathway.

DOI： 10.1212/WNL.0000000000200994

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

Emerging evidence suggests that 7-ketocholesterol (7-KC), one of the most abundant dietary oxysterols, causes inflammation and cardiovascular diseases. Here we show the deteriorating effects of dietary 7-KC on myocardial ischemia–reperfusion (IR) injury and detailed the molecular mechanisms. A high-fat high-cholesterol diet containing 7-KC (7KWD) for 3 weeks increased the plasma 7-KC level compared with high-fat high-cholesterol diet in mice. In wild-type mice but not in CCR2^−/− mice, dietary 7-KC increased the myocardial infarct size after IR. Flow cytometry revealed that the ratio of Ly-6C^high inflammatory monocytes to total monocytes was increased in the 7KWD group. Unbiased RNA sequencing using murine primary macrophages revealed that 7-KC regulated the expression of transcripts related to inflammation and cholesterol biosynthesis. We further validated that in vitro, 7-KC induced endoplasmic reticulum stress, mitochondrial reactive oxygen species production, and nuclear factor-kappa B activation, which are associated with increased mRNA levels of proinflammatory cytokines. Administration of N-acetyl-l-cysteine or siRNA-mediated knockdown of PKR-like endoplasmic reticulum kinase or endoplasmic reticulum oxidase 1α suppressed the levels of 7-KC-induced inflammation. Dietary 7-KC exacerbates myocardial IR injury through monocyte/macrophage-mediated inflammation. Endoplasmic reticulum stress and oxidative stress are involved in the 7-KC-induced proinflammatory response in macrophages.

DOI： 10.1038/s41598-022-19065-z

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Other Link： https://www.nature.com/articles/s41598-022-19065-z

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of the Neurological Sciences  

OBJECTIVE: The current study sought to develop a new indicator for disease progression rate in amyotrophic lateral sclerosis (ALS). METHODS: We used a nonparametric method to score diverse patterns of decline in the percentage of predicted forced vital capacity (%FVC) in patients with ALS. This involved 6317 longitudinal %FVC data sets from 920 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database volunteered by PRO-ACT Consortium members. To assess the utility of the derived scores as a disease indicator, we examined changes over time, the association with prognosis, and correlation with the Risk Profile of the Treatment Research Initiative to Cure ALS (TRICALS). Our local cohort (n = 92) was used for external validation. RESULTS: We derived scores ranging from 35 to 106 points to construct the FVC Decline Pattern scale (FVC-DiP). Individuals' FVC-DiP scores were determined from a single measurement of %FVC and disease duration at assessment. Although the %FVC declined over the disease course (p < 0.0001), the FVC-DiP remained relatively stable. Low FVC-DiP scores were associated with rapid disease progression. Using our cohort, we demonstrated an association between FVC-DiP and the survival prognosis, the stability of the FVC-DiP per individual, and a correlation between FVC-DiP scores and the TRICALS Risk Profile (r2 = 0.904, p < 0.0001). CONCLUSIONS: FVC-DiP scores reflected patterns of declining %FVC over the natural course of ALS and indicated the disease progression rate. The FVC-DiP may enable easy assessment of disease progression patterns and could be used for assessing treatment efficacy.

DOI： 10.1016/j.jns.2022.120389

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The study of facial expression recognition from facial expression discrimination threshold in patients with temporal lobe epilepsy
The present study investigated the ability of facial emotion recognition in patients with temporal lobe epilepsy (TLE). Total of 12 TLE patients and 32 healthy controls were participated. Two tasks consisted of morphing movie task and static picture task were used. Emotions of happiness, anger, sadness and surprise were examined. In the morphing movie task, movies in which face was gradually morphed from neutral emotion expression to maximum emotion expression were presented to the participants, then they were asked to respond when they judged that facial emotion was changed from neutral expression. Reaction time from onset of movie presentation to response was used to calculate facial emotion discrimination threshold. In the static picture task, static image in which face with maximum facial emotion expression was presented, and participants were asked to judge type of emotion. The results showed that the facial emotion discrimination thresholds in emotions of surprise and anger were significantly higher in TLE patients compared with healthy control in the morphing task. No errors were found in the static picture task. TLE patients were able to recognize the facial expression of static image with maximum emotion expression as well as the healthy group, but showed the increase of facial emotion discrimination threshold. The morphing movie task could be detectable increase of facial emotion discrimination threshold in TLE patients.

DOI： 10.20584/neuropsychology.17142

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：株式会社医学書院  

Small-fiber neuropathy (SFN) has few significant laboratory findings and is difficult to diagnose. In 70% of the cases, the cause of SFN is unknown. Among the cases with known etiology, 50% are associated with diabetes, and the causes are autoimmune, amyloidosis, or multifactorial. In recent years, a specific autoantibody-positive group has been identified and has attracted attention because immunotherapy was successful in the autoantibody-positive SFN groups. In the cases reporting to our department, abnormalities could not be detected by various tests, including nerve conduction studies, and the response to symptomatic treatment was poor. An abnormality was identified in the current perception threshold test result, and a positive blood anti-plexin D1 antibody was detected via enzyme-linked immunosorbent assay. Therefore, autoimmune SFN was diagnosed, and plasma exchange therapy was remarkably effective. Subsequently, we aim to introduce general treatments for SFN and COVID-19-related SFN.

DOI： 10.11477/mf.1416202087

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Neuroscience Research  

Oxidative stress is a major risk factor for Alzheimer's disease (AD). Among various oxidized molecules, the marked accumulation of an oxidized form of guanine, 8-oxo-7,8-dihydroguanine (8-oxoG), is observed in the AD brain. 8-oxo-2'-deoxyguanosine triphosphatase (MTH1) and 8-oxoG DNA glycosylase (OGG1) minimize the 8-oxoG accumulation in DNA, and their expression is decreased in the AD brain. MTH1 and/or OGG1 may suppress the pathogenesis of AD; however, their exact roles remain unclear. We evaluated the roles of MTH1 and OGG1 during the pathogenesis of AD using AppNL-G-F/NL-G-F knock-in mice (a preclinical AD model). Six-month-old female AppNL-G-F/NL-G-F mice with MTH1 and/or OGG1 deficiency exhibited reduced anxiety-related behavior, but their cognitive and locomotive functions were unchanged; the alteration was less evident in 12-month-old mice. MTH1 and/or OGG1 deficiency accelerated the 8-oxoG accumulation and microgliosis in the amygdala and cortex of six-month-old mice; the alteration was less evident in 12-month-old mice. Astrocytes and neurons were not influenced. We showed that MTH1 and OGG1 are essential for minimizing oxidative DNA damage in the AppNL-G-F/NL-G-F brain, and the effects are age-dependent. MTH1 and/or OGG1 deficiency reduced anxiety-related behavior in AppNL-G-F/NL-G-F mice with a significant acceleration of the 8-oxoG burden and microgliosis, especially in the cortex and amygdala.

DOI： 10.1016/j.neures.2021.11.009

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Language：Japanese   Publisher：(一社)日本内科学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Societas Neurologica Japonica  

<p>A 48-year-old Japanese male experienced slowly progressive diplopia. He had no family history and was negative for the edrophonium chloride test. Blood analysis showed elevated lactic acid and pyruvic acid levels, suggesting mitochondrial disease. A muscle biopsy from the biceps brachii was performed, but no pathological or genetical mitochondrial abnormalities were detected. Subsequently, he underwent muscle plication for diplopia in which the right inferior rectus muscle was biopsied. Genetic examination of genomic DNA extracted from the extraocular muscle tissue revealed multiple mitochondrial gene deletions, with a heteroplasmy rate of approximately 35%, resulting in the diagnosis of chronic progressive external ophthalmoplegia. In mitochondrial diseases, the tissue distribution of mitochondria with disease-associated variants in mtDNA should be noted, and it is important to select the affected muscle when performing a biopsy for an accurate diagnosis.</p>

DOI： 10.5692/clinicalneurol.cn-001798

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Multiple sclerosis (MS), the most prevalent inflammatory disease of the central nervous system (CNS), is characterized by damaged to myelin sheaths and oligodendrocytes. Because MS patients have variable clinical courses and disease severities, it is important to identify biomarkers that predict disease activity and severity. In this study, we assessed the frequencies of serum autoantibodies against mature oligodendrocytes in MS patients using a tissue-based immunofluorescence assay (IFA) to determine whether anti-oligodendrocyte antibodies are associated with the clinical features of MS patients and whether they might be a biomarker to assess CNS tissue damage in MS patients. We assessed the binding of serum autoantibodies to mouse oligodendrocytes expressing Nogo-A, a reliable mature oligodendrocyte marker, by IFA with mouse brain and sera from 147 MS patients, comprising 103 relapsing–remitting MS (RRMS), 22 secondary progressive MS (SPMS), and 22 primary progressive MS (PPMS) patients, 38 neuromyelitis optica spectrum disorder (NMOSD) patients, 23 other inflammatory neurological disorder (OIND) patients, and 39 healthy controls (HCs). Western blotting (WB) was performed using extracted mouse cerebellum proteins and IgG from anti-oligodendrocyte antibody-positive MS patients. Tissue-based IFA showed that anti-oligodendrocyte antibodies were positive in 3/22 (13.6%) PPMS and 1/22 (4.5%) SPMS patients but not in RRMS, NMOSD, and OIND patients or HCs. WB demonstrated the target CNS proteins recognized by serum anti-oligodendrocyte antibodies were approximately 110 kDa and/or 150 kDa. Compared with anti-oligodendrocyte antibody-negative MS patients, MS patients with anti-oligodendrocyte antibodies were significantly older at the time of serum sampling, scored significantly higher on the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score, and had a higher frequency of mental disturbance. Although the clinical significance of anti-oligodendrocyte antibodies is still unclear because of their low frequency, anti-oligodendrocyte autoantibodies are potential biomarkers for monitoring the disease pathology and progression in MS.

DOI： 10.3389/fneur.2021.681980

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A B S T R A C T It remains unclear whether epileptogenic networks in focal epilepsy develop on physiological networks. This work aimed to explore the association between the rapid spread of ictal fast activity (IFA), a proposed biomarker for epileptogenic networks, and the functional connectivity or networks of healthy subjects. We reviewed 45 patients with focal epilepsy who underwent electrocorticographic (ECoG) recordings to identify the patients showing the rapid spread of IFA. IFA power was quantified as normalized beta-gamma band power. Using published resting state functional magnetic resonance imaging databases, we estimated resting-state functional connectivity of healthy subjects (RSFC-HS) and resting-state networks of healthy subjects (RSNs-HS) at the locations corresponding to the patients' electrodes. We predicted the IFA power of each electrode based on RSFC-HS between electrode locations (RSFC-HS-based prediction) using a recently developed method, termed activity flow mapping. RSNsHS were identified using seed-based and atlas-based methods. We compared IFA power with RSFC-HS-based prediction or RSNs-HS using non-parametric correlation coefficients. RSFC and seed-based RSNs of each patient (RSFC-PT and seed-based RSNs-PT) were also estimated using interictal ECoG data and compared with IFA power in the same way as RSFC-HS and seed-based RSNs-HS. Spatial autocorrelation-preserving randomization tests were performed for significance testing. Nine patients met the inclusion criteria. None of the patients had reflex seizures. Six patients showed pathological evidence of a structural etiology. In total, we analyzed 49 seizures (2- 13 seizures per patient). We observed significant correlations between IFA power and RSFC-HS-based prediction, seed-based RSNs-HS, or atlas-based RSNs-HS in 28 (57.1&#37;), 21 (42.9&#37;), and 28 (57.1&#37;) seizures, respectively. Thirty-two (65.3&#37;) seizures showed a significant correlation with either seed-based or atlas-based RSNs-HS, but this ratio varied across patients: 27 (93.1&#37;) of 29 seizures in six patients correlated with either of them. Among atlas-based RSNs-HS, correlated RSNs-HS with IFA power included the default mode, control, dorsal attention, somatomotor, and temporal-parietal networks. We could not obtain RSFC-PT and RSNs-PT in one patient due to frequent interictal epileptiform discharges. In the remaining eight patients, most of the seizures showed significant correlations between IFA power and RSFC-PT-based prediction or seed-based RSNs-PT. Our study provides evidence that the rapid spread of IFA in focal epilepsy can arise from physiological RSNs. This finding suggests an overlap between epileptogenic and functional networks, which may explain why functional networks in patients with focal epilepsy frequently disrupt.

DOI： 10.1016/j.neuroimage.2021.118104

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<sec id="sec001">
<title>Background and purpose</title>
The impact of the paraoxonase-1 (<italic>PON1</italic>) polymorphism, Q192R, on platelet inhibition in response to clopidogrel remains controversial. We aimed to investigate the association between carrier status of <italic>PON1</italic> Q192R and high platelet reactivity (HPR) with clopidogrel in patients undergoing elective neurointervention.


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<title>Methods</title>
Post-clopidogrel platelet reactivity was measured using a VerifyNow^® P2Y12 assay in P2Y12 reaction units (PRU) for consecutive patients before the treatment. Genotype testing was performed for <italic>PON1</italic> Q192R and <italic>CYP2C19*2</italic> and <italic>*3</italic> (no function alleles), and <italic>*17</italic>. PRU was corrected on the basis of hematocrit. We investigated associations between factors including carrying ≥1 <italic>PON1</italic> 192R allele and HPR defined as original and corrected PRU ≥208.


</sec>
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<title>Results</title>
Of 475 patients (232 men, median age, 68 years), HPR by original and corrected PRU was observed in 259 and 199 patients (54.5&#37; and 41.9&#37;), respectively. Carriers of ≥1 <italic>PON1</italic> 192R allele more frequently had HPR by original and corrected PRU compared with non-carriers (91.5&#37; vs 85.2&#37;, P = 0.031 and 92.5&#37; vs 85.9&#37;, P = 0.026, respectively). In multivariate analyses, carrying ≥1 <italic>PON1</italic> 192R allele was associated with HPR by original (odds ratio [OR] 1.96, 95&#37; confidence interval [CI] 1.03–3.76) and corrected PRU (OR 2.34, 95&#37; CI 1.21–4.74) after adjustment for age, sex, treatment with antihypertensive medications, hematocrit, platelet count, total cholesterol, and carrying ≥1 <italic>CYP2C19</italic> no function allele.


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<title>Conclusions</title>
Carrying ≥1 <italic>PON1</italic> 192R allele is associated with HPR by original and corrected PRU with clopidogrel in patients undergoing elective neurointervention, although alternative results related to other genetic polymorphisms cannot be excluded.


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DOI： 10.1371/journal.pone.0254067

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Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes.

DOI： 10.1016/j.bbi.2021.04.008

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OBJECTIVES: To assess the prevalence of antiplexin D1 antibodies (plexin D1-immunoglobulin G [IgG]) in small fiber neuropathy (SFN) and the effects of these antibodies in vivo. METHODS: We developed an ELISA for plexin D1-IgG using a recombinant extracellular domain of human plexin D1 containing the major epitope and sera from 58 subjects previously studied with a standard tissue-based indirect immunofluorescence assay (TBA). We screened 63 patients with probable SFN and 55 healthy controls (HCs) for serum plexin D1-IgG using ELISA. The results were confirmed by TBA. IgG from 3 plexin D1-IgG-positive patients, 2 plexin D1-IgG-negative inflammatory disease controls, and 2 HCs was intrathecally injected into mice, which were assessed for mechanical and thermal hypersensitivity 24 and 48 hours after injection. RESULTS: The ELISA had 75% sensitivity and 100% specificity using the TBA as a standard, and the coincidence rate of ELISA to TBA was 96.6% (56/58). The frequency of plexin D1-IgG was higher in patients with SFN than in HCs (12.7% [8/63] vs 0.0% [0/55], p = 0.007). Purified IgG from all 3 plexin D1-IgG-positive patients, but not 2 plexin D1-IgG-negative patients, induced significant mechanical and/or thermal hypersensitivity compared with IgG from HCs. In mice injected with plexin D1-IgG-positive but not D1-IgG-negative patient IgG, phosphorylated extracellular signal-regulated protein kinase immunoreactivity, an activation marker, was confined to small dorsal root ganglion neurons and was significantly more abundant than in mice injected with HC IgG. CONCLUSIONS: Plexin D1-IgG is pathogenic but with low prevalence and is a potential biomarker for immunotherapy in SFN.

DOI： 10.1212/NXI.0000000000001028

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Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Brain astroglia are activated preceding the onset of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We characterized the effects of brain astroglia on spinal cord inflammation, focusing on astroglial connexin (Cx)43, because we recently reported that Cx43 has a critical role in regulating neuroinflammation. METHODS: Because glutamate aspartate transporter (GLAST)+ astroglia are enriched in the brain gray matter, we generated Cx43fl/fl;GLAST-CreERT2/+ mice that were brain gray matter astroglia-specific Cx43 conditional knockouts (Cx43 icKO). EAE was induced by immunization with myelin oligodendroglia glycoprotein (MOG) 35-55 peptide 10 days after tamoxifen injection. Cx43fl/fl mice were used as controls. RESULTS: Acute and chronic EAE signs were significantly milder in Cx43 icKO mice than in controls whereas splenocyte MOG-specific responses were unaltered. Histologically, Cx43 icKO mice showed significantly less demyelination and fewer CD45+ infiltrating immunocytes, including F4/80+ macrophages, and Iba1+ microglia in the spinal cord than controls. Microarray analysis of the whole cerebellum revealed marked upregulation of anti-inflammatory A2-specific astroglia gene sets in the pre-immunized phase and decreased proinflammatory A1-specific and pan-reactive astroglial gene expression in the onset phase in Cx43 icKO mice compared with controls. Astroglia expressing C3, a representative A1 marker, were significantly decreased in the cerebrum, cerebellum, and spinal cord of Cx43 icKO mice compared with controls in the peak phase. Isolated Cx43 icKO spinal microglia showed more anti-inflammatory and less proinflammatory gene expression than control microglia in the pre-immunized phase. In particular, microglial expression of Ccl2, Ccl5, Ccl7, and Ccl8 in the pre-immunized phase and of Cxcl9 at the peak phase was lower in Cx43 icKO than in controls. Spinal microglia circularity was significantly lower in Cx43 icKO than in controls in the peak phase. Significantly lower interleukin (IL)-6, interferon-γ, and IL-10 levels were present in cerebrospinal fluid from Cx43 icKO mice in the onset phase compared with controls. CONCLUSIONS: The ablation of Cx43 in brain gray matter astroglia attenuates EAE by promoting astroglia toward an anti-inflammatory phenotype and suppressing proinflammatory activation of spinal microglia partly through depressed cerebrospinal fluid proinflammatory cytokine/chemokine levels. Brain astroglial Cx43 might be a novel therapeutic target for MS.

DOI： 10.1186/s12974-021-02176-1

Language：Japanese   Publishing type：Research paper (scientific journal)  

Granulomatosis with polyangiitis (GPA) is designated as an intractable disease by the Ministry of Health, Labor and Welfare, Japan, and is classified as an antineutrophil cytoplasmic antibody (ANCA)-related vasculitis syndrome. It is associated with upper respiratory tract symptoms (E; ear and nose), pulmonary symptoms (L; lung), renal symptoms (K; kidney), and systemic vasculitis symptoms, and often involves the central/peripheral nervous system. Patients with GPA can be easily diagnosed as they often show positive serum C (Proteinase 3)-ANCA findings. Remission can be induced using multiple immunosuppressants in combination, but caution is required as relapse and infection is common in patients with GPA.

DOI： 10.11477/mf.1416201792

Language：Japanese   Publishing type：Research paper (scientific journal)  

A 35-year-old Sudanese man experienced bitter tastes on the right side of his tongue from January 2012. He was admitted to our hospital in March 2012 because of the appearance of distress, right facial palsy, nausea, and dizziness from late February 2012. A neurological examination revealed Bruns nystagmus, which increased on rightward gaze, as well as total hypoesthesia in the distribution of the maxillary branch of the right trigeminal nerve, moderate right peripheral type facial nerve palsy, and limb ataxia on the right side. Neither muscle weakness nor sensory disturbance was observed. Slight hyperreflexia was noted in the right extremities, and bilateral plantar responses were flexor. He showed wide-based ataxic gait and was unable to do tandem gait. Brain CT scans and magnetic resonance (MR) images revealed a mass lesion in the right pons to the right middle cerebellar peduncle with ring enhancement, suggestive of a "target" sign. Laboratory tests, including hematological and biochemical analyses, tumor markers, and antibodies, had normal values while the tuberculin reaction and QuantiFERON-TB Gold were strongly positive. Cerebrospinal fluid analysis revealed a slight increase in the protein level (76 mg/dl) with a normal cell count (2 per μl), and polymerase chain reaction-based tests and cultures were negative for Mycobacterium tuberculosis three times. Right subclavicular lymph node and right adrenal gland showed accumulation of fluorodeoxyglucose on positron emission tomography-CT, as did the mass lesion in the brainstem. These findings suggested a possibility of a metastatic malignant tumor or extrapleural tuberculoma. Because of the patient's religious belief, we were unable to perform a biopsy of the lymph node, and thus administered anti-tuberculous drugs. With treatment, his neurological symptoms such as facial palsy and ataxia improved steadily except for paradoxical worsening for the initial five days, and the gadolinium-enhanced lesion shrunk markedly. Follow-up MR images demonstrated that the lesions did not expand further for 9 months. From this course of treatment, we diagnosed the patient's tumor as brainstem tuberculoma. Brain tuberculoma sometimes resembles a malignant tumor, and it is therefore challenging to diagnose brainstem tuberculosis in cases without lung lesions. It is important to make a comprehensive diagnosis based on the patient's background, imaging, and course of treatment, and to treat brainstem tuberculoma promptly.

DOI： 10.5692/clinicalneurol.cn-001557

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: Approximately 15%-20% of patients with Guillain-Barré syndrome (GBS) are unable to walk independently at 6 months from the onset of neurological symptom. The modified Erasmus GBS outcome score (mEGOS) has been reported as a prognostic tool.Herein we investigated the association between a poor outcome, inability to walk independently at 6 months and presence of antiganglioside antibodies. METHODS: The clinical and serological data of 177 patients with GBS were retrospectively collected in Japan to assess the associations between a poor outcome and serum IgG antibodies against each ganglioside (GM1, GD1a, GalNAc-GD1a, GQ1b and GT1a). In addition, we investigated whether the combination of mEGOS and serum IgG antibodies against gangliosides is useful in predicting a poor outcome. RESULTS: The patients with IgG anti-GD1a antibodies more frequently showed poor outcomes than those without these antibodies (9 (36%) of 25 vs 8 (6%) of 127 patients, p<0.001). Particularly, 80% showed a poor outcome when they had both serum IgG anti-GD1a antibody and a high mEGOS of ≥10 on day 7 of admission. CONCLUSIONS: The combination of serum IgG anti-GD1a antibodies and a high mEGOS could help in making a more accurate prognosis of patients than mEGOS alone, especially for predicting poor outcomes.

DOI： 10.1136/jnnp-2020-323960

Language：English   Publishing type：Research paper (scientific journal)  

To identify biomarkers for multiple system atrophy-cerebellar type (MSA-C), we used flow cytometry to measure surface marker expression of peripheral blood monocytes from patients with MSA-C or hereditary spinocerebellar degeneration (hSCD) and from healthy controls (HCs). The percentage of intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs and showed significant positive correlations with disease duration and unified MSA rating scale scores. The percentage of CD62L+ intermediate monocytes was significantly lower in MSA-C patients than in hSCD patients and HCs. Early decrease of peripheral blood intermediate monocytes is characteristic of MSA-C and is a biomarker.

DOI： 10.1016/j.jneuroim.2020.577395

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To characterize the frequency and patterns of optic, trigeminal, and facial nerve involvement by neuroimaging and electrophysiology in IgG4 anti-neurofascin 155 antibody-positive (NF155+ ) chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: Thirteen IgG4 NF155+ CIDP patients with mean onset age of 34 years (11 men) were subjected to neurological examination, blink reflex, and visual-evoked potential (VEP) testing, and axial and/or coronal T2-weighted head magnetic resonance imaging (MRI). RESULTS: Among 13 patients, facial sensory impairment, facial weakness, and apparent visual impairment were observed in three (23.1%), two (15.4%), and two (15.4%) patients, respectively. All 12 patients tested had blink reflex abnormalities: absent and/or delayed R1 in 11 (91.7%), and absent and/or delayed R2 in 10 (83.3%). R1 latencies had strong positive correlations with serum anti-NF155 antibody levels (r = 0.9, P ≤ 0.0001 on both sides) and distal and F wave latencies of the median and ulnar nerves. Absent and/or prolonged VEPs were observed in 10/13 (76.9%) patients and 17/26 (65.4%) eyes. On MRI, hypertrophy, and high signal intensity of trigeminal nerves were detected in 9/13 (69.2%) and 10/13 (76.9%) patients, respectively, whereas optic nerves were normal in all patients. The intra-orbital trigeminal nerve width on coronal sections showed a significant positive correlation with disease duration. INTERPRETATION: Subclinical demyelination frequently occurs in the optic, trigeminal, and facial nerves in IgG4 NF155+ CIDP, suggesting that both central and peripheral myelin structures of the cranial nerves are involved in this condition, whereas nerve hypertrophy only develops in myelinated peripheral nerve fibers.

DOI： 10.1002/acn3.51220

Language：English   Publishing type：Research paper (scientific journal)  

TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions.

DOI： 10.1111/bpa.12898

Language：Japanese  

Language：English  

Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-associated vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.

