Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Toru Iwaki Last modified date:2021.06.23

Professor / Pathobiology / Department of Basic Medicine / Faculty of Medical Sciences


Papers
1. Hiroyuki Honda, Kosuke Matsuzono, Kota Satoh, Masayoshi Fujisawa, Satoshi O Suzuki, Chiaki Furuyama, Tetsuyuki Kitamoto, Shigeru Fujimoto, Koji Abe, Toru Iwaki, Detection of cutaneous prion protein deposits could help diagnose GPI-anchorless prion disease with neuropathy., European journal of neurology, 10.1111/ene.14720, 28, 6, 2133-2137, 2021.06, BACKGROUND AND PURPOSE: To investigate prion protein (PrP) deposits in cutaneous tissues of patients of glycosylphosphatidylinositol (GPI)-anchorless prion diseases with neuropathy. METHODS: Cutaneous tissue samples from three patients with GPI-anchorless prion diseases were obtained, two cutaneous biopsy samples from the lower leg of Case 1 (Y162X) and Case 3 (D178fs25), and a cutaneous sample taken from the abdomen during an autopsy of Case 2 (D178fs25). We performed immunohistochemistry for PrP to look for abnormal PrP deposits. RESULTS: PrP deposits were observed in the dermal papilla, the sweat glands, the hair follicles, the arrector pili muscles, and peripheral nerves of all examined cases of GPI-anchorless prion disease with neuropathy. The abnormal PrP accumulation was frequently localized at the basement membrane, and colocalized with laminin. CONCLUSION: Immunohistochemical detection of PrP in cutaneous samples could be used to definitively diagnose GPI-anchorless PrP disease with neuropathy..
2. Shunsuke Yamamoto, Yuhki Koga, Hiroaki Ono, Hironori Goto, Nobuhiro Hata, Hidetaka Yamamoto, Satoshi O Suzuki, Yasunari Sakai, Toru Iwaki, Shouichi Ohga, Alectinib-responsive infantile anaplastic ganglioglioma with a novel VCL-ALK gene fusion., Pediatric blood & cancer, 10.1002/pbc.29122, e29122, 2021.05.
3. Yusuke Funakoshi, Nobuhiro Hata, Kosuke Takigawa, Hideyuki Arita, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yutaka Fujioka, Aki Sako, Toru Umehara, Tadamasa Yoshitake, Osamu Togao, Akio Hiwatashi, Koji Yoshimoto, Toru Iwaki, Masahiro Mizoguchi, Clinical significance of CDKN2A homozygous deletion in combination with methylated MGMT status for IDH-wildtype glioblastoma., Cancer medicine, 10.1002/cam4.3860, 10, 10, 3177-3187, 2021.05, OBJECTIVE: Accumulating evidence from recent molecular diagnostic studies has indicated the prognostic significance of various genetic markers for patients with glioblastoma (GBM). To evaluate the impact of such genetic markers on prognosis, we retrospectively analyzed the outcomes of patients with IDH-wildtype GBM in our institution. In addition, to assess the impact of bevacizumab (BEV) treatment, we compared overall survival (OS) between the pre- and post-BEV eras. METHODS: We analyzed the data of 100 adult patients (over 18 years old) with IDH-wildtype GBM from our database between February 2006 and October 2018. Genetic markers, such as MGMT methylation status, EGFR amplification, CDKN2A homozygous deletion, and clinical factors were analyzed by evaluating the patients' OS. RESULTS: CDKN2A homozygous deletion showed no significant impact on OS in patients with methylated MGMT status (p = 0.5268), whereas among patients with unmethylated MGMT status, there was a significant difference in OS between patients with and without CDKN2A homozygous deletion (median OS: 14.7 and 16.9 months, respectively, p = 0.0129). This difference was more evident in the pre-BEV era (median OS: 10.1 and 15.6 months, respectively, p = 0.0351) but has become nonsignificant in the post-BEV era (median OS: 16.0 and 16.9 months, respectively, p = 0.1010) due to OS improvement in patients with CDKN2A homozygous deletion. However, these findings could not be validated in The Cancer Genome Atlas cohort. CONCLUSIONS: MGMT and CDKN2A status subdivided our cohort into three race-specific groups with different prognoses. Our findings indicate that BEV approval in Japan led to OS improvement exclusively for patients with concurrent unmethylated MGMT status and CDKN2A homozygous deletion..
4. Kazufumi Kikuchi, Osamu Togao, Koji Yamashita, Daichi Momosaka, Tomohiro Nakayama, Yoshiyuki Kitamura, Yoshitomo Kikuchi, Shingo Baba, Koji Sagiyama, Keisuke Ishimatsu, Ryotaro Kamei, Nobutaka Mukae, Koji Iihara, Satoshi O Suzuki, Toru Iwaki, Akio Hiwatashi, Diagnostic accuracy for the epileptogenic zone detection in focal epilepsy could be higher in FDG-PET/MRI than in FDG-PET/CT., European radiology, 10.1007/s00330-020-07389-1, 31, 5, 2915-2922, 2021.05, OBJECTIVES: To examine the utility of FDG-PET/MRI in patients with epilepsy by comparing the diagnostic accuracy of PET/MRI and PET/CT in epileptogenic zone (EZ) detection. METHODS: This prospective study included 31 patients (17 males, 14 females) who underwent surgical resection for EZ. All patients were first scanned using FDG-PET/CT followed immediately with FDG-PET/MRI. Two series of PET plus standalone MR images were interpreted independently by five board-certified radiologists. A 4-point visual score was used to assess image quality. Sensitivities and visual scores from both PETs and standalone MRI were compared using the McNemar test with Bonferroni correction and Dunn's multiple comparisons test. RESULTS: The EZs were confirmed histopathologically via resection as hippocampal sclerosis (n = 11, 35.5%), gliosis (n = 8, 25.8%), focal cortical dysplasia (n = 6, 19.4%), and brain tumours (n = 6, 19.4%) including cavernous haemangioma (n = 3), dysembryoplastic neuroepithelial tumour (n = 1), ganglioglioma (n = 1), and polymorphous low-grade neuroepithelial tumour of the young (n = 1). The sensitivity of FDG-PET/MRI was significantly higher than that of FDG-PET/CT and standalone MRI (FDG-PET/MRI vs. FDG-PET/CT vs. standalone MRI; 77.4-90.3% vs. 58.1-64.5% vs. 45.2-80.6%, p < 0.0001, respectively). The visual scores derived from FDG-PET/MRI were significantly higher than those of FDG-PET/CT, as well as standalone MRI (2.8 ± 1.2 vs. 2.0 ± 1.1 vs. 2.1 ± 1.2, p < 0.0001, respectively). Compared to FDG-PET/CT, FDG-PET/MRI increased the visual score (51.9%, increased visual scores of 2 and 3). CONCLUSIONS: The diagnostic accuracy for the EZ detection in focal epilepsy could be higher in FDG-PET/MRI than in FDG-PET/CT. KEY POINTS: • Sensitivity of FDG-PET/MRI was significantly higher than that of FDG-PET/CT and standalone MRI (FDG-PET/MRI vs. FDG-PET/CT vs. standalone MRI; 77.4-90.3% vs. 58.1-64.5% vs. 45.2-80.6%, p < 0.0001, respectively). • Visual scores derived from FDG-PET/MRI were significantly higher than those of FDG-PET/CT and standalone MRI (2.8 ± 1.2 vs. 2.0 ± 1.1 vs. 2.1 ± 1.2, p < 0.0001, respectively). • Compared to FDG-PET/CT, FDG-PET/MRI increased the visual score (51.9%, increased visual scores of 2 and 3)..
5. Shunsuke Yamamoto, Yuhki Koga, Kenichi Tetsuhara, Noriyuki Kaku, Hiroaki Ono, Satoshi O Suzuki, Toru Iwaki, Shouichi Ohga, Hemorrhagic stroke due to leukostasis in pediatric mixed-phenotype acute leukemia., Blood research, 10.5045/br.2021.2021004, 2021.05.
