Kyushu University Academic Staff Educational and Research Activities Database
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Toru Iwaki Last modified date:2019.02.20

Graduate School
Undergraduate School
Other Organization
Administration Post

Web site of Department of Neuropathology .
Academic Degree
Medical doctor
Country of degree conferring institution (Overseas)
Field of Specialization
Medicine, Pathology, Neuropathology, Neuroscience
Total Priod of education and research career in the foreign country
Outline Activities
Subject of studies
(1) Clinicopathological study on dementia: the Hisayama study
The Hisayama study is a prospective population-based study in a Japanese subrural community, Hisayama Town, which has been carried out by Department of Medicine and Clinical Science, Kyushu University since 1961. The characteristic of the town is that the age, occupational status and nutrient intake of the population are almost identical to those of the general Japanese population. Postmortem examinations of most deceased subjects were performed in Kyushu University Hospital to confirm causes of death and to examine brain pathology. These features have allowed a reliable estimation of the frequency of neurodegenerative diseases relating dementia in a general population and for a detailed analysis of the difference between dementia and non-dementia. Our database based on the Hisayama study would have benefits to examine clinicopathological features of neurodegenerative diseases in a general population.
The prevalence of diabetes is growing at epidemic proportions worldwide, and is becoming a major health problem. Several large longitudinal population-based studies have shown that the rate of cognitive decline is accelerated in elderly people with type 2 diabetes compared with the general population. Similarly, other epidemiologic studies have revealed that diabetes increases the risk of dementia, including Alzheimer disease. Therefore, the effect of diabetes on cognitive function in the elderly has significant public health implications. We examined the association between diabetes-related factors and pathology of Alzheimer disease to evaluate how diabetes affects the pathogenic process of Alzheimer disease. The associations between each diabetes-related factor and Alzheimer disease pathology were examined by analysis of covariance and logistic regression analyses. The results suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate neuritic plague formation in combination with the effects of APOE epsilon4.

(2) Prion diseases
Prion diseases are a group of fatal neurodegenerative disorders, which include Creutzfeldt-Jakob disease (CJD) in humans. We have performed clinicopathological studies on human prion diseases in a planned and consistent way. Prion diseases are associated with abnormal deposition of prion protein (PrP). The normal, cellular PrP (PrPc) is converted into abnormal PrP (PrPsc) through a process of conformational change where a portion of its alpha-helical and coil structure is refolded into a beta-sheet. Prion diseases are conventionally diagnosed by the detection of accumulation of abnormal PrP using immunohistochemistry or the detection of the abnormal PrP with protease resistance (PrPres). It would be highly recommended that the abnormality of PrP molecules should be determined from various perspectives more than protease resistance. We tested several spin columns to detect PrP oligomers by a simplified method applying gel filtration chromatography without protease treatment, in CJD patients with various degree of neuropathological change, and evaluated the correlation between the disease severity and the degree of PrP polymerization.

(1) Undergraduate education
In the undergraduate teaching curriculum, a further investigation of the education for the diseases of the nervous system was established. To give the outline of the clinical neuroscience and neuropathology to the 3rd year students, I am in charge of the classes of clinical pathology and neuropathology.
(2) Postgraduate education
a. Neuropathology training
b. Clinico-pathological conference
Research Interests
  • Morphometric analyses of pathological findings of dementia and identification of the risk factors
    keyword : Alzheimer's disease, dementia, tauopathy
    2014.04~2019.03Clinicopathological study on dementia (the Hisayama study).
  • Pathological study on glioma
    keyword : brain, glioma, metabolism, pathology
    2012.04~2018.03Cell biological study on glioma stem cell.
  • Clinicopathological study on dementia (the Hisayama study)
    keyword : Alzheimer's disease, dementia
    2002.04~2014.03Clinicopathological study on dementia (the Hisayama study).
  • Cell biological study on glioma stem cell
    keyword : glioma, cancer stem cell, tumorigenesis
    2005.04~2007.03Cell biological study on glioma stem cell .
  • Clinicopathological study on prion disease
    keyword : Prion, Creutzfeldt-Jakob disease
    1989.11Clinicopathological study on prion diseases Development of diagnostic tool for prion diseases.
  • Developmental study of the central nervous system
    keyword : central nervous system, development, glia
    2003.01~2011.03Developmental study of the central nervous system.
  • Study on stress proteins in neurological diseases
    keyword : stress protein, alphaB-crystallin, heat shock protein
    1997.05~2006.03Study on stress proteins in neurological diseases.
Current and Past Project
  • The Kyushu University COE Program on Lifestyle-Related Diseases
Academic Activities
1. Chang Shen, Hiroyuki Honda, Satoshi Suzuki, Norihisa Maeda, Masahiro Shijo, Hideomi Hamasaki, Naokazu Sasagasako, Naoki Fujii, Toru Iwaki, Dynactin is involved in Lewy body pathology, Neuropathology, 10.1111/neup.12512, 2018.02, Dynactin forms a protein complex with dynein that retrogradely transports cargo along microtubules. Dysfunction of this dynein-dynactin complex causes several neurodegenerative diseases such as Perry syndrome, motor neuron diseases and progressive supranuclear palsy. Recently, we reported colocalization of phosphorylated α-synuclein (p-SNCA) and the largest subunit of dynactin (DCTN1) in Lewy body (LB)-like structures in Perry syndrome. Previous reports have not focused on the relationship between dynactin and synucleinopathies. Thus, we examined autopsied human brains from patients with Parkinson's disease, dementia with LBs, and multiple system atrophy using immunohistochemistry for p-SNCA, DCTN1, dynactin 2 (DCTN2, dynamitin) and dynein cytoplasmic 1 intermediate chain 1 (DYNC1I1). We also examined microtubule affinity-regulating kinases (MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Both brainstem-type and cortical LBs were immunopositive for DCTN1, DCTN2, DYNC1I1 and p-MARK and their staining often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1, DCTN2 and DYNC1I1. However, p-SNCA-positive inclusions of multiple system atrophy, which included both glial and neuronal cytoplasmic inclusions, were immunonegative for DCTN1, DCTN2, DYNC1I1 and p-MARK. Thus, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can clearly distinguish LBs from neuronal cytoplasmic inclusions. Our results suggest that dynactin is closely associated with LB pathology..
2. Norihisa Maeda, Hiroyuki Honda, Satoshi Suzuki, Naoki Fujii, Jun-Ichi Kira, Toru Iwaki, Mitochondrial dysfunction and altered ribostasis in hippocampal neurons with cytoplasmic inclusions of multiple system atrophy, Neuropathology, 10.1111/neup.12482, 38, 4, 361-371, 2018.08, Multiple system atrophy (MSA) is a sporadic adult-onset neurodegenerative disease. It has recently been shown that patients with MSA accompanied by cognitive decline display numerous neuronal cytoplasmic inclusions (NCIs) in the limbic neurons. We examined potential mechanisms underlying the formation of these NCIs by determining of mitochondrial function and statuses of RNA processing by analyzing 12 pathologically confirmed cases of MSA. Among them, four had cognitive impairment Semiquantitative evaluation using immunohistochemistry analyses revealed a significantly greater NCI burden in the hippocampal cornu ammonis 1 (CA1) subfield, subiculum, and amygdala in the cases with cognitive impairments compared with those without cognitive impairment. Immunofluorescent staining revealed that limbic neurons with NCIs often accelerated production of reactive oxygen species (ROS) and degraded mitochondrial quality control. Immunofluorescent staining also revealed that neurons with these NCIs translocated heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) from the nucleus and aggregated abnormally at the perinuclear rim. Since the NCIs in the hippocampal neurons of MSA with cognitive impairments were more numerous, the neuronal mitochondrial dysfunction and altered ribostasis observed in NCI formation may be involved in the hippocampal degeneration of MSA..
3. Reiji Hommyo, Satoshi Suzuki, Nona Abolhassani, Hideomi Hamasaki, Masahiro Shijo, Norihisa Maeda, Hiroyuki Honda, Yusaku Nakabeppu, Toru Iwaki, Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis, Neuropathology, 10.1111/neup.12466, 38, 3, 247-259, 2018.06, The protein μ-crystallin (CRYM) is a novel component of the marsupial lens that has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. In this study, we examined changes of the expression pattern of CRYM in different rat organs during development using immunohistochemistry and immunoblotting. As CRYM is reportedly expressed in the corticospinal tract, we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS) using immunohistochemistry. In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and corticospinal tract in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. Even within the same regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In the kidney, CRYM was expressed in epithelial cells of the proximal tubule and mesenchymal cells of the medulla in the early postnatal period; however, CRYM expression in the medulla was lost as mesenchymal cell numbers decreased with the rapid growth of the medulla. In human ALS brains, we observed marked loss of CRYM in the corticospinal tract, especially distally. Our results suggest that CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and in the later period, performs cell-specific functions in selected neuronal populations. In the kidney, CRYM may play roles in maturation of renal function. The expression patterns of CRYM may reflect significance of its interactions with T3 or ketimines in these cells and organs. The results also indicate that CRYM may be used as a marker of axonal degeneration in the corticospinal tract..
4. Hiroyuki Honda, Naokazu Sasagasako, Chang Shen, Masahiro Shijo, Hideomi Hamasaki, Satoshi O. Suzuki, Yoshio Tsuboi, Naoki Fujii, Toru Iwaki, DCTN1 F52L mutation case of Perry syndrome with progressive supranuclear palsy-like tauopathy, Parkinsonism Relat Disord. , 10.1016/j.parkreldis.2018.02.038, Epub ahead of print, 2018.03, Introduction: Perry syndrome is a rapidly progressive, autosomal dominant parkinsonism characterized by central hypoventilation, depression and severe weight loss. To date, eight DCTN1 mutations have been identified associated with Perry syndrome. A novel F52L DCTN1 mutation case of Perry syndrome is characterized by late-onset parkinsonism and frontotemporal atrophy.
Methods: A Japanese woman suffered from slowly progressing parkinsonism since age 48. At age 59, she developed central hypoventilation, and required breathing assistance. Gene analysis identified a p.F52L mutation in DCTN1 and she was diagnosed with Perry syndrome. She died of aspiration pneumonia at age 74.
Results: Postmortem examination revealed severe neuronal loss in the substantia nigra and the putamen. Immunohistochemistry for DCTN1 revealed many abnormal aggregates, mainly in neurons in the brainstem and basal ganglia. Additionally, numerous abnormal phosphorylated tau deposits including neurofibrillary tangles, tuft-shaped astrocytes and coiled bodies were observed mainly in the basal ganglia, brainstem and cerebellum. These correspond with the neuropathologic criteria for progressive supranuclear palsy. Colocalization of DCTN1 and tau were occasionally seen. Colocalization of phosphorylated a-synuclein and DCTN1 were also observed in Lewy body-like structures in oculomotor
nuclei. Phosphorylated TARDBP-positive neuronal cytoplasmic inclusions were few.
Conclusion: In conjunction with long disease duration and aging, our findings suggest that the F52L DCTN1 mutation may evoke severe tauopathy and moderate a-synucleinopathy..