DOI： 10.1111/neup.12659

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To determine whether anti-Plexin D1 antibody (Plexin D1-immunoglobulin G [IgG]), which is associated with limb and trunk neuropathic pain (NP) and binds to pain-conducting small unmyelinated dorsal root ganglion (DRG) neurons, exists in patients with idiopathic painful trigeminal neuropathy (IPTN) and whether Plexin D1-IgG binds to trigeminal ganglion (TG) neurons. METHODS: We enrolled 21 consecutive patients with IPTN and 35 age- and sex-matched controls without NP (25 healthy persons and 10 with neurodegenerative diseases). We measured serum Plexin D1-IgG using a mouse DRG tissue-based indirect immunofluorescence assay (IFA) and by Western blotting (WB) using a recombinant human Plexin D1 (rhPlexin D1) accompanied by immunoadsorption tests with rhPlexin D1. The reactivity of Plexin D1-IgG toward mouse TG, brain, heart, and kidney was assessed by tissue-based IFAs. RESULTS: Serum Plexin D1-IgG was detected more frequently in IPTN than in controls by both IFA and WB (14.3&#37; vs 0&#37;, p = 0.048). Three Plexin D1-IgG-positive patients also had limb or trunk NP and commonly showed tongue pain. In tissue-based IFAs, IgG from 2 Plexin D1-IgG-positive patients immunostained small TG neurons, which was prevented by preincubation with rhPlexin D1. Moreover, Plexin D1-IgG immunostaining mostly colocalized with isolectin B4-positive pain-conducting unmyelinated TG neurons. IFAs of other tissues with the same IgG revealed weak immunoreactivity only in endothelial cells, which was prevented by preincubation with rhPlexin D1. CONCLUSIONS: Plexin D1-IgG, which binds to pain-conducting small TG neurons in addition to DRG neurons, can be present in IPTN as well as limb and trunk NP.

DOI： 10.1212/NXI.0000000000000819

Language：English   Publishing type：Research paper (scientific journal)  

There is a wide range of onset age in Alzheimer's disease (AD). Emerging evidence indicates variation of AD manifestations in oldest-old AD (OOAD); however, the pattern of cognitive dysfunctions remains unclear. We aimed to reveal cognitive performance characteristics and changes in brain functional connectivity in OOAD patients by a resting-state fMRI (rs-fMRI) study. We enrolled AD patients who had been referred to Kyushu University Hospital (KUH) or Sanno Hospital, and classified them into middle-old AD (MOAD) (65-79 years old) and OOAD (≥80 years old) according to the age of onset. Our subjects consisted of 19 OOAD, 17 MOAD, and 8 normal subjects. Cognitive performance was evaluated using Mini Mental State Examination-Japanese (MMSE-J) and Clinical Dementia Rating (CDR). rs-fMRI scanning and independent component analysis (ICA) were performed on Sanno Hospital patients and MOAD vs. OOAD patients were compared. The resulting significant regions were used as seeds for ROI-to-ROI analysis of the KUH dataset. Collectively, MMSE-J delayed recall sub-scores were significantly lower in OOAD patients compared with MOAD patients. ICA of the Sanno Hospital data indicated significant connectivity decrease in the default mode network (DMN) in the OOAD group compared with the MOAD group in the right superior parietal lobule (SPL). ROI-to-ROI analysis of the KUH dataset indicated significant disconnection in the OOAD group of the right SPL from the precuneus (p < 0.01). The functional connectivity from the right SPL to the precuneus was positively correlated with the MMSE-J delayed recall sub-score (p = 0.03) and negatively correlated with the CDR memory sub-scale (p = 0.04). These findings indicate that disconnection between the right SPL and the precuneus may contribute to worse memory capability in OOAD compared with MOAD.

DOI： 10.1016/j.heliyon.2020.e04516

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) caused by JC virus (JCV) is a rare but serious complication of some disease-modifying drugs used to treat multiple sclerosis (MS). Japanese MS patients treated with fingolimod were reported to be 10 times more likely to develop PML than equivalent patients in other countries. The strongest susceptibility human leukocyte antigen (HLA) class II alleles for MS are distinct between races (DRB1*15:01 for Caucasians and DRB1*04:05 and DRB1*15:01 for Japanese); therefore, we investigated whether HLA class II alleles modulate anti-JCV antibody serostatus in Japanese MS patients with and without fingolimod. METHODS: We enrolled 128 Japanese patients with MS, in whom 64 (50%) were under fingolimod treatment at sampling, and examined the relationship between HLA class II alleles and anti-JCV antibody serostatus. Serum anti-JCV antibody positivity and index were measured using a second-generation two-step assay and HLA-DRB1 and -DPB1 alleles were genotyped. RESULTS: HLA-DRB1*15 carriers had a lower frequency of anti-JCV antibody positivity (57% vs 78%, p = 0.015), and lower antibody index (median 0.42 vs 1.97, p = 0.037) than non-carriers. Among patients without HLA-DRB1*15, DRB1*04 carriers had a higher seropositivity rate than non-carriers (84% vs 54%, p = 0.030), and DPB1*04:02 carriers had a higher anti-JCV antibody index than non-carriers (3.20 vs 1.34, p = 0.008) although anti-JCV antibody-positivity rates did not differ. Patients treated with fingolimod had a higher antibody index than other patients (1.46 vs 0.64, p = 0.039) and treatment period had a positive correlation with antibody index (p = 0.018). Multivariate logistic regression analysis revealed that age was positively associated, and HLA-DRB1*15 was negatively associated with anti-JCV antibody positivity (odds ratio [OR] = 1.06, p = 0.006, and OR = 0.37, p = 0.028, respectively). Excluding HLA-DRB1*15-carriers, DRB1*04 was an independent risk factor for the presence of anti-JCV antibody (OR = 5.50, p = 0.023). CONCLUSIONS: HLA-DRB1*15 is associated with low anti-JCV antibody positive rate and low JCV antibody index, and in the absence of DRB1*15, DRB1*04 carriers are associated with a high antibody positive rate in Japanese, suggesting the effects of two susceptible HLA-DRB1 alleles on anti-JCV antibody serostatus differ.

DOI： 10.1186/s12974-020-01865-7

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The effects of distinct HLA alleles on the brain and lesion volumes remain to be established, particularly in non-Caucasian populations. Two distinct susceptibility alleles, DRB1*15:01 and DRB1*04:05, are prevalent in the Japanese population; we therefore aimed to clarify the effects of HLA-DRB1 alleles on brain and lesion volumes in multiple sclerosis (MS). METHODS: A total of 66 patients with MS (50 relapsing remitting, 16 progressive) underwent brain MRI volumetry measuring fluid-attenuated inversion recovery (FLAIR) and T1 lesion volumes, and normalized whole-brain (NWBV), white matter (NWMV), gray matter (NGMV), cortical gray matter (NCGMV), deep gray matter (NDGMV) and thalamus (NTV) volumes, and HLA-DRB1 genotyping. RESULTS: Carriers of HLA-DRB1*15:01(+)*04:05(-) and HLA-DRB1*15:01(-)*04:05(+) comprised 25.8% and 31.8% of patients, respectively. HLA-DRB1*15:01 carriers showed negative correlations between disease duration and NWBV (rs = -0.484, p = .036), NWMV (rs = -0.593, p = .008), and NTV (rs = -0.572, p = .011), and positive correlations between disease duration and FLAIR (rs = 0.539, p = .017) and T1 lesion volumes (rs = 0.545, p = .016). By contrast, no significant correlation of any MRI parameters with disease duration was found in HLA-DRB1*04:05 carriers. HLA-DRB1*15:01 carriers had a significantly faster reduction in NWBV and NWMV by disease duration and smaller NDGMV than DRB1*15:01 non-carriers, whereas HLA-DRB1*04:05 carriers had a significantly slower increase in FLAIR and T1 lesion volumes than HLA-DRB1*04:05 non-carriers. CONCLUSIONS: Our study suggests that distinct HLA-DRB1 alleles could differentially influence brain and lesion volumes over the disease course of MS.

DOI： 10.1016/j.jns.2020.116768

Language：English   Publishing type：Research paper (scientific journal)  

Background: The effects of distinct HLA alleles on the brain and lesion volumes remain to be established, particularly in non-Caucasian populations. Two distinct susceptibility alleles, DRB1*15:01 and DRB1*04:05, are prevalent in the Japanese population; we therefore aimed to clarify the effects of HLA-DRB1 alleles on brain and lesion volumes in multiple sclerosis (MS). Methods: A total of 66 patients with MS (50 relapsing remitting, 16 progressive) underwent brain MRI volumetry measuring fluid-attenuated inversion recovery (FLAIR) and T1 lesion volumes, and normalized whole-brain (NWBV), white matter (NWMV), gray matter (NGMV), cortical gray matter (NCGMV), deep gray matter (NDGMV) and thalamus (NTV) volumes, and HLA-DRB1 genotyping. Results: Carriers of HLA-DRB1*15:01(+)*04:05(−) and HLA-DRB1*15:01(−)*04:05(+) comprised 25.8% and 31.8% of patients, respectively. HLA-DRB1*15:01 carriers showed negative correlations between disease duration and NWBV (r_s = −0.484, p = .036), NWMV (r_s = −0.593, p = .008), and NTV (r_s = −0.572, p = .011), and positive correlations between disease duration and FLAIR (r_s = 0.539, p = .017) and T1 lesion volumes (r_s = 0.545, p = .016). By contrast, no significant correlation of any MRI parameters with disease duration was found in HLA-DRB1*04:05 carriers. HLA-DRB1*15:01 carriers had a significantly faster reduction in NWBV and NWMV by disease duration and smaller NDGMV than DRB1*15:01 non-carriers, whereas HLA-DRB1*04:05 carriers had a significantly slower increase in FLAIR and T1 lesion volumes than HLA-DRB1*04:05 non-carriers. Conclusions: Our study suggests that distinct HLA-DRB1 alleles could differentially influence brain and lesion volumes over the disease course of MS.

DOI： 10.1016/j.jns.2020.116768

Language：English   Publishing type：Research paper (scientific journal)  

Early neurological deterioration (END) following intravenous recombinant tissue plasminogen activator (rt-PA) treatment is a serious clinical event that can be caused by hemorrhagic or ischemic insult. We investigated the differences in predictive factors for END due to hemorrhagic and END due to ischemic insults. Consecutive patients from four hospitals who received 0.6 mg/kg intravenous rt-PA for acute ischemic stroke were retrospectively recruited. END was defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within 24 h compared with baseline. END was classified into those due to hemorrhagic (END_h) or ischemic (END_i) insult based on computed tomography (CT) or magnetic resonance imaging. Risk factors associated with END_h and END_i were investigated by comparison with non-END cases. A total of 744 patients (452 men, median 75 years old) were included. END was observed in 79 patients (10.6%), including 22 END_h (3.0%) and 57 END_i (7.7%), which occurred within a median of 7 h after treatment. Multivariate analyses showed that higher pretreatment NIHSS score (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.00–1.13) and pretreatment with antiplatelets (OR 2.84, 95% CI 1.08–7.72) were associated with END_h. Extensive early ischemic change (Alberta Stroke Program Early CT Score ≤ 7 on CT or ≤ 6 on diffusion-weighted imaging; OR 2.80, 95% CI 1.36–5.64) and large artery occlusions (OR 3.09, 95% CI 1.53–6.57) were associated with END_i. Distinct factors were predictive for the END subtypes. These findings could help develop preventative measures for END in patients with the identified risk factors.

DOI： 10.1007/s11239-019-02015-4

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = -0.5879, p = .04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

DOI： 10.1016/j.nbd.2020.104739

Language：English   Publishing type：Research paper (scientific journal)  

The toxic conformer of amyloid β-protein (Aβ) ending at 42 (Aβ42), which contains a unique turn conformation at amino acid residue positions 22 and 23 and tends to form oligomers that are neurotoxic, was reported to play a critical role in the pathomechanisms of Alzheimer's disease (AD), in which diabetes mellitus (DM)-like mechanisms are also suggested to be operative. It remains to be established whether the attenuation of insulin signaling is involved in an increase of toxic Aβ42 conformer levels. The present study investigated the association between impaired insulin metabolism and formation of toxic Aβ42 conformers in the brains of an AD mouse model. In particular, we studied whether insulin deficiency or resistance affected the formation of toxic Aβ42 conformers in vivo. We induced insulin deficiency and resistance in 3xTg-AD mice, a mouse AD model harboring two familial AD-mutant APP (KM670/671NL) and PS1 (M146 V) genes and a mutant TAU (P301L) gene, by streptozotocin (STZ) injection and a high fructose diet (HFuD), respectively. Cognitive impairment was significantly worsened by STZ injection but not by HFuD. Dot blot analysis revealed significant increases in total Aβ42 levels and the ratio of toxic Aβ42 conformer/total Aβ42 in STZ-treated mice compared with control and HFuD-fed mice. Immunostaining showed the accumulation of toxic Aβ42 conformers and hyper-phosphorylated tau protein (p-tau), which was more prominent in the cortical and hippocampal neurons of STZ-treated mice compared with HFuD-fed and control mice. HFuD-fed mice showed only a mild-to-moderate increase of these proteins compared with controls. Toxic Aβ42 conformers were co-localized with p-tau oligomers (Pearson's correlation coefficient = 0.62) in the hippocampus, indicating their co-aggregation. Toxic Aβ42 conformer levels were inversely correlated with pancreatic insulin secretion capacity as shown by fasting immunoreactive insulin levels in STZ-treated mice (correlation coefficient = −0.5879, p =.04441), but not HFuD-fed mice, suggesting a decrease in serum insulin levels correlates with toxic Aβ42 conformer formation. Levels of p-Akt and phosphorylated glycogen synthase kinase-3β measured by a homogeneous time-resolved fluorescence assay were significantly lower in STZ-treated mice than in HFuD-fed mice, suggesting a greater inhibition of brain insulin signaling by STZ than HFuD, although both levels were significantly decreased in these groups compared with controls. Iba1-positive and NOS2-positive areas in the cortex and hippocampus were significantly increased in STZ-treated mice and to a lesser extent in HFuD-fed mice compared with controls. These findings suggest that insulin deficiency rather than insulin resistance and the resultant impairment of brain insulin signaling facilitates the formation of toxic Aβ42 conformer and its co-aggregation with p-tau oligomers, and that insulin deficiency is an important pathogenic factor in the progression of AD.

DOI： 10.1016/j.nbd.2020.104739

Language：Others   Publishing type：Research paper (scientific journal)  

Background: Recently, the coexistence of anti-aquaporin-4 antibody (AQP4-ab) and anti-N-methyl-d-aspartate receptor antibody (NMDAR-ab) were reported in a single case. However, its clinical significance is not well defined. Case presentation: A 42-year-old woman developed hypersomnolence, personality change, and childish or bizarre behavior. Four months later, she exhibited marked reduction of verbal and motor spontaneity. Serum AQP4-ab was positive. Cerebrospinal fluid (CSF) was positive for oligoclonal bands. Brain magnetic resonance imaging (MRI) detected multiple T2-hyperintense lesions without gadolinium enhancement in the pons, midbrain, bilateral internal capsule, basal ganglia, corpus callosum, and deep cerebral white matter. Spinal MRI was negative. Because clinical symptoms and clinical course were atypical for neuromyelitis optica spectrum disorders (NMOSD), CSF NMDAR-ab was tested and found to be positive. Whole-body examination revealed cystic lesions in the right ovary, which were later found not to be malignant tumors. In accordance with the proposed algorithm for the treatment of NMDAR encephalitis (NMDARE), she was treated with three courses of intravenous methylprednisolone pulse therapy, followed by oral prednisolone, intravenous immunoglobulin therapy, and five courses of bimonthly intravenous cyclophosphamide pulse therapy. Her symptoms gradually improved, and she returned to her daily life without major sequelae. Conclusions: Although her main symptoms were compatible with NMDARE, MRI findings were more compatible with NMOSD. Therefore, we interpreted her clinical and imaging features as a mixed phenotype of NMOSD and NMDARE. This case report provides additional evidence that double positivity for AQP4-ab and NMDAR-ab is associated with a mixed phenotype of NMOSD and NMDARE.

DOI： 10.1111/cen3.12571

Language：English   Publishing type：Research paper (scientific journal)  

Connexins, which comprise gap junctions (GJs) via homotypic/heterotypic oligomerization, act as channels to connect opposing cells, mainly in solid organs such as the skin, liver, heart, and central/peripheral nervous system. Connexins are synthesized in the endoplasmic reticulum, assembled in the Golgi apparatus as hexamers, and inserted into the cell membrane as hemichannels. These hemichannels are closed under normal conditions until they combine to form clusters and connect to neighboring cells via GJs in a head-to-head configuration. Opening of hemichannels, which depends on the intra- or extracellular environment, allows various bioactive molecules to enter into or be released from the host cells. Recent pathological studies on human demyelinating diseases have revealed alterations of connexin expression patterns in demyelinating lesions. To elucidate the molecular mechanisms of connexins in the pathomechanisms of inflammatory demyelination, we induced experimental autoimmune encephalomyelitis (EAE) in connexin 30 (Cx30)-deficient mice, oligodendroglia-specific Cx47-ablated mice, and astroglia-specific Cx43-ablated mice. We found that both astroglial-Cx30-deficient mice and Cx43-ablated mice showed amelioration of the clinical course of EAE, while oligodendroglial-Cx47-ablated mice showed aggravation. These findings indicate the distinct role of connexins expressed in different cell types and the substantial contribution of connexin-mediated pathology to demyelinating disorders. The imbalance in connexin expression, which is caused by the inflammatory environment, results in an increase in hemichannels in glial cells. The release of proinflammatory molecules induced by the increase in hemichannels on activated glial cells is a crucial mechanism of demyelinating disorders.

DOI： 10.1111/cen3.12568

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Background: Recently, the coexistence of anti-aquaporin-4 antibody (AQP4-ab) and anti-N-methyl-d-aspartate receptor antibody (NMDAR-ab) were reported in a single case. However, its clinical significance is not well defined. Case presentation: A 42-year-old woman developed hypersomnolence, personality change, and childish or bizarre behavior. Four months later, she exhibited marked reduction of verbal and motor spontaneity. Serum AQP4-ab was positive. Cerebrospinal fluid (CSF) was positive for oligoclonal bands. Brain magnetic resonance imaging (MRI) detected multiple T2-hyperintense lesions without gadolinium enhancement in the pons, midbrain, bilateral internal capsule, basal ganglia, corpus callosum, and deep cerebral white matter. Spinal MRI was negative. Because clinical symptoms and clinical course were atypical for neuromyelitis optica spectrum disorders (NMOSD), CSF NMDAR-ab was tested and found to be positive. Whole-body examination revealed cystic lesions in the right ovary, which were later found not to be malignant tumors. In accordance with the proposed algorithm for the treatment of NMDAR encephalitis (NMDARE), she was treated with three courses of intravenous methylprednisolone pulse therapy, followed by oral prednisolone, intravenous immunoglobulin therapy, and five courses of bimonthly intravenous cyclophosphamide pulse therapy. Her symptoms gradually improved, and she returned to her daily life without major sequelae. Conclusions: Although her main symptoms were compatible with NMDARE, MRI findings were more compatible with NMOSD. Therefore, we interpreted her clinical and imaging features as a mixed phenotype of NMOSD and NMDARE. This case report provides additional evidence that double positivity for AQP4-ab and NMDAR-ab is associated with a mixed phenotype of NMOSD and NMDARE.

DOI： 10.1111/cen3.12571

Language：English   Publishing type：Research paper (scientific journal)  

Neuropathic pain (NeP) is an intractable pain caused by a lesion or disease of the somatosensory nervous system. NeP is often challenging to manage because most of the mechanisms remain to be elucidated. Recent investigations in the field of autoimmune neurology have demonstrated that specific autoantibodies against antigens in the somatosensory pathway can cause NeP. Detection of pathogenic autoantibodies in NeP adds to the understanding of the mechanism of pain, which might aid in the development of novel immunotherapies. Therefore, it is necessary to explore novel NeP-related autoantibodies to improve the management of intractable pain. Recently, we screened serum autoantibodies that bound to pain-conducting small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients. We detected a novel autoantibody that bound to unmyelinated C-fiber–type small DRG neurons. The positive rate in patients with NeP was 10%. We identified plexin D1 as the target antigen. NeP patients with plexin D1-IgG developed burning pain and thermal hyperalgesia. The main comorbidities were allergy, collagen vascular disease, and cancer. Plasma exchange and intravenous methylprednisolone pulse therapy are effective for NeP in patients with plexin D1-IgG, indicating that these autoantibodies might be pathogenic in NeP. Indeed, our in vitro study demonstrated that plexin D1-IgG induced the membrane hyperpermeability of DRG neurons. In this review, we describe the discovery of plexin D1-IgG and discuss the association between plexin D1 and pain, allergy, and cancer.

DOI： 10.1111/cen3.12570

Language：English   Publishing type：Research paper (scientific journal)  

To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP.

DOI： 10.1016/j.jneuroim.2019.577139

Language：English   Publishing type：Research paper (scientific journal)  

Background: This study was designed to detect and assess the frequency and severity of nonmotor symptoms (NMSs) in advanced Parkinson’s disease (PD) and to investigate the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on NMSs. Methods: We developed an online PC–based questionnaire program to assess NMSs in PD. Twenty-six PD patients who underwent bilateral STN-DBS were assessed. The NMS questionnaire consisted of 54 NMSs in three categories, based on Witjas et al. (2002). For each NMS, the patients were asked whether or not it was present, whether or not the fluctuating manifestations correlated with the timing of levodopa-induced motor fluctuations, and how severe the NMS was. Patients were assessed by this system before surgery and at the follow-up visit, 3 to 6 months after surgery. At the postoperative assessment, patients were also assessed on preoperative NMSs using recall. Results: The most frequent preoperative NMSs were constipation and visual disorders, while the most frequent postoperative NMSs were difficulty in memorizing and pollakiuria. The ranking of most frequent NMSs changed from before to after surgery. NMSs of drenching sweats, dysphagia, and constipation were significantly ameliorated, while NMSs of dyspnea and slowness of thinking were significantly deteriorated after surgery. The preoperative assessment by postoperative recall gave very different results from that of the preoperative assessment. Conclusion: An online questionnaire system to assess NMSs in patients with advanced PD suggested that STN-DBS might influence the frequencies of some kinds of NMSs.

DOI： 10.1007/s00701-019-04182-y

Language：English   Publishing type：Research paper (scientific journal)  

Background: The prevalence of multiple sclerosis (MS) has been increasing worldwide in recent years, especially among females. The same increasing trends are even observed in East Asian countries, where the prevalence of MS is relatively low compared with Northern European ancestries. Whether the environmental risk factors for MS are shared between Asian and North European ancestries, and the types of environmental factors that contribute to the low and recent increase in MS prevalence in Asian countries remain unknown. This study provides the first comprehensive survey of environmental risks for MS in East Asia. Methods: Patients with MS were recruited from the Department of Neurology at Kyushu University Hospital, Japan between 01 April 2017 and 31 March 2018. Healthy controls (HCs) were recruited by public notification. All participants were residents of Kyushu Island and were required to complete medical history and lifestyle questionnaires. Dietary data were collected using a Food Frequency Questionnaire comprising intake of approximately 140 food and beverage items in the past 1 year. One hundred and three patients with MS and 124 healthy controls (HCs) completed the questionnaires. Age at onset and disability score measured by the Kurtzke Expanded Disability Status Scale (EDSS) were obtained from medical records. Results: Frequency of obesity (body mass index ≥25 kg/m²) at present time was higher in MS patients than in HCs (19.4% vs. 7.4%, p = 0.009), while body mass index at age 18–20 years did not differ between the two groups. Frequency of current or ex-smokers was higher in MS patients than in HCs (50.5% vs. 22.8%, p < 0.0001) and disability measured by the EDSS was more severe in MS patients with active smoking history than in patients without such history (p = 0.006 after adjusting for sex). Passive smoking after age 16 years was also a risk factor for MS (odds ratio: 1.31, 95% confidence interval: 1.05–1.63, p = 0.015). Longer sunlight exposure in early childhood was a protective factor for MS (odds ratio: 0.65 during summer and 0.71 during winter at age 6–10 years; 0.71 during summer and 0.72 during winter at age 11–15 years). MS patients had earlier age of menarche than HCs (mean: 12.4 years vs. 12.9 years, p = 0.031). Intake of grains was lower in MS patients than in HCs, with intake of rice in particular being significantly lower in MS patients than in HCs (mean: 235.2 g/day vs. 280.6 g/day, p = 0.006). Previously reported foods associated with MS in Northern European ancestries were not replicated in Japanese people. Conclusion: Smoking and earlier age of menarche are positively associated and sunlight exposure in early childhood is negatively associated with MS in Japanese people as shown in Caucasians. Intake of steamed short-grain white rice, a staple food in Japan, is newly found to be negatively associated with MS in Japanese people. Although the causality is unclear because the participants were prevalent cases, these environmental factors may be involved in the rising prevalence of MS in Japanese females.

DOI： 10.1016/j.msard.2019.101872

Language：English   Publishing type：Research paper (scientific journal)  

The authors regret that the legend of Fig. 4 in the above article contained errors. The sample sizes for right-sided seizures (n = 27) and left-sided seizures (n = 27) are wrong. The corrected sentence is as follows: Red lines indicate right-sided seizures (n = 24), and blue lines indicate left-sided seizures (n = 24). This is a simple typographical error and does not change the conclusions of the paper. The authors would like to apologize for any inconvenience caused.