6. Yuichi Yamada, Kenichi Kohashi, Izumi Kinoshita, Hidetaka Yamamoto, Takeshi Iwasaki, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yoshihiro Ito, Yuki Kuma, Yui Yamada-Nozaki, Yutaka Koga, Mikiko Hashisako, Daisuke Kiyozawa, Daichi Kitahara, Fumiya Narutomi, Yusuke Kuboyama, Takahito Nakamura, Takeshi Inoue, Munenori Mukai, Yumi Honda, Gouji Toyokawa, Kenji Tsuchihashi, Fumiyoshi Fushimi, Kenichi Taguchi, Kenichi Nishiyama, Sadafumi Tamiya, Yumi Oshiro, Masutaka Furue, Yasuharu Nakashima, Satoshi Suzuki, Toru Iwaki, Yoshinao Oda, Histological background of dedifferentiated solitary fibrous tumour., Journal of clinical pathology, 10.1136/jclinpath-2020-207311, 2021.05, AIMS: Dedifferentiation is a histological phenomenon characterised by abrupt transition of histology to a sarcomatous component with high-grade malignant potential in solitary fibrous tumour (SFT). The authors histologically reviewed SFT cases to reveal the histological background of dedifferentiated SFTs. METHODS: Clinicopathological and histopathological findings of 145 SFT cases were reviewed. Immunohistochemical staining and genetic analysis were also performed. RESULTS: The non-dedifferentiated components showed a cellular component in 45 of 145 (31%), high mitotic rate (≥4/10 high-powered field) in 12 of 145 (8.2%) tumours, necrosis in 7 of 145 (4.8%) tumours, multinodular growth pattern in 39 of 132 (29.5%) available tumours and intratumoural fibrous septa in 37 of 131 (28.2%). Immunohistochemically, the non-dedifferentiated components were positive for CD34 in 128 of 141 (90.7%), bcl-2 in 101 of 133 (75.9%), nuclear pattern of β-catenin in 64 of 127 (50.3%) and p16 in 22 of 140 (15.7%). Loss of Rb protein expression was detected in 17 of 110 (15.4%) cases. Statistically, cellular component, multinodular structure, p16 overexpression and Rb protein loss were significantly associated with dedifferentiation. Moreover, cellular component and multinodular structure were significantly associated with p16 overexpression and Rb protein loss. All the non-deddifferentiated components showed wild type of p53 expression. The dedifferentiated components of all 10 dedifferentiated tumours presented positivity for p16 in 9 of 10 (90%) and mutational type of p53 in 5 of 10 (50%). Loss of Rb protein expression was detected in 6 of 10 (60%). CONCLUSIONS: The authors propose that cellular or multinodular transformation may be associated with dedifferentiation. They also suggest that cellular and multinodular transformation may be associated with p16 overexpression and Rb downregulation..
7. Shinichiro Mori, Hiroyuki Honda, Hideomi Hamasaki, Naokazu Sasagasako, Satoshi O Suzuki, Hirokazu Furuya, Takayuki Taniwaki, Toru Iwaki, Transactivation response DNA-binding protein of 43 kDa proteinopathy and lysosomal abnormalities in spastic paraplegia type 11., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12733, 2021.05, Spastic paraplegia type 11 (SPG11) is the most common autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. Spatacsin, a protein encoded by the SPG11 gene, is associated with autophagy. SPG11 patients show spastic paraplegia, intellectual disability, dementia, and parkinsonism. A previous neuropathological analysis of SPG11 cases reported neurodegeneration mimicking amyotrophic lateral sclerosis without transactivation response DNA-binding protein of 43 kDa (TDP-43) deposits and unique sequestosome 1 (SQSTM1)-positive neuronal inclusions. We performed a neuropathological examination of two Japanese patients with complicated spastic paraplegia with thinning of the corpus callosum from different families, and one was genetically diagnosed as having SPG11. Both cases showed diffuse atrophy of the brain and spinal cord. Depigmentation of the substantia nigra was also observed. Immunohistochemistry revealed widespread distribution of areas showing TDP-43 aggregation in the central nervous system. The TDP-43 deposits in the thalamus and substantia nigra especially resembled skein-like inclusions. Unique SQSTM1-positive neuronal inclusions, as previously reported, were widespread in the whole central nervous system as well as the dorsal root ganglia. Double-labeling immunofluorescence of the dorsal root ganglia revealed that the unique, large SQSTM1-positive cytoplasmic inclusions of the ganglion cells were labeled with lysosome-associated membrane protein 1 and lysosome-associated membrane protein 2. This is the first report showing TDP-43 pathology in SPG11. The common neuropathological findings of TDP-43-positive inclusions in both the cases imply a causal connection between the TDP-43 proteinopathy and autophagy dysfunction in SPG11..
8. Hiroyuki Honda, Shinichiro Mori, Akihiro Watanabe, Naokazu Sasagasako, Shoko Sadashima, Trang Đồng, Katsuya Satoh, Noriyuki Nishida, Toru Iwaki, Abnormal prion protein deposits with high seeding activities in the skeletal muscle, femoral nerve, and scalp of an autopsied case of sporadic Creutzfeldt-Jakob disease., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12717, 41, 2, 152-158, 2021.04, We report the general autopsy findings of abnormal prion protein (PrP) deposits with their seeding activities, as assessed by the real-time quaking-induced conversion (RT-QuIC) method, in a 72-year-old female patient with sporadic Creutzfeldt-Jakob disease (sCJD). At 68 years of age, she presented with gait disturbance and visual disorders. Electroencephalography showed periodic synchronous discharge. Myoclonus was also observed. A genetic test revealed that PRNP codon 129 was methionine/methionine (MM). She died of pneumonia three years and four months after disease onset, and a general autopsy was performed. The brain weighed 650 g and appeared markedly atrophic. Immunohistochemistry for PrP revealed synaptic PrP deposits and coarse PrP deposits in the cerebral cortices, basal ganglia, cerebellum, and brainstem. Western blot analysis identified type 1 proteinase-K-resistant PrP in frontal cortex samples. PrP deposits were also observed in systemic organs, including the femoral nerve, psoas major muscle, abdominal skin, adrenal medulla, zona reticularis of the adrenal gland, islet cells of the pancreas, and thyroid gland. The RT-QuIC method revealed positive seeding activities in all examined organs, including the frontal cortex, femoral nerve, psoas major muscle, scalp, abdominal skin, adrenal gland, pancreas, and thyroid gland. The following 50% seeding dose (SD50 ) values were 9.5 (frontal cortex); 8 ± 0.53 (femoral nerve); 7 ± 0.53 (psoas major muscle); and 7.88 ± 0.17 (scalp). The SD50 values for the adrenal gland, dermis, pancreas, and thyroid gland were 6.12 ± 0.53, 5.25, 4.75, and 4.5, respectively. PrP deposits in general organs may be associated with long-term disease duration. This case indicated the necessity for general autopsies in sCJD cases to establish strict infection control procedures for surgical treatment and to examine certain organs..
9. Shinichiro Mori, Satoshi O Suzuki, Hiroyuki Honda, Hideomi Hamasaki, Nobutaka Sakae, Naokazu Sasagasako, Hirokazu Furuya, Toru Iwaki, Symmetrical glial hyperplasia in the brainstem of fibrodysplasia ossificans progressiva., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12715, 41, 2, 146-151, 2021.04, Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disease, characterized by the progressive ossification of skeletal muscles, fascia, tendons, and ligaments. In most cases, the great toes of patients show symmetrical congenital malformations. The causative gene for FOP has been identified as the activin A receptor, type 1 (ACVR1) gene (ACVR1). The ACVR1 R206H mutation is the most common mutation among FOP patients, and the ACVR1 G356D mutation has been identified as a rare mutation in a Japanese FOP patient with slow progression. In addition to musculoskeletal abnormalities, a series of autopsy studies described one FOP case, without genetic testing to identify ACVR1 mutation, showing nodular heterotopia at the edge of the fourth ventricle. Here, we report the general autopsy findings for a 75-year-old man with FOP, caused by the ACVR1 G356D mutation, including the precise examination of brainstem lesions. Postmortem examination revealed unique symmetrical glial hyperplasia of the pons and medulla oblongata. Microscopically, lesions of the pons involving residual neurons and lesions of the medulla oblongata consisted of subependymal cells. Immunohistochemical analysis of these lesions revealed developmental anomalies, with different cellular components. In this report, for the first time, we present the neuropathological description of a patient with genetically confirmed FOP and symmetrical glial hyperplasia of the pons and medulla oblongata. The presented pathological findings, in conjunction with previous reports implying that the glial hyperplasia of the brainstem is common in FOP, suggest that ACVR1 may play an unclarified developmental role in the human brainstem..