5. Tomoyuki Ohara, Jun Hata, Daigo Yoshida, Mukai N, Masaharu Nagata, Toru Iwaki, Kitazono T, Kanba S, Yutaka Kiyohara, Toshiharu Ninomiya, Trends in dementia prevalence, incidence, and survival rate in a Japanese community, Neurology, 10.1212/WNL.0000000000003932, 88, 20, 1925-1932, 2017.05, OBJECTIVE: To investigate secular trends in the prevalence, incidence, and survival rate of dementia in a Japanese elderly population in a comprehensive manner.
METHODS: Five cross-sectional surveys of dementia were conducted among residents of a Japanese community, aged ≥65 years, in 1985, 1992, 1998, 2005, and 2012. We also established 2 cohorts consisting of the residents of this age group without dementia in 1988 (n = 803) and 2002 (n = 1,231), and each was followed for 10 years.
RESULTS: The age-standardized prevalence of all-cause dementia and Alzheimer disease (AD) increased with time (for all-cause dementia: 6.8% in 1985, 4.6% in 1992, 5.3% in 1998, 8.4% in 2005, and 11.3% in 2012, p for trend <0.01; for AD: 1.5%, 1.4%, 2.4%, 3.9%, and 7.2%, respectively, p for trend <0.01), while no secular change was observed for vascular dementia (VaD) (2.4%, 1.6%, 1.5%, 2.4%, and 2.4%, respectively, p for trend = 0.59). The age- and sex-adjusted incidence of all-cause dementia and AD, but not VaD, increased from the 1988 cohort to the 2002 cohort (for all-cause dementia: adjusted hazard ratio [aHR] 1.68, 95% confidence interval [CI] 1.38-2.06; for AD: aHR 2.07, 95% CI 1.59-2.70; for VaD: aHR 1.18, 95% CI 0.83-1.69). The 5-year survival rate of all-cause dementia and AD improved from the 1988 cohort to the 2002 cohort (for all-cause dementia: 47.3% to 65.2%; for AD: 50.7% to 75.1%; all p < 0.01).
CONCLUSIONS: The increased incidence and improved survival rate of AD could have resulted in the steep increase in AD prevalence in the Japanese elderly..
6. Hideomi Hamasaki, Hiroyuki Honda, Tsuyoshi Okamoto, Sachiko Koyama, Satoshi O Suzuki, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Toru Iwaki, Recent Increases in Hippocampal Tau Pathology in the Aging Japanese Population: The Hisayama Study, J Alzheimers Dis., 10.3233/JAD-160521, 55, 2, 613-624, 2017.01, BACKGROUND: The Hisayama study is a prospective cohort study of lifestyle-related diseases that commenced in 1961. Through it, a significant increasing trend in the prevalence of Alzheimer's disease has been observed over the past 18 years.
OBJECTIVES: We sought to investigate the increases in brain pathology related to Alzheimer's disease using automated MATLAB morphometric analyses for quantifying tau pathology.
METHODS: We examined a series of autopsied cases from Hisayama residents obtained between 1998 and 2003 (group A: 203 cases), and between 2009 and 2014 (group B: 232 cases). We developed custom software in MATLAB to analyze abnormal tau deposits quantitatively. Specimens were immunostained with both anti-amyloid-β-protein and anti-phosphorylated tau antibodies.
RESULTS: Both the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria for senile plaques and Braak stage for NFT were higher in group B. Morphometric analyses of the hippocampi also revealed a trend toward increased tau pathology in both men and women over 80 years of age in group B. The increases were also significant when the subjects were examined independently according to high or low CERAD scores and in all levels of AD neuropathologic change according to the National Institute on Aging-Alzheimer's Association guidelines (2012).
CONCLUSION: We revealed a recent trend of increased tauopathy in the older people, which is partly independent of amyloid-β pathology..
7. Masahiro Shijo, Hiroyuki Honda, Satoshi O Suzuki, Hideomi Hamasaki, Masaaki Hokama, ABOLHASSANI NONA, Yusaku Nakabeppu, Toshiharu Ninomiya, Kitazono T, Toru Iwaki, Association of adipocyte enhancer-binding protein 1 with Alzheimer's disease pathology in human hippocampi, Brain Pathol., 10.1111/bpa.12475, Epub ahead of print, 2016.12, Adipocyte enhancer binding protein 1 (AEBP1) activates inflammatory responses via the NF-κB pathway in macrophages and regulates adipogenesis in preadipocytes. Up-regulation of AEBP1 in the hippocampi of patients with Alzheimer's disease (AD) has been revealed by microarray analyses of autopsied brains from the Japanese general population (the Hisayama study). In this study, we compared the expression patterns of AEBP1 in normal and AD brains, including in the hippocampus, using immunohistochemistry. The subjects were 24 AD cases and 52 non-AD cases. Brain specimens were immunostained with antibodies against AEBP1, tau protein, amyloid β protein, NF-κB, GFAP and Iba-1. In normal brains, AEBP1 immunoreactivity mainly localized to the perikarya of hippocampal pyramidal neurons, and its expression was elevated in the pyramidal neurons and some astrocytes in AD hippocampi. Although AEBP1 immunoreactivity was almost absent in neurons containing neurofibrillary tangles, AEBP1 was highly expressed in neurons with pretangles and in the tau-immunopositive, dystrophic neurites of senile plaques. Nuclear localization of NF-κB was also observed in certain AEBP1-positive neurons in AD cases. Comparison of AD and non-AD cases suggested a positive correlation between the expression level of AEBP1 and the degree of amyloid β pathology. These findings imply that AEBP1 protein has a role in the progression of AD pathology..
8. Hiroyuki Honda, Matsuzono K, Fushimi S, Sato K, Satoshi O Suzuki, Abe K, Toru Iwaki, C-Terminal-Deleted Prion Protein Fragment Is a Major Accumulated Component of Systemic PrP Deposits in Hereditary Prion Disease With a 2-Bp (CT) Deletion in PRNP Codon 178, J Neuropathol Exp Neurol, 10.1093/jnen/nlw077, 75, 11, 1008-1019, 2016.11, Prion protein (PrP) has 2 glycosylated sites and a glycosylphosphatidylinositol (GPI) anchor on the C-terminal. Reports on genetic prion disease with GPI anchorless PrP are very limited. In this study, we characterized the molecular alterations of mutated PrP in a 37-year-old female autopsy case with a recently identified PRNP mutation involving a 2-bp deletion in codon 178 that results in a premature stop codon mutation in codon 203. Postmortem examination revealed numerous irregularly shaped coarse PrP deposits and multicentric plaques in the brain that were mainly comprised of C-terminal deleted abnormal PrP primarily derived from the mutant allele. Additionally, abnormal PrP deposits were detected in almost all other examined organs. PrP was mainly deposited in peripheral nerves, smooth muscles, and blood vessels in non-CNS tissues. Western blot analysis after proteinase K treatment showed protease-resistant PrP (PrPres) signals with a molecular weight of 9 kDa; weak PrPres smear signals of 9 to ∼80 kDa were also noted. Gel filtration revealed that PrPres oligomers were mainly composed of the PrP fragments. In conclusion, the mutated PrP lacking that GPI anchor was truncated shortly and deposited in almost every examined organ..
9. Hiroyuki Honda, Kensuke Sasaki, Hideomi Hamasaki, Masahiro Shijo, Sachiko Koyama, Tomoyuki Ohara, Toshiharu Ninomiya, Yutaka Kiyohara, Satoshi O Suzuki, Toru Iwaki, Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study, Neuropathology, 10.1111/neup.12298, 36, 4, 383-387, 2016.08, We investigated the trends in dementia over the past 29 years in the town of Hisayama, Japan using 1266 autopsy specimens. The Hisayama study is a prospective cohort study of lifestyle-related diseases that was started in 1961. Clinical examination of dementia was started in 1985 with five detailed cross-sectional assessments conducted in 1985, 1992, 1998, 2005 and 2012. To examine the trends in dementia, we divided the 1266 autopsy samples into five groups according to the year of death: I (1986-1991, 257 cases), II (1992-1997, 268 cases), III (1998-2004, 318 cases), IV (2005-2011, 296 cases) and V (2012-2014, 127 cases). The prevalence of all-cause dementia significantly increased over time (28.4% in group I, 22.4% in group II, 32.1% in group III, 30.1% in group IV, 51.2% in group V; P for trend <0.001). A similar trend was observed for Alzheimer's disease (AD) (15.2%, 11.9%, 17.3%, 20.6% and 33.1%, respectively; P for trend <0.001). A significant increasing trend was observed in both men and women. A rapid increase in senile dementia of the NFT type (SD-NFT) in recent years was notable. Vascular dementia was the most common type of dementia in men prior to 2004; however, its prevalence decreased over time. Our study revealed that tauopathies, including AD and SD-NFT, significantly increased in the aged Japanese population over the course of this study. The neuritic plaque pathology of AD was associated with metabolic disorders such as insulin resistance and abnormal lipid metabolism, whereas the risk factors for tau pathology remain unclear. Although aging is considered one of the important risk factors accelerating tau pathology, there could be other risk factors associated with lifestyle diseases..
10. ABOLHASSANI NONA, Julio Leon, 岡 素雅子, Hideomi Hamasaki, Toru Iwaki, Yusaku Nakabeppu, Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain, Mech Ageing Dev., 10.1016/j.mad.2016.05.005, 2016.05, In normal brain, neurons in the cortex and hippocampus produce insulin, which modulates glucose metabolism and cognitive functions. It has been shown that insulin resistance impairs glucose metabolism and mitochondrial function, thus increasing production of reactive oxygen species. Recent progress in Alzheimer's disease (AD) research revealed that insulin production and signaling are severely impaired in AD brain, thereby resulting in mitochondrial dysfunction and increased oxidative stress. Among possible oxidative DNA lesions, 8-oxoguanine (8-oxoG) is highly accumulated in the brain of AD patients. Previously we have shown that incorporating 8-oxoG in nuclear and mitochondrial DNA promotes MUTYH (adenine DNA glycosylase) dependent neurodegeneration. Moreover, cortical neurons prepared from MTH1 (8-oxo-dGTPase)/OGG1 (8-oxoG DNA glycosylase)-double deficient adult mouse brains is shown to exhibit significantly poor neuritogenesis in vitro with increased 8-oxoG accumulation in mitochondrial DNA in the absence of antioxidants. Therefore, 8-oxoG can be considered involved in the neurodegenerative process in AD brain. In mild cognitive impairment, mitochondrial dysfunction and oxidative damage may induce synaptic dysfunction due to energy failures in neurons thus resulting in impaired cognitive function. If such abnormality lasts long, it can lead to vicious cycles of oxidative damage, which may then trigger the neurodegenerative process seen in Alzheimer type dementia..
11. Hiroyuki Honda, Hideomi Hamasaki, Tomihiro Wakamiya, Sachiko Koyama, Satoshi O Suzuki, Naoki Fujii, Toru Iwaki, Loss of hnRNPA1 in ALS spinal cord motor neurons with TDP-43-positive inclusions, Neuropathology, 10.1111/neup.12153, 35, 1, 37-43, 2015.02, Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by loss of motor neurons and appearance of skein-like inclusions.The inclusions are composed of trans-activation response (TAR) DNA-binding protein 43 (TDP-43), a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. hnRNPA1 and hnRNPA2/B1 are hnRNPs that interact with the C-terminus of TDP-43. Using immunohistochemistry, we investigated the association between TDP-43 and hnRNPA1 in ALS spinal motor neurons. We examined spinal cords of seven ALS cases and six muscular dystrophy cases (used as controls) for the presence of TDP-43 and hnRNPA1 protein. In the control cases, hnRNPA1 immunoreactivity in motor neurons was intense in the nucleus and weak in the cytoplasm where it showed a fine granular appearance. In the ALS cases, hnRNPA1 immunoreactivity in motor neurons was reduced in the nuclei of neurons with skein-like inclusions but was not detected in the skein-like inclusions. The marked loss of hnRNPA1 in motor neurons with concomitant cytoplasmic aggregation of TDP-43 may represent a severe disturbance of mRNA processing, suggesting a key role in progressive neuronal death in ALS..