DOI： 10.1016/j.yebeh.2019.106865

Language：English   Publishing type：Research paper (scientific journal)  

Background: Nuclear antigen released from central nervous system (CNS) cells undergoing destruction may induce production of antinuclear antibodies (ANA). We characterized the CNS-specific production of ANA in multiple sclerosis (MS). Methods: We assessed CNS-ANA binding to mouse cerebellar cell nuclei by immunofluorescence assay (IFA) with sera from 104 MS patients (91 relapsing-remitting; 13 secondary progressive), 30 patients with neuromyelitis optica spectrum disorders (NMOSD), and 30 healthy controls (HCs). Conventional ANA (cANA) was detected by IFA using human epithelial type-2 cells. CNS-ANA-positive cANA-negative patients were termed CNS-specific ANA-positive. Western blotting (WB) was performed using mouse cerebellar nuclear fractions. Results: CNS-specific ANA were more frequent in MS than in NMOSD patients or HCs (13.5% vs 0% for both comparisons, both p < .05) and were associated with HLA-DRB1*15:01 (p = .0174). WB revealed a common 55 kDa band in seven MS patients. Compared with CNS-specific ANA-negative MS patients, those with 55 kDa band-immunoreactive CNS-specific ANA showed a higher frequency of secondary progressive MS (42.9% vs 10.0%, p = .0387) and greater Expanded Disability Status Scale scores (4.50 ± 2.02 vs 2.92 ± 2.27, p = .0506). Conclusions: The CNS-specific ANA was more frequently detected in MS patients than NMOSD patients or HCs. 55 kDa band-reactive CNS-specific ANA may reflect clinical disease progression in MS.

DOI： 10.1016/j.jns.2019.116619

Language：English   Publishing type：Research paper (scientific journal)  

Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry–Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.

DOI： 10.1111/neup.12614

Language：English  

Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations.

DOI： 10.1111/neup.12614

Language：English   Publishing type：Research paper (scientific journal)  

To clarify the immunogenetic background of patients with immunoglobulin G (IgG)4 anti-neurofascin 155 (NF155) antibody-positive chronic inflammatory demyelinating polyneuropathy (CIDP), we genotyped the extended human leukocyte antigen (HLA) haplotypes in 22 Japanese patients with this disorder and compared them with those of healthy Japanese controls. All IgG4 anti-NF155 antibody-positive CIDP patients exclusively carried either HLA-DRB1*15:01-DRB5*01:01-DQA1*01:02-DQB1*06:02 or -(A*24:02)-B*52:01-C*12:02-DRB1*15:02-DRB5*01:02-DQA1*01:03-DQB1*06:01, resulting in significantly increased HLA-DRB1*15, -DRB1*15:01, -DQB1*06:01/06:02, -DQB1*06:02, and -DRB1*15:01-DQB1*06:02 frequencies compared with healthy Japanese controls. These findings indicate the involvement of specific HLA class II molecules in the pathomechanisms of IgG4 anti-NF155 antibody-positive CIDP.

DOI： 10.1016/j.jneuroim.2019.577139

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: This study was designed to detect and assess the frequency and severity of nonmotor symptoms (NMSs) in advanced Parkinson's disease (PD) and to investigate the effects of subthalamic nucleus deep brain stimulation (STN-DBS) on NMSs. METHODS: We developed an online PC-based questionnaire program to assess NMSs in PD. Twenty-six PD patients who underwent bilateral STN-DBS were assessed. The NMS questionnaire consisted of 54 NMSs in three categories, based on Witjas et al. (2002). For each NMS, the patients were asked whether or not it was present, whether or not the fluctuating manifestations correlated with the timing of levodopa-induced motor fluctuations, and how severe the NMS was. Patients were assessed by this system before surgery and at the follow-up visit, 3 to 6 months after surgery. At the postoperative assessment, patients were also assessed on preoperative NMSs using recall. RESULTS: The most frequent preoperative NMSs were constipation and visual disorders, while the most frequent postoperative NMSs were difficulty in memorizing and pollakiuria. The ranking of most frequent NMSs changed from before to after surgery. NMSs of drenching sweats, dysphagia, and constipation were significantly ameliorated, while NMSs of dyspnea and slowness of thinking were significantly deteriorated after surgery. The preoperative assessment by postoperative recall gave very different results from that of the preoperative assessment. CONCLUSION: An online questionnaire system to assess NMSs in patients with advanced PD suggested that STN-DBS might influence the frequencies of some kinds of NMSs.

DOI： 10.1007/s00701-019-04182-y

Language：English  

DOI： 10.1016/j.yebeh.2019.106865

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Nuclear antigen released from central nervous system (CNS) cells undergoing destruction may induce production of antinuclear antibodies (ANA). We characterized the CNS-specific production of ANA in multiple sclerosis (MS). METHODS: We assessed CNS-ANA binding to mouse cerebellar cell nuclei by immunofluorescence assay (IFA) with sera from 104 MS patients (91 relapsing-remitting; 13 secondary progressive), 30 patients with neuromyelitis optica spectrum disorders (NMOSD), and 30 healthy controls (HCs). Conventional ANA (cANA) was detected by IFA using human epithelial type-2 cells. CNS-ANA-positive cANA-negative patients were termed CNS-specific ANA-positive. Western blotting (WB) was performed using mouse cerebellar nuclear fractions. RESULTS: CNS-specific ANA were more frequent in MS than in NMOSD patients or HCs (13.5% vs 0% for both comparisons, both p < .05) and were associated with HLA-DRB1*15:01 (p = .0174). WB revealed a common 55 kDa band in seven MS patients. Compared with CNS-specific ANA-negative MS patients, those with 55 kDa band-immunoreactive CNS-specific ANA showed a higher frequency of secondary progressive MS (42.9% vs 10.0%, p = .0387) and greater Expanded Disability Status Scale scores (4.50 ± 2.02 vs 2.92 ± 2.27, p = .0506). CONCLUSIONS: The CNS-specific ANA was more frequently detected in MS patients than NMOSD patients or HCs. 55 kDa band-reactive CNS-specific ANA may reflect clinical disease progression in MS.

DOI： 10.1016/j.jns.2019.116619

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jns.2019.116501

Language：English   Publishing type：Research paper (scientific journal)  

In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injury-response phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation.

DOI： 10.1073/pnas.1901294117

Language：English  

DOI： 10.1016/j.jns.2019.116501

Language：English   Publishing type：Research paper (scientific journal)  

Background and purpose: The cervical and thoracic cross-sectional spinal cord area (CS-SCA) in multiple sclerosis (MS) correlates with disability, whilst such a correlation remains to be established in neuromyelitis optica spectrum disorder (NMOSD). Our aim was to clarify differences between MS and NMOSD in spinal cord segments where CS-SCA is associated with disability. Methods: The CS-SCA at C2/C3, C3/C4, T8/T9 and T9/T10 vertebral disc levels was measured in 140 MS patients (111 with relapsing–remitting MS and 29 with progressive MS) and 42 NMOSD patients with anti-aquaporin-4 immunoglobulin G. Disability was evaluated by Expanded Disability Status Scale (EDSS) scores. Multivariate associations between CS-SCA and disability were assessed by stepwise forward multiple linear regression. Results: Thoracic CS-SCA was significantly smaller in NMOSD patients than in MS patients even after adjusting for age, sex and disease duration (P = 0.002 at T8/T9), whilst there was no difference in cervical CS-SCA between the two diseases. Cervical and thoracic CS-SCA had a negative correlation with EDSS scores in MS patients (P < 0.0001 at C3/C4 and P = 0.0002 at T8/T9) whereas only thoracic CS-SCA correlated with EDSS scores in NMOSD patients (P = 0.0006 at T8/T9). By multiple regression analyses, predictive factors for disability in MS were smaller cervical CS-SCA, progressive course, older age and a higher number of relapses, whilst those in NMOSD were smaller thoracic CS-SCA and older age. Conclusions: Thoracic CS-SCA is a useful predictive marker for disability in patients with NMOSD whilst cervical CS-SCA is associated with disability in patients with MS.

DOI： 10.1111/ene.14038

Language：English   Publishing type：Research paper (scientific journal)  

In multiple sclerosis plaques, oligodendroglial connexin (Cx) 47 constituting main gap junction channels with astroglial Cx43 is persistently lost. As mice with Cx47 single knockout exhibit no demyelination, the roles of Cx47 remain undefined. We aimed to clarify the effects of oligodendroglia-specific Cx47 inducible conditional knockout (icKO) on experimental autoimmune encephalomyelitis (EAE) induced by myelin oligodendrocyte glycoprotein peptide (MOG35-55) in PLP/CreERT;Cx47fl/fl mice at 14 d after tamoxifen injection. Cx47 icKO mice demonstrated exacerbation of acute and chronic relapsing EAE with more pronounced demyelination than Cx47 flox (fl)/fl littermates. CD3+ T cells more abundantly infiltrated the spinal cord in Cx47 icKO than in Cx47 fl/fl mice throughout the acute to chronic phases. CXCR3-CCR6+CD4+ and IL17+IFNγ-CD4+ helper T (Th) 17 cells isolated from spinal cord and brain tissues were significantly increased in Cx47 icKO mice compared with Cx47 fl/fl mice, while MOG35-55-specific proliferation and proinflammatory cytokine production of splenocytes were unaltered. Microarray analysis of isolated microglia revealed stronger microglial activation toward proinflammatory and injuryresponse phenotypes with increased expressions of chemokines that can attract Th17 cells, including Ccl2, Ccl3, Ccl4, Ccl7, and Ccl8, in Cx47 icKO mice compared with Cx47 fl/fl mice. In Cx47 icKO mice, NOS2+ and MHC class II+ microglia were more enriched immunohistochemically, and A1-specific astroglial gene expressions and astroglia immunostained for C3, a representative A1 astrocyte marker, were significantly increased at the acute phase, compared with Cx47 fl/fl mice. These findings suggest that oligodendroglia-specific Cx47 ablation induces severe inflammation upon autoimmune demyelination, underscoring a critical role for Cx47 in regulating neuroinflammation.

DOI： 10.1073/pnas.1901294117

Language：English   Publishing type：Research paper (scientific journal)  

Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-containing vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy.

DOI： 10.1111/neup.12659

Language：English   Publishing type：Research paper (scientific journal)  

Allergic diseases are associated with central and peripheral nervous system diseases such as autism spectrum disorders and eosinophilic granulomatosis with polyangiitis, which frequently causes mononeuritis multiplex. Thus, it is possible that patients with an atopic constitution might develop multifocal inflammation in central and peripheral nervous system tissues. In a previous study in Japan, we reported a rare form of myelitis with persistent neuropathic pain (NeP) in patients with allergic disorders. However, the underlying mechanism of allergic inflammation-related NeP remains to be elucidated. First, we analyzed the effect of allergic inflammation on the nociceptive system in the spinal cord. Mice with atopy showed microglial and astroglial activation in the spinal cord and tactile allodynia. In a microarray analysis of isolated microglia from the spinal cord, endothelin receptor type B (EDNRB) was the most upregulated cell surface receptor in mice with atopy. Immunohistochemical analysis demonstrated EDNRB expression was upregulated in microglia and astroglia. The EDNRB antagonist BQ788 abolished glial activation and allodynia. These findings indicated that allergic inflammation induced widespread glial activation through the EDNRB pathway and NeP. Second, we investigated whether autoantibody-mediated pathogenesis underlies allergic inflammation-related NeP. We detected specific autoantibodies to small dorsal root ganglion (DRG) neurons and their nerve terminals in the dorsal horns of NeP patients with allergic disorders. An analysis of IgG subclasses revealed a predominance of IgG2. These autoantibodies were mostly colocalized with isolectin B4- and P2X3-positive unmyelinated C-fiber type small DRG neurons. By contrast, immunostaining for S100β, a myelinated DRG neuron marker, showed no colocalization with patient IgG. Immunoprecipitation and liquid chromatography-tandem mass spectrometry identified plexin D1 as a target autoantigen. Patients with anti-plexin D1 antibodies often present with burning pain and thermal hyperalgesia. Immunotherapies, including plasma exchange, are effective for NeP management. Therefore, anti-plexin D1 antibodies may be pathogenic for immune-mediated NeP, especially under allergic inflammation conditions. Thus, allergic inflammation may induce NeP through glial inflammation in the spinal cord and the anti-plexin D1 antibody-mediated impairment of small DRG neurons.

DOI： 10.3389/fneur.2019.01337

Language：Japanese  

Language：Japanese  

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Language：English   Publishing type：Research paper (scientific journal)  

Early neurological deterioration (END) following intravenous recombinant tissue plasminogen activator (rt-PA) treatment is a serious clinical event that can be caused by hemorrhagic or ischemic insult. We investigated the differences in predictive factors for END due to hemorrhagic and END due to ischemic insults. Consecutive patients from four hospitals who received 0.6 mg/kg intravenous rt-PA for acute ischemic stroke were retrospectively recruited. END was defined as a National Institutes of Health Stroke Scale (NIHSS) score ≥ 4 points within 24 h compared with baseline. END was classified into those due to hemorrhagic (ENDh) or ischemic (ENDi) insult based on computed tomography (CT) or magnetic resonance imaging. Risk factors associated with ENDh and ENDi were investigated by comparison with non-END cases. A total of 744 patients (452 men, median 75 years old) were included. END was observed in 79 patients (10.6&#37;), including 22 ENDh (3.0&#37;) and 57 ENDi (7.7&#37;), which occurred within a median of 7 h after treatment. Multivariate analyses showed that higher pretreatment NIHSS score (odds ratio [OR] 1.06, 95&#37; confidence interval [CI] 1.00-1.13) and pretreatment with antiplatelets (OR 2.84, 95&#37; CI 1.08-7.72) were associated with ENDh. Extensive early ischemic change (Alberta Stroke Program Early CT Score ≤ 7 on CT or ≤ 6 on diffusion-weighted imaging; OR 2.80, 95&#37; CI 1.36-5.64) and large artery occlusions (OR 3.09, 95&#37; CI 1.53-6.57) were associated with ENDi. Distinct factors were predictive for the END subtypes. These findings could help develop preventative measures for END in patients with the identified risk factors.

DOI： 10.1007/s11239-019-02015-4

Language：English   Publishing type：Research paper (scientific journal)  

Demyelination diseases involving the central and peripheral nervous systems are etiologically heterogeneous with both cell-mediated and humoral immunities playing pathogenic roles. Recently, autoantibodies against nodal and paranodal proteins, such as neurofascin186 (NF186), neurofascin155 (NF155), contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1) and gliomedin, have been discovered in not only chronic demyelinating conditions, such as multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy, but also in acute demyelinating conditions, such as Guillain-Barré syndrome. Only a minority of these patients harbor anti-nodal/paranodal protein antibodies; however, these autoantibodies, especially IgG4 subclass autoantibodies to paranodal proteins, are associated with unique features and these conditions are collectively termed nodopathy or paranodopathy. Establishing a concept of IgG4-related nodopathy/paranodopathy contributes to diagnosis and treatment strategy because IgG4 autoantibody-related neurological diseases are often refractory to conventional immunotherapies. IgG4 does not fix complements, or internalize the target antigens, because IgG4 exists in a monovalent bispecific form in vivo. IgG4 autoantibodies can bock protein-protein interaction. Thus, the primary role of IgG4 anti-paranodal protein antibodies may be blockade of interactions between NF155 and CNTN1/CASPR1, leading to conduction failure, which is consistent with the sural nerve pathology presenting paranodal terminal loop detachment from axons with intact internodes in the absence of inflammation. However, it still remains to be elucidated how these autoantibodies belonging to the same IgG4 subclass can cause each IgG4 autoantibody-specific manifestation. Another important issue is to clarify the mechanism by which IgG4 antibodies to nodal/paranodal proteins emerge. IgG4 antibodies develop on chronic antigenic stimulation and can block antibodies that alleviate allergic inflammation by interfering with the binding of allergen-specific IgE to allergens. Thus, environmental antigens cross-reacting with nodal and paranodal proteins may warrant future study.

DOI： 10.1016/j.neuint.2018.12.011

Language：Japanese  

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Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Intravenous recombinant tissue plasminogen activator (rt-PA) has become a common treatment for acute ischemic stroke and has highly time-dependent benefits. We aimed to clarify temporal trends regarding the frequency and characteristics of patients receiving rt-PA and explore factors associated with door-to-needle time (DNT) in Japanese emergency hospitals. METHODS: Consecutive patients who received intravenous rt-PA for acute ischemic stroke from October 2005 to December 2015 were retrospectively registered from 4 hospitals. Temporal trends in the frequency and characteristics of patients receiving rt-PA and factors associated with DNT were investigated. RESULTS: A total of 750 patients, including 688 (420 men, median 75 years old) with out-of-hospital stroke, were registered. The frequency of patients receiving intravenous rt-PA for acute ischemic stroke continuously increased from 1.8&#37; in 2005 to 9.5&#37; in 2015. The proportion of patients who were elderly or had prestroke disability increased over time, while pretreatment stroke severity declined. The DNT gradually decreased (median 105 minutes in 2005, 61 minutes in 2015). According to multivariate regression analysis with correction for multiple comparisons, activation of a code stroke system (standardized partial regression coefficient (β) -.50, P < .001, q < .001), onset-to-door time (β -.15, P < .001, q < .001), pretreatment with antithrombotic agents (β .12, P < .001, q = .001), and year of treatment (β .11, P = .007, q = .011) were associated with DNT. CONCLUSIONS: Intravenous rt-PA was widely adopted in Japanese emergency hospitals. Characteristics of patients receiving intravenous rt-PA have changed over the past decade. Several factors, including the year of treatment, were associated with DNT, which has shortened over time.

DOI： 10.1016/j.jstrokecerebrovasdis.2019.104305

Language：English   Publishing type：Research paper (scientific journal)  

The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3&#37;). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0&#37;, specificity 59.8&#37;, c-statistic 0.625), ≤ 6 (sensitivity 53.3&#37;, specificity 80.9&#37;, c-statistic 0.718), and ≤ 8 (sensitivity 86.7&#37;, specificity 55.9&#37;, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95&#37; confidence interval 1.30-35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.

DOI： 10.1007/s11239-019-01979-7

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155+ CIDP) or those lacking anti-NF155 antibodies (NF155- CIDP). METHODS: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155+ CIDP, 36 with NF155- CIDP, and 28 with non-inflammatory neurological disease (NIND). RESULTS: CSF CXCL8/IL-8, IL-13, TNF-α, CCL11/eotaxin, CCL2/MCP-1, and IFN-γ were significantly higher, while IL-1β, IL-1ra, and G-CSF were lower, in NF155+ CIDP than in NIND. Compared with NF155- CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1β, IL-1ra, and IL-6 were lower, in NF155+ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1α, CCL4/MIP-1β, and TNF-α levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1β, CCL3/MIP-1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155+ CIDP patients examined longitudinally. By contrast, NF155- CIDP had significantly increased IFN-γ compared with NIND, and exhibited positive correlations of IFN-γ, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155+ and NF155- CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. INTERPRETATION: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155+ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155+ CIDP.

DOI： 10.1002/acn3.50931

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The prevalence of multiple sclerosis (MS) has been increasing worldwide in recent years, especially among females. The same increasing trends are even observed in East Asian countries, where the prevalence of MS is relatively low compared with Northern European ancestries. Whether the environmental risk factors for MS are shared between Asian and North European ancestries, and the types of environmental factors that contribute to the low and recent increase in MS prevalence in Asian countries remain unknown. This study provides the first comprehensive survey of environmental risks for MS in East Asia. METHODS: Patients with MS were recruited from the Department of Neurology at Kyushu University Hospital, Japan between 01 April 2017 and 31 March 2018. Healthy controls (HCs) were recruited by public notification. All participants were residents of Kyushu Island and were required to complete medical history and lifestyle questionnaires. Dietary data were collected using a Food Frequency Questionnaire comprising intake of approximately 140 food and beverage items in the past 1 year. One hundred and three patients with MS and 124 healthy controls (HCs) completed the questionnaires. Age at onset and disability score measured by the Kurtzke Expanded Disability Status Scale (EDSS) were obtained from medical records. RESULTS: Frequency of obesity (body mass index ≥25 kg/m2) at present time was higher in MS patients than in HCs (19.4&#37; vs. 7.4&#37;, p = 0.009), while body mass index at age 18-20 years did not differ between the two groups. Frequency of current or ex-smokers was higher in MS patients than in HCs (50.5&#37; vs. 22.8&#37;, p < 0.0001) and disability measured by the EDSS was more severe in MS patients with active smoking history than in patients without such history (p = 0.006 after adjusting for sex). Passive smoking after age 16 years was also a risk factor for MS (odds ratio: 1.31, 95&#37; confidence interval: 1.05-1.63, p = 0.015). Longer sunlight exposure in early childhood was a protective factor for MS (odds ratio: 0.65 during summer and 0.71 during winter at age 6-10 years; 0.71 during summer and 0.72 during winter at age 11-15 years). MS patients had earlier age of menarche than HCs (mean: 12.4 years vs. 12.9 years, p = 0.031). Intake of grains was lower in MS patients than in HCs, with intake of rice in particular being significantly lower in MS patients than in HCs (mean: 235.2 g/day vs. 280.6 g/day, p = 0.006). Previously reported foods associated with MS in Northern European ancestries were not replicated in Japanese people. CONCLUSION: Smoking and earlier age of menarche are positively associated and sunlight exposure in early childhood is negatively associated with MS in Japanese people as shown in Caucasians. Intake of steamed short-grain white rice, a staple food in Japan, is newly found to be negatively associated with MS in Japanese people. Although the causality is unclear because the participants were prevalent cases, these environmental factors may be involved in the rising prevalence of MS in Japanese females.

DOI： 10.1016/j.msard.2019.101872

Language：English   Publishing type：Research paper (scientific journal)  

Background: Intravenous recombinant tissue plasminogen activator (rt-PA) has become a common treatment for acute ischemic stroke and has highly time-dependent benefits. We aimed to clarify temporal trends regarding the frequency and characteristics of patients receiving rt-PA and explore factors associated with door-to-needle time (DNT) in Japanese emergency hospitals. Methods: Consecutive patients who received intravenous rt-PA for acute ischemic stroke from October 2005 to December 2015 were retrospectively registered from 4 hospitals. Temporal trends in the frequency and characteristics of patients receiving rt-PA and factors associated with DNT were investigated. Results: A total of 750 patients, including 688 (420 men, median 75 years old) with out-of-hospital stroke, were registered. The frequency of patients receiving intravenous rt-PA for acute ischemic stroke continuously increased from 1.8% in 2005 to 9.5% in 2015. The proportion of patients who were elderly or had prestroke disability increased over time, while pretreatment stroke severity declined. The DNT gradually decreased (median 105 minutes in 2005, 61 minutes in 2015). According to multivariate regression analysis with correction for multiple comparisons, activation of a code stroke system (standardized partial regression coefficient (β) −.50, P < .001, q < .001), onset-to-door time (β −.15, P < .001, q < .001), pretreatment with antithrombotic agents (β .12, P < .001, q = .001), and year of treatment (β .11, P = .007, q = .011) were associated with DNT. Conclusions: Intravenous rt-PA was widely adopted in Japanese emergency hospitals. Characteristics of patients receiving intravenous rt-PA have changed over the past decade. Several factors, including the year of treatment, were associated with DNT, which has shortened over time.

DOI： 10.1016/j.jstrokecerebrovasdis.2019.104305

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To characterize the CSF cytokine profile in chronic inflammatory demyelinating polyneuropathy (CIDP) patients with IgG4 anti-neurofascin 155 (NF155) antibodies (NF155⁺ CIDP) or those lacking anti-NF155 antibodies (NF155⁻ CIDP). Methods: Twenty-eight CSF cytokines/chemokines/growth factors were measured by multiplexed fluorescent immunoassay in 35 patients with NF155⁺ CIDP, 36 with NF155⁻ CIDP, and 28 with non-inflammatory neurological disease (NIND). Results: CSF CXCL8/IL-8, IL-13, TNF-α, CCL11/eotaxin, CCL2/MCP-1, and IFN-γ were significantly higher, while IL-1β, IL-1ra, and G-CSF were lower, in NF155⁺ CIDP than in NIND. Compared with NF155⁻ CIDP, CXCL8/IL-8 and IL-13 were significantly higher, and IL-1β, IL-1ra, and IL-6 were lower, in NF155⁺ CIDP. CXCL8/IL-8, IL-13, CCL11/eotaxin, CXCL10/IP-10, CCL3/MIP-1α, CCL4/MIP-1β, and TNF-α levels were positively correlated with markedly elevated CSF protein, while IL-13, CCL11/eotaxin, and IL-17 levels were positively correlated with increased CSF cell counts. IL-13, CXCL8/IL-8, CCL4/MIP-1β, CCL3/MIP-1α, and CCL5/RANTES were decreased by combined immunotherapies in nine NF155⁺ CIDP patients examined longitudinally. By contrast, NF155⁻ CIDP had significantly increased IFN-γ compared with NIND, and exhibited positive correlations of IFN-γ, CXCL10/IP-10, and CXCL8/IL-8 with CSF protein. Canonical discriminant analysis of cytokines/chemokines revealed that NF155⁺ and NF155⁻ CIDP were separable, and that IL-4, IL-10, and IL-13 were the three most significant discriminators. Interpretation: Intrathecal upregulation of type 2 helper T (Th2) cell cytokines is characteristic of IgG4 NF155⁺ CIDP, while type 1 helper T cell cytokines are increased in CIDP regardless of the presence or absence of anti-NF155 antibodies, suggesting that overproduction of Th2 cell cytokines is unique to NF155⁺ CIDP.