10. Yutaka Fujioka, Nobuhiro Hata, Yojiro Akagi, Daisuke Kuga, Ryusuke Hatae, Yuhei Sangatsuda, Yuhei Michiwaki, Takeo Amemiya, Kosuke Takigawa, Yusuke Funakoshi, Aki Sako, Toru Iwaki, Koji Iihara, Masahiro Mizoguchi, Molecular diagnosis of diffuse glioma using a chip-based digital PCR system to analyze IDH, TERT, and H3 mutations in the cerebrospinal fluid., Journal of neuro-oncology, 10.1007/s11060-020-03682-7, 152, 1, 47-54, 2021.03, PURPOSE: Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). METHODS: CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. RESULTS: We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. CONCLUSION: We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas..
11. Motoi Yoshimura, Hiroyuki Honda, Naokazu Sasagasako, Shinichiro Mori, Hideomi Hamasaki, Satoshi O Suzuki, Takashi Ishii, Toshiharu Ninomiya, Jun-Ichi Kira, Toru Iwaki, PCBP2 Is Downregulated in Degenerating Neurons and Rarely Observed in TDP-43-Positive Inclusions in Sporadic Amyotrophic Lateral Sclerosis., Journal of neuropathology and experimental neurology, 10.1093/jnen/nlaa148, 80, 3, 220-228, 2021.02, Various heterogeneous nuclear ribonucleoproteins (hnRNPs) are deposited in pathological inclusions of amyotrophic lateral sclerosis (ALS) and related diseases, such as frontotemporal lobar degeneration (FTLD). Recently, poly (rC)-binding protein 2 (PCBP2, hnRNP-E2), a member of the hnRNP family, was reported to be colocalized with transactivation-responsive DNA-binding protein 43 kDa (TDP-43)-immunopositive inclusions in cases of FTLD-TDP. Here, we used immunohistochemical methods to investigate PCBP1 and PCBP2 expression in the spinal cords of sporadic ALS patients, with special reference to TDP-43-positive inclusions. Thirty autopsy cases of sporadic ALS were examined by immunohistochemistry using antibodies against PCBP1, PCBP2, sequestosome 1 (p62), and TDP-43. In control subjects without neurological disorders, neurons predominantly expressed PCBP2, rather than PCBP1, in their cytoplasm and nuclei. Anterior horn cells of sporadic ALS patients often had various levels of PCBP2 expression, and motor neurons with skein-like inclusions often had reduced or lost cytoplasmic and nuclear PCBP2 staining. Notably, one case with FTLD-TDP subtype B pathology had marked colocalization of TDP-43 and PCBP2 in the cytoplasmic inclusions and dystrophic neurites of the cerebral cortex, hippocampus, and spinal cord. In conclusion, PCBP2 was reduced in anterior horn cells of sporadic ALS, but its occurrence in TDP-43 inclusions was a rare phenomenon..
12. Shoko Sadashima, Satoshi O Suzuki, Hironori Haruyama, Nobutaka Mukae, Yutaka Fujioka, Nobuhiro Hata, Masahiro Mizoguchi, Keisuke Ishimatsu, Akio Hiwatashi, Toru Iwaki, A juvenile case of epilepsy-associated, isocitrate dehydrogenase wild-type/histone 3 wild-type diffuse glioma with a rare BRAF A598T mutation., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12693, 40, 6, 646-650, 2020.12, Here, we report a juvenile (18-year-old male) case of epilepsy-associated, isocitrate dehydrogenase wild-type/histone 3 wild-type diffuse glioma with a rare BRAF mutation and a focal atypical feature resembling diffuse astrocytoma. The patient presented with refractory temporal lobe epilepsy. Subsequently, magnetic resonance imaging revealed a hyperintense lesion in the right temporal lobe on fluid attenuated inversion recovery images. The patient underwent right lateral temporal lobectomy and amygdalohippocampectomy. Histopathologically, the tumor showed isomorphic, diffuse, infiltrative proliferation of glial tumor cells and intense CD34 immunoreactivity. The tumor cells were immunonegative for isocitrate dehydrogenase 1 (IDH1) R132H and BRAF V600E. Notably, the tumor cells showed the lack of nuclear staining for α-thalassemia/mental retardation syndrome, X-linked (ATRX). In addition, the Ki-67 labeling index, using a monoclonal antibody MIB-1, was elevated focally at tumor cells with p53 immunoreactivity. Molecular analyses identified a BRAFA598T mutation, the first case reported in a glioma. BRAFA598T is predicted to result in loss of kinase action; however, inactive mutants can stimulate mitogen-activated protein kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) signaling through CRAF activation. Thus, according to the recent update of the consortium to inform molecular and practical approaches to central nervous system tumor taxonomy (cIMPACT-NOW update 4), our case is also compatible with diffuse glioma with the mitogen-activated protein kinase (MAPK) pathway alteration. Thorough immunohistochemical and molecular studies are necessary for diagnosis of epilepsy-associated, diffuse gliomas. Partial resemblance in histopathological and molecular genetic features to diffuse astrocytoma also calls for attention..
13. Shotaro Hayashida, Katsuhisa Masaki, Satoshi O Suzuki, Ryo Yamasaki, Mitsuru Watanabe, Sachiko Koyama, Noriko Isobe, Takuya Matsushita, Kazuya Takahashi, Takeshi Tabira, Toru Iwaki, Jun-Ichi Kira, Distinct microglial and macrophage distribution patterns in the concentric and lamellar lesions in Baló's disease and neuromyelitis optica spectrum disorders., Brain pathology (Zurich, Switzerland), 10.1111/bpa.12898, 30, 6, 1144-1157, 2020.11, TMEM119 and purinergic receptor P2Y12 (P2RY12), which are not expressed by recruited peripheral blood macrophages, are proposed to discriminate microglia from macrophages. Therefore, we investigated the distribution patterns of microglia and macrophages in 10 concentric lesions from four autopsied Baló's disease cases and one neuromyelitis optica spectrum disorder (NMOSD) case, using quantitative immunohistochemistry for the markers TMEM119, P2RY12, CD68, CD163 and GLUT5. Three cases with Baló's disease had distal oligodendrogliopathy (DO) showing preferential loss of myelin-associated glycoprotein and early active demyelination in the outermost demyelinating layer (termed DMY-MO). In DMY-MO with DO, TMEM119-positive activated microglia expressing upregulated GLUT5 but markedly downregulated P2RY12 were significantly increased. These activated microglia expressed inducible nitric oxide synthase. Oligodendrocytes and their precursors showed apoptotic-like nuclear condensation in DMY-MO. TMEM119-negative and CD68/CD163-positive macrophages were distributed throughout the lesion center of DMY-MO with DO and these cells demonstrated foamy morphology only in the inner portion but not in the outer portion. In concentric demyelinating lesions from another Baló's case and lamellar demyelinating lesions in an NMOSD case, which had late active demyelination without DO, the densities of TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology were significantly increased in myelinated layers but not in demyelinating layers. In particular, in the NMOSD case, TMEM119-positive microglia were confined to the outer portion of the myelinated layers. CD68-positive macrophages with foamy morphology also expressing CD163 accumulated in myelinated as well as in demyelinated layers. These findings suggest that activated microglia expressing TMEM119 and GLUT5, but not P2RY12, are associated with apoptosis of oligodendrocytes in the leading edge of Baló's concentric lesions with DO, whereas TMEM119-, GLUT5- and P2RY12-positive microglia with ramified morphology are associated with myelin preservation in concentric lesions without DO in Baló's disease and NMOSD. These two types of microglia appear to play distinct roles in the formation of concentric lesions..
14. Kosuke Matsuzono, Younhee Kim, Hiroyuki Honda, Yuhei Anan, Masato Tsunoda, Yusuke Amano, Noriyoshi Fukusima, Toru Iwaki, Tetsuyuki Kitamoto, Shigeru Fujimoto, Prion Gene PRNP Y162X Truncation Mutation Can Induce a Refractory Esophageal Achalasia., The American journal of gastroenterology, 10.14309/ajg.0000000000001044, 2020.11.