12. Tomihiro Wakamiya, Satoshi O Suzuki, Hideomi Hamasaki, Hiroyuki Honda, Masahiro Mizoguchi, Koji Yoshimoto, Toru Iwaki, Elevated expression of fatty acid synthase and nuclear localization of carnitine palmitoyltransferase 1C are common among human gliomas., Neuropathology, 10.1111/neup.12132, 34, 5, 465-474, 2014.10, Fatty acid synthase (FASN) and carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform of the CPT1 family, are upregulated in certain types of cancer including gliomas. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis, and its phosphorylated form inhibits lipid synthesis. We examined the expression and subcellular localization of these fatty acid metabolism-related molecules in human gliomas. We performed immunostaining of two glioma cell lines (U373MG and U87MG) and 41 surgical specimens of diffuse gliomas with various histological grades with the isocitrate dehydrogenase 1(IDH1) R132H mutation and 20 without the mutation]. In the cultured glioma cells, CPT1C and phosphorylated ACC (p-ACC) were mainly localized to the nuclei, whereas FASN localized to the cytoplasm. In the surgical specimens, most glioma tissues showed nuclear staining for CPT1C and p-ACC, and cytoplasmic staining for FASN, regardless of the genetic status of IDH1 and the histological grade. Therefore, elevated cytoplasmic expression of FASN and nuclear localization of CPT1C are common among human diffuse gliomas, which may be regulated by the differential phosphorylation status of ACC in the cellular compartment..
13. Hideomi Hamasaki, Hiroyuki Honda, Satoshi O Suzuki, Masaaki Hokama, Yutaka Kiyohara, Yusaku Nakabeppu, Toru Iwaki, Down-regulation of MET in hippocampal neurons of Alzheimer's disease brains., Neuropathology, 10.1111/neup.12095, 34, 3, 284-290, 2014.06, We found that mRNA of MET, the receptor of hepatocyte growth factor (HGF), is significantly decreased in the hippocampus of Alzheimer’s disease (AD) patients. Therefore, we tried to determine the cellular componentdependent changes of MET expressions. In this study, we examined cellular distribution of MET in the cerebral neocortices and hippocampi of 12 AD and 11 normal controls without brain diseases. In normal brains, MET immunoreactivity was observed in the neuronal perikarya and a subpopulation of astrocytes mainly in the subpial layer and white matter. In AD brains, we found marked decline of MET in hippocampal pyramidal neurons and granule cells of dentate gyrus. The decline was more obvious in the pyramidal neurons of the hippocampi than that in the neocortical neurons. In addition, we found strong MET immunostaining in reactive astrocytes, including those near senile plaques. Given the neurotrophic effects of the HGF/MET pathway, this decline may adversely affect neuronal survival in AD cases. Because it has been reported that HGF is also up-regulated around senile plaques, β-amyloid deposition might be associated with astrocytosis through the HGF signaling pathway..
14. Shibano S, Sasaki K, Kidoaki S, Iwaki T., Detection of prion protein oligomers by single molecule fluorescence imaging., Neuropathology, 10.1111/j.1440-1789.2012.01316.x., 33, 1, 1-6, 2012 Apr 27 [Epub ahead of print], 2013.02, The degree of polymerization of PrP has a close relationship with the pathological mechanisms of prion diseases. We examined, at the molecular level, the polymerization state of PrP in lysates of prion-infected cells using total internal reflection fluorescence microscopy (TIRFM). The crude lysates were fractionated by gel-filtration spin columns according to their molecular size. Both the oligomer-rich and the monomer-rich fractions were probed with fluorescein-labeled anti-PrP antibodies (mAb SAF70 and mAb 8G8). Fluorescent spots of varying intensity were detected, with the ratio of intense fluorescent spots being greater in the oligomer fraction samples with mAb SAF70 than those with 8G8, the specific epitope of which is thought to be buried in abnormal PrP molecules. The results indicated that PrP oligomers could be specifically detected and conformational changes of abnormal PrP molecules observed. Imaging by TIRFM may aid in determining the polymerization state and properties of PrP oligomers in pathological processes..
15. Honda H, Sasaki K, Minaki H, Masui K, Suzuki SO, Doh-Ura K, Iwaki T, Protease-resistant PrP and PrP oligomers in the brain in human prion diseases after intraventricular pentosan polysulfate infusion., Neuropathology, 10.1111/j.1440-1789.2011.01245.x., 32, 2, 124-132, Epub 2011 Aug 1, 2012.04, Intraventricular infusion of pentosan polysulfate (PPS) as a treatment for various human prion diseases has been applied in Japan. To evaluate the influence of PPS treatment we performed pathological examination and biochemical analyses of PrP molecules in autopsied brains treated with PPS (one case of sporadic Creutzfeldt-Jakob disease (sCJD, case 1), two cases of dura mater graft-associated CJD (dCJD, cases 2 and 4), and one case of Gerstmann-Sträussler-Scheinker disease (GSS, case 3). Six cases of sCJD without PPS treatment were examined for comparison. Protease-resistant PrP (PrP(res) ) in the frontal lobe was evaluated by Western blotting after proteinase K digestion. Further, the degree of polymerization of PrP molecules was examined by the size-exclusion gel chromatography assay. PPS infusions were started 3-10 months after disease onset, but the treatment did not achieve any clinical improvements. Postmortem examinations of the treated cases revealed symmetrical brain lesions, including neuronal loss, spongiform change and gliosis. Noteworthy was GFAP in the cortical astrocytes reduced in all treated cases despite astrogliosis. Immunohistochemistry for PrP revealed abnormal synaptic deposits in all treated cases and further plaque-type PrP deposition in case 3 of GSS and case 4 of dCJD. Western blotting showed relatively low ratios of PrP(res) in case 2 of dCJD and case 3 of GSS, while in the treated sCJD (case 1), the ratio of PrP(res) was comparable with untreated cases. The indices of oligomeric PrP were reduced in one sCJD (case 1) and one dCJD (case 2). Although intraventricular PPS infusion might modify the accumulation of PrP oligomers in the brains of patients with prion diseases, the therapeutic effects are still uncertain..
16. Harada S, Suzuki SO, Seki Y, Nakamura S, Iwaki T, Differential activation of proapoptotic molecules between mouse and rat models of distal motor trigeminal denervation., J. Oral Pathol. Med., 10.1111/j.1600-0714.2011.01109.x, 41, 4, 354-360, Epub 2011 Nov 16., 2012.04, Background:  We previously developed a rat trigeminal motor neuron axotomy model involving masseter and temporal muscle resection to study pathological changes of the central nucleus after peripheral nerve injury caused by oral surgery. Because motor neurons are reported to be more vulnerable to axotomy in mice than rats, we compared the degeneration process of the trigeminal motor nucleus in the rat model with a similar mouse model. Methods:  We removed masseter and temporal muscles of adult mice or rats. Animals were sacrificed at 3, 7, 14, 28, 42, and 56 days post-operation, and the trigeminal motor nuclei were histologically analyzed. Results:  Size reduction, but no neuronal loss, was seen in the trigeminal motor nuclei in both mice and rats. Time-dependent Noxa expression, starting at 1 week post-operation (wpo), was seen in the mouse model. By 8 wpo, mice expressed a higher level of Noxa than rats. Additionally, we noted persistent expression of cleaved caspase-3 in mice but not in rats. Conversely, apoptosis-inducing factor (AIF), which executes DNA fragmentation in the nucleus, was not translocated to the nucleus in either model. Conclusions:  Our findings indicate differential activation of motor neuron apoptosis pathways after axotomy in mice and rats. Lack of activation of caspase-independent pathways and distal end denervation in our model might be related to the survival of motor neurons after axonal injury. These findings could be relevant to future neuroprotective strategies for peripheral nerve injury caused by oral surgeries..
17. Suzuki SO, Iwaki T, Arakawa K, Furuya H, Fujii N, Iwaki A., An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene., Acta Neuropathol., 10.1007/s00401-011-0916-x, 122, 6, 775-781, Epub 2011 Nov 20., 2011.12, We report an autopsy case of rare adult-onset spastic paraplegia type 2 (SPG2) with a novel missense mutation in exon 7 of the proteolipid protein 1 gene (PLP1). The patient was a 67-year-old man whose elder brother had died of a similar disease with onset in his 40s. Thirty-three years before death at the age of 35, he noticed difficulty in walking. He gradually became abasic over a period of 6 years. He also developed progressive dementia and eventually became bed-ridden by 28 years after onset. At autopsy, gross inspection revealed diffuse, moderate atrophy of the cerebrum with a dilated ventricular system and softening of the white matter throughout the central nervous system (CNS). Histopathologically, the CNS showed widespread myelin pallor in the white matter. By contrast, the gray matter and peripheral nerves were well preserved. Some white matter tracts, including the corticospinal tracts, were preferentially affected, and severe axonal degeneration was observed in these tracts. Genetic analysis revealed a novel mutation, p.Tyr263Cys, in exon 7 of PLP1. This case represents an adult-onset SPG2 patient with one of the oldest ages of onset reported to date. The late onset and long clinical course suggest that this novel mutation does not affect the maturation of oligodendrocytes, but is related to insufficient maintenance of myelin..
18. Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, Kanba S, Kiyohara Y, Glucose tolerance status and risk of dementia in the community: the Hisayama Study., Neurology, 10.1212/WNL.0b013e31822f0435, 77, 12, 1126-1134, 2011.09, OBJECTIVE: We investigated the association between glucose tolerance status defined by a 75-g oral glucose tolerance test (OGTT) and the development of dementia.
METHODS: A total of 1,017 community-dwelling dementia-free subjects aged ≥60 years who underwent the OGTT were followed up for 15 years. Outcome measure was clinically diagnosed dementia.
RESULTS: The age- and sex-adjusted incidence of all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD) were significantly higher in subjects with diabetes than in those with normal glucose tolerance. These associations remained robust even after adjustment for confounding factors for all-cause dementia and AD, but not for VaD (all-cause dementia: adjusted hazard ratio [HR] = 1.74, 95% confidence interval [CI] = 1.19 to 2.53, p = 0.004; AD: adjusted HR = 2.05, 95% CI = 1.18 to 3.57, p = 0.01; VaD: adjusted HR = 1.82, 95% CI = 0.89 to 3.71, p = 0.09). Moreover, the risks of developing all-cause dementia, AD, and VaD significantly increased with elevated 2-hour postload glucose (PG) levels even after adjustment for covariates, but no such associations were observed for fasting plasma glucose (FPG) levels: compared with those with 2-hour PG levels of <6.7 mmol/L, the multivariable-adjusted HRs of all-cause dementia and AD significantly increased in subjects with 2-hour PG levels of 7.8 to 11.0 mmol/L or over, and the risk of VaD was significantly higher in subjects with levels of ≥11.1 mmol/L.