DOI： 10.1002/acn3.50931

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12544

Language：English   Publishing type：Research paper (scientific journal)  

Background: Posterior reversible encephalopathy syndrome (PRES) is characterized by reversible vasogenic brain edema on magnetic resonance imaging. PRES is frequently associated with blood pressure (BP) fluctuation. Although Guillain–Barré syndrome (GBS) is often complicated by BP fluctuation, PRES is rarely reported. Here, we describe the first reported case of GBS in a patient who developed PRES mainly affecting the brainstem. Case presentation: A 43-year-old man presented with impaired consciousness and was hospitalized after a diagnosis of infectious meningoencephalitis. His consciousness was improved by treatment; however, he presented with polyneuropathy and BP fluctuation. We diagnosed him with GBS and started intravenous immunoglobulin therapy (IVIg); however, his consciousness became impaired again after IVIg. Brain magnetic resonance imaging showed hyperintense areas of the pons, cerebellar peduncle, midbrain and basal ganglia in the apparent diffusion coefficient image and the fluid-attenuated inversion recovery image. Diffusion-weighted imaging showed that hyperintense and hypointense lesions were present within the same regions. We diagnosed brainstem PRES complicated with GBS. Achievement of BP control improved his consciousness and hyperintense lesions on the diffusion-weighted imaging and apparent diffusion coefficient image map. Conclusions: BP fluctuation and IVIg might have caused PRES in the present case. Neurologists should consider PRES as a differential diagnosis when consciousness is impaired in GBS, especially at the time of IVIg therapy or BP fluctuation.

DOI： 10.1111/cen3.12530

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We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances.

DOI： 10.1016/j.msard.2019.06.033

Language：Japanese  

Language：Japanese  

Language：English  

Language：English   Publishing type：Research paper (scientific journal)  

We report a patient with neuromyelitis optica spectrum disorders (NMOSD) with anti-aquaporin 4 (AQP4) antibodies, who developed intractable axonal neuropathy presenting with multifocal peripheral nerve swelling by magnetic resonance (MR) neurography. A 52-year-old woman with a 12-year history of polymyositis and rheumatoid arthritis had been treated with prednisolone, tacrolimus, and abatacept (CTLA-4-Ig). She developed progressive numbness and tingling sensations in the distal parts of all limbs at the age of 50 years, followed by weakness of both upper limbs 6 months later. Neurological examination revealed severe muscle weakness and atrophy of the right upper limb with proximal dominance, diffuse moderate weakness of the left upper limb, severe sensory impairment of all modalities of four limbs in glove and stocking distribution, wide-based gait with positive Romberg's sign, and absence of all tendon reflexes. She was diagnosed with NMOSD due to positive serum anti-AQP4 antibodies and a longitudinally extensive cervical spinal cord lesion on MR images. Intravenous methylprednisolone pulse therapy, plasma exchange and intravenous immunoglobulin administration were performed, which improved the spinal cord lesion on MRI, but did not ameliorate her symptoms. Notably, she also had axonal neuropathy characterized by asymmetrical, multifocal swelling of peripheral nerves by MR neurography. Histopathological examination of the biopsied sural nerve revealed axonal degeneration and endoneurial edema but no inflammatory cell infiltration. Although she was treated with intravenous methylprednisolone, intravenous immunoglobulin, oral prednisolone, tacrolimus and tocilizumab, her symptoms gradually progressed. Neurologists should be aware of co-existing intractable axonal neuropathy in NMOSD cases presenting as immunotherapy-resistant sensorimotor disturbances.

DOI： 10.1016/j.msard.2019.06.033

Language：English   Publishing type：Research paper (scientific journal)  

Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.

DOI： 10.1097/j.pain.0000000000001596

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Levels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined. RESULTS: For both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p = 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0&#37; and a specificity of 75.8&#37;. CONCLUSIONS: sGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.

DOI： 10.1212/WNL.0000000000008160

Language：English   Publishing type：Research paper (scientific journal)  

Pain is a frequent and disabling symptom in patients with multiple sclerosis (MS); however, the underlying mechanisms of MS-related pain are not fully understood. Here, we demonstrated that cathepsin E (CatE) in neutrophils contributes to the generation of mechanical allodynia in experimental autoimmune encephalomyelitis, an animal model of MS. We showed that CatE-deficient (CatE) mice were highly resistant to myelin oligodendrocyte glycoprotein (MOG35-55)-induced mechanical allodynia. After MOG35-55 immunization, neutrophils immediately accumulated in the dorsal root ganglion (DRG). Adoptive transfer of MOG35-55-stimulated wild-type neutrophils into the dorsal root ganglion induced mechanical allodynia in the recipient C57BL/6 mice. However, the pain threshold did not change when MOG35-55-stimulated CatE neutrophils were transferred into the recipient C57BL/6 mice. MOG35-55 stimulation caused CatE-dependent secretion of elastase in neutrophils. Behavioral analyses revealed that sivelestat, a selective neutrophil elastase inhibitor, suppressed mechanical allodynia induced by adoptively transferred MOG35-55-stimulated neutrophils. MOG35-55 directly bound to toll-like receptor 4, which led to increased production of CatE in neutrophils. Our findings suggest that inhibition of CatE-dependent elastase production in neutrophil might be a potential therapeutic target for pain in patients with MS.

DOI： 10.1097/j.pain.0000000000001596

Language：English   Publishing type：Research paper (scientific journal)  

ObjectiveTo test the hypothesis that serum levels of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL), which are an intermediate astrocyte and neuron filaments, respectively, are clinically useful biomarkers of disease activity and disability in neuromyelitis optica spectrum disorders (NMOSD).MethodsLevels of GFAP and NfL in serum (sGFAP and sNfL, respectively) and in CSF samples were measured in healthy controls (HCs) (n = 49; 49 serum samples), patients with NMOSD (n = 33; 42 CSF and 102 serum samples), and patients with multiple sclerosis (MS) (n = 49; 53 CSF and 91 serum samples) by ultrasensitive single-molecule array assays. Association of sGFAP and sNfL levels with clinical parameters was determined.ResultsFor both GFAP and NfL, CSF and serum levels were strongly correlated. Both were higher in the serum of patients with NMOSD than in HCs (both p < 0.001). Moreover, sGFAP was higher in NMOSD than in MS (median 207.7 vs 121.1 pg/mL, p < 0.001). In NMOSD, sGFAP concentration increased after recent relapse (540.9 vs 152.9 pg/mL, p < 0.001). Multivariate analyses indicated that sGFAP and sNfL were associated with Expanded Disability Status Scale score in NMOSD (p = 0.026 and p < 0.001, respectively). Higher sGFAP/sNfL quotient at relapse differentiated NMOSD from MS with a sensitivity of 73.0% and a specificity of 75.8%.ConclusionssGFAP and sNfL are likely to be good biomarkers of disease activity and disability, and the sGFAP/sNfL quotient at relapse is a potential diagnostic marker for NMOSD.

DOI： 10.1212/WNL.0000000000008160

Language：English   Publishing type：Research paper (scientific journal)  

Objectives: The objectives of this study were to determine how hemispheric laterality of seizure activity influences periictal heart rate variability (HRV) and investigate the ability of HRV parameters to discriminate right- and left-sided seizures. Methods: Long-term video electroencephalogram-electrocardiogram recordings of 54 focal seizures in 25 patients with focal epilepsy were reviewed. Using linear mixed models, we examined the effect of seizure laterality on linear (standard deviation of R-R intervals [SDNN], root mean square of successive differences [RMSSD], low frequency [LF] and high frequency [HF] power of HRV, and LF/HF) and nonlinear (standard deviation [SD]1, SD2, and SD2/SD1 derived from Poincaré plots) periictal HRV parameters, the magnitude of heart rate (HR) changes, and the onset time of increased HR. Receiver operating characteristics (ROC) were used to determine the ability of these parameters to discriminate between right- and left-sided seizures. Results: Postictal SDNN, RMSSD, LF, HF, SD1, and SD2 were higher in right- than left-sided seizures. Root mean square of successive difference and HF were decreased after left- but not right-sided seizures. Standard deviation of R-R intervals, LF, and SD1 were increased after right- but not left-sided seizures. Increased ictal HR was earlier and larger in right- than left-sided seizures. Postictal HF showed the greatest area under the ROC curve (AUC) (0.87) for discriminating right- and left-sided seizures. Conclusions: Our data suggest that postictal parasympathetic activity is higher, whereas ictal HR increase is greater, in right- than left-sided seizures. Involvement of the right hemisphere may be associated with postictal autonomic instability. Postictal HRV parameters may provide useful information on hemispheric laterality of seizure activity.

DOI： 10.1016/j.yebeh.2019.05.026

Language：Japanese  

Language：Japanese  

Language：English  

DOI： 10.1111/neup.12563

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: The objectives of this study were to determine how hemispheric laterality of seizure activity influences periictal heart rate variability (HRV) and investigate the ability of HRV parameters to discriminate right- and left-sided seizures. METHODS: Long-term video electroencephalogram-electrocardiogram recordings of 54 focal seizures in 25 patients with focal epilepsy were reviewed. Using linear mixed models, we examined the effect of seizure laterality on linear (standard deviation of R-R intervals [SDNN], root mean square of successive differences [RMSSD], low frequency [LF] and high frequency [HF] power of HRV, and LF/HF) and nonlinear (standard deviation [SD]1, SD2, and SD2/SD1 derived from Poincaré plots) periictal HRV parameters, the magnitude of heart rate (HR) changes, and the onset time of increased HR. Receiver operating characteristics (ROC) were used to determine the ability of these parameters to discriminate between right- and left-sided seizures. RESULTS: Postictal SDNN, RMSSD, LF, HF, SD1, and SD2 were higher in right- than left-sided seizures. Root mean square of successive difference and HF were decreased after left- but not right-sided seizures. Standard deviation of R-R intervals, LF, and SD1 were increased after right- but not left-sided seizures. Increased ictal HR was earlier and larger in right- than left-sided seizures. Postictal HF showed the greatest area under the ROC curve (AUC) (0.87) for discriminating right- and left-sided seizures. CONCLUSIONS: Our data suggest that postictal parasympathetic activity is higher, whereas ictal HR increase is greater, in right- than left-sided seizures. Involvement of the right hemisphere may be associated with postictal autonomic instability. Postictal HRV parameters may provide useful information on hemispheric laterality of seizure activity.

DOI： 10.1016/j.yebeh.2019.05.026

Language：English   Publishing type：Research paper (scientific journal)  

Background: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. Methods: Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. Results: Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. Conclusions: Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases.

DOI： 10.1016/j.msard.2019.03.008

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- and MLS-responsible proteins: chorein and XK protein. Methods: Erythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies. Results: All suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction. Conclusions: In this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.

DOI： 10.1212/NXG.0000000000000328

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. METHODS: Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. RESULTS: Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. CONCLUSIONS: Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases.

DOI： 10.1016/j.msard.2019.03.008

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ObjectiveTo identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- A nd MLS-responsible proteins: Chorein and XK protein.MethodsErythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies.ResultsAll suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction.ConclusionsIn this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.

DOI： 10.1212/NXG.0000000000000328

Language：English   Publishing type：Research paper (scientific journal)  

Hypertrophic pachymeningitis (HP) is a rare neurologic disease causing inflammatory fibrous thickening of the brain and spinal dura mater. We investigated the cerebrospinal fluid cytokine profile of HP by measuring 28 cytokines/chemokines/growth factors with a multiplexed fluorescent immunoassay in 8 patients with HP (6 idiopathic, 1 IgG4-related, 1 anti-neutrophil cytoplasmic antibody-related), and 11 with other non-inflammatory neurologic diseases (OND). Interleukin (IL)-4, IL-5, IL-9, IL-10, TNF-α, and CXCL8/IL-8 levels were significantly higher in idiopathic HP (IHP) than OND. Cluster analyses disclosed two major clusters: one mainly consisted of IHP and the other of OND, suggesting a unique cytokine profile in IHP.

DOI： 10.1016/j.jneuroim.2019.01.010

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

We report a 60-year-old male with anti-myelin oligodendrocyte glycoprotein (MOG) antibody who developed progressive cognitive deterioration and behavioral changes, with no other focal signs, over 9 months. MRI showed numerous T2-hyperintense lesions with partial contrast enhancement in white and grey matter of cerebrum, cerebellum and spinal cord. A brain biopsy revealed perivascular inflammatory cell infiltration, disturbed vascular continuity and no demyelination, indicative of a lymphocytic pattern of primary CNS vasculitis (PCNSV). Contrast enhancement disappeared after immunotherapy; however, cognitive impairment was not improved. Neurologists should note that MOG antibody disease can present as immunotherapy-resistant progressive cognitive impairment with PCNSV-like histopathology.

DOI： 10.1016/j.msard.2019.01.053

Language：English   Publishing type：Research paper (scientific journal)  

Hypertrophic pachymeningitis (HP) is a rare neurologic disease causing inflammatory fibrous thickening of the brain and spinal dura mater. We investigated the cerebrospinal fluid cytokine profile of HP by measuring 28 cytokines/chemokines/growth factors with a multiplexed fluorescent immunoassay in 8 patients with HP (6 idiopathic, 1 IgG4-related, 1 anti-neutrophil cytoplasmic antibody-related), and 11 with other non-inflammatory neurologic diseases (OND). Interleukin (IL)-4, IL-5, IL-9, IL-10, TNF-α, and CXCL8/IL-8 levels were significantly higher in idiopathic HP (IHP) than OND. Cluster analyses disclosed two major clusters: one mainly consisted of IHP and the other of OND, suggesting a unique cytokine profile in IHP.

DOI： 10.1016/j.jneuroim.2019.01.010

Language：English   Publishing type：Research paper (scientific journal)  

We report a 60-year-old male with anti-myelin oligodendrocyte glycoprotein (MOG) antibody who developed progressive cognitive deterioration and behavioral changes, with no other focal signs, over 9 months. MRI showed numerous T2-hyperintense lesions with partial contrast enhancement in white and grey matter of cerebrum, cerebellum and spinal cord. A brain biopsy revealed perivascular inflammatory cell infiltration, disturbed vascular continuity and no demyelination, indicative of a lymphocytic pattern of primary CNS vasculitis (PCNSV). Contrast enhancement disappeared after immunotherapy; however, cognitive impairment was not improved. Neurologists should note that MOG antibody disease can present as immunotherapy-resistant progressive cognitive impairment with PCNSV-like histopathology.

DOI： 10.1016/j.msard.2019.01.053

Language：English   Publishing type：Research paper (scientific journal)  

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.

DOI： 10.1111/neup.12548

Language：English  

Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy.

DOI： 10.1111/neup.12548

Language：English   Publishing type：Research paper (scientific journal)  

Objective: Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods: We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results: LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220⁺ B cells, IgG1⁺ cells, CD138⁺ plasma cells, CD3⁺ T cells, F4/80⁺ macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-β1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF-βRI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-β1, TGF-βRI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-βRI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation: TGF-β1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.

DOI： 10.1002/acn3.715

Language：Japanese  

糖尿病網膜症におけるCD206+CX3CR1+硝子体界面マクロファージ局所増殖

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Objective: Immunoglobulin (Ig)G4-related disease is a major cause of hypertrophic pachymeningitis (HP), presenting as a progressive thickening of the dura mater. HP lacks an animal model to determine its underlying mechanisms. We developed a suitable animal model for the treatment of HP. Methods: We longitudinally evaluated dura in mice with a mutation (Y136F) in the linker for activation of T cells (LAT), which induced type 2 T helper (Th2) cell proliferation and IgG1 (IgG4 human equivalent) overexpression. Mice were therapeutically administered daily oral irbesartan from 3 to 6 weeks of age. Human IgG4-related, anti-neutrophil cytoplasmic antibody-related, and idiopathic HP dura were also immunohistochemically examined. Results: LATY136F mice showing dural gadolinium enhancement on magnetic resonance imaging had massive infiltration of B220+ B cells, IgG1+ cells, CD138+ plasma cells, CD3+ T cells, F4/80+ macrophages, and polymorphonuclear leukocytes in the dura at 3 weeks of age, followed by marked fibrotic thickening. In dural lesions, transforming growth factor (TGF)-β1 was produced preferentially in B cells and macrophages while TGF-β receptor I (TGF-β RI) was markedly upregulated on fibroblasts. Quantitative western blotting revealed significant upregulation of TGF-β1, TGF-β RI, and phosphorylated SMAD2/SMAD3 in dura of LATY136F mice aged 13 weeks. A similar upregulation of TGF-β RI, SMAD2/SMAD3, and phosphorylated SMAD2/SMAD3 was present in autopsied dura of all three types of human HP. Irbesartan abolished dural inflammatory cell infiltration and fibrotic thickening in all treated LATY136F mice with reduced TGF-β1 and nonphosphorylated and phosphorylated SMAD2/SMAD3. Interpretation: TGF-β1/SMAD2/SMAD3 pathway is critical in HP and is a potential novel therapeutic target.

DOI： 10.1002/acn3.715

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12488

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease (AD) patients exhibit various cognitive dysfunctions, including impairment of orientation for time (OT). The brain regions underlying OT impairment remain to be elucidated. A previous single-photon emission computed tomography study has indicated hypoperfusion of the posterior cingulate cortex (PCC) in relation to deterioration of OT. In this study, we investigated whole brain functional connectivity changes of PCC using resting-state functional magnetic resonance imaging. Voxel-based functional connectivity with PCC was analyzed in OT-poor or OT-good AD patients, classified according to the mean OT scores of the Mini-Mental State Examination subscale. The connectivities of dorsal frontal lobe, and lateral parietal and lateral temporal lobes with PCC in the right hemisphere were reduced in the OT-poor AD group compared with the OT-good AD group. A subtraction connectivity map of OT score differences (OT-good minus OT-poor) revealed the right middle temporal gyrus near the temporo-parietal junction as a significantly connected region with PCC. These results suggest that the right posterior part of the middle temporal gyrus may play an important role in OT in conjunction with PCC, and that disconnection between PCC and the right ventral attention network may cause OT disturbance in AD patients.

DOI： 10.1007/s11682-018-9860-x

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer’s disease (AD) patients exhibit various cognitive dysfunctions, including impairment of orientation for time (OT). The brain regions underlying OT impairment remain to be elucidated. A previous single-photon emission computed tomography study has indicated hypoperfusion of the posterior cingulate cortex (PCC) in relation to deterioration of OT. In this study, we investigated whole brain functional connectivity changes of PCC using resting-state functional magnetic resonance imaging. Voxel-based functional connectivity with PCC was analyzed in OT-poor or OT-good AD patients, classified according to the mean OT scores of the Mini-Mental State Examination subscale. The connectivities of dorsal frontal lobe, and lateral parietal and lateral temporal lobes with PCC in the right hemisphere were reduced in the OT-poor AD group compared with the OT-good AD group. A subtraction connectivity map of OT score differences (OT-good minus OT-poor) revealed the right middle temporal gyrus near the temporo-parietal junction as a significantly connected region with PCC. These results suggest that the right posterior part of the middle temporal gyrus may play an important role in OT in conjunction with PCC, and that disconnection between PCC and the right ventral attention network may cause OT disturbance in AD patients.

DOI： 10.1007/s11682-018-9860-x

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: MR neurography is known to be useful to evaluate nerve pathology. The purpose of this study was to evaluate the usefulness of simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy subjects. Materials and methods: This retrospective study included 13 patients with CIDP and five healthy subjects from 2015 to 2017. The T2 relaxation time and the size of the cervical ganglia and roots of the brachial plexus were measured. Statistical analyses were performed with the Mann-Whitney U test and receiver operating characteristics (ROC) analysis. Results: The T2 relaxation times of the ganglia and roots were longer in patients with CIDP (119.31 ± 35.53 msec and 111.15 ± 33.82 msec) than in healthy subjects (101.42 ± 26.42 msec and 85.29 ± 13.22 msec, P = 0.0007 and P < 0.0001, respectively). The sizes of the ganglia and the roots were larger in patients with CIDP (6.25 ± 1.56 mm and 4.37 ± 1.71 mm) than in healthy subjects (5.59 ± 1.08 mm and 3.50 ± 0.62 mm, P = 0.0114 and P = 0.0014, respectively). ROC analysis revealed that T2 relaxation time of the roots was best at distinguishing CIDP patients from healthy subjects (the area under the curve = 0.748). Conclusion: Patients with CIDP could be distinguished from healthy subjects using simultaneous apparent T2 mapping and neurography with SHINKEI.

DOI： 10.1016/j.mri.2018.09.025

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: MR neurography is known to be useful to evaluate nerve pathology. The purpose of this study was to evaluate the usefulness of simultaneous apparent T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy subjects. MATERIALS AND METHODS: This retrospective study included 13 patients with CIDP and five healthy subjects from 2015 to 2017. The T2 relaxation time and the size of the cervical ganglia and roots of the brachial plexus were measured. Statistical analyses were performed with the Mann-Whitney U test and receiver operating characteristics (ROC) analysis. RESULTS: The T2 relaxation times of the ganglia and roots were longer in patients with CIDP (119.31 ± 35.53 msec and 111.15 ± 33.82 msec) than in healthy subjects (101.42 ± 26.42 msec and 85.29 ± 13.22 msec, P = 0.0007 and P < 0.0001, respectively). The sizes of the ganglia and the roots were larger in patients with CIDP (6.25 ± 1.56 mm and 4.37 ± 1.71 mm) than in healthy subjects (5.59 ± 1.08 mm and 3.50 ± 0.62 mm, P = 0.0114 and P = 0.0014, respectively). ROC analysis revealed that T2 relaxation time of the roots was best at distinguishing CIDP patients from healthy subjects (the area under the curve = 0.748). CONCLUSION: Patients with CIDP could be distinguished from healthy subjects using simultaneous apparent T2 mapping and neurography with SHINKEI.

DOI： 10.1016/j.mri.2018.09.025

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/neup.12563

Language：English  

Multiple sclerosis (MS) is an inflammatory demyelinating disorder. Although all MS patients initially show a relapsing-remitting course, 20–50% subsequently enter a chronic progressive course at 10–20 years after onset that greatly influences their activities of daily living. There are 2.5 million MS patients worldwide with large regional and racial differences. In particular, there are many MS patients among Caucasians living in Europe, while the disease is relatively rare in Asians and Africans. Although MS is regarded as an autoimmune disease, many factors such as genetic background, environmental factors, and sex are involved in its pathogenesis. While the immunological mechanisms remain to be fully elucidated, invasion of autoreactive T cells into the central nervous system (CNS) tissue is considered the first step of the disease. These T cells react with myelin antigens and initiate demyelination of the CNS by activating cytotoxic T cells, macrophages, and B cells through the release of inflammatory cytokines. As a treatment option, disease-modifying therapies have recently been developed to prevent the recurrence of MS in addition to conventional treatment with corticosteroids for acute relapse. However, there are still few effective treatments for the chronic progressive phase, and it is thus imperative to decipher the mechanism for chronic progression.

DOI： 10.1007/978-981-32-9636-7_14

Language：English   Publishing type：Research paper (scientific journal)  

The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used for the assessment of early ischemic changes (EICs) before thrombolysis. However, for symptomatic intracerebral hemorrhage (sICH) following intravenous recombinant tissue plasminogen activator (rt-PA), the prediction abilities of CT-ASPECTS, diffusion-weighted imaging (DWI)-ASPECTS, and DWI-ASPECTS including EICs in deep white matter (DWI-ASPECTS + W) are unclear. We investigated associations between each score and sICH following intravenous rt-PA. Data from consecutive patients who received intravenous rt-PA for acute ischemic stroke from 2005 to 2015 in four hospitals were retrospectively screened. We included data from patients who had undergone both CT and magnetic resonance imaging before thrombolysis and without evidence of posterior circulation stroke. We analyzed the ability of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W to predict sICH, accompanied by an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 within the initial 36 h. Of 455 patients (273 men, median 75 years old), sICH occurred in 15 patients (3.3%). Receiver operating characteristics curve analysis showed that the optimal cut-offs of CT-ASPECTS, DWI-ASPECTS, and DWI-ASPECTS + W for predicting sICH were ≤ 9 (sensitivity 60.0%, specificity 59.8%, c-statistic 0.625), ≤ 6 (sensitivity 53.3%, specificity 80.9%, c-statistic 0.718), and ≤ 8 (sensitivity 86.7%, specificity 55.9%, c-statistic 0.756), respectively. A DWI-ASPECTS + W of ≤ 8 was independently associated with sICH (odds ratio 5.21, 95% confidence interval 1.30–35.31) after adjustment for pretreatment with antithrombotic agents, pretreatment NIHSS score, and large artery occlusions. DWI-ASPECTS + W predicted sICH in patients with acute anterior circulation stroke receiving intravenous rt-PA.