15. Yuki Yanagihara, Shintaro Hayashi, Junpei Koge, Hiroyuki Honda, Ryo Yamasaki, Yuichi Yamada, Yoshinao Oda, Toru Iwaki, Jun-Ichi Kira, Immunotherapy-refractory vacuolar myopathy with mucin deposition in scleromyxedema: A possible role of fibroblast growth factor 2., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12659, 40, 5, 492-495, 2020.10, Scleromyxedema (SME) is characterized by widespread waxy papules on the skin, with mucin deposits in the upper dermis. Twenty-one SME cases of myopathy have been reported; of the cases, six showed vacuolar formation, and two showed mucin deposition. We report the first case of SME with mucin-associated vacuolated fibers. A 45-year-old woman with SME developed progressive proximal muscle weakness. Muscle biopsy revealed myopathic changes with numerous vacuoles linked to mucin in the affected muscle fibers, which were heavily immunostained for fibroblast growth factor 2 (FGF2). Despite repeated high dose oral prednisolone and intravenous immunoglobulin administrations, muscle weakness recurred continuingly, culminating in death due to congestive heart failure. Immunotherapy was partly effective in our case, although it was refractory. Treatment responsiveness in patients with SME myopathy varied; however, due to its rarity, the mechanism remains to be elucidated. To address this issue, we investigated muscle specimens immunohistochemically and detected marked upregulation of FGF2 in the affected muscle fibers of our patient. FGF2, a strong myogenesis inhibitor, may exert a suppressive effect on muscle fiber regeneration, which may have conferred refractoriness to our patient's SME myopathy..
16. Shiroh Miura, Kengo Kosaka, Tomofumi Shimojo, Eiji Matsuura, Kazuhito Noda, Ryuta Fujioka, Shin-Ichiro Mori, Fujio Umehara, Toru Iwaki, Ken Yamamoto, Hirotomo Saitsu, Hiroki Shibata, Intronic variant in IQGAP3 associated with hereditary neuropathy with proximal lower dominancy, urinary disturbance, and paroxysmal dry cough., Journal of human genetics, 10.1038/s10038-020-0761-7, 65, 9, 717-725, 2020.09, In 2008, we reported a clinically and genetically new type of autosomal dominant disorder of motor and sensory neuropathy with proximal dominancy in the lower extremities, urinary disturbance, and paroxysmal dry cough. To identify the nucleotide variant causative of this disease, we reanalyzed the linkage of the original Japanese pedigree including seven newly ascertained subjects with updated information. We assigned the locus of the disease to 1p13.3-q23 (maximum logarithm-of-odds score = 2.71). Exome sequencing for five patients and one healthy relative from the pedigree revealed 2526 patient-specific single-nucleotide variants (SNVs). By rigorous filtering processes using public databases, our linkage results, and functional prediction, followed by Sanger sequencing of the pedigree and 520 healthy Japanese individuals, we identified an intronic SNV in IQGAP3, a gene known to be associated with neurite outgrowth. Upon pathological examination of the sural nerve, moderate, chronic, mainly axonal neuropathy was observed. By histochemical analyses, we observed a patient-specific increase of IQGAP3 expression in the sural nerve. We concluded that the variant of IQGAP3 is associated with the disease in our pedigree..
17. Masaoki Kusunoki, Kazufumi Kikuchi, Osamu Togao, Koji Yamashita, Daichi Momosaka, Yoshitomo Kikuchi, Daisuke Kuga, Nobuhiro Hata, Masahiro Mizoguchi, Koji Iihara, Satoshi O Suzuki, Toru Iwaki, Yuta Akamine, Akio Hiwatashi, Differentiation of high-grade from low-grade diffuse gliomas using diffusion-weighted imaging: a comparative study of mono-, bi-, and stretched-exponential diffusion models., Neuroradiology, 10.1007/s00234-020-02456-2, 62, 7, 815-823, 2020.07, PURPOSE: Diffusion-weighted imaging (DWI) plays an important role in the preoperative assessment of gliomas; however, the diagnostic performance of histogram-derived parameters from mono-, bi-, and stretched-exponential DWI models in the grading of gliomas has not been fully investigated. Therefore, we compared these models' ability to differentiate between high-grade and low-grade gliomas. METHODS: This retrospective study included 22 patients with diffuse gliomas (age, 23-74 years; 12 males; 11 high-grade and 11 low-grade gliomas) who underwent preoperative 3 T-magnetic resonance imaging from October 2014 to August 2019. The apparent diffusion coefficient was calculated from the mono-exponential model. Using 13 b-values, the true-diffusion coefficient, pseudo-diffusion coefficient, and perfusion fraction were obtained from the bi-exponential model, and the distributed-diffusion coefficient and heterogeneity index were obtained from the stretched-exponential model. Region-of-interests were drawn on each imaging parameter map for subsequent histogram analyses. RESULTS: The skewness of the apparent diffusion, true-diffusion, and distributed-diffusion coefficients was significantly higher in high-grade than in low-grade gliomas (0.67 ± 0.67 vs. - 0.18 ± 0.63, 0.68 ± 0.74 vs. - 0.08 ± 0.66, 0.63 ± 0.72 vs. - 0.15 ± 0.73; P = 0.0066, 0.0192, and 0.0128, respectively). The 10th percentile of the heterogeneity index was significantly lower (0.77 ± 0.08 vs. 0.88 ± 0.04; P = 0.0004), and the 90th percentile of the perfusion fraction was significantly higher (12.64 ± 3.44 vs. 7.14 ± 1.70%: P < 0.0001), in high-grade than in low-grade gliomas. The combination of the 10th percentile of the true-diffusion coefficient and 90th percentile of the perfusion fraction showed the best area under the receiver operating characteristic curve (0.96). CONCLUSION: The bi-exponential model exhibited the best diagnostic performance for differentiating high-grade from low-grade gliomas..
18. [An autopsied case of severe varicella zoster virus-associated encephalomyelitis under immunosuppressant therapy].
The patient was a 40-year-old woman who was previously diagnosed with systemic lupus erythematosus and myasthenia gravis and had received prednisolone and tacrolimus for more than 7 years. In February 2017, she noticed pain in her lower back and weakness of the lower limbs, and was referred to our hospital on day 5. She had shingles in the right lower thoracic dermatomes and Brown-Séquard syndrome with right-sided dominant weakness in her lower limbs and left-sided superficial sensory disturbance below the L1 level. Varicella zoster virus (VZV)-associated myelopathy was suspected because of her symptoms and clinical findings. Despite the immediate administration of intravenous acyclovir after hospitalization, she lost consciousness and experienced a seizure related to cerebral hemorrhage in the left temporal lobe on the night of day 5. MRI showed enhanced lesions along the spinal cord and leptomeninges of the brainstem and temporal lobe. VZV-IgG and VZV-DNA were positive in the cerebrospinal fluid. Based on these clinical features and laboratory findings, she was diagnosed as VZV-associated vasculopathy and myelopathy. She subsequently had multiple cerebral infractions and hemorrhage, and developed sudden cardiopulmonary arrest on day 6, culminating in death on day 17. Autopsy showed that inflammatory mononuclear cells had infiltrated the vascular walls of the spinal cord. Immunohistochemistry revealed that some neurons and macrophages in the white matter of the spinal cord were positive for VZV. In addition, atrophic neurons, satellite cells surrounding these neurons, and infiltrating macrophages were immune-positive for VZV at the L2 dorsal root ganglia. These findings were consistent with VZV-associated vasculopathy and myelitis. Under immunosuppressive conditions, VZV can cause shingles and neuronal complications such as vasculopathy and myelitis, which are sometimes fatal despite the immediate administration of intravenous acyclovir. New treatment drugs or drugs to prevent VZV activation are desired..