CONCLUSIONS: Our findings suggest that diabetes is a significant risk factor for all-cause dementia, AD, and probably VaD. Moreover, 2-hour PG levels, but not FPG levels, are closely associated with increased risk of all-cause dementia, AD, and VaD..
19. Matsuzaki T, Sasaki K, Hata J, Hirakawa Y, Fujimi K, Ninomiya T, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T, Association of Alzheimer's disease pathology with abnormal lipid metabolism: the Hisayama Study., Neurology, 10.1212/WNL.0b013e31822e145d, 77, 11, 1068-1075, Comment in Neurology. 2012 Jan 10;78(2):151; author reply 151-2. , 2011.09, OBJECTIVE: The relationship between lipid profiles and Alzheimer disease (AD) pathology at the population level is unclear. We searched for evidence of AD-related pathologic risk of abnormal lipid metabolism.
METHODS: This study included brain specimens from a series of 147 autopsies performed between 1998 and 2003 of residents in Hisayama town, Japan (76 men and 71 women), who underwent clinical examinations in 1988. Lipid profiles, such as total cholesterol (TC), triglycerides, and high-density lipoprotein cholesterol (HDLC), were measured in 1988. Low-density lipoprotein cholesterol (LDLC) was calculated using the Friedewald formula. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines (CERAD) and neurofibrillary tangles (NFTs) were assessed according to Braak stage. Associations between each lipid profile and AD pathology were examined by analysis of covariance and logistic regression analyses.
RESULTS: Adjusted means of TC, LDLC, TC/HDLC, LDLC/HDLC, and non-HDLC (defined as TC-HDLC) were significantly higher in subjects with NPs, even in sparse to moderate stages (CERAD = 1 or 2), compared to subjects without NPs in multivariate models including APOE ε4 carrier and other confounding factors. The subjects in the highest quartiles of these lipid profiles had significantly higher risks of NPs compared to subjects in the lower respective quartiles, which may suggest a threshold effect. Conversely, there was no relationship between any lipid profile and NFTs.
CONCLUSION: The results of this study suggest that dyslipidemia increases the risk of plaque-type pathology..
20. Matsuoka T, Suzuki SO, Suenaga T, Iwaki T, Kira J., Reappraisal of aquaporin-4 astrocytopathy in asian neuromyelitis optica and multiple sclerosis patients., Brain Pathol., 10.1111/j.1750-3639.2011.00475.x., 21, 5, 516-532, Epub 2011 Feb 14., 2011.09, Selective aquaporin-4 (AQP4) loss and vasculocentric complement and immunoglobulin deposition are characteristic of neuromyelitis optica (NMO). We recently reported extensive AQP4 loss in demyelinated and myelinated layers of Baló's lesions without perivascular immunoglobulin and complement deposition. We aimed to reappraise AQP4 expression patterns in NMO and multiple sclerosis (MS). We evaluated AQP4 expression relative to glial fibrillary acidic protein, extent of demyelination, lesion staging (CD68 staining for macrophages), and perivascular deposition of complement and immunoglobulin in 11 cases with NMO and NMO spectrum disorders (NMOSD), five with MS and 30 with other neurological diseases. The lesions were classified as actively demyelinating (n = 66), chronic active (n = 86), chronic inactive (n = 48) and unclassified (n = 12). Six NMO/NMOSD and two MS cases showed preferential AQP4 loss beyond the demyelinated areas, irrespective of lesion staging. Five NMO and three MS cases showed AQP4 preservation even in actively demyelinating lesions, despite grave tissue destruction. Vasculocentric deposition of complement and immunoglobulin was detected only in NMO/NMOSD patients, with less than 30% of actively demyelinating lesions showing AQP4 loss. Our present and previous findings suggest that antibody-independent AQP4 loss can occur in heterogeneous demyelinating conditions, including NMO, Baló's disease and MS..
21. Seki Y, Suzuki SO, Masui K, Harada S, Nakamura S, Kanba S, Iwaki T., A simple and high-yield method for preparation of rat microglial cultures utilizing Aclar plastic film., Neuropathology, 10.1111/j.1440-1789.2010.01163.x., 31, 3, 215-222, Epub 2010 Nov 24., 2011.06.
22. Torisu R, Suzuki SO, Masui K, Yoshimoto K, Mizoguchi M, Hashizume M, Canoll P, Goldman JE, Sasaki T, Iwaki T, Persistent roles of signal transduction of platelet-derived growth factor B in genesis, growth and anaplastic transformation of gliomas in an in vivo serial transplantation model., Brain Tumor Pathol., 10.1007/s10014-010-0006-0, 28, 1, 33-42, 2011.02, We previously reported that retrovirally transduced platelet-derived growth factor-B (PDGFB) in glial progenitors of the rat cerebral white matter, subventricular zone, or brain stem induced malignant brain tumors closely resembling human glioblastoma (GBM). While human GBMs may progress over the period of several months to a few years, prospective, long-term in-vivo observation of histological changes of the tumor tissues is not feasible in these models, because the animals undergo rapid tumor progression and mortality within approximately 1 month. We thus performed successive, long-term in-vivo transplantation of the PDGFB-induced tumor cells into the rat cerebrum. Primary retroviral transduction of PDGFB in the glial progenitors of the rat basal ganglia induced malignant glioma resembling human GBM or anaplastic oligodendroglioma (AOL) consisting of relatively monomorphous tumor cells expressing markers for the oligodendrocyte lineage. In the course of long-term successive transplantation, tumor cells presented pleomorphism as well as focal GFAP expression. This suggests that secondary chromosomal aberration and dysregulation of gene expression following accelerated cell cycle by PDGFB stimulation would induce morphological and immunophenotypic changes in tumor cells. Furthermore, while the primary tumors contained only a minor fraction of proviral GFP-expressing or hemagglutinin-expressing cells, most tumor cells came to express these proviral genes in the course of serial transplantation suggesting a persistent role of PDGFB-expressing cells in maintenance and growth of the tumors. This model would be useful for investigation of the long-term effects of PDGFB stimulation in glioma tissues on anaplastic evolution..
23. Matsuoka T, Suzuki SO, Iwaki T, Tabira T, Ordinario AT, Kira J., Aquaporin-4 astrocytopathy in Baló's disease., Acta Neuropathol., 10.1007/s00401-010-0733-7, 120, 5, 651-660, Epub 2010 Aug 3., 2010.11, Baló's concentric sclerosis (BCS) is considered to be a rare variant of multiple sclerosis and characterized by alternating rings of demyelinated and preserved myelin layers. The mechanism underlying BCS remains to be elucidated. Recently, occurrence of concentric rings of Baló was described in the brainstem of a patient with neuromyelitis optica (NMO). Because selective loss of aquaporin-4 (AQP4) and vasculocentric deposition of complement and immunoglobulins are characteristic in NMO, we aimed to assess AQP4 expression in the concentric demyelinating lesions of BCS patients. We evaluated AQP4 expression relative to expression of another astrocytic marker (glial fibrillary acidic protein), the extent of demyelination, lesion staging and perivascular deposition of complement and immunoglobulin in four cases with BCS, and 30 individuals with other neurological diseases. All cases with BCS demonstrated extensive AQP4 loss in both demyelinated and myelinated layers of all actively demyelinating lesions, with perivascular lymphocytic cuffing of T cells, but no deposition of immunoglobulins or complement around vessels. These findings suggest that AQP4 loss occurs in heterogeneous demyelinating conditions, namely NMO and BCS. Furthermore, acute BCS lesions are characterized by extensive AQP4 loss without vasculocentric deposition of complement or immunoglobulin..
24. Matsuzaki T, Sasaki K, Tanizaki Y, Hata J, Fujimi K, Matsui Y, Sekita A, Suzuki SO, Kanba S, Kiyohara Y, Iwaki T, Insulin resistance is associated with the pathology of Alzheimer’s disease: the Hisayama Study., Neurology, 10.1212/WNL.0b013e3181eee25f, 75, 9, 764-770, Epub 2010 Aug 25., 2010.08, タイトル:インスリン抵抗性はアルツハイマー病の脳病理と関連する
Objective: We examined the association between diabetes-related factors and pathology of Alzheimer disease (AD) to evaluate how diabetes affects the pathogenic process of AD.
Methods: This study included specimens from a series of 135 autopsies of residents of the town of Hisayama in Fukuoka prefecture (74 men and 61 women) performed between 1998 and 2003, who underwent a 75-g oral glucose tolerance test in clinical examinations in 1988. We measured diabetes-related factors including fasting glucose, 2-hour post-load plasma glucose, fasting insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) in 1988. Neuritic plaques (NPs) were assessed according to the Consortium to Establish a Registry for Alzheimer's Disease guidelines and neurofibrillary tangles (NFTs) were assessed according to Braak stage. The associations between each factor and AD pathology were examined by analysis of covariance and logistic regression analyses.
Results: Higher levels of 2-hour post-load plasma glucose, fasting insulin, and HOMA-IR were associated with increased risk for NPs after adjustment for age, sex, systolic blood pressure, total cholesterol, body mass index, habitual smoking, regular exercise, and cerebrovascular disease. However, there were no relationships between diabetes-related factors and NFTs. Regarding the effects of APOE genotype on the risk of AD pathology, the coexistence of hyperglycemia and APOE epsilon 4 increased the risk for NP formation. A similar enhancement was observed for hyperinsulinemia and high HOMA-IR.
Conclusion: The results of this study suggest that hyperinsulinemia and hyperglycemia caused by insulin resistance accelerate NP formation in combination with the effects of APOE epsilon 4..
25. Masui K, Suzuki SO, Torisu R, Goldman JE, Canoll P, Iwaki T., Glial progenitors in the brainstem give rise to malignant gliomas by platelet-derived growth factor stimulation., Glia, 10.1002/glia.20986, 58, 9, 1050-1065, Published online 29 March 2010, 2010.07, Glial progenitors in the white matter and the subventricular zone are the major population of cycling cells in the postnatal central nervous system, and thought to be candidates for glioma-initiating cells. However, less is known about the dividing cell populations in the brainstem than those in the cerebrum, leading to the lag of basic understanding of brainstem gliomas. We herein demonstrate much fewer cycling glial progenitors exist in the brainstem than in the cerebrum. We also show that infecting brainstem glial progenitors with PDGFB-green fluorescent protein (GFP)-expressing retrovirus induced tumors that closely resembled human malignant gliomas. Of note, brainstem tumors grew more slowly than cerebral tumors induced by the same retrovirus, and >80% tumor cells in the brainstem consisted of GFP-positive, infected progenitors while GFP-positive cells in the cerebral tumors were <20%. These indicate that cerebral tumors progressed rapidly by recruiting resident progenitors via paracrine mechanism whereas brainstem tumors grew more slowly by clonal expansion of the infected population. The cerebral and brainstem glial progenitors similarly showed reversible dedifferentiation upon PDGF stimulation in vitro and did not show the intrinsic difference in terms of the responsiveness to PDGF. We therefore suggest that slower, monoclonal progression pattern of the brainstem tumors is at least partly due to the environmental factors including the cell density of the glial progenitors. Together, these findings are the first implications regarding the cell-of-origin and the gliomagenesis in the brainstem..