DOI： 10.1007/s11239-019-01979-7

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12525

Language：English   Publishing type：Research paper (scientific journal)  

Background: To maximize the effect of intravenous (IV) thrombolysis and/or endovascular therapy (EVT) for acute ischemic stroke (AIS), stroke centers need to establish a parallel workflow on the basis of a code stroke (CS) protocol. At Kokura Memorial Hospital (KMH), we implemented a CS system in January 2014; however, the process of information sharing within the team has occasionally been burdensome. Objective: To solve this problem using information communication technology (ICT), we developed a novel application for smart devices, named “Task Calc. Stroke” (TCS), and aimed to investigate the impact of TCS on AIS care. Methods: TCS can visualize the real-time progress of crucial tasks for AIS on a dashboard by changing color indicators. From August 2015 to March 2017, we installed TCS at KMH and recommended its use during normal business hours (NBH). We compared the door-to-computed tomography time, the door-to-complete blood count (door-to-CBC) time, the door-to-needle for IV thrombolysis time, and the door-to-puncture for EVT time among three treatment groups, one using TCS (“TCS-based CS”), one not using TCS (“phone-based CS”), and one not based on CS (“non-CS”). A questionnaire survey regarding communication problems was conducted among the CS teams at 3 months after the implementation of TCS. Results: During the study period, 74 patients with AIS were transported to KMH within 4.5 h from onset during NBH, and 53 were treated using a CS approach (phone-based CS: 26, TSC-based CS: 27). The door-to-CBC time was significantly reduced in the TCS-based CS group compared to the phone-based CS group, from 31 to 19 min (p = 0.043). Other processing times were also reduced, albeit not significantly. The rate of IV thrombosis was higher in the TCS-based CS group (78% vs. 46%, p = 0.037). The questionnaire was correctly filled in by 34/38 (89%) respondents, and 82% of the respondents felt a reduction in communication burden by using the TCS application. Conclusions: TCS is a novel approach that uses ICT to support information sharing in a parallel CS workflow in AIS care. It shortens the processing times of critical tasks and lessens the communication burden among team members.

DOI： 10.3389/fneur.2019.01118

Language：English   Publishing type：Research paper (scientific journal)  

We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3 + T, F4/80 + , and CD169 + cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.

DOI： 10.1038/s41598-018-20390-5

Language：Japanese  

膜性腎症を伴うCIDPにおける抗paranode、抗podocyte抗体、並びに抗contactin1抗体陽性CIDPとの病像の比較

Language：Japanese  

Language：Japanese  

近年、慢性炎症性多発神経炎症例の一部でランビエ絞輪部およびその周辺の膜蛋白に対する自己抗体が複数同定された。特にランビエ傍絞輪部に局在するneurofascin 155(NF155)および、contactin 1に対する自己抗体は診断的価値が証明され、病的意義についても明らかにされつつある。本稿では抗NF155抗体を中心に自己抗体陽性CIDPの臨床像および病態機序について概説する。(著者抄録)

Language：Japanese  

Language：Japanese  

抗Neurofascin 155抗体陽性CIDPの分子生物的基盤と臨床像

Language：Japanese  

Language：Japanese  

Language：Japanese  

急性期虚血性脳卒中に対する経静脈的血栓溶解療法後の早期神経症候増悪例の頻度と特徴

Language：Japanese  

Language：Japanese  

安静時機能的MRIを用いたアルツハイマー病治療薬による脳機能的結合変化の研究

Language：Japanese  

Language：Japanese  

多系統萎縮症の病態形成における自然免疫の関与とバイオマーカーの探索

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE:: To evaluate the usefulness of simultaneous T2 mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in the lumbar plexus to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy controls. METHODS:: Our institutional review boards approved this retrospective study, and written informed consent was waived. 10 patients with CIDP from 2015 to 2017 were studied along with 5 healthy controls on a 3 T scanner. The T2 relaxation time and the size of the dorsal root ganglia and nerves of the lumbar plexus at L3-S1 were measured. Statistical analyses were performed with the Mann-Whitney U test and a receiver operating characteristics analysis. RESULTS:: The T2 relaxation times of the dorsal root ganglia and the nerves of the lumbar plexus were longer in the CIDP patients (133.34  ±  41.36 and 130.40 ± 47.78 ms) compared to the healthy controls (114.69 ± 24.90 and 83.72 ± 17.51 ms, p = 0.0265 and p < 0.0001, respectively). The sizes of the nerves were larger in the CIDP patients (6.19  ±  2.28 mm) compared to the controls (4.54  ±  0.86 mm, p < 0.0001). However, there was no significant difference between the sizes of the ganglia in the CIDP patients and the controls. The receiver operating characteristics analysis revealed that the T2 relaxation time of the nerves was best at distinguishing the CIDP patients from the controls (Az  =  0.848). CONCLUSION:: Patients with CIDP could be distinguished from healthy controls using simultaneous T2 mapping and neurography with SHINKEI in the lumbar plexus. ADVANCES IN KNOWLEDGE:: Patients with CIDP could be distinguished from healthy controls using simultaneous T2 mapping and neurography with SHINKEI in the lumbar plexus.

DOI： 10.1259/bjr.20180501

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods: Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results: We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions: We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

DOI： 10.1212/NXG.0000000000000292

Language：English   Publishing type：Research paper (scientific journal)  

Objective To characterize the genetic and clinical features of patients with autosomal dominant adult-onset demyelinating leukodystrophy (ADLD) carrying duplication and deletion upstream of lamin B1 (LMNB1). Methods Ninety-three patients with adult-onset leukoencephalopathy of unknown etiology were genetically analyzed for copy numbers of LMNB1 and its upstream genes. We examined LMNB1 expression by reverse transcription-qPCR using total RNA extracted from peripheral leukocytes. Clinical and MRI features of the patients with ADLD were retrospectively analyzed. Results We identified 4 patients from 3 families with LMNB1 duplication. The duplicated genomic regions were different from those previously reported. The mRNA expression level of LMNB1 in patients with duplication was significantly increased. The clinical features of our patients with LMNB1 duplication were similar to those reported previously, except for the high frequency of cognitive impairment in our patients. We found 2 patients from 1 family carrying a 249-kb genomic deletion upstream of LMNB1. Patients with the deletion exhibited relatively earlier onset, more prominent cognitive impairment, and fewer autonomic symptoms than patients with duplication. The presence of cerebellar symptoms and lesions may be characteristic in our patients with the deletion compared with the previously reported family with the deletion. Magnetic resonance images of patients with the deletion exhibited a widespread distribution of white matter lesions including the anterior temporal region. Conclusions We identified 4 Japanese families with ADLD carrying duplication or deletion upstream of LMNB1. There are differences in clinical and MRI features between the patients with the duplication and those with the deletion upstream of LMNB1.

DOI： 10.1212/NXG.0000000000000292

Language：English   Publishing type：Research paper (scientific journal)  

Background: Several case reports have described the concurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) and membranous nephropathy (MN). The presence of autoantibodies against podocyte antigens phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain containing 7A (THSD7A) in MN suggests an autoimmune mechanism. Some CIDP patients also harbor autoantibodies against paranodal proteins such as neurofascin 155 (NF155) and contactin-1 (CNTN1). We investigated the relationship between CIDP and MN by assaying autoantibodies against paranodal and podocyte antigens in a CIDP patient with MN, and by a literature survey on the clinical features of CIDP with MN. Methods: Anti-CNTN1 and NF155 antibodies were measured by flow cytometry using HEK293 cell lines stably expressing human CNTN1 or NF155. Binding capacity of antibodies was validated by immunostaining mouse teased sciatic nerve fibers. Anti-PLA2R antibodies were measured by enzyme-linked sorbent assay and anti-THSD7A antibodies by indirect immunofluorescence assay. Clinical features between 14 CIDP with MN cases including two with anti-CNTN1 antibodies and 20 anti-CNTN1 antibody-positive CIDP cases were compared. Results: A patient whose ages was in the late 70 s complained of progressive weakness and superficial and deep sensory impairment in four extremities over 6 months. Nerve conduction studies showed prominent demyelination patterns. The patient presented with nephrotic syndrome. Renal biopsy disclosed basement membrane thickening with local subepithelial projections and glomerular deposits of IgG4, compatible with MN. Autoantibody assays revealed the presence of IgG4 and IgG1 anti-CNTN1 antibodies, but an absence of anti-NF155, anti-PLA2R, and anti-THSD7A antibodies. The patient's serum stained paranodes of teased sciatic nerves. CIDP with MN and anti-CNTN1 antibody-positive CIDP commonly showed male preponderance, relatively higher age of onset, acute to subacute onset in 35-50% of cases, distal dominant sensorimotor neuropathy, proprioceptive impairment leading to sensory ataxia, and very high cerebrospinal fluid protein levels. However, 11 of 13 CIDP patients with MN had a favorable response to mono- or combined immunotherapies whereas anti-CNTN1 antibody-positive CIDP was frequently refractory to corticosteroids and intravenous immunoglobulin administration. Conclusion: CIDP with MN and anti-CNTN1 antibody-positive CIDP show considerable overlap but are not identical. CIDP with MN is probably heterogeneous and some cases harbor anti-CNTN1 antibodies.

DOI： 10.3389/fneur.2018.00997

Language：Japanese  

難病法施行後の難病医療提供体制整備事業の実態を明らかにした。47都道府県庁の難病担当部局課係を対象とする質問紙調査を行った(回収率100&#37;)。難病医療ネットワーク事業は98&#37;実施されていた。難病医療コーディネーターは、42都道府県に60名配置されていた。難病法施行後も難病医療ネットワーク事業の県による差異は大きく、共通して専門的な知識を有する人材の確保の困難さが課題であることがわかった。難病相談・支援センター等との有機的な連携により難病患者の支援体制がより充実すると期待される。(著者抄録)

Language：Japanese  

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抗neurofascin155抗体陽性CIDPにおける免疫遺伝学的背景因子とT細胞性免疫の関与

Language：Japanese  

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GBS/CIDP:病態と治療の新たな展開-1 GBS/CIDPの自己抗体 蛋白抗原

Language：Japanese  

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Facial onset sensory and motor neuronopathy症候群は早期からoral phase dysphagiaを呈する

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Connexin36 (Cx36) forms gap junctions between neurons, which are called electrical synapses, enabling adjacent neurons to communicate directly. The participation of chemical synapses in neurodegeneration in amyotrophic lateral sclerosis (ALS) has long been indicated, but it remains unclear whether electrical synapses are involved in the pathogenesis of ALS. We performed extensive immunopathological analyses using mutant superoxide dismutase 1 (SOD1G93A) transgenic mice and their littermates to investigate whether Cx36-made electrical synapses are affected in motor neuron diseases. We found that in the lamina IX of the lumbar spinal cord from wild type mice, about half of the Cx36 puncta existed independently of chemical synapse markers, while the rest coexisted with chemical synapse markers, such as vesicular glutamate transporter 1 (VGLUT1), which is a glutamatergic axon terminal marker, and/or glutamate decarboxylase 65 (GAD65), which is a GABAergic axon terminal marker. Cx36 single or Cx36/GAD65 double positive puncta, but not VGLUT1-containing puncta, were preferentially decreased on neuronal and dendritic surfaces of the anterior horn cells in the early stage of SOD1G93A ALS mice. Moreover, in five human autopsied sporadic ALS cases with bulbar or upper limb onset, Cx36 immunoreactivity was diminished in the proximal dendrites and neuropils of well-preserved large motor neurons in the lumbar anterior horns. These findings suggest that downregulation of neuronal and dendritic Cx36 in the spinal anterior horns commonly occurs from the early stage of hereditary and sporadic ALS. Cx36-made electrical synapses without glutamatergic signaling appear to be more vulnerable than other chemical synapses and electrical synapses with glutamatergic signaling in the early stage of motor neuron degeneration, suggesting involvement of Cx36-made electrical synapses in the pathogenesis of human ALS.

DOI： 10.3389/fnins.2018.00894

Language：English   Publishing type：Research paper (scientific journal)  

Glial connexins (Cxs) form gap junction channels through which a pan-glial network plays key roles in maintaining homeostasis of the central nervous system (CNS). In multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), expression of astrocytic Cx43 is lost in acute lesions but upregulated in chronic plaques, while astrocytic Cx30 is very low in normal white matter and changes in its expression have not been convincingly shown. In Cx30 or Cx43 single knockout (KO) mice and even in Cx30/Cx43 double KO mice, acute EAE is unaltered. However, the effects of Cx30/Cx43 deficiency on chronic EAE remains to be elucidated. We aimed to clarify the roles of Cx30 in chronic neuroinflammation by studying EAE induced by myelin oligodendrocyte glycoprotein peptide 35-55 in Cx30 KO mice. We found that Cx30 deficiency improved the clinical symptoms and demyelination of chronic but not acute EAE without influencing CD3+ T cell infiltration. Furthermore, increased ramified microglia in the naïve state and induced earlier and stronger microglial activation in the acute and chronic phases of EAE was observed. These activated microglia had an anti-inflammatory phenotype, as shown by the upregulation of arginase-1 and brain-derived neurotrophic factor and the downregulation of nitric oxide synthase 2. In the naïve state, Cx30 deficiency induced modest enlargement of astrocytic processes in the spinal cord gray matter and a partial reduction of Cx43 expression in the spinal cord white matter. These astrocytes in Cx30 KO mice showed earlier and stronger activation during the acute phase of EAE, with upregulated A2 astrocyte markers and a significant decrease in Cx43 in the chronic phases. Spinal cord neurons and axons were more preserved in Cx30 KO mice than in littermates in the chronic phase of EAE. These findings suggest that Cx30 deficiency increased ramified microglia in the CNS in the naïve state and improved chronic EAE through redirecting microglia toward an anti-inflammatory phenotype, suggesting a hitherto unknown critical role of astrocytic Cx30 in regulating microglial number and functional state.

DOI： 10.3389/fimmu.2018.02588

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Background: We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability. Methods: From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured. Results: Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm
³
vs. 85 mm
³
, p < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients (p < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores (p < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients (p = 0.03 and p = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration (p = 0.046, p = 0.01, p = 0.005, and p = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV (p = 0.001), particularly for thalamic volume (p = 0.001), with disease duration compared with Caucasian patients. Conclusions: Gray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients.

DOI： 10.1186/s12974-018-1295-1

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: We compared the magnetic resonance imaging (MRI) features between Japanese and Caucasian patients with multiple sclerosis (MS), and identified the relationships between MRI features and disability. METHODS: From the baseline data of phase II fingolimod trials, 95 Japanese and 246 Caucasian relapsing-remitting MS patients were enrolled. The number, volume, and distribution of brain MRI lesions were evaluated using T2-weighted (T2W) images. Cross-sectional total normalized brain volume (NBV), normalized cortical gray matter volume, normalized deep gray matter volume (NDGMV), normalized white matter volume (NWMV), and normalized thalamic volume were measured. RESULTS: Japanese patients had significantly lower Expanded Disability Status Scale (EDSS) scores than Caucasian patients (mean 2.0 vs. 2.3, p = 0.008), despite a similar disease duration. Japanese patients showed a trend towards fewer T2W-lesions (median 50 vs. 65, p = 0.08) and significantly lower frequencies of cerebellar and parietal lobe lesions (p = 0.02 for both) than Caucasian patients. There were no differences in T2W-lesion volume between races, whereas Japanese patients had a significantly larger T2W-lesion volume per lesion compared with Caucasian patients (median 140 mm3 vs. 85 mm3, p < 0.0001). T2W-lesion volumes were positively correlated with EDSS scores in Japanese patients (p < 0.0001). In both races, NBV, normalized cortical gray matter volume, NDGMV, and thalamic volume were negatively correlated with disease duration and EDSS scores (p < 0.01 for all). NWMV was negatively correlated with disease duration and EDSS scores only in Caucasian patients (p = 0.03 and p = 0.004, respectively). NBV, NDGMV, NWMV, and thalamic volume were consistently smaller in Japanese compared with Caucasian patients throughout the entire examined disease duration (p = 0.046, p = 0.01, p = 0.005, and p = 0.04, respectively). Japanese patients had a significantly faster reduction in NDGMV (p = 0.001), particularly for thalamic volume (p = 0.001), with disease duration compared with Caucasian patients. CONCLUSIONS: Gray matter atrophy is a common denominator for disability in Japanese and Caucasian patients. Additional contributory factors for disability include T2W-lesion volume in Japanese patients and white matter atrophy in Caucasian patients. Less frequent parietal and cerebellar involvement with fewer T2W-lesions may underlie milder disability in Japanese patients.

DOI： 10.1186/s12974-018-1295-1

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To identify novel autoantibodies for neuropathic pain (NeP). Methods: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. Results: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100β-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti–small DRG neuron antibody-positive patients had anti–plexin D1 antibodies. Application of anti–plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti–plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. Interpretation: Anti–plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP.

DOI： 10.1002/ana.25279

Language：Japanese  

Language：English  

An elevated end-diastolic (ED) ratio of the common carotid artery (CCA) is an indicator of occlusive lesions of the distal portion of the internal carotid artery. We report 2 cases of cerebral arteriovenous malformation (AVM) showing an elevated ED ratio of the CCA, which decreased after surgery. Case 1 was a 28-year-old man with chronic recurrent headache with aura, and case 2 was a 29-year-old woman with sudden-onset headache and intracerebral hemorrhage without neurologic abnormality. In both cases, digital subtraction angiography revealed a Spetzler-Martin Grade IV AVM, which was mainly fed by branches of the left middle cerebral artery with venous drainage into superficial and deep cerebral veins. Preoperative carotid ultrasonography showed an elevated CCA ED ratio (1.38 in case 1 and 1.47 in case 2; left > right) without atherosclerotic lesions. Patients' AVMs were successfully resected. In both cases, the ED ratio was decreased after surgery (to 1.05 in case 1 and 1.20 in case 2). A decrease in vascular resistance on 1 side caused by cerebral AVM can result in an increase in the CCA ED ratio comparable to that of carotid axis occlusion.

DOI： 10.1016/j.radcr.2018.06.007

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The first pathology observed in Parkinson's disease (PD) is 'dying back' of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice. METHODS: On days 1 and 7 after MPTP administration, we evaluated changes in astrocytic Cx30, Cx43, glial fibrillary acidic protein, and ionised calcium-binding adapter molecule 1 expression by immunostaining and biochemical analysis. Loss of DA neurons was evaluated by tyrosine hydroxylase immunostaining. Gene expression was analysed using A1, A2, pan-reactive astrocyte microarray gene sets, and M1, M2, and M1/M2 mixed microglial microarray gene sets. Real-time PCR and in situ hybridisation were performed to evaluate glial cell-derived neurotrophic factor (Gdnf) and S100a10 expression. Striatal GDNF protein levels were determined by enzyme-linked immunosorbent assay. RESULTS: MPTP treatment induced upregulation of Cx30 and Cx43 levels in the striatum of WT and KO mice. DA neuron loss was accelerated in Cx30 KO compared with WT mice after MPTP administration, despite no change in the striatal concentration of methyl-4-phenylpyridinium+. Astrogliosis in the striatum of Cx30 KO mice was attenuated by MPTP, whereas microglial activation was unaffected. Microarrays of the striatum showed reduced expression of pan-reactive and A2 astrocyte genes after MPTP treatment in Cx30 KO compared with WT mice, while M1, M2, and M1/M2 mixed microglial gene expression did not change. MPTP reduced the number of striatal astrocytes co-expressing Gdnf mRNA and S100β protein or S100a10 mRNA and S100β protein and also reduced the level of GDNF in the striatum of Cx30 KO compared with WT mice. CONCLUSIONS: These findings indicate that Cx30 plays critical roles in astrocyte neuroprotection in an MPTP PD model.

DOI： 10.1186/s12974-018-1251-0

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To identify novel autoantibodies for neuropathic pain (NeP). METHODS: We screened autoantibodies that selectively bind to mouse unmyelinated C-fiber type dorsal root ganglion (DRG) neurons using tissue-based indirect immunofluorescence assays (IFA) with sera from 110 NeP patients with various inflammatory and allergic neurologic diseases or other neuropathies, and 50 controls without NeP including 20 healthy subjects and 30 patients with neurodegenerative diseases or systemic inflammatory diseases. IgG purified from IFA-positive patients' sera was subjected to Western blotting (WB) and immunoprecipitation (IP) using mouse DRG lysates. Immunoprecipitates were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify target autoantigens. RESULTS: Antiunmyelinated C-fiber type DRG neuron antibodies were more frequent in patients with NeP than non-NeP subjects (10% vs 0%; p < 0.05). These autoantibodies were all from the IgG2 subclass and colocalized mostly with isolectin B4- and P2X3-positive pain-conducting small neurons but not with S100β-positive myelinated neurons. WB revealed a common immunoreactive band (approximately 220kDa). IP and LC-MS/MS studies identified plexin D1 as a target autoantigen. Immunoadsorption tests with recombinant human plexin D1 in IFA revealed that all 11 anti-small DRG neuron antibody-positive patients had anti-plexin D1 antibodies. Application of anti-plexin D1 antibody-positive patient sera to cultured DRG neurons increased membrane permeability, leading to cellular swelling. NeP patients with anti-plexin D1 antibodies commonly developed burning pain and current perception threshold abnormalities for C-fibers. Main comorbidities were atopy and collagen-vascular disease. Immunotherapies ameliorated NeP in 7 treated cases. INTERPRETATION: Anti-plexin D1 antibodies are a novel biomarker for immunotherapy-responsive NeP. Ann Neurol 2018;84:208-224.

DOI： 10.1002/ana.25279

Language：English   Publishing type：Research paper (scientific journal)  

An elevated end-diastolic (ED) ratio of the common carotid artery (CCA) is an indicator of occlusive lesions of the distal portion of the internal carotid artery. We report 2 cases of cerebral arteriovenous malformation (AVM) showing an elevated ED ratio of the CCA, which decreased after surgery. Case 1 was a 28-year-old man with chronic recurrent headache with aura, and case 2 was a 29-year-old woman with sudden-onset headache and intracerebral hemorrhage without neurologic abnormality. In both cases, digital subtraction angiography revealed a Spetzler-Martin Grade IV AVM, which was mainly fed by branches of the left middle cerebral artery with venous drainage into superficial and deep cerebral veins. Preoperative carotid ultrasonography showed an elevated CCA ED ratio (1.38 in case 1 and 1.47 in case 2; left > right) without atherosclerotic lesions. Patients’ AVMs were successfully resected. In both cases, the ED ratio was decreased after surgery (to 1.05 in case 1 and 1.20 in case 2). A decrease in vascular resistance on 1 side caused by cerebral AVM can result in an increase in the CCA ED ratio comparable to that of carotid axis occlusion.

DOI： 10.1016/j.radcr.2018.06.007

Language：English   Publishing type：Research paper (scientific journal)  

Background: The first pathology observed in Parkinson's disease (PD) is 'dying back' of striatal dopaminergic (DA) terminals. Connexin (Cx)30, an astrocytic gap junction protein, is upregulated in the striatum in PD, but its roles in neurodegeneration remain elusive. We investigated Cx30 function in an acute PD model by administering 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to wild-type (WT) and Cx30 knockout (KO) mice. Methods: On days 1 and 7 after MPTP administration, we evaluated changes in astrocytic Cx30, Cx43, glial fibrillary acidic protein, and ionised calcium-binding adapter molecule 1 expression by immunostaining and biochemical analysis. Loss of DA neurons was evaluated by tyrosine hydroxylase immunostaining. Gene expression was analysed using A1, A2, pan-reactive astrocyte microarray gene sets, and M1, M2, and M1/M2 mixed microglial microarray gene sets. Real-time PCR and in situ hybridisation were performed to evaluate glial cell-derived neurotrophic factor (Gdnf) and S100a10 expression. Striatal GDNF protein levels were determined by enzyme-linked immunosorbent assay. Results: MPTP treatment induced upregulation of Cx30 and Cx43 levels in the striatum of WT and KO mice. DA neuron loss was accelerated in Cx30 KO compared with WT mice after MPTP administration, despite no change in the striatal concentration of methyl-4-phenylpyridinium
⁺
. Astrogliosis in the striatum of Cx30 KO mice was attenuated by MPTP, whereas microglial activation was unaffected. Microarrays of the striatum showed reduced expression of pan-reactive and A2 astrocyte genes after MPTP treatment in Cx30 KO compared with WT mice, while M1, M2, and M1/M2 mixed microglial gene expression did not change. MPTP reduced the number of striatal astrocytes co-expressing Gdnf mRNA and S100β protein or S100a10 mRNA and S100β protein and also reduced the level of GDNF in the striatum of Cx30 KO compared with WT mice. Conclusions: These findings indicate that Cx30 plays critical roles in astrocyte neuroprotection in an MPTP PD model.

DOI： 10.1186/s12974-018-1251-0

Language：English   Publishing type：Research paper (scientific journal)  

We herein report a woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom positivity for anti-neurofascin 155 antibodies was revealed 23 years after the onset of neuropathy. The patient initially reported numbness in the face at 50 years of age and subsequently manifested features compatible to typical CIDP. Steroid administration initiated at 54 years of age ameliorated her neuropathic symptoms. Although the nerve conduction indices at 59 years of age deteriorated, those at 68, 72, and 73 years of age showed a gradual recovery. The deterioration and subsequent restoration of compound muscle action potential amplitudes was the most dramatic, suggesting that a conduction block can be reversed earlier than other electrophysiological indices.

DOI： 10.2169/internalmedicine.0455-17

Language：English   Publishing type：Research paper (scientific journal)  

Introduction: Facial onset motor and sensory neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, upper trunk, and upper extremities in a rostral–caudal direction. Although bulbar involvement is frequently observed in FOSMN, dysphagia in these patients has not been fully described. In this study, we aimed to characterize dysphagia as a prognostic factor in FOSMN by investigating our institutional case series. Methods: We retrospectively reviewed the medical records, including swallowing function tests, of six patients with FOSMN (three men and three women) who were thoroughly examined at Kyushu University Hospital between 1 January 2005 and 30 November 2017. Results: Average age at onset was 58.5 years; average disease duration was 5.7 years. All patients developed bulbar dysfunction and dysphagia (at an average of 1.8 and 2.6 years from onset, respectively), resulting in choking episodes in three patients, percutaneous endoscopic gastrostomy placement in three, and recurrent aspiration pneumonia in one. Four of five patients evaluated with videofluoroscopic swallowing studies had poor oral retention, leading to bolus flowing into the pharynx before swallowing; the fifth patient showed poor lingual transfer. Fiberoptic endoscopic evaluation of swallowing revealed leakage of blue-dyed water from the mouth to the pharynx in three patients because of poor oral retention, but only mild pharyngeal phase dysphagia in all four cases evaluated. Conclusions: Oral phase dysphagia predominates in the early stage of FOSMN.