19. Shoko Sadashima, Hiroyuki Honda, Satoshi O Suzuki, Masahiro Shijo, Shinichi Aishima, Keita Kai, Junichi Kira, Toru Iwaki, Accumulation of Astrocytic Aquaporin 4 and Aquaporin 1 in Prion Protein Plaques., Journal of neuropathology and experimental neurology, 10.1093/jnen/nlaa010, 79, 4, 419-429, 2020.04, Gerstmann-Sträussler-Scheinker (GSS) disease with P102L mutation and familial Creutzfeldt-Jakob disease (CJD) with V180I mutation are 2 major hereditary prion diseases in Japan. GSS and some familial CJD [V180I] exhibit characteristic prion protein (PrP) plaques. Overexpression of the astrocytic water channel proteins aquaporin (AQP) 1 and AQP4 was recently reported in sporadic CJD. To clarify the pathological characteristics of AQP1 and AQP4 in prion disease patient brains with plaque-type deposition, we investigated 5 patients with GSS, 2 patients with CJD [V180I], and 2 age-matched control cases without neurological diseases using immunohistochemistry and double immunofluorescence methods. We demonstrated that there is the intense expression of AQP1 and AQP4 around prion plaques, especially in distal astrocytic processes deep inside these plaques. Similar results have been reported in the senile plaques and ghost tangles of Alzheimer disease brains and a protective role of AQP4 in which AQP4 is redistributed toward the plaques and works as a barrier against the deleterious effects of these plaques has been suggested. Our results, which show a similar clustering of AQPs around PrP plaques, therefore support the possibility that AQPs also have a protective role in plaque formation in prion diseases..
20. Ryo Yamasaki, Tomomi Yonekawa, Saeko Inamizu, Koji Shinoda, Hirofumi Ochi, Takuya Matsushita, Noriko Isobe, Gaku Tsuji, Shoko Sadashima, Yuki Kuma, Yoshinao Oda, Toru Iwaki, Masutaka Furue, Jun-Ichi Kira, A case of overlapping adult-onset linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic involvement., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12614, 40, 1, 109-115, 2020.02, Linear scleroderma is a variant of localized scleroderma. We report a 43-year-old woman who had developed left arm weakness and linear scleroderma on her back during pregnancy at 25 years of age, followed by left hemifacial atrophy and left leg weakness. She had multiple linear scleroderma lesions on her trunk and left limbs, left eyelid ptosis, impairment of vertical movement and abduction of the left eye, left hemifacial atrophy, and weakness and atrophy of the sternocleidomastoid, trapezius, and proximal limb muscles on the left side. On serology, antibodies to U1-ribonucleoprotein and Jo-1 were positive; anti-scleroderma-70 antibody was negative. Skin biopsy demonstrated increased hypertrophic collagen fibers without inflammatory infiltrates. Needle electromyography of left limb muscles revealed mild neurogenic patterns; left quadriceps muscle biopsy showed chronic neurogenic changes. Brain magnetic resonance imaging revealed mild left hemispheric atrophy. This is a rare case of linear scleroderma and Parry-Romberg syndrome presenting with widespread ipsilateral neurogenic manifestations..
21. Yuhei Michiwaki, Nobuhiro Hata, Masahiro Mizoguchi, Akio Hiwatashi, Daisuke Kuga, Ryusuke Hatae, Yojiro Akagi, Takeo Amemiya, Yutaka Fujioka, Osamu Togao, Satoshi O. Suzuki, Koji Yoshimoto, Toru Iwaki, Koji Iihara, Relevance of calcification and contrast enhancement pattern for molecular diagnosis and survival prediction of gliomas based on the 2016 World Health Organization Classification, Clinical Neurology and Neurosurgery, 10.1016/j.clineuro.2019.105556, 187, 2019.12, Objectives: The significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. Patients and methods: We evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. Results: A total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as “molecular GBM.” IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. Conclusion: GdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting “molecular GBM” by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients..
22. K. Yamashita, Hiwatashi Akio, Osamu Togao, K. Kikuchi, D. Momosaka, Nobuhiro Hata, Yojiro Akagi, S. O. Suzuki, Toru Iwaki, Koji Iihara, H. Honda, Differences between primary central nervous system lymphoma and glioblastoma topographic analysis using voxel-based morphometry, Clinical Radiology, 10.1016/j.crad.2019.06.017, 74, 10, 816.e1-816.e8, 2019.10, AIM: To evaluate the diagnostic feasibility of probabilistic analysis using voxel-based morphometry (VBM) in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma (GBM). MATERIALS AND METHODS: In total, 118 patients with GBM (57 males, 61 females; mean [± standard deviation] age, 56.9±19.3 years; median, 61 years) and 52 patients with PCNSL (37 males, 15 females; mean age, 62±13.3 years, median, 66 years) were studied retrospectively. Each patient underwent preoperative contrast-enhanced T1-weighted imaging (CE-T1WI) using a 1.5 or 3 T magnetic resonance imaging (MRI) system. To assess preferential occurrence sites, images from CE-T1WI were co-registered and spatially normalised using the MNI152 T1 template. Subsequently, a region of interest (ROI) was placed in the centre of the enhancing tumour in normalised images with 1-mm isotropic resolution. The same ROI between normalised and T1 template images was set up using an ROI manager function in ImageJ software. A spherical volume of interest (VOI) with a radius of 10 mm was determined. A probability map was created by overlaying each image with the VOI. Each VOI was removed from T1 template images for VBM analysis. VBM analysis was performed using statistical parametric mapping (SPM) 12 software under default settings. RESULTS: VBM analysis showed significantly higher frequency in the splenium of the corpus callosum among PCNSL patients than among GBM patients (p<0.05; family-wise error correction). CONCLUSION: Topographic analysis using VBM provides useful information for differentiating PCNSL from GBM..
23. Yuichi Yamada, Kenichi Kohashi, Izumi Kinoshita, Hidetaka Yamamoto, Takeshi Iwasaki, Masato Yoshimoto, Shin Ishihara, Yu Toda, Yoshihiro Itou, Yutaka Koga, Mikiko Hashisako, Yui Nozaki, Daisuke Kiyozawa, Daichi Kitahara, Takeshi Inoue, Munenori Mukai, Yumi Honda, Gouji Toyokawa, Kenji Tsuchihashi, Yoshifumi Matsushita, Fumiyoshi Fushimi, Kenichi Taguchi, Sadafumi Tamiya, Yumi Oshiro, Masutaka Furue, Yasuharu Nakashima, Satoshi Suzuki, Toru Iwaki, Yoshinao Oda, Clinicopathological review of solitary fibrous tumors: dedifferentiation is a major cause of patient death., Virchows Archiv : an international journal of pathology, 10.1007/s00428-019-02622-9, 475, 4, 467-477, 2019.10, Solitary fibrous tumor (SFT) is a soft-tissue neoplasm of intermediate malignant potential, presenting a wide histopathological spectrum. Poorer prognosis of hemangiopericytoma of the central nervous system (CNS), hypoglycemic SFT, and dedifferentiation are well-known characters of SFT, but their clinical significance were not demonstrated enough by large-sized study. Here, the clinicopathological features of SFTs are reviewed and the relationship between genetics and clinicopathological features is examined using 145 SFT cases. All cases were STAT6 IHC-positive and/or NAB2-STAT6 fusion gene-positive. Tumor location was classified into three categories: 30 pleuropulmonary, 96 non-pleuropulmonary/non-central nervous system (CNS), and 18 CNS tumors. The tumor developed recurrence in 21 of 93 available cases (22.5%), metastasis in 11 of 93 (11.8%), and tumor death in 9 of 93 (9.6%). Hypoglycemia occurred in 2 primary tumors and 1 metastatic tumor among 63 reviewable cases, and dedifferentiation occurred in 10 cases (6.8%) including 6 primary tumors, 2 recurrent tumors, and 2 metastatic tumors. Recurrence was positively associated with CNS location (p = 0.0109) and hypoglycemia (p = 0.001); metastasis was positively associated with CNS location (p = 0.0231), hypoglycemia (p < 0.0001), and dedifferentiation (p < 0.0001), while metastasis was negatively correlated with pleural location (p = 0.0471). Tumor death was positively associated with male sex (p = 0.0154), larger size (p = 0.0455), hypoglycemia (p < 0.0001), and dedifferentiation (p < 0.0001). Multivariate analysis revealed independent statistical significance of dedifferentiation for overall survival (p = 0.0467). Exon variant of the fusion gene had no statistical correlation with clinical outcome. In conclusion, dedifferentiation is a major prognostic factor of SFT, and specific location such as cerebromeningeal and intra-abdominal site and hypoglycemia also had a high risk for unfavorable prognosis..