26. Tateishi T, Hokonohara T, Yamasaki R, Miura S, Kikuchi H, Iwaki A, Tashiro H, Furuya H, Nagara Y, Ohyagi Y, Nukina N, Iwaki T, Fukumaki Y, Kira J. I., Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation., Acta Neuropathol., DOI 10.1007/s00401-009-0621-1, 119, 3, 355-364, 2010.03, Mutations in the fused in sarcoma gene (FUS) were recently found in patients with familial amyotrophic lateral sclerosis (ALS). The present study aimed to clarify unique features of familial ALS caused by FUS mutation in the Japanese population. We carried out clinical, neuropathological, and genetic studies on a large Japanese pedigree with familial ALS. In six successive generations of this family, 16 individuals of both sexes were affected by progressive muscle atrophy and weakness, indicating an autosomal dominant trait. Neurological examination of six patients revealed an age at onset of 48.2 +/- A 8.1 years in fourth generation patients, while it was 31 and 20 years in fifth and sixth generation patients, respectively. Motor paralysis progressed rapidly in these patients, culminating in respiratory failure within 1 year. The missense mutation c.1561 C > T (p.R521C) was found in exon 15 of FUS in the four patients examined. Neuropathological study of one autopsied case with the FUS mutation revealed multiple system degeneration in addition to upper and lower motor neuron involvement: the globus pallidus, thalamus, substantia nigra, cerebellum, inferior olivary nucleus, solitary nucleus, intermediolateral horn, Clarke's column, Onuf's nucleus, central tegmental tract, medial lemniscus, medial longitudinal fasciculus, superior cerebellar peduncle, posterior column, and spinocerebellar tract were all degenerated. Argyrophilic and basophilic neuronal or glial cytoplasmic inclusions immunoreactive for FUS, GRP78/BiP, p62, and ubiquitin were detected in affected lesions. The FUS R521C mutation in this Japanese family caused familial ALS with pathological features of multiple system degeneration and neuronal basophilic inclusions..
27. Seki Y, Suzuki SO, Nakamura S, Iwaki T., Degenerative and protective reactions of the rat trigeminal motor nucleus after removal of the masseter and temporal muscles., J. Oral Pathol. Med., 38, 10, 777-784, 38(10): 777-784, 2009.11.
28. Sasaki K, Minaki H, Iwaki T, Development of oligomeric prion-protein aggregates in a mouse model of prion disease., J. Pathol., 219, 1, 123-130, 219(1): 123-130, 2009.09.
29. Fujimi K, Sasaki K, Noda K, Wakisaka Y, Tanizaki Y, Matsui Y, Sekita A, Iida M, Kiyohara Y, Kanba S, Iwaki T., Clinicopathological outline of dementia with Lewy bodies applying the revised criteria: The Hisayama study., Brain Pathol., 18, 3, 317-325, 18 (3): 317–325, 2008.07, [URL].
30. Noda K. Sasaki K. Fujimi K. Wakisaka Y. Tanizaki Y. Wakugawa Y. Kiyohara Y. Iida M. Aizawa H. Iwaki T., Quantitative analysis of neurofibrillary pathology in a general population to reappraise neuropathological criteria for senile dementia of the neurofibrillary tangle type(tangle-only dementia):The Hisayama study., Neuropathology, 10.1111/j.1440-1789.2006.00722.x, 26, 6, 508-518, 2006.12.
31. Sasaki K, Doh-ura K, Ironside JW, Mabbott N, Iwaki T., Clusterin expression in follicular dendritic cells associated with prion protein accumulation., J. Pathol., 10.1002/path.2009, 209, 4, 484-491, 2006.08.
32. Sasaki K, Doh-ura K, Wakisaka Y, Tomoda H, Iwaki T, Fatal familial insomnia with an unusual prion protein deposition pattern: An autopsy report with an experimental transmission study., Neuropathol. Appl. Neurobiol., 10.1111/j.1365-2990.2004.00592.x, 31, 1, 80-87, 2005.02.
33. Doh-ura K, Ishikawa K, Murakami-Kubo I, Sasaki K, Mohri S, Race R, Iwaki T, Treatment of transmissible spongiform encehalopathy by intraventricular drug infusion in animal models, J. Virol., 10.1128/JVI.78.10.4999-5006.2004, 78, 10, 4999-5006, 2004.05.
34. Murakami-Kubo I, Doh-ura K, Ishikawa K, Kawatake S, Sasaki K, Kira J, Ohta S, Iwaki T, Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies, J. Virol., 10.1128/JVI.78.3.1281-1288.2004, 78, 3, 1281-1288, 2004.02.
35. Wakisaka Y, Furuta A, Masuda K, Morikawa W, Kuwano M, Iwaki T, Cellular distribution of NDRG1 protein in the rat kidney and brain during normal postnatal development, J. Histochem. Cytochem., 51, 11, 1515-1525, 2003.11.
36. Wakisaka Y, Furuta A, Tanizaki Y, Kiyohara Y, Iida M, Iwaki T, Age-associated prevalence and risk factors of Lewy body pathology in a general population: the Hisayama study, Acta Neuropathol., 10.1007/s00401-003-0750-x, 106, 4, 374-382, 2003.10, In dementia with Lewy bodies (DLB), the Lewy bodies (LBs) are an essential substrate. Although LB pathology has gained increasing attention as one of the major causes of dementia, little is known about the exact prevalence of LB pathology in the general population. In addition, the pathology of Alzheimer-type dementia (ATD) is frequently associated with DLB. To investigate the prevalence of LB pathology in a community-based population and to evaluate the relationship between LB and ATD pathology, we performed an analysis of 102 consecutive autopsy cases. The survey extended over 2.5 years and autopsy rate was 70.5%. LB pathology was detected using alpha-synuclein immunohistochemistry and was assessed based on consensus guidelines for DLB. ATD pathology was evaluated by both CERAD and NIA-RI criteria. Twenty-nine subjects were clinically demented. LB pathology was present in 23 (22.5%) of 102 cases, and in 12 (41.4%) of the demented subjects. The LB score was not significantly different between DLB cases and non-demented subjects with LB pathology (nd-LB), while the Braak stages were significantly different between the two groups. Prevalence of LB pathology constantly increased with age. DLB cases accompanying severe ATD pathology showed more rapid increase of LB scores than did DLB cases without severe ATD pathology. Moreover, DLB cases with severe ATD pathology had poorer prognoses than those without severe ATD pathology. Our results suggested that aging and severe ATD pathology have a strong effect on the evolution of LB pathology..
37. Furuta A, Noda M, Suzuki SO, Goto Y, Kanahori Y, Rothstein JD, Iwaki T, Translocation of glutamate transporter subtype excitatory amino acid carrier 1 protein in kainic acid-induced rat epilepsy, Am. J. Pathol., 10.1016/S0002-9440(10)63705-4, 163, 2, 779-787, 2003.08.
38. Osoegawa M. Ochi H. Kikuchi H. Shirabe S. Nagashima T. Tsumoto T. Tamura Y. Yamabe K. Takahashi H. Iwaki T. Kira J., Eosinophilic myelitis associated with atopic diathesis: a combined neuroimaging and histopathological study., Acta Neuropathologica, 10.1007/s00401-002-0645-2, 105, 3, 289-295, 105(3):289-295, 2003.03.
39. Kawashima M. Doh-ura K. Mekada E. Fukui M. Iwaki T., CD9 expression in solid non-neuroepithelial tumors and infiltrative astrocytic tumors., Journal of Histochemistry & Cytochemistry, 50, 9, 1195-1203, 50(9):1195-1203, 2002.09.
40. Nomura H. Furuta A. Iwaki T., Dorsal root rupture injury induces extension of astrocytic processes into the peripheral nervous system and expression of GDNF in astrocytes., Brain Research, 10.1016/S0006-8993(02)02982-7, 950, 1-2, 21-30, 950(1-2):21-30, 2002.09.
41. Sasaki K. Doh-ura K. Wakisaka Y. Iwaki T., Clusterin/apolipoprotein J is associated with cortical Lewy bodies: immunohistochemical study in cases with alpha-synucleinopathies., Acta Neuropathol., 10.1007/s00401-002-0546-4, 104, 3, 225-230, 104(3):225-230, 2002.09.
42. Takao T, Iwaki T., A comparative study of localization of heat shock protein 27 and heat shock protein 72 in the developmental and degenerative intervertebral discs., Spine, 10.1097/00007632-200202150-00007, 27, 4, 361-367, 27:361-368, 2002.01.
43. Sasaki K, Doh-ura K, Ironside WJ, Iwaki T., Increased clusterin (apolipoprotein J) expression in human and mouse brains infected with transmissible spongiform encephalopathies., Acta Neuropathol, 10.1007/s004010100456, 103, 3, 199-208, 103:199-208, 2002.01.
44. Furuta A, Iida T, Nakabeppu Y, Iwaki T., Expression of hMTHI in the hippocampi of control and Alzheimer's disease., NeuroReport, 10.1097/00001756-200109170-00028, 12, 13, 2895-2899, 12:2895-2899, 2001.01.
45. Nomura H, Furuta A, Suzuki OS, Iwaki T., Dorsal horn lesion resulting from spinal root avulsion leads to the accumulation of stress-responsive proteins, Brain Res., 10.1016/S0006-8993(00)03291-1, 893, 1-2, 84-94, 893:84-94, 2001.01.
46. Fujii N, Furuta A, Yamaguchi H, Nakanishi K, Iwaki T., Limbic encephalitis associated with recurrent thymoma: A postmortem study, Neurology, 57, 2, 344-347, 57:344-347, 2001.01.
47. Fukamachi S, Furuta A, Ikeda T, Ikenoue T, Kaneoka T, Rothstein J.D., Iwaki T., Altered expressions of glutamate transporter subtypes in rat model of neonatal cerebral hypoxia-ischemia, Dev Brain Res, 10.1016/S0165-3806(01)00303-0, 132, 2, 131-139, 132:131-139, 2001.01.
48. Tsuruta Y, Furuta A, Furuta K, Yamada T, Kira J, Iwaki T., Expression of the lysosome-associated membrane proteins in myopathies with rimmed vacuoles., Acta Neuropathol., 101, 6, 579-584, 101:579-584, 2001.01.
49. Suzuki O.S., Iwaki T, Amplification and overexpression of mdm2 gene in ependymomas, Mod. Pathol., 10.1038/modpathol.3880095, 13, 5, 548-553, 13: 548-553, 2000.01.
50. Doh-ura K., Iwaki T., Caughey B, Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation, J. Virol., 10.1128/JVI.74.10.4894-4897.2000, 74, 10, 4894-4897, 74: 4894-4897, 2000.01.
51. Suzuki T., Nishiyama K., Yamamoto A., Inazawa J., Iwaki T., Yamada T., Kanazawa I., Sakaki Y, Molecular cloning of a novel apoptosis-related gene, human Nap1 (NCKAP1 ), and its possible relation to Alzheimer disease, Genomics, 10.1006/geno.1999.6053, 63, 2, 246-254, 63: 246-254, 2000.01.
52. Suzuki O.S., Iwaki T, Non-isotopic in situ hybridization of CD44 transcript in formalin-fixed paraffin-embedded sections, Brain Res. Protocols, 10.1016/S1385-299X(98)00058-0, 4, 1, 29-35, 4: 29-35, 1999.01.