DOI： 10.1002/brb3.999

Language：Japanese  

Language：Japanese  

神経障害性疼痛(neuropathic pain:NeP)は、様々な病態を含む難治性疼痛の一つである。その病態機序はほとんど明らかとなっておらず、根治的な治療法は存在しない。私たちは、近年アレルギー性炎症を背景としたNePの新規発症機序を明らかにした。アトピー性疾患モデルマウスでは脊髄後角のグリア炎症がNePを惹起することを見出し、またNePを有するアレルギー性疾患患者の血清において、痛みに関連する後根神経節の小型ニューロンと脊髄後角に結合する自己抗体を見出した。アレルギー性炎症はNeP発症に関わる病態の一つと考えられる。(著者抄録)

Language：Japanese  

Facial onset sensory and motor neuronopathy(FOSMN症候群)は、顔面の感覚障害で発症し、構音・嚥下障害を伴い、感覚障害、運動障害が次第に尾側に広がる特徴を有する孤発性の神経疾患である。緩徐進行性であり、剖検症例の特徴から、本疾患は神経変性疾患と考えられる。一方、免疫療法が部分的に有効な例があるため、免疫学的機序の関与も想定される。またFOSMN症候群では嚥下障害が予後規定因子と考えられ、早期から口腔相が障害される特徴を有する。そのため顔面の感覚障害で発症した患者を診た際には、FOSMN症候群を鑑別に挙げ、球症状の出現に注意を払うべきである。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Safety and efficacy of eculizumab in Guillain-Barré syndrome: a multicentre, double-blind, randomised phase 2 trial.
BACKGROUND: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. METHODS: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90&#37; CI boundary exceeding 50&#37;. This trial is registered with ClinicalTrials.gov, number, NCT02493725. FINDINGS: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61&#37; (90&#37; CI 42-78; n=14) in the eculizumab group, and 45&#37; (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. INTERPRETATION: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. FUNDING: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

DOI： 10.1016/S1474-4422(18)30114-5

Language：English   Publishing type：Research paper (scientific journal)  

INTRODUCTION: Facial onset motor and sensory neuronopathy (FOSMN) is a rare disease whose cardinal features are initial asymmetrical facial sensory deficits followed by bulbar symptoms and spreading of sensory and motor deficits from face to scalp, neck, upper trunk, and upper extremities in a rostral-caudal direction. Although bulbar involvement is frequently observed in FOSMN, dysphagia in these patients has not been fully described. In this study, we aimed to characterize dysphagia as a prognostic factor in FOSMN by investigating our institutional case series. METHODS: We retrospectively reviewed the medical records, including swallowing function tests, of six patients with FOSMN (three men and three women) who were thoroughly examined at Kyushu University Hospital between 1 January 2005 and 30 November 2017. RESULTS: Average age at onset was 58.5 years; average disease duration was 5.7 years. All patients developed bulbar dysfunction and dysphagia (at an average of 1.8 and 2.6 years from onset, respectively), resulting in choking episodes in three patients, percutaneous endoscopic gastrostomy placement in three, and recurrent aspiration pneumonia in one. Four of five patients evaluated with videofluoroscopic swallowing studies had poor oral retention, leading to bolus flowing into the pharynx before swallowing; the fifth patient showed poor lingual transfer. Fiberoptic endoscopic evaluation of swallowing revealed leakage of blue-dyed water from the mouth to the pharynx in three patients because of poor oral retention, but only mild pharyngeal phase dysphagia in all four cases evaluated. CONCLUSIONS: Oral phase dysphagia predominates in the early stage of FOSMN.

DOI： 10.1002/brb3.999

Language：English   Publishing type：Research paper (scientific journal)  

Background: Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome. Methods: This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3–5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ≤2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Findings: Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42–78; n=14) in the eculizumab group, and 45% (20–73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. Interpretation: The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. Funding: The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

DOI： 10.1016/S1474-4422(18)30114-5

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1177/1352458517734072

Language：Japanese  

Language：Japanese  

ALS患者と家族が必要としている医療資源を把握するため、全国的なアンケート調査を行った。集計の結果、訪問介護の頻度、痰の吸引やTPPV施行時の介護者の確保、TPPV導入時期、意思伝達装置導入時期に対する満足度が低いことがわかった。また障害者総合支援法による重度訪問介護、重度障害者入院時コミュニケーション支援事業に対する認知度と利用率の低さが明らかとなった。ALS患者の療養において介護者の負担軽減は依然として大きな課題であり、個々の患者の病状や介護者の状況にあわせ、適切な制度の利用や医療処置・福祉器具の導入を進めていけるよう、医療従事者および福祉関係者による積極的で継続的な関わりが必要と考えられる。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Chronic administration of 3,3'-iminodipropionitrile (IDPN) causes axonal impairment. Although controversy still remains, it has been suggested that IDPN intoxication mimics the axonopathy of amyotrophic lateral sclerosis (ALS). Interestingly, recent studies including our own showed that signal transducer and activator of transcription 3 (STAT3) in spinal α-motoneurons was activated in both IDPN-treated mice and SOD1 G93A mice, a genetic model of familial ALS. Because activation of STAT3 occurs in response to various stimuli, such as axonal injury, ischemia, and excessive glutamate, here we focused on a potential link between phosphorylated STAT3 (pSTAT3, an active form) and vesicular glutamate transporter 2 (VGluT2, a regulator of glutamate storage and release) in IDPN-treated mice and SOD1 G93A mice. Impairment of axonal transport was confirmed by western blot analysis: the expression levels of phosphorylated neurofilament H were elevated in both models. As shown in SOD1 G93A mice, the expression frequencies of VGluT2 in synaptophysin-positive (SYP)+ presynaptic terminals around spinal α-motoneurons were significantly higher in IDPN-treated mice than in vehicle controls. The coverages of spinal α-motoneurons by VGluT2+ presynaptic terminals were more elevated around pSTAT3+ cells than around pSTAT3- cells in IDPN-treated mice and SOD1 G93A mice. Considering that excessive glutamate is shown to be involved in axonal impairment and STAT3 activation, the present results suggest that IDPN-induced upregulation of VGluT2 may result in an increase in glutamate, which might cause axonopathy and induction of pSTAT3. The link between upregulation of VGluT2 and activation of STAT3 via glutamate may represent a common pathological feature of IDPN-treated mice and SOD1 G93A mice.

DOI： 10.1007/s12640-017-9822-x

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1212/NXI.0000000000000447

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12456

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Hopkins syndrome (HS) is a rare disorder presenting with acute flaccid paralysis of the limbs following an asthma attack. Neurologists encounter a diagnostic challenge if patients without a history of bronchial asthma develop neurologic features mimicking HS following acute respiratory distress. We report a case of HS occurring after a first episode of bronchial asthma associated with enterovirus D68 infection. CASE PRESENTATION: A 5-year-old girl developed acute respiratory distress. On the fourth hospital day, both her legs became paralyzed except for slight muscle contraction in the right lower limb. Tendon reflexes in the lower limbs were diminished and there was a positive Babinski sign on the right. Sensation was normal in all modalities, and there was no uro-rectal disturbance. Spinal magnetic resonance imaging identified T2-hyperintense lesions with spinal cord edema, mainly involving the bilateral T11 to L1 anterior horns, with left side dominance extending to the left posterior horn. The neurological and neuro-radiological findings of our case were suggestive of HS; however, she had no history of bronchial asthma. An acetylcholine inhalation challenge eventually proved the presence of reversible airway hyper-responsiveness, allowing us to diagnose HS. We identified enterovirus D68 in the patient's intratracheal aspirates using a sensitive polymerase chain reaction assay. Intravenous immunoglobulin administrations at 2 g/kg2 for 5 consecutive days were repeated every month up to four times. After these treatments, the muscle strength of her right lower limb slightly improved while her left lower leg remained completely paralyzed. CONCLUSION: This case emphasizes the importance of provocation tests to reveal the presence of airway hyper-responsiveness when a child shows neurological signs mimicking HS following acute respiratory distress. Furthermore, the present case suggests a possible link between HS and acute flaccid paralysis following lower respiratory tract infection by enterovirus D68.

DOI： 10.1186/s12883-018-1075-7

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cortical lesions (CLs) frequently observed in Caucasian patients with multiple sclerosis (MS) contribute to disability. However, it remains unclear whether CLs are associated with clinical features and genetic risk factors, such as HLA-DRB1*15:01 and -DRB1*04:05 in Asian MS patients. OBJECTIVE: To elucidate the frequency of CLs and their association with HLA-DRB1 and DPB1 alleles in Japanese MS patients. METHODS: Three-dimensional double inversion recovery imaging and clinical information were retrospectively obtained from 92 Japanese MS patients. RESULTS: CLs of any type, intracortical lesions (ICLs), and leukocortical lesions (LCLs) were detected in 39.1&#37;, 26.1&#37;, and 28.3&#37; of patients, respectively. MS patients with ICLs had a significantly higher frequency of secondary progression and greater Expanded Disability Status Scale (EDSS) scores than those without ICLs. Similar trends were observed with CLs and LCLs. The number of all three lesion types positively correlated with EDSS scores. The frequency and number of ICLs were significantly higher in HLA-DRB1*15:01 carriers than in HLA-DRB1*15:01 non-carriers, but significantly lower in HLA-DRB1*04:05 carriers than in HLA-DRB1*04:05 non-carriers. Multivariate logistic regression analysis revealed a negative association of HLA-DRB1*04:05 with ICLs. CONCLUSION: ICLs are associated with greater disease severity in Japanese MS patients and are partly suppressed by the HLA-DRB1*04:05 allele.

DOI： 10.1177/1352458517707067

Language：English  

DOI： 10.1177/1352458517734072

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12456

Language：English   Publishing type：Research paper (scientific journal)  

Chronic administration of 3,3′-iminodipropionitrile (IDPN) causes axonal impairment. Although controversy still remains, it has been suggested that IDPN intoxication mimics the axonopathy of amyotrophic lateral sclerosis (ALS). Interestingly, recent studies including our own showed that signal transducer and activator of transcription 3 (STAT3) in spinal α-motoneurons was activated in both IDPN-treated mice and SOD1^G93A mice, a genetic model of familial ALS. Because activation of STAT3 occurs in response to various stimuli, such as axonal injury, ischemia, and excessive glutamate, here we focused on a potential link between phosphorylated STAT3 (pSTAT3, an active form) and vesicular glutamate transporter 2 (VGluT2, a regulator of glutamate storage and release) in IDPN-treated mice and SOD1^G93A mice. Impairment of axonal transport was confirmed by western blot analysis: the expression levels of phosphorylated neurofilament H were elevated in both models. As shown in SOD1^G93A mice, the expression frequencies of VGluT2 in synaptophysin-positive (SYP)⁺ presynaptic terminals around spinal α-motoneurons were significantly higher in IDPN-treated mice than in vehicle controls. The coverages of spinal α-motoneurons by VGluT2⁺ presynaptic terminals were more elevated around pSTAT3⁺ cells than around pSTAT3⁻ cells in IDPN-treated mice and SOD1^G93A mice. Considering that excessive glutamate is shown to be involved in axonal impairment and STAT3 activation, the present results suggest that IDPN-induced upregulation of VGluT2 may result in an increase in glutamate, which might cause axonopathy and induction of pSTAT3. The link between upregulation of VGluT2 and activation of STAT3 via glutamate may represent a common pathological feature of IDPN-treated mice and SOD1^G93A mice.

DOI： 10.1007/s12640-017-9822-x

Language：English   Publishing type：Research paper (scientific journal)  

Background: Hopkins syndrome (HS) is a rare disorder presenting with acute flaccid paralysis of the limbs following an asthma attack. Neurologists encounter a diagnostic challenge if patients without a history of bronchial asthma develop neurologic features mimicking HS following acute respiratory distress. We report a case of HS occurring after a first episode of bronchial asthma associated with enterovirus D68 infection. Case presentation: A 5-year-old girl developed acute respiratory distress. On the fourth hospital day, both her legs became paralyzed except for slight muscle contraction in the right lower limb. Tendon reflexes in the lower limbs were diminished and there was a positive Babinski sign on the right. Sensation was normal in all modalities, and there was no uro-rectal disturbance. Spinal magnetic resonance imaging identified T2-hyperintense lesions with spinal cord edema, mainly involving the bilateral T11 to L1 anterior horns, with left side dominance extending to the left posterior horn. The neurological and neuro-radiological findings of our case were suggestive of HS; however, she had no history of bronchial asthma. An acetylcholine inhalation challenge eventually proved the presence of reversible airway hyper-responsiveness, allowing us to diagnose HS. We identified enterovirus D68 in the patient's intratracheal aspirates using a sensitive polymerase chain reaction assay. Intravenous immunoglobulin administrations at 2 g/kg² for 5 consecutive days were repeated every month up to four times. After these treatments, the muscle strength of her right lower limb slightly improved while her left lower leg remained completely paralyzed. Conclusion: This case emphasizes the importance of provocation tests to reveal the presence of airway hyper-responsiveness when a child shows neurological signs mimicking HS following acute respiratory distress. Furthermore, the present case suggests a possible link between HS and acute flaccid paralysis following lower respiratory tract infection by enterovirus D68.

DOI： 10.1186/s12883-018-1075-7

Language：English   Publishing type：Research paper (scientific journal)  

We recently reported that deletion-type copy number variations of the T cell receptor (TCR) γ, α, and δ genes greatly enhanced susceptibility to multiple sclerosis (MS). However, the effect of abnormal TCR γδ gene rearrangement on MS pathogenesis remains unknown. In the present study, we aimed to clarify γδ TCR repertoire alterations and their relationship to clinical and immunological parameters in MS patients by comprehensive flow cytometric immunophenotyping. Peripheral blood mononuclear cells obtained from 30 untreated MS patients in remission and 23 age- and sex-matched healthy controls (HCs) were stained for surface markers and intracellular cytokines after stimulation with phorbol 12-myristate 13-acetate and ionomycin, and analyzed by flow cytometry. MS patients showed significantly decreased percentages of Vδ2⁺ and Vδ2⁺Vγ9⁺ cells in γδ T cells (p^corr = 0.0297 and p^corr = 0.0288, respectively) and elevated Vδ1/Vδ2 ratios compared with HCs (p = 0.0033). The percentages of interferon (IFN)-γ⁺Vδ2⁺ and interleukin (IL)-17A⁺IFN-γ⁺Vδ2⁺ cells in γδ T cells, as well as IFN-γ⁺ cells in Vδ2⁺ γδ T cells, were significantly lower in MS patients than in HCs (p^corr < 0.0009, p^corr = 0.0135, and p^corr = 0.0054, respectively). The percentages of Vδ2⁺ and Vδ2⁺Vγ9⁺ cells in γδ T cells were negatively correlated with both the Expanded Disability Status Scale score (r = -0.5006, p = 0.0048; and r = -0.5040, p = 0.0045, respectively) and Multiple Sclerosis Severity Score (r = -0.4682, p = 0.0091; and r = -0.4706, p = 0.0087, respectively), but not with age at disease onset, disease duration, or annualized relapse rate. In HCs, the percentages of Vδ2⁺ and Vδ2⁺Vγ9⁺ cells of total CD3⁺ T cells had strong positive correlations with the percentage of CD25⁺CD127^low/- cells in CD4⁺ T cells (r = 0.7826, p < 0.0001; and r = 0.7848, p < 0.0001, respectively), whereas such correlations were totally absent in MS patients. These findings suggest that decreased Vδ2⁺Vγ9⁺ γδ T cells are associated with disability in MS. Therefore, the Vδ1/Vδ2 ratio might be a candidate biomarker for predicting disease severity in MS.

DOI： 10.3389/fimmu.2018.00748

Language：English   Publishing type：Research paper (scientific journal)  

Safety and efficacy of eculizumab in Guillain-Barr? syndrome: a multicentre, double-blind, randomised phase 2 trial.
Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barr? syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barr? syndrome. This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barr? syndrome were aged 18 years or older and could not walk independently (Guillain-Barr? syndrome functional grade 3-5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently [functional grade ?2] at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725. Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ?2) was 61% (90% CI 42-78; n=14) in the eculizumab group, and 45% (20-73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred. The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials. The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.

DOI： 10.1016/S1474-4422(18)30114-5

Language：English   Publishing type：Research paper (scientific journal)  

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

DOI： 10.1038/s41588-018-0067-2

Language：English   Publishing type：Research paper (scientific journal)  

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

DOI： 10.1038/s41588-018-0067-2

Language：English   Publishing type：Research paper (scientific journal)  

Gap junctions or hemichannels are expressed on all cells in our body, and have a highly significant role in homeostasis and in disease states. There are 21 connexins found in humans and they have distinct characteristics that compensate for each other. The anatomical expression pattern also differs between each connexin; some of them are expressed together and some are not. Genetically mutated connexin genes induce inheritable diseases, but acquired disorders can also be caused by primary or secondary connexin dysfunctions. In the central nervous system, glial cells are the main connexin-expressing cells. They utilize connexin gap junctions to assemble glial networks. The present review not only describes the basic structures and functions of connexins, it also examines the relationships between connexins and their role in disease pathology.

DOI： 10.1111/cen3.12433

Language：Japanese  

多発性硬化症は代表的な脱髄性疾患で、再発寛解を繰り返す。再発を繰り返すと神経障害が蓄積され、数年から十数年で二次進行型に移行する。この慢性進行期は、末梢の免疫反応にかかわらず中枢神経系で徐々に神経障害が悪化していく。そのメカニズムに深く関わるのが、中枢のグリア細胞という非神経細胞の活性化(=グリア炎症)である。グリア炎症は様々な要因に左右されるが、その重要な一つがギャップ結合蛋白コネキシンの機能異常である。多発性硬化症の急性期にはアストログリアのコネキシンが低下し、慢性期では逆に発現上昇する一方、オリゴデンドログリアのコネキシンは低下し続ける。この現象が神経保護的に働くのか障害性に働くのか、現時点では不明である。このメカニズム解明が、現在まで治療法のない慢性進行期の多発性硬化症治療薬開発につながる。(著者抄録)

Language：English  

Gap junctions or hemichannels are expressed on all cells in our body, and have a highly significant role in homeostasis and in disease states. There are 21 connexins found in humans and they have distinct characteristics that compensate for each other. The anatomical expression pattern also differs between each connexin
some of them are expressed together and some are not. Genetically mutated connexin genes induce inheritable diseases, but acquired disorders can also be caused by primary or secondary connexin dysfunctions. In the central nervous system, glial cells are the main connexin-expressing cells. They utilize connexin gap junctions to assemble glial networks. The present review not only describes the basic structures and functions of connexins, it also examines the relationships between connexins and their role in disease pathology.

DOI： 10.1111/cen3.12433

Language：English   Publishing type：Research paper (scientific journal)  

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an intractable inflammatory disease affecting peripheral nerves. The etiology of CIDP remains to be established, but it is regarded as a mixture of heterogeneous conditions presenting a variety of clinical and electrophysiological manifestations. In recent years, autoantibodies against paranodal cell adhesion molecules, such as neurofascin 155 (NF155), contactin 1 and contactin-associated protein 1, have been detected in subsets of CIDP patients. The clinical characteristics of anti-NF155 antibody-positive CIDP have been delineated, and include a younger onset age, higher frequency of distal muscle weakness, sensory ataxia and tremor, higher cerebrospinal fluid protein levels, more conspicuous demyelination on nerve conduction studies, and nerve root hypertrophy on magnetic resonance neurography, when compared with anti-NF155 antibody-negative CIDP patients. Predominant elevation of immunoglobulin G4 subclass is also a characteristic of this disease. Sural nerve biopsy specimens of anti-NF155 antibody-positive CIDP patients show axo-glial detachment in paranodes without inflammatory cell infiltrates or onion bulb formation. While intravenous immunoglobulin is not as effective as expected against anti-NF155 antibody-positive CIDP patients, other immunotherapies, such as corticosteroids, plasmapheresis and B-cell depletion therapy, seem to be effective. Early diagnosis and treatment is important for preventing secondary axonal degeneration. The present review summarizes the emerging details of anti-NF155 antibody-related neuropathy.

DOI： 10.1111/cen3.12444

Language：English  

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an intractable inflammatory disease affecting peripheral nerves. The etiology of CIDP remains to be established, but it is regarded as a mixture of heterogeneous conditions presenting a variety of clinical and electrophysiological manifestations. In recent years, autoantibodies against paranodal cell adhesion molecules, such as neurofascin 155 (NF155), contactin 1 and contactin-associated protein 1, have been detected in subsets of CIDP patients. The clinical characteristics of anti-NF155 antibody-positive CIDP have been delineated, and include a younger onset age, higher frequency of distal muscle weakness, sensory ataxia and tremor, higher cerebrospinal fluid protein levels, more conspicuous demyelination on nerve conduction studies, and nerve root hypertrophy on magnetic resonance neurography, when compared with anti-NF155 antibody-negative CIDP patients. Predominant elevation of immunoglobulin G4 subclass is also a characteristic of this disease. Sural nerve biopsy specimens of anti-NF155 antibody-positive CIDP patients show axo-glial detachment in paranodes without inflammatory cell infiltrates or onion bulb formation. While intravenous immunoglobulin is not as effective as expected against anti-NF155 antibody-positive CIDP patients, other immunotherapies, such as corticosteroids, plasmapheresis and B-cell depletion therapy, seem to be effective. Early diagnosis and treatment is important for preventing secondary axonal degeneration. The present review summarizes the emerging details of anti-NF155 antibody-related neuropathy.

DOI： 10.1111/cen3.12444

Language：English   Publishing type：Research paper (scientific journal)  

Background The long-term clinical course and closely related biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with anti-neurofascin 155 (NF155) antibodies remain to be elucidated. Methods We retrospectively studied the longitudinal clinical courses of three Japanese male anti-NF155 antibody-positive CIDP patients. Anti-NF155 antibody levels were measured by flow cytometry using HEK293 cell lines stably expressing human NF155. Results All three patients presented with chronic progressive sensorimotor disturbance, with ages at onset of 16, 26, and 34 years old, and they were followed for 58, 31, and 38 months, respectively, from the onset. All patients had postural tremor and generalized decreased deep tendon reflexes. Peak cerebrospinal fluid protein levels were > 400 mg/dl, and nerve conduction studies (NCS) showed severe demyelination patterns. Combined immunotherapies including intravenous immunoglobulin, plasma exchange, corticosteroids, and other immunosuppressants ameliorated clinical severity and NCS abnormalities, with improvements of > 10 kg in grip strength and at least 20% in F-wave latencies. However, their symptoms exacerbated after the immunotherapies were tapered. Anti-NF155 antibody levels varied in parallel with the clinical and electrophysiological changes, or preceded them. Conclusion The patients’ clinical courses suggest that anti-NF155 antibody levels and NCS findings could be disease activity markers in anti-NF155 antibody-positive CIDP.

DOI： 10.1016/j.jns.2017.11.035

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The long-term clinical course and closely related biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) with anti-neurofascin 155 (NF155) antibodies remain to be elucidated. METHODS: We retrospectively studied the longitudinal clinical courses of three Japanese male anti-NF155 antibody-positive CIDP patients. Anti-NF155 antibody levels were measured by flow cytometry using HEK293 cell lines stably expressing human NF155. RESULTS: All three patients presented with chronic progressive sensorimotor disturbance, with ages at onset of 16, 26, and 34years old, and they were followed for 58, 31, and 38months, respectively, from the onset. All patients had postural tremor and generalized decreased deep tendon reflexes. Peak cerebrospinal fluid protein levels were >400mg/dl, and nerve conduction studies (NCS) showed severe demyelination patterns. Combined immunotherapies including intravenous immunoglobulin, plasma exchange, corticosteroids, and other immunosuppressants ameliorated clinical severity and NCS abnormalities, with improvements of >10kg in grip strength and at least 20% in F-wave latencies. However, their symptoms exacerbated after the immunotherapies were tapered. Anti-NF155 antibody levels varied in parallel with the clinical and electrophysiological changes, or preceded them. CONCLUSION: The patients' clinical courses suggest that anti-NF155 antibody levels and NCS findings could be disease activity markers in anti-NF155 antibody-positive CIDP.

DOI： 10.1016/j.jns.2017.11.035

Language：English   Publishing type：Research paper (scientific journal)  

Novel disease-modifying anti-rheumatic drug iguratimod suppresses chronic experimental autoimmune encephalomyelitis by down-regulating activation of macrophages/microglia through an NF-κB pathway.
We aimed to elucidate the effects of iguratimod, a widely used anti-rheumatic drug with no severe side effects, on chronic experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Iguratimod was orally administered to mice immunised with myelin oligodendrocyte glycoprotein peptide 35-55. Preventive administration of iguratimod from the time of immunisation was found to markedly reduce the clinical severity of acute and chronic EAE. Pathologically, iguratimod treatment significantly reduced demyelination and infiltration of CD3+ T, F4/80+, and CD169+ cells into the spinal cord, and suppressed macrophage/microglia activation in the parenchyma at the acute and chronic stages compared with vehicle treatment. Therapeutic administration of iguratimod after the onset of clinical symptoms significantly ameliorated the clinical severity of chronic EAE and reduced demyelination, T helper (Th)1/Th17 cell infiltration, macrophage/microglia activation, and nuclear factor (NF)-κB p65 and cyclooxygenase-2 expression in the spinal cord. In vitro, iguratimod treatment inhibited nuclear translocation of NF-κB p65 and down-regulated pro-inflammatory responses in macrophages and microglia. Our results suggest that iguratimod ameliorates acute and chronic EAE by suppressing inflammatory cell infiltration and immune cell activation, partly through inhibition of NF-κB p65, supporting the therapeutic potential of this drug for not only acute, but also chronic MS.