24. Shinichiro Mori, Hiroyuki Honda, Takashi Ishii, Motoi Yoshimura, Naokazu Sasagasako, Satoshi O. Suzuki, Takayuki Taniwaki, Toru Iwaki, Expanded polyglutamine impairs normal nuclear distribution of fused in sarcoma and poly (rC)-binding protein 1 in Huntington's disease, Neuropathology, 10.1111/neup.12600, 39, 5, 358-367, 2019.10, Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Immunohistochemical studies using the 1C2 antibody for polyglutamine expansion have detected characteristic intranuclear inclusions (INIs) in affected neurons in HD. Further, in vitro and mouse models of HD have shown that the INIs recruit several proteins relating to RNA splicing and translation. In the present study, we immunohistochemically investigated the association of INIs with various heterogeneous nuclear ribonucleoproteins in the cerebral cortex of four autopsy cases of HD. Fused in sarcoma (FUS) was colocalized with 1C2-positive nuclear inclusions in all examined cases. Localization of poly (rC)-binding protein 1 (PCBP1) in 1C2-positive nuclear inclusions was also observed. Double immunofluorescence revealed complete or partial loss of the normal, diffuse nuclear distribution of FUS or PCBP1 in neurons with 1C2-positive nuclear inclusions. This maldistribution of FUS in cortical neurons suggests a severe disturbance of messenger RNA processing, which may be a common pathogenetic mechanism of FUS-related familial amyotrophic lateral sclerosis..
25. Hiroyuki Honda, Masaki Matsumoto, Masahiro Shijo, Hideomi Hamasaki, Shoko Sadashima, Satoshi O. Suzuki, Shinichi Aishima, Keita Kai, Keiichi I. Nakayama, Naokazu Sasagasako, Toru Iwaki, Frequent Detection of Pituitary-Derived PrPres in Human Prion Diseases, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlz075, 78, 10, 922-929, 2019.10, Human prion diseases including sporadic Creutzfeldt-Jakob disease (sCJD), inherited prion diseases, and acquired human prion diseases are lethal neurodegenerative diseases. One of the major sources of iatrogenic Creutzfeldt-Jakob disease was human growth hormone (hGH-iCJD) derived from contaminated cadaveric pituitaries. The incidence of hGH-iCJD has decreased since changing from growth hormone extracted from human cadaveric pituitaries to recombinant pituitary hormones. However, extensive analysis on the localization and detecting of abnormal prion protein in the pituitary gland are limited. In this study, we examined 9 autopsied brains and pituitary glands from 6 patients with prion disease (3 Gerstmann-Sträussler-Scheinker disease, 2 sCJD, and 1 dura mater graft-associated CJD) and 3 individuals with nonprion diseases. Western blot analysis of pituitary samples demonstrated unique glycoforms of normal cellular prion protein with molecular weights of 30-40 kDa, which was higher than the typical 25-35 kDa prion protein in brains. Proteomic analysis also revealed prion protein approximately the molecular weight of 40 kDa in pituitary samples. Moreover, proteinase K-resistant Prion protein was frequently detected in pituitary samples of the prion diseases. Immunohistochemistry for Prion protein revealed mosaic cellular distribution preferentially in growth hormone- or prolactin-producing cells..
26. Masahiro Shijo, Hideomi Hamasaki, Hiroyuki Honda, Satoshi O. Suzuki, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Koji Iihara, Toru Iwaki, Upregulation of Annexin A1 in Reactive Astrocytes and Its Subtle Induction in Microglia at the Boundaries of Human Brain Infarcts, Journal of Neuropathology and Experimental Neurology, 10.1093/jnen/nlz079, 78, 10, 961-970, 2019.10, Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage..
27. Takayuki Fujii, Hiroyuki Honda, Ryo Yamasaki, Toru Iwaki, Jun-Ichi Kira, Multiple mtDNA deletions due to mitochondrion toxicity of anti-hepadnaviral drugs: Comments to the letter from J. Finsterer., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12563, 39, 4, 326-327, 2019.08.
28. Tauopathy in basal ganglia involvement is exacerbated in a subset of patients with Alzheimer's disease: The Hisayama study..
29. Atsushi Kobayashi, Yasushi Iwasaki, Masaki Takao, Yuko Saito, Toru Iwaki, Zechen Qi, Ryouta Torimoto, Taishi Shimazaki, Yoshiko Munesue, Norikazu Isoda, Hirofumi Sawa, Keisuke Aoshima, Takashi Kimura, Hinako Kondo, Shirou Mohri, Tetsuyuki Kitamoto, A Novel Combination of Prion Strain Co-Occurrence in Patients with Sporadic Creutzfeldt-Jakob Disease, American Journal of Pathology, 10.1016/j.ajpath.2019.02.012, 189, 6, 1276-1283, 2019.06, Six subgroups of sporadic Creutzfeldt-Jakob disease have been identified by distinctive clinicopathologic features, genotype at polymorphic codon 129 [methionine (M)/valine (V)] of the PRNP gene, and type of abnormal prion proteins (type 1 or 2). In addition to the pure subgroups, mixed neuropathologic features and the coexistence of two types of abnormal prion proteins in the same patient also have been reported. Here, we found that a portion of the patients previously diagnosed as MM1 had neuropathologic characteristics of the MM2 thalamic form (ie, neuronal loss of the inferior olivary nucleus of the medulla). Furthermore, coexistence of biochemical features of the MM2 thalamic form also was confirmed in the identified cases. In addition, in transmission experiments using prion protein–humanized mice, the brain material from the identified case showed weak infectivity and generated characteristic abnormal prion proteins in the inoculated mice resembling those after inoculation with brain material of MM2 thalamic form. Taken together, these results show that the co-occurrence of MM1 and MM2 thalamic form is a novel entity of sporadic Creutzfeldt-Jakob disease prion strain co-occurrence. The present study raises the possibility that the co-occurrence of the MM2 thalamic form might have been overlooked so far because of the scarcity of abnormal prion protein accumulation and restricted neuropathology..
30. Toshikazu Baba, Koji Shinoda, Mitsuru Watanabe, Shoko Sadashima, Dai Matsuse, Noriko Isobe, Ryo Yamasaki, Kimihiko Kaneko, Toshiyuki Takahashi, Toru Iwaki, Jun-Ichi Kira, MOG antibody disease manifesting as progressive cognitive deterioration and behavioral changes with primary central nervous system vasculitis., Multiple sclerosis and related disorders, 10.1016/j.msard.2019.01.053, 30, 48-50, 2019.05, We report a 60-year-old male with anti-myelin oligodendrocyte glycoprotein (MOG) antibody who developed progressive cognitive deterioration and behavioral changes, with no other focal signs, over 9 months. MRI showed numerous T2-hyperintense lesions with partial contrast enhancement in white and grey matter of cerebrum, cerebellum and spinal cord. A brain biopsy revealed perivascular inflammatory cell infiltration, disturbed vascular continuity and no demyelination, indicative of a lymphocytic pattern of primary CNS vasculitis (PCNSV). Contrast enhancement disappeared after immunotherapy; however, cognitive impairment was not improved. Neurologists should note that MOG antibody disease can present as immunotherapy-resistant progressive cognitive impairment with PCNSV-like histopathology..
31. Takayuki Fujii, Kei-Ichiro Takase, Hiroyuki Honda, Nobutoshi Kawamura, Ryo Yamasaki, Michiyo Urata, Takeshi Uchiumi, Toru Iwaki, Jun-Ichi Kira, Toxic myopathy with multiple deletions in mitochondrial DNA associated with long-term use of oral anti-viral drugs for hepatitis B: A case study., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12548, 39, 2, 162-167, 2019.04, Oral nucleoside analogs (NAs) reduce hepatitis B virus (HBV) replication by inhibiting HBV DNA polymerase. However, NAs can also affect human mitochondrial DNA (mtDNA) polymerase, which can lead to mtDNA depletion (quantitative abnormality). Indeed, several mitochondrial myopathy cases have been reported in which a reduced mtDNA copy number was induced by oral NAs for hepatitis B. Herein, we report a case of toxic myopathy with multiple mtDNA deletions (qualitative abnormality) associated with long-term use of NAs for hepatitis B. A 68-year-old woman, who underwent long-term treatment with lamivudine and adefovir for chronic hepatitis B, developed proximal muscle weakness in the four extremities. Neurological examination showed mild proximal muscle weakness and atrophy in the four extremities. Upon admission to our hospital, her blood lactate/pyruvate ratio during an aerobic exercise test was elevated. Myogenic patterns were observed in lower limb muscles on electromyographic examination. Muscle magnetic resonance imaging revealed diffuse atrophy of proximal muscles in the four extremities with no signal changes. A biopsy from the biceps brachii muscle showed an abnormally large variation in fiber size, scattered muscle fibers with decreased cytochrome c oxidase activity, and ragged-red fibers. Analysis of mtDNA from skeletal muscle revealed no decrease in copy number but increased incidence of multiple deletions, including a deletion of 4977 base pairs (known as the common deletion) reflecting oxidative stress-induced mtDNA damage. This case study indicates that long-term oral antiviral therapy for hepatitis B can induce chronic oxidative damage to mtDNA resulting in qualitative mtDNA abnormalities and toxic myopathy..