53. Hitotsumatsu T, Iwaki T, Kitamoto T, Mizoguchi M, Suzuki SO, Hamada Y, Fukui M, Tateishi J, Expression of neurofibromatosis 2 protein in human brain tumors: an immunohistochemical study., Acta Neuropathol., 93, 3, 225-232, 1997.03, The neurofibromatosis 2 (NF2) gene-encoded protein, named merlin, may function as a molecular linkage connecting cytoskeleton and plasma membrane. Merlin is thought to play a crucial role as a tumor suppressor not only in hereditary NF2-related tumors, but also in sporadic tumors such as schwannomas, meningiomas and gliomas. Using a merlin-expression vector system, we raised specific antiserum against merlin. We observed the intracellular distribution of merlin in cultured glioma cells, and further investigated merlin expression in 116 human brain tumors. Immunofluorescence microscopy revealed that merlin was localized beneath the cell membrane and concentrated at cell-to-cell adhesion sites, where actin filaments are densely associated with plasma membrane. By immunohistochemistry, none of the schwannomas from either NF2 patients or sporadic cases showed any immunoreactivity, while normal Schwann cells of cranial nerves were immunopositive. In meningiomas, merlin expression was frequently seen in the meningothelial subtype (8/10, 80%), but no expression could be detected in either the fibrous or the transitional variant. Most normal astrocytes were negative; however, reactive astrocytes often expressed merlin. Glioblastomas and anaplastic astrocytomas were found to be strongly positive, and focal positive staining was observed in fibrillary and pilocytic astrocytomas. Thus, the loss of merlin appears to be integral to schwannoma formation and the differential pathogenesis of meningioma subtypes. However, merlin alterations do not appear to play a critical role in either the tumorigenesis or malignant transformation of neoplastic astrocytes..
54. Kawashima T, Furukawa H, Doh-ura K, Iwaki T, Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy., Lancet, 10.1016/S0140-6736(05)66274-5, 350, 9070, 68-69, 350: 68-69, 1997.01.
55. Iwaki A, Nagano T, Nakagawa M, Iwaki T, Fukumaki Y, Identification and characterization of the gene encoding a new member of the alpha-crystallin/small hsp family, closely linked to the alphaB-crystallin gene in a head-to-head manner., Genomics, 10.1006/geno.1997.4956, 45, 2, 386-394, 45: 386-394, 1997.01.
56. Suzuki SO, Mizoguchi M, Iwaki T, Detection of SV40 T antigen genome in human gliomas., Brain Tumor Pathol., 14: 125-129, 1997.01.
57. Suzuki SO, Iwaki T, Kitamoto T, Fukui M, Tateishi J, Differential expression of CD44 variants among meningioma subtypes., J. Clin. Pathol: Clin. Mol. Pathol., 49, 3, M140-M146, 49: M140-M146, 1996., 1996.01.
58. Hitotsumatsu T, Iwaki T, Fukui, M, Tateishi J, Distinctive immunohistochemical profiles of small heat shock proteins (heat shock protein 27 and alphaB-crystallin) in human brain tumors., Cancer, 10.1002/(SICI)1097-0142(19960115)77:2<352::AID-CNCR19>3.0.CO;2-0, 77, 2, 352-361, 77: 352-361, 1996.01.
59. Kegel KB, Iwaki A, Iwaki T, Goldman JE, alphaB-crystallin protects glial cells from hypertonic stress., Am. J. Physiol. Cell Physiol., 270, 3, C903-C909, 39(3): C903-C909, 1996.01.
60. Enjoji M, Iwaki T, Nawata H, Watanabe T, IgH intronic enhancer element HE2 (muB) functions as a cis-activator in choroid plexus cells at the cellular level as well as in transgenic mice., J. Neurochem., 64, 3, 961-966, 64: 961-966, 1995.01.
61. Iwaki T, Iwaki A, Fukumaki Y, Tateishi J, alphaB-crystallin in C6 glioma cells supports their survival in elevated extracellula K+: the implication of protective role of alphaB-crystallin accumulation in reactive glia., Brain Res., 10.1016/0006-8993(94)01393-V, 673, 1, 47-52, 673: 47-52, 1995.01.
62. Iwaki T, Miyazono M, Hitotsumatsu T, Tateishi J, An immunohistochemical study of tissue transglutaminase in gliomas with reference to their cell dying processes., Am. J. Pathol., 145, 4, 776-781, 1994.10, Tissue transglutaminase is a Ca2+-dependent enzyme that catalyzes the formation of protein cross-links by an acyl transfer reaction. Recent reports have suggested that tissue transglutaminase is induced by tumor progression and apoptosis. In this study we immunohistochemically investigated a series of gliomas by using an antiserum against a dodecapeptide from the COOH-terminal of tissue transglutaminase. Among the gliomas the presence of positive immunoreactivity tended to increase in malignant counterparts. It is also noteworthy to mention that glioblastoma cells surrounding the zonal necrosis in a palisade fashion were strongly immunolabeled The degenerating products in tumor cells, such as round granulated bodies, were primarily immunopositive, whereas Rosenthal fibers were negative. Dying cells through apoptosis in the metastatic brain tumors could be easily recognized by the presence of tissue transglutaminase. In conclusion, tissue transglutaminase may therefore be valuable in the prognostic characterization of gliomas with respect to the detection of dying cells. However, the appearance of tissue transglutaminase-positive neoplastic cells tons not limited to apoptotic bodies but could also be detected in necrobiotic cell nests..
63. Hara H, Morita M, Iwaki T, Hatae T, Itoyama Y, Kitamoto T, Akizuki S, Goto I, Watanabe T, Detection of human T lymphotrophic virus type I (HTLV-I) proviral DNA and analysis of T cell receptor Vb CDR3 sequences in spinal cord lesions of HTLV-I-associated myelopathy/tropical spastic paraparesis., J. Exp. Med., 10.1084/jem.180.3.831, 180, 3, 831-839, 180: 831-839, 1994.01.
64. Iwaki T, Iwaki A, Tateishi J, Goldman JE, Sense and antisense modification of glial alphaB-crystallin production results in alterations of stress fiber formation and thermoresistance., J. Cell Biol., 10.1083/jcb.125.6.1385, 125, 6, 1385-1393, 125:1385-1393, 1994.01.
65. Ohta M, Iwaki T, Kitamoto T, Takeshita I, Fukui M, Tateishi J, MIB1 staining index and scoring of histological features in meningioma., Cancer., 10.1002/1097-0142(19941215)74:12<3176::AID-CNCR2820741217>3.0.CO;2-N, 74, 12, 3176-3189, 74: 3176-3189, 1994.01.
66. Iwaki T, Iwaki A, Goldman JE, alphaB-crystallin in oxidative muscle fibers and its accumulation in ragged-red fibers: a comparative immunohistochemical and histochemical study in human skeletal muscle., Acta Neuropathol., 85, 5, 475-480, 1993.04, The alphaB-crystallin gene is abundantly expressed in the vertebrate lens and at lower levels in various non-lenticular tissues. Among the non-lenticular tissues, alphaB-crystallin is present at high levels in the heart and skeletal muscle. Using a specific antibody against alphaB-crystallin, the cellular localization of alphaB-crystallin was studied in biopsies of human skeletal muscles. Expression of alphaB-crystallin was observed in normal oxidative muscle fibers that show positive reactions for NADH-tetrazolium reductase and cytochrome c oxidase. In muscle diseases increased immunoreactivity for alphaB-crystallin was found in ragged-red fibers, which stained darkly with histochemistry for succinate dehydrogenase. Since alphaB-crystallin is related to small heat-shock proteins and can be induced by various stress conditions, the increased alphaB-crystallin immunoreactivity of ragged-red fibers could result from profound oxidative stress produced by the abnormal mitochondrial metabolism..
67. Iwaki T, Iwaki A, Tateishi J, Sakaki Y, Goldman JE, alphaB-crystallin and 27 kilodalton heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers., Am. J. Pathol., 143, 2, 487-495, 1993.03, To understand the significance of the accumulation of alphaB-crystallin in Rosenthal fibers within astrocytes, the expression and metabolism of alphaB-crystallin in glioma cell lines were examined under the conditions of beat and oxidative stress. alphaB-crystallin mRNA was increased after both stresses, and alphaB-crystallin protein moved from a detergent-soluble to a detergent-insoluble form In addition, Western blotting of Alexander's disease brain homogenates revealed that the 27-kd beat shock protein (HSP27), which is related to alphaB-crystallin, accumulates along with alphaB-crystallin. The presence of HSP27 in Rosenthal fibers was directly demonstrated by immunohistochemistry. Our results suggest that astrocytes in Alexander's disease may be involved in an as yet unknown kind of stress reaction that causes the accumulation of alphaB-crystallin and HSP27 and results in Rosenthal fiber formation..
68. Iwaki A, Muramoto T, Iwaki T, Furumi H, Dario-deLeon ML, Tateishi J, Fukumaki Y, A missense mutation in the proteolipid protein gene responsible for Pelizaeus-Merzbacher disease in a Japanese family., Hum. Mol. Genet., 10.1093/hmg/2.1.19, 2, 1, 19-22, 2:19-22, 1993.01.
69. Iwaki T, Wisniewski T, Iwaki A, Corbin E, Tomokane N, Tateishi J, Goldman JE:, Accumulation of alphaB-crystallin in central nervous system glia and neurons in pathologic conditions., Am. J. Pathol., 140, 2, 345-356, 1992.02.
70. Iwaki A, Iwaki T, Goldman JE, Ogomori K, Tateishi J, Sakaki Y:, Accumulation of alphaB-crystallin in brains of patients with Alexander's disease is not due to an abnormality of the 5'-flanking and coding sequence of the genomic DNA., Neurosci. Lett., 10.1016/0304-3940(92)90689-5, 140, 1, 89-92, 140: 89-92, 1992.01.
71. Shin R-W, Iwaki T, Kitamoto T, Sato Y and Tateishi J, Massive accumulation of modified tau and severe depletion of normal tau characterize the cerebral cortex and white matter of Alzheimer's disease. Demonstration using the hydrated autoclaving method., Am. J. Pathol., 140, 4, 937-945, 140: 937-945, 1992.01.
72. Iwak T, Tateishi J, Immunohistochemical demonstration of alphaB-crystallin in hamartomas of tuberous sclerosis., Am. J. Pathol., 139, 6, 1303-1308, 1991.12, Autopsy material from two individuals with tuberous sclerosis were examined immunohistochemically for the expression of alpha-B-crystallin. Positive immunoreactions were detected in the harmartomas of various organs. Abnormal expression of alpha-B-crystallin in the hamartomas in conjunction with the alpha-B-crystallin gene locus on chromosome 11q22-23 overlapping with one of the candidates of tuberous sclerosis loci suggest that tuberous sclerosis may involve the altered regulation of alpha-B-crystallin gene expression..