DOI： 10.1038/s41598-018-20390-5

Language：English   Publishing type：Research paper (scientific journal)  

We herein report a woman with chronic inflammatory demyelinating polyneuropathy (CIDP) in whom positivity for anti-neurofascin 155 antibodies was revealed 23 years after the onset of neuropathy. The patient initially reported numbness in the face at 50 years of age and subsequently manifested features compatible to typical CIDP. Steroid administration initiated at 54 years of age ameliorated her neuropathic symptoms. Although the nerve conduction indices at 59 years of age deteriorated, those at 68, 72, and 73 years of age showed a gradual recovery. The deterioration and subsequent restoration of compound muscle action potential amplitudes was the most dramatic, suggesting that a conduction block can be reversed earlier than other electrophysiological indices.

DOI： 10.2169/internalmedicine.0455-17

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To evaluate the usefulness of simultaneous T₂ mapping and neurography with nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in the lumbar plexus to distinguish patients with chronic inflammatory demyelinating polyneuropathy (CIDP) from healthy controls. Methods: Our institutional review boards approved this retrospective study, and written informed consent was waived. 10 patients with CIDP from 2015 to 2017 were studied along with 5 healthy controls on a 3 T scanner. The T₂ relaxation time and the size of the dorsal root ganglia and nerves of the lumbar plexus at L3-S1 were measured. Statistical analyses were performed with the Mann-Whitney U test and a receiver operating characteristics analysis. Results: The T₂ relaxation times of the dorsal root ganglia and the nerves of the lumbar plexus were longer in the CIDP patients (133.34 ± 41.36 and 130.40 ± 47.78 ms) compared to the healthy controls (114.69 ± 24.90 and 83.72 ± 17.51 ms, p = 0.0265 andp < 0.0001, respectively). The sizes of the nerves were larger in the CIDP patients (6.19 ± 2.28 mm) compared to the controls (4.54 ± 0.86 mm, p < 0.0001). However, there was no significant difference between the sizes of the ganglia in the CIDP patients and the controls. The receiver operating characteristics analysis revealed that the T₂ relaxation time of the nerves was best at distinguishing the CIDP patients from the controls (Az = 0.848). Conclusion: Patients with CIDP could be distinguished from healthy controls using simultaneous T₂ mapping and neurography with SHINKEI in the lumbar plexus. Advances in knowledge: Patients with CIDP could be distinguished from healthy controls using simultaneous T₂ mapping and neurography with SHINKEI in the lumbar plexus.

DOI： 10.1259/bjr.20180501

Language：English   Publishing type：Research paper (scientific journal)  

Multiple sclerosis (MS) is one of the most prominent demyelinating disorders with a phenotype of relapsing and remitting neurological deficits. The recurrence of relapse contributes to the accumulation of neuronal damage, which leads to the transition of the disease into secondaryprogressive MS (SPMS). The mechanisms of SPMS are unknown, making the invention of new therapeutic options for SPMS difficult. In the progressive phase, "glial inflammation" is assumed to be the major player in neurodegeneration. Recently, our group and others have shown that gap junction proteins called connexins are important in the pathomechanisms of SPMS in the context of "glial inflammation". The expression of glia in connexins differs between cell types. Astroglial connexins are down regulated in the acute phase and up regulated in the chronic phase of MS, while oligodendroglial connexins are down regulated through the course of the disease. The modification and malfunction of gap junction connexins are thought to play roles in the pathomechanisms of SPMS. Further elucidation of their mechanisms may provide clues useful for the invention of new therapeutic options for SPMS.

DOI： 10.11476/shinkeiganka.35.4

Language：English   Publishing type：Research paper (scientific journal)  

Guillain-Barré syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (ΔIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and ΔIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (≥5 points) were associated with an increased risk for mechanical ventilation. Patients with ΔIgG <1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and ΔIgG in GBS are clinically relevant in Japan.

DOI： 10.1111/jns.12234

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近年ランビエ傍絞輪部の細胞膜蛋白であるneurofascin 155およびcontactin-1に対する自己抗体と慢性炎症性脱髄性多発根ニューロパチー(CIDP)との関係が明らかにされつつある。特に抗neurofascin 155抗体陽性CIDPについてはこれまでに本邦から60例以上の報告がなされ、疾患概念が確立されつつある。私たちはこれまでに得られた知見を踏まえ、「抗neurofascin 155抗体関連ニューロパチー」として暫定診断基準を策定し、全国臨床調査を実施中である。(著者抄録)

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Markers for Guillain-Barré syndrome with poor prognosis: a multi-center study.
Guillain-Barré syndrome (GBS) is an acute monophasic neuropathy. Prognostic tools include the modified Erasmus GBS outcome score (mEGOS), Erasmus GBS respiratory insufficiency score (EGRIS), and the increase in serum IgG levels (ΔIgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment. Given that proportions of GBS subtypes differ between Western countries and Japan, the usefulness of these tools in Japan or other countries remains unknown. We enrolled 177 Japanese patients with GBS from 15 university hospitals and retrospectively obtained mEGOS and EGRIS for all and ΔIgG status for 79 of them. High mEGOS scores on admission or on day 7 were significantly associated with poorer outcomes (unable to walk independently at 6 months). High EGRIS scores (≥5 points) were associated with an increased risk for mechanical ventilation. Patients with ΔIgG <1,108 mg/dl had significantly poorer outcomes. We suggest that mEGOS, EGRIS, and ΔIgG in GBS are clinically relevant in Japan.

DOI： 10.1111/jns.12234

Language：English   Publishing type：Research paper (scientific journal)  

Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models. Mouse cerebral microglia in vitro demonstrated that stimulation of TLR4 with lipopolysaccharide, widely used to examine microglial reactions, caused the activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) and enhanced production of reactive oxygen species (ROS). The increase in the ROS level activated 5′ adenosine monophosphate-activated protein kinase (AMPK), and facilitated elongation of mitochondria along the microtubule tracks. These results suggest that the polymorphic regulation of mitochondrial fission and fusion in reactive microglia is mediated by distinct signaling under inflammatory conditions, and modulates microglial phenotypes through the production of ROS.

DOI： 10.1038/s41598-017-05232-0

Language：English   Publishing type：Research paper (scientific journal)  

Phagocytosis by astrocytes is important in the developing brain and in central nervous system lesions. Astroglial phagocytosis usually contributes to the repair of damaged lesions, but, depending on the local milieu, astrocytes can become activated “A1” type astroglia, which release neurotoxic substances and accelerate regional damage.

DOI： 10.1111/cen3.12413

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Language：English  

Phagocytosis by astrocytes is important in the developing brain and in central nervous system lesions. Astroglial phagocytosis usually contributes to the repair of damaged lesions, but, depending on the local milieu, astrocytes can become activated “A1” type astroglia, which release neurotoxic substances and accelerate regional damage.

DOI： 10.1111/cen3.12413

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

DOI： 10.1073/pnas.1707151114

Language：English   Publishing type：Research paper (scientific journal)  

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by pathology of accumulated amyloid β (Aβ) and phosphorylated tau proteins in the brain. Postmortem degradation and cellular complexity within the brain have limited approaches to molecularly define the causal relationship between pathological features and neuronal dysfunction in AD. To overcome these limitations, we analyzed the neuron-specific DNA methylome of postmortem brain samples from AD patients, which allowed differentially hypomethylated region of the BRCA1 promoter to be identified. Expression of BRCA1 was significantly up-regulated in AD brains, consistent with its hypomethylation. BRCA1 protein levels were also elevated in response to DNA damage induced by Aβ. BRCA1 became mislocalized to the cytoplasm and highly insoluble in a tau-dependent manner, resulting in DNA fragmentation in both in vitro cellular and in vivo mouse models. BRCA1 dysfunction under Aβ burden is consistent with concomitant deterioration of genomic integrity and synaptic plasticity. The Brca1 promoter region of AD model mice brain was similarly hypomethylated, indicating an epigenetic mechanism underlying BRCA1 regulation in AD. Our results suggest deterioration of DNA integrity as a central contributing factor in AD pathogenesis. Moreover, these data demonstrate the technical feasibility of using neuron-specific DNA methylome analysis to facilitate discovery of etiological candidates in sporadic neurodegenerative diseases.

DOI： 10.1073/pnas.1707151114

Language：English   Publishing type：Research paper (scientific journal)  

Charcot–Marie–Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H.

DOI： 10.1016/j.nmd.2017.07.011

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Paranodal axo-glial detachment in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies

DOI： 10.1016/j.jns.2017.08.226

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Lamin B1関連常染色体優性遺伝性白質脳症 コピー数多型と臨床的特徴

Language：Japanese  

Language：English   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (other academic)  

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DOI： 10.1016/j.jns.2017.07.040

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: End-diastolic ratio, calculated by the side-to-side ratio of end-diastolic flow velocities of the common carotid arteries, is an indicator for large artery intracranial occlusive disease. However, the diagnostic ability of end-diastolic ratios derived from different measurement conditions is unclear. METHODS: End-diastolic ratios were measured twice by single carotid duplex ultrasonography. End-diastolic ratio1st was calculated from separate end-diastolic flow velocities measured during routine assessment. End-diastolic ratio2nd was calculated almost simultaneously without head rotation. For each end-diastolic ratio, the measurement conditions and prediction ability for occlusions of the internal carotid artery or proximal portion of the middle cerebral artery using an established cutoff of 1.4 or greater were compared. RESULTS: Two hundred thirty-three patients (147 men, median 67 years) were registered, with available intracranial artery information in 158 patients (67.8&#37;) and occlusions detected in 7 patients (4.4&#37;). End-diastolic ratio1st was significantly higher than end-diastolic ratio2nd (median 1.21 versus 1.08, P < .001). Compared with end-diastolic ratio1st, end-diastolic ratio2nd had a significantly shorter time interval (median 709 versus 28 seconds, P < .001) and smaller pulse rate difference (1.54 ± 5.10 versus .25 ± 4.63 beats per minute, P = .004). To predict occlusions, the sensitivity, specificity, and overall accuracy for end-diastolic ratio1st of 1.4 or greater were 85.7&#37;, 70.9&#37;, and 71.5&#37;, respectively, and for end-diastolic ratio2nd of 1.4 or greater were 85.7&#37;, 98.0&#37;, and 97.5&#37;, respectively. End-diastolic ratio2nd had better specificity and overall accuracy than end-diastolic ratio1st (P < .001). CONCLUSIONS: End-diastolic ratio varies with measurement conditions. Combined end-diastolic flow velocities measurement may improve diagnostic ability for large artery intracranial occlusive disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.05.038

Language：English   Publishing type：Research paper (scientific journal)  

Charcot-Marie-Tooth disease type 4H (CMT4H) is a rare variant of autosomal recessive hereditary neuropathy. It is caused by FGD4 mutations and characterized by early infantile onset, slowly progressive distal muscle weakness, scoliosis, and myelin outfoldings visible in nerve biopsy samples. Here, we report a 65-year-old male born to consanguineous parents, who carries a novel homozygous FGD4 c.724C>T nonsense mutation. He developed lower limb weakness in his teens, which progressed slowly and was accompanied by diplopia, bilateral hearing loss, and erectile dysfunction from his twenties. At the age of 65, he was wheelchair-bound and had mild scoliosis, bilateral ophthalmoplegia, facial muscle weakness, inner ear hearing loss, distal-dominant weakness, and sensory disturbance, but no cognitive deterioration. Magnetic resonance imaging revealed enlarged bilateral trigeminal and facial nerves. Accordingly, we believe that this mutation causes slowly progressive sensorimotor neuropathy with apparent cranial nerve involvement, thereby further expanding the clinical spectrum of CMT4H.

DOI： 10.1016/j.nmd.2017.07.011

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jns.2017.07.040

Language：English   Publishing type：Research paper (scientific journal)  

Background End-diastolic ratio, calculated by the side-to-side ratio of end-diastolic flow velocities of the common carotid arteries, is an indicator for large artery intracranial occlusive disease. However, the diagnostic ability of end-diastolic ratios derived from different measurement conditions is unclear. Methods End-diastolic ratios were measured twice by single carotid duplex ultrasonography. End-diastolic ratio_1st was calculated from separate end-diastolic flow velocities measured during routine assessment. End-diastolic ratio_2nd was calculated almost simultaneously without head rotation. For each end-diastolic ratio, the measurement conditions and prediction ability for occlusions of the internal carotid artery or proximal portion of the middle cerebral artery using an established cutoff of 1.4 or greater were compared. Results Two hundred thirty-three patients (147 men, median 67 years) were registered, with available intracranial artery information in 158 patients (67.8%) and occlusions detected in 7 patients (4.4%). End-diastolic ratio_1st was significantly higher than end-diastolic ratio_2nd (median 1.21 versus 1.08, P <.001). Compared with end-diastolic ratio_1st, end-diastolic ratio_2nd had a significantly shorter time interval (median 709 versus 28 seconds, P <.001) and smaller pulse rate difference (1.54 ± 5.10 versus.25 ± 4.63 beats per minute, P =.004). To predict occlusions, the sensitivity, specificity, and overall accuracy for end-diastolic ratio_1st of 1.4 or greater were 85.7%, 70.9%, and 71.5%, respectively, and for end-diastolic ratio_2nd of 1.4 or greater were 85.7%, 98.0%, and 97.5%, respectively. End-diastolic ratio_2nd had better specificity and overall accuracy than end-diastolic ratio_1st (P <.001). Conclusions End-diastolic ratio varies with measurement conditions. Combined end-diastolic flow velocities measurement may improve diagnostic ability for large artery intracranial occlusive disease.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.05.038

Language：English   Publishing type：Research paper (other academic)  

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Language：English   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (scientific journal)  

Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1^G93A mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)⁺ cells – choline acetyltransferase (ChAT)⁺ α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)⁺ microglia, and S100β⁺ astrocytes in SOD1^G93A mice. The FCs of pSTAT3⁺ microglia and pSTAT3⁺ astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3⁺ α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3⁺ α-motoneurons compared with pSTAT3⁻ α-motoneurons at 9 weeks of age. We then compared the following pharmacological models – the chronic administration of 3,3′-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3⁺ α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3⁺ microglia were increased in LPS-treated mice. The FCs of pSTAT3⁺ astrocytes were higher in SOD1^G93A mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.

DOI： 10.1111/ejn.13650

Language：Japanese  

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DOI： 10.1016/j.jns.2017.06.002

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To evaluate whether 3D SHINKEI in the lumbar plexus could identify patients with chronic inflammatory demyelinating polyneuropathy (CIDP). MATERIALS AND METHODS: Twenty-one patients with CIDP and 15 non-CIDP patients were studied in this retrospective study. The SNR, contrast-to-noise ratio (CNR), contrast ratio (CR) and the size of the lumbar ganglions and roots were measured. Statistical analyses were performed with Mann-Whitney U test and receiver operating characteristics (ROC) analysis. RESULTS: The SNRs of the ganglions and roots were larger in patients with CIDP (8.30±4.87 and 8.24±4.92) than in non-CIDP patients (4.95±2.05 and 5.08±1.97, P<0.0001, respectively). The CNRs of the ganglions and roots were larger in patients with CIDP (40.79±43.19 and 37.16±48.31) than in non-CIDP patients (25.90±10.41 and 18.37±32.83, P<0.0001, respectively). The CRs of the ganglions and roots were larger in patients with CIDP (0.74±0.13 and 0.66±0.17) than in non-CIDP patients (0.72±0.12 and 0.50±0.17, P=0.004 and P<0.0001, respectively). The sizes of the ganglions and the roots were larger in patients with CIDP (6.62±1.81mm and 5.76±3.24mm) than in non-CIDP patients (5.23±1.17mm and 4.24±1.11mm, P<0.0001, respectively). ROC analysis showed the best diagnostic performance with the CNR of the roots. CONCLUSION: Patients with CIDP could be distinguished from controls on 3D SHINKEI.

DOI： 10.1016/j.ejrad.2017.05.031

Language：English   Publishing type：Research paper (scientific journal)  

Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1G93A mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)+ cells - choline acetyltransferase (ChAT)+ α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)+ microglia, and S100β+ astrocytes in SOD1G93A mice. The FCs of pSTAT3+ microglia and pSTAT3+ astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3+ α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3+ α-motoneurons compared with pSTAT3- α-motoneurons at 9 weeks of age. We then compared the following pharmacological models - the chronic administration of 3,3'-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3+ α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3+ microglia were increased in LPS-treated mice. The FCs of pSTAT3+ astrocytes were higher in SOD1G93A mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.

DOI： 10.1111/ejn.13650

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.jns.2017.06.002

Language：English   Publishing type：Research paper (scientific journal)  

Purpose To evaluate whether 3D SHINKEI in the lumbar plexus could identify patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Materials and methods Twenty-one patients with CIDP and 15 non-CIDP patients were studied in this retrospective study. The SNR, contrast-to-noise ratio (CNR), contrast ratio (CR) and the size of the lumbar ganglions and roots were measured. Statistical analyses were performed with Mann-Whitney U test and receiver operating characteristics (ROC) analysis. Results The SNRs of the ganglions and roots were larger in patients with CIDP (8.30 ± 4.87 and 8.24 ± 4.92) than in non-CIDP patients (4.95 ± 2.05 and 5.08 ± 1.97, P < 0.0001, respectively). The CNRs of the ganglions and roots were larger in patients with CIDP (40.79 ± 43.19 and 37.16 ± 48.31) than in non-CIDP patients (25.90 ± 10.41 and 18.37 ± 32.83, P < 0.0001, respectively). The CRs of the ganglions and roots were larger in patients with CIDP (0.74 ± 0.13 and 0.66 ± 0.17) than in non-CIDP patients (0.72 ± 0.12 and 0.50 ± 0.17, P = 0.004 and P < 0.0001, respectively). The sizes of the ganglions and the roots were larger in patients with CIDP (6.62 ± 1.81 mm and 5.76 ± 3.24 mm) than in non-CIDP patients (5.23 ± 1.17 mm and 4.24 ± 1.11 mm, P < 0.0001, respectively). ROC analysis showed the best diagnostic performance with the CNR of the roots. Conclusion Patients with CIDP could be distinguished from controls on 3D SHINKEI.

DOI： 10.1016/j.ejrad.2017.05.031

Language：English   Publishing type：Research paper (scientific journal)  

Signal transducer and activator of transcription (STAT) proteins are activated by phosphorylation in the spinal cord of patients suffering from amyotrophic lateral sclerosis (ALS). The major scope of our study is a comprehensive histological characterization of the mechanisms underlying neuronal and glial STAT3 activation in the pathogenesis of ALS using SOD1(G93A) mice. We calculated the fold changes (FCs, ratios vs. appropriate controls) of the numerical densities of the following phosphorylated STAT3-positive (pSTAT3)(+) cells - choline acetyltransferase (ChAT)(+) α-motoneurons, ionized calcium-binding adapter molecule 1 (Iba1)(+) microglia, and S100β(+) astrocytes in SOD1(G93A) mice. The FCs of pSTAT3(+) microglia and pSTAT3(+) astrocytes were increased from 9 to 15 weeks of age and then plateaued until 21 weeks. In contrast, the FCs of pSTAT3(+) α-motoneurons peaked at 9 weeks and then decreased until 21 weeks. The immunoreactivity for nonphosphorylated neurofilament protein (SMI-32), a marker of axonal impairment, was decreased in pSTAT3(+) α-motoneurons compared with pSTAT3(-) α-motoneurons at 9 weeks of age. We then compared the following pharmacological models - the chronic administration of 3,3'-iminodipropionitrile (IDPN), which models axonal impairment, and the acute administration of lipopolysaccharide (LPS), which is a model of neuroinflammation. The FCs of pSTAT3(+) α-motoneurons were increased in IDPN-treated mice, while those of pSTAT3(+) microglia were increased in LPS-treated mice. The FCs of pSTAT3(+) astrocytes were higher in SOD1(G93A) mice at 9 weeks compared with IDPN- and LPS-treated mice. Our results indicate that axonopathy and neuroinflammation may trigger the respective activation of neuronal and glial STAT3, which is observed during ALS pathogenesis.

DOI： 10.1111/ejn.13650

Language：English   Publishing type：Research paper (scientific journal)  

From a view point of the glutamate excitotoxicity theory, several studies have suggested that abnormal glutamate homeostasis via dysfunction of glial glutamate transporter-1 (GLT-1) may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). However, the detailed role of GLT-1 in the pathogenies of ALS remains controversial. To assess this issue, here we elucidated structural alterations associated with dysregulation of glutamate homeostasis using SOD1^G93A mice, a genetic model of familial ALS. We first examined the viability of α-motoneurons in the lumbar spinal cord of SOD1^G93A mice. Measurement of the soma size and density indicated that α-motoneurons might be intact at 9 weeks of age (presymptomatic stage), then soma shrinkage began at 15 weeks of age (progressive stage), and finally neuronal density declined at 21 weeks of age (end stage). Next, we carried out the line profile analysis, and found that the coverage of α-motoneurons by GLT-1-positive (GLT-1⁺) astrocytic processes was decreased only at 21 weeks of age, while the reduction of coverage of α-motoneurons by synaptophysin-positive (SYP⁺) presynaptic terminals began at 15 weeks of age. Interestingly, the coverage of α-motoneurons by VGluT2⁺ presynaptic terminals was transiently increased at 9 weeks of age, and then gradually decreased towards 21 weeks of age. On the other hand, there were no time-dependent alterations in the coverage of α-motoneurons by GABAergic presynaptic terminals. These findings suggest that VGluT2 and GLT-1 may be differentially involved in the pathogenesis of ALS via abnormal glutamate homeostasis at the presymptomatic stage and end stage of disease, respectively.

DOI： 10.1016/j.neuroscience.2017.05.014

Language：English   Publishing type：Research paper (scientific journal)  

Microglia are the resident macrophages of the central nervous system and play complex roles in the milieu of diseases including the primary diseases of myelin. Although mitochondria are critical for cellular functions and survival in the nervous system, alterations in and the roles of mitochondrial dynamics and associated signaling in microglia are still poorly understood. In the present study, by combining immunohistochemistry and 3D ultrastructural analyses, we show that mitochondrial fission/fusion in reactive microglia is differentially regulated from that in monocyte-derived macrophages and the ramified microglia of normal white matter in myelin disease models. Mouse cerebral microglia in vitro demonstrated that stimulation of TLR4 with lipopolysaccharide, widely used to examine microglial reactions, caused the activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1) and enhanced production of reactive oxygen species (ROS). The increase in the ROS level activated 5' adenosine monophosphate-activated protein kinase (AMPK), and facilitated elongation of mitochondria along the microtubule tracks. These results suggest that the polymorphic regulation of mitochondrial fission and fusion in reactive microglia is mediated by distinct signaling under inflammatory conditions, and modulates microglial phenotypes through the production of ROS.

DOI： 10.1038/s41598-017-05232-0

Language：English   Publishing type：Research paper (scientific journal)  

Differential involvement of vesicular and glial glutamate transporters around spinal α-motoneurons in the pathogenesis of SOD1G93A mouse model of amyotrophic lateral sclerosis.
From a view point of the glutamate excitotoxicity theory, several studies have suggested that abnormal glutamate homeostasis via dysfunction of glial glutamate transporter-1 (GLT-1) may underlie neurodegeneration in amyotrophic lateral sclerosis (ALS). However, the detailed role of GLT-1 in the pathogenies of ALS remains controversial. To assess this issue, here we elucidated structural alterations associated with dysregulation of glutamate homeostasis using SOD1G93A mice, a genetic model of familial ALS. We first examined the viability of α-motoneurons in the lumbar spinal cord of SOD1G93A mice. Measurement of the soma size and density indicated that α-motoneurons might be intact at 9weeks of age (presymptomatic stage), then soma shrinkage began at 15weeks of age (progressive stage), and finally neuronal density declined at 21weeks of age (end stage). Next, we carried out the line profile analysis, and found that the coverage of α-motoneurons by GLT-1-positive (GLT-1+) astrocytic processes was decreased only at 21weeks of age, while the reduction of coverage of α-motoneurons by synaptophysin-positive (SYP+) presynaptic terminals began at 15weeks of age. Interestingly, the coverage of α-motoneurons by VGluT2+ presynaptic terminals was transiently increased at 9weeks of age, and then gradually decreased towards 21weeks of age. On the other hand, there were no time-dependent alterations in the coverage of α-motoneurons by GABAergic presynaptic terminals. These findings suggest that VGluT2 and GLT-1 may be differentially involved in the pathogenesis of ALS via abnormal glutamate homeostasis at the presymptomatic stage and end stage of disease, respectively.

DOI： 10.1016/j.neuroscience.2017.05.014

Language：English  

Differential activation of neuronal and glial STAT3 in the spinal cord of the SOD1G93A mouse model of amyotrophic lateral sclerosis.