32. Yuhei Michiwaki, Nobuhiro Hata, Toshiyuki Amano, Satoshi O. Suzuki, Yojiro Akagi, Daisuke Kuga, Daisuke Onozuka, Seiya Momosaki, Akira Nakamizo, Koji Yoshimoto, Toru Iwaki, Koji Iihara, Predictors of recurrence and postoperative outcomes in patients with non-skull base meningiomas based on modern neurosurgical standards, Interdisciplinary Neurosurgery: Advanced Techniques and Case Management, 10.1016/j.inat.2018.10.007, 15, 30-37, 2019.03, Background: Advances in neurosurgical techniques and neuroimaging resolution questions the modern-day reliability of the Simpson grade for predicting meningioma recurrence. Therefore, we evaluated the reliability of predictors for recurrence and outcomes in detail in patients with non-skull base meningiomas (NSBMs). Methods: We retrospectively analyzed data from consecutive 175 NSBMs underwent surgical resection. We performed Kaplan–Meier analyses of recurrence-free survival (RFS) according to Simpson and World Health Organization (WHO) grades. Predictors of RFS and clinical deterioration were estimated by univariate and multivariate analyses. Correlation between the Simpson grade and change in Karnofsky Performance Scale scores was assessed by Fisher's exact test. Results: Log-rank tests revealed significant correlations of both the Simpson and WHO grades with RFS for the overall cohort, convexity, and falx/tentorium meningioma. Unlike patients undergoing Simpson grade I and II resections, RFS in patients with WHO grade I and II/III tumors differed significantly from the early postoperative stage. Multivariate analysis identified tumor size, Simpson grade, and MIB-1 labeling index as significant predictors of RFS. Clinical deterioration was more frequent among patients undergoing less aggressive resection. Tumor location was the only significant predictor of clinical deterioration. Conclusions: Our findings indicate that tumor size, Simpson and WHO grades, and MIB-1 labeling index are significant predictors of NSBM recurrence. Moreover, the risk of recurrence markedly decreases within the follow-up duration of 80 months. Aggressive resection appears to minimize the risk of recurrence without evidence of clinical deterioration. Follow-up schedules should be based on the WHO grade and extent of resection..
33. K. Yamashita, R. Hatae, Hiwatashi Akio, Osamu Togao, kazufumi kikuchi, D. Momosaka, Y. Yamashita, Daisuke Kuga, Nobuhiro Hata, K. Yoshimoto, S. O. Suzuki, Toru Iwaki, Koji Iihara, Hiroshi Honda, Predicting TERT promoter mutation using MR images in patients with wild-type IDH1 glioblastoma, Diagnostic and Interventional Imaging, 10.1016/j.diii.2019.02.010, 2019.01, Purpose: The purpose of this study was to identify magnetic resonance imaging (MRI) features that are associated with telomerase reverse transcriptase promoter mutation (TERTm) in glioblastoma. Materials and methods: A total of 112 patients with glioblastoma who had MRI at 1.5- or 3.0-T were retrospectively included. There were 43 patients with glioblastoma with wild-type TERT (TERTw) (22 men, 21 women; mean age, 47 ± 25 [SD] years; age range: 3–84 years) and 69 patients with glioblastoma with TERTm (34 men, 35 women; mean age 64 ± 11 [SD] years; age range, 41-–85 years). The feature vectors consist of 11 input units for two clinical parameters (age and gender) and nine MRI characteristics (tumor location, subventricular extension, cortical extension, multiplicity, enhancing volume, necrosis volume, the percentage of necrosis volume, minimum apparent diffusion coefficient [ADC] and normalized ADC). First, the diagnostic performance using univariate and multivariate logistic regression analyses was evaluated. Second, the cross-validation of the support vector machine (SVM) was performed by using leave-one-out method with 43 TERTw and 69 TERTm to evaluate the diagnostic performance. In addition, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for the differentiation between TERTw and TERTm were compared between logistic regression analysis and SVM. Results: With multivariate analysis, the percentage of necrosis volume and age were significantly greater in TERTm glioblastoma than in TERTw glioblastoma. SVM allowed discriminating between TERTw glioblastoma and TERTm glioblastoma with sensitivity, specificity, PPV, NPV, and accuracy of 85.7% [60/70; 95% confidence interval (CI): 75.3–92.9%], 54.8% (23/42; 95% CI: 38.7–70.2%), 75.9% (60/79; 95% CI: 69.1–81.7%), 69.7% (23/33; 95% CI: 54.9–81.3%) and 74.1% (83/112; 95% CI: 65.0–81.9%), respectively. Conclusion: The percentage of necrosis volume and age may surrogate for predicting TERT mutation status in glioblastoma..
34. K. Kikuchi, Hiwatashi Akio, O. Togao, K. Yamashita, R. Kamei, D. Momosaka, N. Hata, K. Iihara, S. O. Suzuki, Toru Iwaki, H. Honda, Intravoxel incoherent motion MR imaging of pediatric intracranial tumors Correlation with histology and diagnostic utility, American Journal of Neuroradiology, 10.3174/ajnr.A6052, 40, 5, 878-884, 2019.01, BACKGROUND AND PURPOSE: Intravoxel incoherent motion imaging, which simultaneously measures diffusion and perfusion parameters, is promising for brain tumor grading. However, intravoxel incoherent motion imaging has not been tested in children. The purpose of this study was to evaluate the correlation between intravoxel incoherent motion parameters and histology to assess the accuracy of intravoxel incoherent motion imaging for pediatric intracranial tumor grading. MATERIALS AND METHODS: Between April 2013 and September 2015, 17 children (11 boys, 6 girls; 2 months to 15 years of age) with intracranial tumors were included in this retrospective study. Intravoxel incoherent motion parameters were fitted using 13 b-values for a biexponential model. The perfusion-free diffusion coefficient, pseudodiffusion coefficient, and perfusion fraction were measured in highand low-grade tumors. These intravoxel incoherent motion parameters and the ADC were compared using the unpaired t test. The correlations between the intravoxel incoherent motion parameters and microvessel density or the MIB-1 index were analyzed using the Spearman correlation test. Receiver operating characteristic analysis was used to evaluate diagnostic performance. RESULTS: The perfusion-free diffusion coefficient and ADC were lower in high-grade than in low-grade tumors (perfusion-free diffusion coefficient, 0.85 ± 0.40 versus 1.53 ± 0.21 × 10-3 mm2/s, P < .001; ADC, 1.04 ± 0.33 versus 1.60 ± 0.21 × 10-3 mm2/s, P < .001). The pseudodiffusion coefficient showed no difference between the groups. The perfusion fraction was higher in high-grade than in low-grade tumors (21.7 ± 8.2% versus 7.6 ± 4.3%, P < .001). Receiver operating characteristic analysis found that the combined perfusion-free diffusion coefficient and perfusion fraction had the best diagnostic performance for tumor differentiation (area under the curve=0.986). CONCLUSIONS: Intravoxel incoherent motion imaging reflects tumor histology and may be a helpful, noninvasive method for pediatric intracranial tumor grading..
35. Shijo M, Honda H, Suzuki SO, Hamasaki H, Hokama M, Abolhassani N, Nakabeppu Y, Ninomiya T, Kitazono T, Iwaki T., Association of adipocyte enhancer-binding protein 1 with Alzheimer's disease pathology in human hippocampi, Brain Pathol., 10.1111/bpa.12475, 28, 1, 58-71, 2019.01, 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..
36. 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..