73. Iwaki T, Iwaki A, Liem RKH, Goldman JE, Expression of alphaB-crystallin in the developing rat kidney., Kidney Int., 10.1038/ki.1991.178, 40, 1, 52-56, 1991.07, The expression and cellular localization of alphaB-crystallin during rat renal development was studied by Northern blot analysis and by immunocytochemistry. Northern blotting of total RNA extracted from whole kidneys revealed that the messenger RNA for alphaB-crystallin rapidly increased after birth to reach adult levels by 20 days. At the same time, immunohistochemistry for alphaB-crystallin demonstrated that the prominent elongation of Henle's loop during the first 10 days of life was accompanied by increased alphaB-crystallin expression. Thus, the development of alphaB-crystallin expression is correlated temporally with the acquisition of tubule function in early post-natal life..
74. Tomokane N, Iwaki T, Tateishi J, Iwaki A, Goldman JE, Rosenthal fibers share epitopes with alphaB-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin. Immunoelectron microscopy with colloidal gold., Am. J. Pathol., 138, 4, 875-885, 1991.04, Ultrastructural immunoreactivities of alpha-B-crystallin, glial fibrillary acidic protein (GFAP), ubiquitin, and vimentin in Rosenthal fibers (RFs) isolated from an Alexander's disease brain were investigated using nonosmium and low-temperature embedding technique. The morphology of RFs embedded in Lowicryl K4M resin was well preserved after treatment with 0.5% Triton X-100. alpha-B-crystallin immunoreactivity was present in RFs of various sizes and was the strongest in loosely scattered deposits, which were considered to be the initial stage of RFs. Glial fibrillary acidic protein immunoreactivity in RFs was heavy, homogeneous throughout RFs, and equivalent to that in networks of glial filaments. Immunoreactivities of both alpha-B-crystallin and GFAP were mainly restricted to the high electron-dense areas within RFs and were proved to exist close to each other by double immunolabeling. Rosenthal fibers were negative for vimentin. Ubiquitin immunoreactivity was relatively homogeneous in RFs with small diameters, but in RFs with large diameters, the immunoreactivity diminished in the center. Based on these observations, combined with the tendency of self-aggregation of alpha-B-crystallin, it is conceivable that RFs are huge aggregation products of alpha-B-crystallin involving GFAP, and that ubiquitination may be a consequent phenomenon, as it may be in other intracytoplasmic inclusions, such as neurofibrillary tangles and Lewy bodies..
75. Iwaki T, Iwaki A, Miyazono M, Goldman JE:, Preferential expression of alphaB-crystallin in astrocytic elements of neuroectodermal tumors., Cancer., 10.1002/1097-0142(19911115)68:10<2230::AID-CNCR2820681023>3.0.CO;2-7, 68, 10, 2230-2240, 68: 2230-2240, 1991.01.
76. Shin R-W, Iwaki T, Kitamoto T, Tateishi J, Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues., Lab. Invest., 64: 693-702, 1991.01.
77. Miyazono M, Iwaki T, Kitamoto T, Kaneko Y, Doh-ura K, Tateishi J:, A comparative immunohistochemical study of Kuru and senile plaques with a special reference to glial reactions at various stages of amyloid plaque formation., Am. J. Pathol., 139, 3, 589-598, 139: 589-598, 1991.01.
78. Iwaki T, Kume-Iwaki A, Goldman JE:, Cellular distribution of alphaB-crystallin in non-lenticular tissues., J. Histochem. Cytochem., 38, 1, 31-39, 1990.01, alpha B-Crystallin is a subunit of alpha-crystallin, a major protein component of the vertebrate lens. Recently, its expression in various extra-lenticular tissues has been demonstrated by both Western and Northern blotting. In this study, the cellular distribution of alpha B-crystallin in rat organs was examined in detail using immunohistochemistry. Positive reactions were observed in lens, iris, heart, skeletal muscle (type 1 and type 2A fibers), striated muscle in skin and esophagus, Henle's loop and medullary collecting duct of the kidney, Schwann cells of peripheral nerves, glia of the central nervous system, and decidual cells of the placenta. A close correlation with markers of oxidative activity suggests that alpha B-crystallin is expressed in cells that have high levels of oxidative function..
79. Iwaki A, Iwaki T, Goldman JE, Liem RKH:, Multiple mRNAs of rat brain alpha-crystallin B chain result from alternative transcriptional initiation., J. Biol. Chem., 265 :22197-22203, 1990.01.
80. Iwaki T, Kume-Iwaki A, Liem RKH, Goldman JE, alphaB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain., Cell, 10.1016/0092-8674(89)90173-6, 57, 1, 71-78, 1989.04, Rosenthal fibers (RFs) are abnormal inclusions within astrocytes, characteristic of Alexander's disease. We have previously isolated a 22 kd protein component of RFs from Alexander's disease brain. By Western blotting, we detected its equivalent in several rat organs, with the highest level in heart, and in a human astrocytoma cell line (U-373MG). A cDNA library established from U-373MG was screened with an anti-RF protein antibody. A partial cDNA clone encoding the lens protein alpha B-crystallin was isolated. The anti-RF protein antibodies react with lens alpha B-crystallin. Furthermore, the distribution of alpha B-crystallin mRNA in rat organs is consistent with the Western blots. Therefore, alpha B-crystallin is not lens-specific and it can accumulate in large amounts in astrocytes in pathological conditions..
81. Iwaki T, Fukui M, Takeshita I, Tsuneyoshi M, Tateishi J:, Hemangiopericytoma of the meninges: a clinicopathologic and immunohistochemical study., Clin. Neuropathol., 7, 3, 93-99, 1988.05, This clinicopathologic study concerns 15 cases of hemangiopericytoma of the meninges (so-called hemangiopericytic meningioma) among approximately 300 examined cases. Ages of the patients at the first surgery ranged from 25 to 67 years, with a median of 44 years. According to follow-up information, 9 of the 15 died between 1 year and 15 years after the initial treatment. Histologically, the tumor was indistinguishable from the hemangiopericytomas in other tissues and was characterized by a homogeneous vascular pattern, a uniform cell population and a wide range of cellular anaplasia. The presence of prominent mitotic activity suggested a highly active biological behavior. Immunohistochemical analyses for epithelial membrane antigen (EMA) were done in 35 various meningiomas, 12 meningeal hemangiopericytomas, and three extracranial hemangiopericytomas. Most of the meningiomas of meningotheliomatous, transitional, fibroblastic, papillary, angiomatous, and anaplastic types showed a positive immunoreactivity for EMA, while all of the meningeal hemangiopericytomas and extracranial hemangiopericytomas examined were negative for EMA. Our immunohistochemical study may support the concept that the meningeal hemangiopericytoma is composed of poorly differentiated cells which may originate from a perivascular mesenchymal cell of the meninges but not from the arachnoidal cap cell..
82. Iwaki T, Takeshita I, Fukui M, Kitamura K:, Cell kinetics of the malignant evolution of meningothelial meningioma., Acta Neuropathol., 74, 3, 243-247, 74: 243-247, 1987.01.
83. Iwaki T, Fukui M, Kondo A, Matsushima T, Takeshita I, Epithelial properties of pleomorphic xanthoastrocytomas determined in ultrastructural and immunohistochemical studies., Acta Neuropathol., 74, 2, 142-150, 1987.01.
84. Iwaki T, Kondo A, Takeshita I, Nakagaki H, Kitamura K, Tateishi J, Proliferative potential of folliculo-stellate cells in human pituitary adenomas. Immunohistochemical and electron microscopic analysis., Acta Neuropathol, 71, 3-4, 233-242, 1986.03, Folliculo-stellate cells (FS cells) in 40 pituitary adenomas and portions of anterior pituitary adjacent to the tumor in 26 cases were investigated immunohistochemically, using polyclonal antisera to S-100 protein (S-100) and glial fibrillary acidic protein (GFAP). The objective was to clarify the histological behavior of the FS cells. In most pituitary adenomas there were few or no S-100- or GFAP-positive cells, in comparison with numerous positive cells in the parts of the adenohypophyses compressed by adenomas. However, positive FS cells were observed in some types of pituitary adenomas. Growth hormone and prolactin producing adenomas frequently contained significant amounts of FS cells. In non-functioning adenomas, an unique case of FS cell adenoma was present. The adenoma was composed mainly of FS cells and immature glandular cells. The FS cells were sometimes located around follicles containing Periodic acid Schiff-positive material. Therefore, the FS cell adenoma is characterized by S-100- and GFAP-positive FS cells and PAS-positive follicles. In this type of adenoma, FS cells seemed to be the main proliferating component. In parts of the adenohypophyses adjacent to the adenomas, GFAP-positive FS cells were numerous. In the pathological conditions FS cells may possess the potential of reactive proliferation..
1. Hideomi Hamasaki, Hiroyuki Honda, Tsuyoshi Okamoto, Satoshi O Suzuki, Toshiharu Ninomiya, Toru Iwaki, Putaminal Tau Pathology in the Aging Japanese Population: The Hisayama Study, The 19th International Congress of Neuropathology, 2018.09, Introduction: Hisayama study is a prospective cohort study commenced in 1961 in the town of Hisayama in Fukuoka Prefecture, Japan. In principle, all residents of the town of
Hisayama are proposed to be autopsied when they die, and the total autopsy rate is about 75%. We previously reported that Alzheimer's disease (AD) and hippocampal tau deposits were increasing in recent years in Japan. In this study, we extend our observation towards putaminal tau pathology in the aging Japanese population.
Methods: We examined a series of autopsied cases from Hisayama residents obtained between 2009 and 2014 (224 cases). To evaluate tau pathology quantitatively, we performed immunohistochemistry with AT8 antibody and automated quantitative analysis using a platform called MATLAB.
Results: Tau deposits in putamen gradually increased around 70 years of age, and were correlated with the Braak stage. Certain AD cases showed severe tau deposits in putamen. Amyloid deposition in the putamen was not necessarily correlated with the putaminal tau deposition. We subdivided all cases into low CERAD (CERAD score 0-1) and high CERAD (CERAD score 2-3) groups to examine the effect of cerebral amyloid deposits on the putaminal tau pathology. The areal mean of putaminal tau deposition was significantly higher in the high CERAD group.
Conclusion: The cases with severe tau deposits in putamen were largely attributed to AD in the aging population..
2. Masahiro Shijo, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Hiroyuki Honda, Satoshi O Suzuki, Toru Iwaki, Upregulation of annexin A1 in reactive astrocytes at the boundaries of human brain infarcts, The 19th International Congress of Neuropathology, 2018.09, Introduction: Annexin A1 (ANXA1) is mainly expressed in astrocytes and ependymal cells of normal human brains. Regarding acute ischemic brain, increased expression of ANXA1 in microglia and vascular endothelium has been shown with rodent models; however, astrocytic expression of ANXA1 in infarcted brain tissues has been little focused on.
Methods: We performed immunohistochemistry in autopsied human brain tissues from 15 cases with cerebral infarction, and the brain tissues of CB-17 mouse stroke model
generated by occlusion of the middle cerebral artery. Result: Marked expression of ANXA1 was noted in the viable regions adjacent to necrosis. ANXA1 was mainly distributed in
astrocytes rather than microglia at the viable boundary area, as well as in macrophages and endothelium at the necrotic area. Compared with the area of fibrillary gliosis revealed by GFAP, ANXA1-immunopositive area was restricted in the narrow band of viable periinfarct region. TMEM119-immunopositive resident microglia gathered in the periphery of necrosis, but this population was decreased in the ANXA1-immunopositive periinfarct areas. ANXA1 expression in microglia, macrophages and endothelium was also noted in the mouse ischemic brains, however, astrocytic ANXA1 was not observed regardless of the duration of ischemia.