DOI： 10.1016/j.neuroscience.2017.05.014

Language：Japanese  

Plexin D1は小径無髄後根神経節神経細胞を標的とした免疫介在性神経障害性疼痛の責任自己抗原である

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese  

症例は56歳女性。出産時大量出血した既往がある。53歳頃より両下肢の筋硬直と腰曲がりが徐々に出現した。初診時は股関節と膝関節の可動域制限があり、触診で下肢筋に硬直と疼痛を認めた。抗VGKC複合体抗体が弱陽性だったことから、stiff-person症候群やIsaacs症候群を疑ったがジアセパム内服に反応しなかった。一方、血液検査で内分泌学的異常を認めたため精査し、出産時出血後の汎下垂体機能低下症と診断した。ホルモン補充療法の開始後下肢筋の硬直が著明に改善した。汎下垂体機能低下症でstiff-person症候群様の症状を来す例を稀に認め、鑑別に挙げる必要がある。(著者抄録)

Language：English   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. METHODS: We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. RESULTS: Characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p<0.05). CONCLUSIONS: Paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo-glial junctional molecules.

DOI： 10.1136/jnnp-2016-314895

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: To evaluate cerebral blood flow (CBF) laterality derived from arterial spin labeling (ASL) in early-stage Parkinson's disease (PD) patients compared with those with advanced stages. MATERIALS AND METHODS: Thirty-eight patients with PD (21 patients in early stages, 17 patients in advanced stages) were retrospectively studied. The CBF maps derived from 3T ASL data were co-registered to the corresponding 3DT1WI using SPM 12 software. Caudate nucleus (CN), putamen (PT), globus pallidus (GP), and thalamus (TH) were manually traced on the representative axial slices of 3DT1WI. CBF of the CN, PT, GP, and TH was measured using corresponding pixels on the co-registered CBF maps. A laterality index (LI) was calculated as the ratio of the contralateral CBF to primary affected side CBF. Each LI was compared between early and advanced stages of PD using the Mann-Whitney U-test. The LIs were also compared between each stage of PD. RESULTS: In the CN, the LIs were significantly higher in early stages (mean LI ± SD, 95&#37; confidence interval = 1.06 ± 0.14, 1.00-1.13) than in advanced stages (0.94 ± 0.14, 0.87-1.01; P < 0.05). We also observed a tendency toward decreased LIs with disease severity (1.10 ± 0.14, 0.99-1.21 for Hoehn and Yahr stage I; 1.04 ± 0.14, 0.92-1.12 for stage II; 0.96 ± 0.11, 0.89-1.10 for stage III; 0.93 ± 0.17, 0.81-1.05 for stage IV). CONCLUSION: The evaluation of CBF laterality pattern in the CN using ASL may be useful for assessing the disease severity of PD patients. LEVEL OF EVIDENCE: 3 J. MAGN. RESON. IMAGING 2017;45:1821-1826.

DOI： 10.1002/jmri.25489

Language：Japanese   Publishing type：Research paper (scientific journal)  

We report a case of flexion contractures in a patient's legs secondary to postpartum hypopituitarism. A 56-year-old woman presented with a 3-year history of worsening flexion contractures of the hips and knees. On admission, her hips and knees could not be extended, and she had muscle stiffness and tenderness to palpation of the lower extremities. We first suspected stiff-person syndrome or Isaacs' syndrome because of her muscle stiffness. However, multiple hormones did not respond to stimulation tests, and an MRI of the brain showed atrophy of the pituitary gland with an empty sella. A subsequent interview revealed that she had suffered a severe hemorrhage while delivering her third child. She was diagnosed with panhypopituitarism and started on cortisol replacement therapy. After 1 week of treatment with hydrocortisone (10 mg/day), her symptoms quickly improved. We then added 75 μg/day of thyroid hormone. During the course of her treatment, autoantibodies against VGKC complex were found to be weakly positive. However, we considered the antibodies to be unrelated to her disease, because her symptoms improved markedly with low-dose steroid treatment. There are a few reports describing flexion contractures of the legs in patients with primary and secondary adrenal insufficiency. As these symptoms are similar to those seen in stiff-person syndrome, adrenal and pituitary insufficiency should be taken into account to achieve the correct diagnosis and treatment in patients with flexion contractures and muscle stiffness.

DOI： 10.5692/clinicalneurol.cn-001008

Language：English   Publishing type：Research paper (scientific journal)  

Objective To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. Methods We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. Results Characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p<0.05). Conclusions Paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo-glial junctional molecules.

DOI： 10.1136/jnnp-2016-314895

Language：English   Publishing type：Research paper (scientific journal)  

Purpose: To evaluate cerebral blood flow (CBF) laterality derived from arterial spin labeling (ASL) in early-stage Parkinson's disease (PD) patients compared with those with advanced stages. Materials and Methods: Thirty-eight patients with PD (21 patients in early stages, 17 patients in advanced stages) were retrospectively studied. The CBF maps derived from 3T ASL data were co-registered to the corresponding 3DT1WI using SPM 12 software. Caudate nucleus (CN), putamen (PT), globus pallidus (GP), and thalamus (TH) were manually traced on the representative axial slices of 3DT1WI. CBF of the CN, PT, GP, and TH was measured using corresponding pixels on the co-registered CBF maps. A laterality index (LI) was calculated as the ratio of the contralateral CBF to primary affected side CBF. Each LI was compared between early and advanced stages of PD using the Mann-Whitney U-test. The LIs were also compared between each stage of PD. Results: In the CN, the LIs were significantly higher in early stages (mean LI ± SD, 95% confidence interval = 1.06 ± 0.14, 1.00–1.13) than in advanced stages (0.94 ± 0.14, 0.87–1.01; P < 0.05). We also observed a tendency toward decreased LIs with disease severity (1.10 ± 0.14, 0.99–1.21 for Hoehn and Yahr stage I; 1.04 ± 0.14, 0.92–1.12 for stage II; 0.96 ± 0.11, 0.89–1.10 for stage III; 0.93 ± 0.17, 0.81–1.05 for stage IV). Conclusion: The evaluation of CBF laterality pattern in the CN using ASL may be useful for assessing the disease severity of PD patients. Level of Evidence: 3. J. MAGN. RESON. IMAGING 2017;45:1821–1826.

DOI： 10.1002/jmri.25489

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English  

DOI： 10.1111/cen3.12384

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Studies of longitudinally extensive spinal cord lesions (LESCLs) in neuromyelitis optica (NMO) have focused on gray matter, where the relevant antigen, aquaporin-4 (AQP4), is abundant. Because spinal white matter pathology in NMO is not well characterized, we aimed to clarify spinal white matter pathology of LESCLs in NMO. METHODS: We analyzed 50 spinal cord lesions from eleven autopsied NMO/NMO spectrum disorder (NMOSD) cases. We also evaluated LESCLs with three or fewer spinal cord attacks by 3-tesla MRI in 15 AQP4 antibody-positive NMO/NMOSD patients and in 15 AQP4 antibody-negative multiple sclerosis (MS) patients. RESULTS: Pathological analysis revealed seven cases of AQP4 loss and four predominantly demyelinating cases. Forty-four lesions from AQP4 loss cases involved significantly more frequently posterior columns (PC) and lateral columns (LC) than anterior columns (AC) (59.1&#37;, 63.6&#37;, and 34.1&#37;, respectively). The posterior horn (PH), central portion (CP), and anterior horn (AH) were similarly affected (38.6&#37;, 36.4&#37; and 31.8&#37;, respectively). Isolated perivascular inflammatory lesions with selective loss of astrocyte endfoot proteins, AQP4 and connexin 43, were present only in white matter and were more frequent in PC and LC than in AC (22.7&#37;, 29.5&#37; and 2.3&#37;, Pcorr  = 0.020, and Pcorr  = 0.004, respectively). MRI indicated LESCLs more frequently affected PC and LC than AC in anti-AQP4 antibody-seropositive NMO/NMOSD (86.7&#37;, 60.0&#37; and 20.0&#37;, Pcorr  = 0.005, and Pcorr  = 0.043, respectively) and AQP4 antibody-seronegative MS patients (86.7&#37;, 73.3&#37; and 33.3&#37;, Pcorr  = 0.063, and Pcorr  = 0.043, respectively). PH, CP and AH were involved in 93.3&#37;, 86.7&#37; and 73.3&#37; of seropositive patients, respectively, and in 53.3&#37;, 60.0&#37; and 40.0&#37; of seronegative patients, respectively. CONCLUSIONS: NMO frequently and extensively affects spinal white matter in addition to central gray matter, especially in PC and LC, where isolated perivascular lesions with astrocyte endfoot protein loss may emerge. Spinal white matter involvement may also appear in early NMO, similar to cerebral white matter lesions.

DOI： 10.1111/bpa.12386

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12384

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Cortical lesions (CLs) frequently observed in Caucasian patients with multiple sclerosis (MS) contribute to disability. However, it remains unclear whether CLs are associated with clinical features and genetic risk factors, such as HLA-DRB1*15:01 and -DRB1*04:05 in Asian MS patients.
OBJECTIVE: To elucidate the frequency of CLs and their association with HLA-DRB1 and DPB1 alleles in Japanese MS patients.
METHODS: Three-dimensional double inversion recovery imaging and clinical information were retrospectively obtained from 92 Japanese MS patients.
RESULTS: CLs of any type, intracortical lesions (ICLs), and leukocortical lesions (LCLs) were detected in 39.1%, 26.1%, and 28.3% of patients, respectively. MS patients with ICLs had a significantly higher frequency of secondary progression and greater Expanded Disability Status Scale (EDSS) scores than those without ICLs. Similar trends were observed with CLs and LCLs. The number of all three lesion types positively correlated with EDSS scores. The frequency and number of ICLs were significantly higher in HLA-DRB1*15:01 carriers than in HLA-DRB1*15:01 non-carriers, but significantly lower in HLA-DRB1*04:05 carriers than in HLA-DRB1*04:05 non-carriers. Multivariate logistic regression analysis revealed a negative association of HLA-DRB1*04:05 with ICLs.
CONCLUSION: ICLs are associated with greater disease severity in Japanese MS patients and are partly suppressed by the HLA-DRB1*04:05 allele.

DOI： 10.1177/1352458517707067

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Background: The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however, cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). Methods: We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons was studied by magnetic resonance imaging. Results: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1β and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C. Conclusions: Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.

DOI： 10.1186/s12974-017-0863-0

Language：Japanese  

A 58-year-old man (height, 160.5 cm; weight 46.7 kg) underwent partial esophagectomy under general anesthesia. A resident anesthesiologist punctured the right internal jugular vein (IJV) (20 mm wide, 4.7-7.6 mm long antero-posteriorly, and 7.6 mm deep) with a 22-gauge metal puncture needle under ultrasono- graphic guidance to secure a central venous catheter (CVC) after surgery under artificial respiration. After obtaining venous blood return without an ultrasono- graphic image of the needle tip inside the IJV, the anesthesiologist advanced a flexible straight-type guidewire into the IJV without resistance. Longitudinal ultrasonography of the guidewire outside the IJV indi- cated extravasation. After withdrawing the guidewire, the anesthesiologist re-punctured the IJV. After obtain- ing blood return with two-echo enhancement inside the IJV, indicating the needle tip, the anesthesiologist advanced the guidewire without resistance and ultra- sonographically confirmed the course of the guidewire inside the IJV along the posterior wall. CVC placement was confirmed via plain radiography of the chest Even a flexible guidewire can penetrate the IJV at posterior wall if a puncture needle tip is positioned near the pos- terior wall Longitudinal ultrasonographic imaging of guidewires can help physicians avoid misplacing dila- tors.

Language：Japanese   Publishing type：Research paper (scientific journal)  

A case of superficial siderosis ameliorated after closure of dural deficit detected by MRI-CISS (constructive interference in steady state) imaging.
A 64-year-old male developed headache, dizziness, and difficulty hearing, two years after an operation for chronic subdural hematoma due to head injury. These symptoms gradually worsened over the following 15 years. As he showed bloody cerebrospinal fluid (CSF) and marginal hypointensity on the surface of the brain and spinal cord on T2/T2*-weighted MRI, he was diagnosed with superficial siderosis (SS), although the source of the bleeding was unclear and anti-hemorrhagic drugs were ineffective. When he was admitted to our hospital, neurological examination disclosed horizontal gaze-evoked nystagmus, severe bilateral hearing loss, scanning speech, and limb and truncal ataxia. CISS (constructive interference in steady state) MRI detected a dural defect at the Th2-3 level on the anterior side of the spinal canal. On operation, a 2 mm × 6 mm size dural defect with blood clots was found at the Th2-3 level. After closure of the dural defect, bloody CSF became transparent, and his persistent headache, dizziness, and hearing impairment improved. Brain and whole spine MRI, especially CISS imaging, should be considered for detecting the source of bleeding in intractable cases of SS.

DOI： 10.5692/clinicalneurol.cn-000960

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: The pathology of multiple system atrophy cerebellar-type (MSA-C) includes glial inflammation; however, cerebrospinal fluid (CSF) inflammatory cytokine profiles have not been investigated. In this study, we determined CSF cytokine/chemokine/growth factor profiles in MSA-C and compared them with those in hereditary spinocerebellar ataxia (SCA). METHODS: We collected clinical data and CSF from 20 MSA-C patients, 12 hereditary SCA patients, and 15 patients with other non-inflammatory neurological diseases (OND), and measured 27 cytokines/chemokines/growth factors using a multiplexed fluorescent bead-based immunoassay. The size of each part of the hindbrain and hot cross bun sign (HCBS) in the pons was studied by magnetic resonance imaging. RESULTS: Granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-6, IL-7, IL-12, and IL-13 levels were significantly higher in MSA-C and SCA compared with OND. In MSA-C, IL-5, IL-6, IL-9, IL-12, IL-13, platelet-derived growth factor-bb, macrophage inflammatory protein (MIP)-1α, and GM-CSF levels positively correlated with anteroposterior diameters of the pontine base, vermis, or medulla oblongata. By contrast, in SCA patients, IL-12 and MIP-1α showed significant negative correlations with anteroposterior diameters of the pontine base, and unlike MSA-C, there was no cytokine with a positive correlation in SCA. IL-6 was significantly higher in MSA-C patients with the lowest grade of HCBS compared with those with the highest grade. Macrophage chemoattractant protein-1 (MCP-1) had a significant negative correlation with disease duration only in MSA-C patients. Tumor necrosis factor-alpha, IL-2, IL-15, IL-4, IL-5, IL-10, and IL-8 were all significantly lower in MSA-C and SCA compared with OND, while IL-1ra, an anti-inflammatory cytokine, was elevated only in MSA-C. IL-1β and IL-8 had positive correlations with Unified Multiple System Atrophy Rating Scale part 1 and 2, respectively, in MSA-C. CONCLUSIONS: Although CSF cytokine/chemokine/growth factor profiles were similar between MSA-C and SCA, pro-inflammatory cytokines, such as IL-6, GM-CSF, and MCP-1, correlated with the disease stage in a way higher at the beginning only in MSA-C, reflecting early stronger intrathecal inflammation.

DOI： 10.1186/s12974-017-0863-0

Language：English   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (other academic)  

Language：English   Publishing type：Research paper (other academic)  

Language：English  

DOI： 10.1111/cen3.12372

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: To evaluate the usefulness of 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: This institutional review board-approved retrospective study included 14 CIDP patients and nine normal subjects. The signal-to-noise ratio (SNR), contrast ratio (CR), and the size of the cervical ganglions and roots were measured by two raters. RESULTS: The SNRs of the ganglions and roots were larger in patients with CIDP (9.55 ± 3.87 and 9.81 ± 3.64) than in normal subjects (7.21 ± 2.42 and 5.70 ± 2.14, P < 0.0001, respectively). The CRs of the ganglions and roots were larger in patients with CIDP (0.77 ± 0.08 and 0.68 ± 0.12) than in normal subjects (0.72 ± 0.07 and 0.53 ± 0.11, P < 0.0001, respectively). The sizes of the ganglions and the roots were larger in patients with CIDP (6.44 ± 1.61 mm and 4.89 ± 1.94 mm) than in normal subjects (5.24 ± 1.02 mm and 3.39 ± 0.80 mm, P < 0.0001, respectively). CONCLUSIONS: Patients with CIDP could be distinguished from controls on 3D SHINKEI. KEY POINTS: • 3D SHINKEI could visualize brachial plexus with high spatial resolution. • CIDP patients showed increased SNR, CR, and the size of brachial plexus. • 3D SHINKEI could discriminate CIDP patients from normal subjects.

DOI： 10.1007/s00330-016-4406-3

Language：English   Publishing type：Research paper (scientific journal)  

Objective: To evaluate the usefulness of 3D nerve-sheath signal increased with inked rest-tissue rapid acquisition of relaxation enhancement imaging (SHINKEI) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods: This institutional review board-approved retrospective study included 14 CIDP patients and nine normal subjects. The signal-to-noise ratio (SNR), contrast ratio (CR), and the size of the cervical ganglions and roots were measured by two raters. Results: The SNRs of the ganglions and roots were larger in patients with CIDP (9.55 ± 3.87 and 9.81 ± 3.64) than in normal subjects (7.21 ± 2.42 and 5.70 ± 2.14, P < 0.0001, respectively). The CRs of the ganglions and roots were larger in patients with CIDP (0.77 ± 0.08 and 0.68 ± 0.12) than in normal subjects (0.72 ± 0.07 and 0.53 ± 0.11, P < 0.0001, respectively). The sizes of the ganglions and the roots were larger in patients with CIDP (6.44 ± 1.61 mm and 4.89 ± 1.94 mm) than in normal subjects (5.24 ± 1.02 mm and 3.39 ± 0.80 mm, P < 0.0001, respectively). Conclusions: Patients with CIDP could be distinguished from controls on 3D SHINKEI. Key points: • 3D SHINKEI could visualize brachial plexus with high spatial resolution. • CIDP patients showed increased SNR, CR, and the size of brachial plexus. • 3D SHINKEI could discriminate CIDP patients from normal subjects.

DOI： 10.1007/s00330-016-4406-3

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/cen3.12372

Language：English   Publishing type：Research paper (scientific journal)  

We report a case of flexion contractures in a patient's legs secondary to postpartum hypopituitarism. A 56-year-old woman presented with a 3-year history of worsening flexion contractures of the hips and knees. On admission, her hips and knees could not be extended, and she had muscle stiffness and tenderness to palpation of the lower extremities. We first suspected stiff-person syndrome or Isaacs' syndrome because of her muscle stiffness. However, multiple hormones did not respond to stimulation tests, and an MRI of the brain showed atrophy of the pituitary gland with an empty sella. A subsequent interview revealed that she had suffered a severe hemorrhage while delivering her third child. She was diagnosed with panhypopituitarism and started on cortisol replacement therapy. After 1 week of treatment with hydrocortisone (10 mg/day), her symptoms quickly improved. We then added 75 μg/day of thyroid hormone. During the course of her treatment, autoantibodies against VGKC complex were found to be weakly positive. However, we considered the antibodies to be unrelated to her disease, because her symptoms improved markedly with low-dose steroid treatment. There are a few reports describing flexion contractures of the legs in patients with primary and secondary adrenal insufficiency. As these symptoms are similar to those seen in stiff-person syndrome, adrenal and pituitary insufficiency should be taken into account to achieve the correct diagnosis and treatment in patients with flexion contractures and muscle stiffness.

DOI： 10.5692/clinicalneurol.cn-001008

Language：English   Publishing type：Research paper (scientific journal)  

Apomorphine (APO) promotes intraneuronal amyloid-β (Aβ) degradation and improves memory function in an Alzheimer's disease (AD) model, 3xTg-AD mice. Since insulin resistance is increased in AD neurons, we investigated the effects of APO on brain insulin resistance in 3xTg-AD mice at early and late stages. After 1-month subcutaneous injection of Apokyn^® to 3xTg-AD mice at 6 or 12 months of age, memory function was significantly improved in both age groups. Protein levels of insulin-degrading enzyme (IDE), which is linked to insulin signaling and degrades Aβ, significantly increased in the 3xTg-AD mice brain compared with non-transgenic mice, and were further increased by APO. Protein levels of two types of serine-phosphorylated insulin receptor substrate-1 (IRS-1), pS⁶¹⁶ and pS^636/639, significantly decreased following APO treatment in the 13-month-old 3xTg-AD mice brain, suggesting improved brain insulin resistance. Immunostaining of the IDE, pS⁶¹⁶ and pS^636/639 IRS-1 demonstrated similar changes due to APO treatment. Thus, brain insulin resistance is considered an important therapeutic target in AD, and APO may provide improved neuronal insulin resistance.

DOI： 10.3233/JAD-160344

Language：English   Publishing type：Research paper (scientific journal)  

A 64-year-old male developed headache, dizziness, and difficulty hearing, two years after an operation for chronic subdural hematoma due to head injury. These symptoms gradually worsened over the following 15 years. As he showed bloody cerebrospinal fluid (CSF) and marginal hypointensity on the surface of the brain and spinal cord on T₂/T₂∗-weighted MRI, he was diagnosed with superficial siderosis (SS), although the source of the bleeding was unclear and anti-hemorrhagic drugs were ineffective. When he was admitted to our hospital, neurological examination disclosed horizontal gaze-evoked nystagmus, severe bilateral hearing loss, scanning speech, and limb and truncal ataxia. CISS (constructive interference in steady state) MRI detected a dural defect at the Th2-3 level on the anterior side of the spinal canal. On operation, a 2 mm × 6 mm size dural defect with blood clots was found at the Th2-3 level. After closure of the dural defect, bloody CSF became transparent, and his persistent headache, dizziness, and hearing impairment improved. Brain and whole spine MRI, especially CISS imaging, should be considered for detecting the source of bleeding in intractable cases of SS.

DOI： 10.5692/clinicalneurol.cn-000960

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

近年、ランビエ絞輪部およびその周辺の分子機構の解明が進み、自己抗体の標的部位としての側面にも注目が集まるようになった。特にランビエ傍絞輪部の細胞膜蛋白であるcontactin-1およびneurofascin155に対する自己抗体が慢性炎症性脱髄性多発根ニューロパチー症例の一部で陽性になることが立て続けに報告され、臨床的特徴が明らかにされつつある。治療反応性に関する報告もなされ、今後これらの自己抗体が診断および治療選択マーカーとして用いられることが期待される。(著者抄録)

Language：Japanese  

Language：English  

DOI： 10.1111/ene.13190

Language：English   Publishing type：Research paper (scientific journal)  

We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNγ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS.

DOI： 10.1038/srep38387

Language：English   Publishing type：Research paper (scientific journal)  

We aimed to validate the diagnostic utility of enzyme-linked immunosorbent assay (ELISA) for the detection of anti-neurofascin (NF) 155 antibody in 191 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Human NF155-based ELISA clearly distinguished between anti-NF155 antibody-positive and -negative sera. Fifteen CIDP patients (8&#37;) were IgG4 anti-human NF155 antibody-positive, which were confirmed by western blot, cell-based assay and immunohistochemical study. None of disease controls or healthy subjects had positive results. Clinical presentation of IgG4 anti-NF155 antibody-positive patients was consistent with those in previous reports. This ELISA combined with determination of the IgG4 subclass is useful in screening for anti-NF155 antibodies.

DOI： 10.1016/j.jneuroim.2016.10.013

Language：English   Publishing type：Research paper (scientific journal)  

We previously reported early and extensive loss of astrocytic connexin 43 (Cx43) in acute demyelinating lesions of multiple sclerosis (MS) patients. Because it is widely accepted that autoimmune T cells initiate MS lesions, we hypothesized that infiltrating T cells affect Cx43 expression in astrocytes, which contributes to MS lesion formation. Primary mixed glial cell cultures were prepared from newborn mouse brains, and microglia were isolated by anti-CD11b antibody-conjugated magnetic beads. Next, we prepared astrocyte-rich cultures and astrocyte/microglia-mixed cultures. Treatment of primary mixed glial cell cultures with interferon (IFN) γ, interleukin (IL)-4, or IL-17 showed that only IFNβ or IL-17 at high concentrations reduced Cx43 protein levels. Upon treatment of astrocyte-rich cultures and astrocyte/microglia-mixed cultures with IFNγ;, Cx43 mRNA/protein levels and the function of gap junctions were reduced only in astrocyte/microglia-mixed cultures. IFNγ-treated microglia-conditioned media and IL-1β, which was markedly increased in IFNγ-treated microglia-conditioned media, reduced Cx43 protein levels in astrocyte-rich cultures. Finally, we confirmed that Th1 cell-conditioned medium decreased Cx43 protein levels in mixed glial cell cultures. These findings suggest that Th1 cell-derived IFNγ activates microglia to release IL-1β that reduces Cx43 gap junctions in astrocytes. Thus, Th1-dominant inflammatory states disrupt astrocytic intercellular communication and may exacerbate MS.

DOI： 10.1038/srep38387

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1111/ene.13190

Language：English   Publishing type：Research paper (scientific journal)  

We aimed to validate the diagnostic utility of enzyme-linked immunosorbent assay (ELISA) for the detection of anti-neurofascin (NF) 155 antibody in 191 patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Human NF155-based ELISA clearly distinguished between anti-NF155 antibody-positive and -negative sera. Fifteen CIDP patients (8%) were IgG4 anti-human NF155 antibody-positive, which were confirmed by western blot, cell-based assay and immunohistochemical study. None of disease controls or healthy subjects had positive results. Clinical presentation of IgG4 anti-NF155 antibody-positive patients was consistent with those in previous reports. This ELISA combined with determination of the IgG4 subclass is useful in screening for anti-NF155 antibodies.

DOI： 10.1016/j.jneuroim.2016.10.013