Conclusion: ANXA1 expression was elevated in reactive astrocytes around necrosis during acute ischemia of human brains. Astrocytic ANXA1 could affect the behavior of resident
microglia through the strong anti-inflammatory properties. The act of ANXA1 during focal brain ischemia might be different between human and mouse species..
3. Shinichirou Mori, Akihiro Watanabe, Masahiro Shijo, Hiroyuki Honda, Satoshi O Suzuki, Naokazu Sasagasako, Toru Iwaki, An autopsy case of SPG11 with peculiar p62-immunopositive intracytoplasmic inclusions, The 19th International Congress of Neuropathology, 2018.09, Introduction: SPG11 is an autosomal recessive inherited spastic paraplegia with thin corpus callosum. Biallelic mutation in the SPG11 gene can also cause juvenile-onset amyotrophic lateral sclerosis-5 (ALS5) and Charcot-Marie-Tooth disease type 2X (CMT2X), different neurodegenerative disorders with overlapping features. Here, we report an autopsy case of SPG11 with IVS18+1G>T homozygous mutation.
Clinical summary: At 27 years of age, the patient developed lower limb spasticity, and the symptom gradually worsened. Her elderly brother also suffered to same symptom. By age 44 years, she was wheelchair-bound and severely demented. She died of esophageal perforation at the age of 57 years. A cardiac uptake of 123I-metaiodobenzylguanidine is reduced, suggesting the cardiac sympathetic denervation.Autopsy findings: The brain weighed 786g. Severe cerebral atrophy and thin corpus callosum were noted. Histologically, large intracytoplasmic eosinophilic granular structures with vacuoles were observed in spinal root ganglia. Many coarse eosinophilic granules are also noted throughout the CNS. These eosinophilic structures are highlighted by immunohistochemistry for p62, but negative for p-TDP43 and p-tau. Additionally, rather small p-TDP43 positive neuronal inclusions are observed in the brain and spinal cord, however, no skein-like inclusions were detected. Neuronal loss of substantia nigra was severe. Tyrosine hydroxylase-positive nerve fibers were markedly diminished at the pericardium.
Conclusion: The autopsy findings demonstrated that SPG11 involved widespread neuronal structures: cerebral cortex, corticospinal tracts, extrapyramidal nuclei, and peripheral nervous system including sympathetic nerves. Large eosinophilic bodies in the spinal ganglion cells with vacuoles may be most notable characteristic feature of SPG11. p-TDP43 depositions were also widely observed..
4. Reiji Hommyo, Satoshi O Suzuki, Nona Abolhassani, Hideomi Hamasaki, Masahiro Shijo, Norihisa Maeda, Hiroyuki Honda, Yusaku Nakabeppu, Toru Iwaki, Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis, The 19th International Congress of Neuropathology, 2018.09, Introduction: Down-regulation of μ-crystallin (CRYM) in the hippocampi of patients with Alzheimer's disease was revealed by microarray analyses of autopsied brains from the
Japanese general population (the Hisayama study). CRYM reportedly has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. We examined the expression pattern of CRYM in the rat brain during development. As CRYM is reportedly expressed in the corticospinal tract (CST), we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS).
Methods: CRYM expression in developing rat brains was examined by immunohistochemistry and immunoblotting. CRYM expression in human ALS brains was examined by immunohistochemistry. Results: In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and CST in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. In these regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In human ALS brains, we observed marked loss of CRYM in the CST, especially distally.
Conclusion: CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and later performs cell-specific functions in selected neuronal populations. The expression patterns of CRYM may reflect interactions with T3 or ketimines. The results also indicate that CRYM can be used as a marker of axonal degeneration in the
5. Hiroyuki Honda, Chang Shen, Satoshi O Suzuki, Naokazu Sasagasako, Toru Iwaki, Dynactin is involved in Lewy body pathology, The 19th International Congress of Neuropathology, 2018.09, Introduction: Dynactin forms a protein complex with dynein and the complex transports cargo retrogradely along microtubules. Dysfunction of the dynein-dynactin complex causes several neurodegenerative disorders, such as Perry syndrome. Recently, we reported colocalization of phosphorylated alpha-synuclein (p-SCNA) and the largest subunit of dynactin (DCTN1) in Lewy body-like structures in Perry syndrome. However, the relationship between dynactin and synucleinopathies has not been clarified. In this study, we examined the possible involvement of the dynein-dynactin complex in synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Methods: We examined 13 autopsied human brains of patients with synucleinopathy (5 PD, 5 DLB and 3 MSA). Immunohistochemistry for p-SNCA, DCTN1 (dynactin) and DYNC1I1 (dynein) was performed. We also examined microtubule affinity regulating kinases (p-MARKs), which phosphorylate microtubule-associated proteins and trigger microtubule disruption. Double immunofluorescence was also performed. Results: Both brainstem and cortical Lewy bodies were immunopositive for DCTN1, DYNC1I1 and p-MARK and their stainings often overlapped with p-SNCA. Lewy neurites were also immunopositive for DCTN1 and DYNC1I1. However, p-SNCA-positive inclusions of MSA such as glial cytoplasmic inclusions and neuronal cytoplasmic inclusions were negative for DCTN1, DYNC1I1 and p-MARK. Conclusion: Our results suggest that dynactin is closely associated with Lewy body pathology. In addition, immunohistochemistry for dynein-dynactin complex molecules, especially DCTN1, can distinguish Lewy bodies clearly from neuronal cytoplasmic inclusions of MSA..
6. Morphometric study of abnormal phosphorylated tau deposits in hippocampi: Recent trends by the Hisayama study.
7. Masahiro Shijo, Hideomi Hamasaki, Hiroyuki Honda, Satoshi O Suzuki, Yusaku Nakabeppu, Toru Iwaki, Correlation between neuropathologic changes of Alzheimer’s disease and cellular distribution of AE-binding protein 1 (AEBP1) in human hippocampi
, 第38回日本分子生物学会, 2015.12, Adipocyte enhancer binding protein 1 (AE-binding protein 1, AEBP1) has functions to activate inflammatory response via NF-κB pathway in macrophages and to regulate adipogenesis in preadipocytes. Whereas the function of AEBP1 in CNS is unknown, we have previously reported increased mRNA of AEBP1 in human hippocampi of Alzheimer’s disease (AD) patients. In this research we examined cellular distribution of AEBP1 protein in human hippocampi and correlation to neuropathologic changes of AD in autopsy cases of Hisayama residents. Immunohistochemistry revealed that AEBP1 was mainly localized in neuronal perikarya of human hippocampi, and expression of AEBP1 was elevated in pyramidal cells and some astrocytes of AD patients. Although AEBP1 was depleted in the neurons bearing neurofibrillary tangles, AEBP1 was highly expressed in the neurons with pretangles and in the dystrophic neurites of senile plaques. Nuclear localization of NF-κB was also observed in many AEBP1-positive neurons of AD patients. The comparison of AD cases and non AD cases showed there seemed to be positive correlation between AEBP1 expression and progression of β amyloid pathology. These findings may imply that AEBP1 protein has a role in progression of AD. On the other hand, constitutive expression of AEBP1 in neurons suggest that AEBP1 may also contribute to normal neuronal function.
8. Molecular pathophysiology of mitochondrial dysfunction and insulin resistance in Alzheimer's disease brain.
9. Hideomi Hamasaki, HIROYUKI HONDA, Tomihiro Wakamiya, Satoshi O Suzuki, Toru Iwaki, Distribution of carnitine palmitoyltransferase(CPT) 1C in the subdivisions of human hippocampi and the alterations in Alzheimer’s disease brains., 第37回日本分子生物学会, 2014.11, The previous study has shown mRNA of carnitine palmitoyltransferase 1C (CPT1C), a brain-specific isoform of the CPT1 family, downregulated in Alzheimer’s disease (AD) brain, which highlighted in hippocampus. 3 Therefore, we examined the cellular component-dependent changes of CPT1C expressions in human hippocampus. For immunohistochemistry we examined the medial temporal lobe including hippocampus using an anti-CPT1C antibody, which recognizes its internal region. The subjects were 17 AD cases and 21 normal controls without brain diseases. In normal brains, CPT1C immunoreactivity was mainly perikarya of the neurons. Some nuclei of neurons and glial cells are immunopositive for CPT1C. In AD brains, we found decline of CPT1C immunoreactivity in perikarya of the pyramidal cells dominantly in CA1 area. On the other hand, granulovacuolar degeneration was strongly immunopositive for CPT1C. Given CPT1C is concerned with memory function, the reduction of CPT1C in AD hippocampus indicates CPT1C is one of the cause of memory dysfunction in AD..
10. Hideomi Hamasaki, HIROYUKI HONDA, Satoshi O Suzuki, Toru Iwaki, Altered expression of c-Met in Alzheimer’s disease brains., 第35回日本分子生物学会, 2012.12, The Hisayama study using a series of autopsied brains revealed that messenger RNA of c-Met, the receptor of hepatocyte growth factor (HGF), was significantly decreased in the hippocampus of Alzheimer’s disease (AD) patients. Therefore, we examined the expression pattern of c-Met by immunohistochemistry. In normal controls, c-Met immunostaining was observed in the perikarya of pyramidal neurons of hippocampi and a subpopulation of astrocytes mainly at the subpial layer and perivascular regions. In AD brains, we found marked decline of perikaryal staining of hippocampal neurons. Additionally, we found the strong immunostaining of c-Met in reactive astrocytes including those in the vicinity of senile plaques. Since it has been reported that HGF was also up-regulated around the senile plaques, b-amyloid deposition may be associated with reactive astrocytosis through HGF signaling pathway. On the contrary, HGF signaling in the hippocampal neurons may be markedly reduced by depletion of c-Met. In the transgenic mouse model, overexpression of HGF in neurons resulted in enhanced memory function. Thus, the neuronal depletion of c-Met in AD brains may be associated with the cognitive impairment..
11. Epidemiological and pathological study on dementia in Hisayama town.
12. In vitro characterization of sphere-forming glioma 'stem' cells. What is the stemness?.
13. Glial degeneration with referece to glial inclusion bodies.
14. Molecular pathology of brain tumors
Iwaki T
The 26th General Assembly of the Japan Medical Congress (Fukuoka) April 5, 2003.
Membership in Academic Society
  • Japanese Society of Neuropathology
  • Japanese Society of Pathology
  • Japan Society of Brain Tumor Pathology
  • Molecular Biology Society of Japan
  • International Society of Neuropathology
Educational Activities
1) Postgraduate education
Department of Neuropathology, Graduate School of Medical Sciences.
2) Undergraduate education
Medical history (2nd year), Medical School
Pathology (3rd year), Medical School
Neurological Course of Clinical Medicine (3rd year), Medical School
Chairman of Committee of Student Affairs, Medical School (2001)
Member of Committees of Student Affairs and Education, Medical School (2000-2011)
Other Educational Activities
  • 2010.04.
Professional and Outreach Activities
The Japanese Society of Neuropathology (Board)
The International Society of Neuropathology(Councilor)
The Japan Society of Brain Tumor Pathology (Board)
The Japanese Society of Pathology(Councilor)
Neuropathology (Editor in Chief, 2012-2017)
Pathology International (Editor)
Brain Tumor Pathology (Editor).