37. Tomohiro Okuda, Nobuhiro Hata, Satoshi Suzuki, Koji Yoshimoto, Koichi Arimura, Takeo Amemiya, Yojiro Akagi, Daisuke Kuga, Utako Oba, Yuhki Koga, Shoichi Ohga, Toru Iwaki, Koji Iihara, Pediatric ganglioglioma with an H3 K27M mutation arising from the cervical spinal cord, Neuropathology, 10.1111/neup.12471, 38, 4, 422-427, 2018.08, The 2016 edition of the World Health Organization Classification of Tumors of the Central Nervous System introduced “diffuse midline glioma H3 K27M mutant” as a new diagnostic entity. These tumors predominately affect pediatric patients and arise from midline structures such as the brainstem, thalamus and spinal cord. Here, we report a rare patient with spinal ganglioglioma carrying an H3 K27M mutation. A 10-year-old boy presented with an intramedullary tumor in the cervical spinal cord. The lesion was partially removed and histologically diagnosed as ganglioglioma. After the remnant tumor grew within 3 months after surgery, the patient underwent radiotherapy. Genetic analyses revealed an H3F3A K27M mutation but no other genetic alterations such as IDH and BRAF mutations. This case may point to pathological heterogeneity in gliomas with H3 K27M mutations..
38. 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 and Related Disorders, 10.1016/j.parkreldis.2018.02.038, 51, 105-110, Epub ahead of print, 2018.06, 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 α-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 α-synucleinopathy..
39. 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., Neuropathology : official journal of the Japanese Society of 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..
40. Shinkichi Takamori, Gouji Toyokawa, Mototsugu Shimokawa, Fumihiko Kinoshita, Yuka Kozuma, Taichi Matsubara, Naoki Haratake, Takaki Akamine, Nobutaka Mukae, Fumihiko Hirai, Tetsuzo Tagawa, Yoshinao Oda, Toru Iwaki, Koji Iihara, Hiroshi Honda, Yoshihiko Maehara, Radiological features of brain metastases from non-small cell lung cancer harboring EGFR mutation, Anticancer Research, 10.21873/anticanres.12653, 38, 6, 3731-3734, 2018.06, Aim: To investigate the radiological features on computed tomography (CT) of brain metastasis (BM) from epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Patients and Methods: Thirty-four patients with NSCLC with BMs who underwent surgical resection of the BMs at the Department of Neurosurgery, Kyushu University from 2005 to 2016 were enrolled in the study. The EGFR statuses of the 34 BMs were investigated. Radiological features, including the number, size, and location of the tumor, were delineated by CT. Results: Patients with EGFR-mutated BMs had significantly higher frequencies of multiple metastases than those with the non-EGFR-mutated type (p=0.042). BMs harboring mutations in EGFR were more frequently observed in the central area of the brain compared to those without mutations in EGFR (p=0.037). Conclusion: Careful follow-up of patients with EGFR-mutated NSCLC may be necessary given the high frequencies of multiple BMs and their location in the central area of the brain..
41. Yuri Mizuno, Norihisa Maeda, Hideomi Hamasaki, Hajime Arahata, Naokazu Sasagasako, Hiroyuki Honda, Naoki Fujii, Toru Iwaki, Four-repeat tau dominant pathology in a congenital myotonic dystrophy type 1 patient with mental retardation, Brain Pathology, 10.1111/bpa.12603, 28, 3, 431-433, 2018.05.
42. Kazufumi Kikuchi, Akio Hiwatashi, Osamu Togao, Koji Yamashita, Ryotaro Kamei, Koji Yoshimoto, Koji Iihara, Satoshi O. Suzuki, Toru Iwaki, Yuriko Suzuki, Hiroshi Honda, Arterial spin-labeling is useful for the diagnosis of residual or recurrent meningiomas, European Radiology, 10.1007/s00330-018-5404-4, 1-9, 2018.04, Objectives: ASL is useful in evaluating tumour blood flow and in detecting hypervascular tumours. The purpose of this study was to assess the additive value of ASL to non-contrast and contrast-enhanced (NC/CE)-T1WI for diagnosing residual or recurrent meningiomas. Methods: This retrospective study included 25 postoperative patients (20 women, 5 men
median age, 65 [32–85] years) with and 25 gender- and age-matched postoperative patients without residual or recurrent meningiomas. ASL was performed using a pseudocontinuous method. Seven independent observers (two radiology residents, two general radiologists and three neuroradiologists) participated in two reading sessions consisting of only NC/CE-T1WI (first session) or NC/CE-T1WI with ASL (second session). We evaluated the sensitivity and diagnostic performance for the detection of residual or recurrent meningiomas. The diagnostic performance was assessed using a figure of merit (FOM) calculated via jackknife free-response receiver-operating characteristics. Statistical analysis was performed with paired t tests, with a significance level of p <
.05. Results: The sensitivities were as follows (NC/CE-T1WI vs. NC/CE-T1WI with ASL): residents (62.1% vs. 70.7%), general radiologists (75.9% vs. 87.9%), neuroradiologists (97.7% vs. 100%) and all observers (81.3% vs. 88.2%). The FOMs were as follows (NC/CE-T1WI vs. NC/CE-T1WI with ASL): residents (0.76 vs. 0.83), general radiologists (0.83 vs. 0.93), neuroradiologists (0.95 vs. 0.99) and all observers (0.86 vs. 0.93). The addition of ASL significantly improved the diagnostic parameters for all observers except neuroradiologists (p <
. 05). Conclusions: ASL improved the detection rate of residual or recurrent meningiomas on NC/CE-T1WI among both radiology residents and general radiologists. Key Points: • ASL improved diagnostic performance for residual/recurrent meningioma compare to NC/CE-T1WI alone.• Diagnostic sensitivity was increased after adding ASL compared with NC/CE-T1WI.• FOM was increased after adding ASL compared with NC/CE-T1WI..
43. Yojiro Akagi, Koji Yoshimoto, Nobuhiro Hata, Daisuke Kuga, Ryusuke Hatae, Takeo Amemiya, Yuhei Sangatsuda, Satoshi Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, Reclassification of 400 consecutive glioma cases based on the revised 2016WHO classification, Brain Tumor Pathology, 10.1007/s10014-018-0313-4, 1-9, 2018.03, In this study, we reclassified 400 consecutive glioma cases including pediatric cases, using the revised 2016 WHO classification with samples collected from the Kyushu University Brain Tumor Bank. The IDH1/2, H3F3A, key genetic markers in the 2016 classification, were analyzed using high-resolution melting, with DNA extracted from frozen tissues. The 1p/19q codeletions were evaluated using a microsatellite-based loss of heterozygosity analysis, with 18 markers, to detect loss of the entire chromosome arm. In the integrated diagnosis, 29 oligodendroglioma cases and 28 anaplastic oligodendroglioma cases were diagnosed as “IDH-mutant and 1p/19q-codeleted,” while 2 oligodendroglioma cases and 5 anaplastic oligodendroglioma cases were diagnosed as not otherwise specified (NOS). These “NOS” cases were either IDH-mutants or 1p/19q-codeleted, although characteristic oligodendroglial features were evident histologically. Better overall survival of patients with oligodendroglioma correlated with the molecular characteristic of “IDH-mutant and 1p/19q-codeleted,” rather than the WHO grade. Eleven “glioblastoma, IDH-wild-type” cases were classified as “1p/19q-codeleted”, however, chromosome 10 loss was also detected in 10 out of 11 cases. The 2016 WHO criteria for glioma classification leads to better diagnosis of patients. However, there are technical pitfalls and problems to be solved in the molecular analysis of routine diagnostics..
44. Koji Yoshimoto, Ryusuke Hatae, Satoshi Suzuki, Nobuhiro Hata, Daisuke Kuga, Yojiro Akagi, Takeo Amemiya, Yuhei Sangatsuda, Nobutaka Mukae, Masahiro Mizoguchi, Toru Iwaki, Koji Iihara, High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas, Neuropathology, 10.1111/neup.12408, 38, 1, 3-10, 2018.02, Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent β-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia..
45. 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..
46. Toshiki Uchihara, Toru Iwaki, Le hazard ou la nécessité? Comorbid pathologies of neurodegenerative diseases, Neuropathology, 10.1111/neup.12444, 38, 1, 62-63, 2018.02.
47. Masahiro Shijo, Hiroyuki Honda, Satoshi O. Suzuki, Hideomi Hamasaki, Masaaki Hokama, Nona Abolhassani, Yusaku Nakabeppu, Toshiharu Ninomiya, Takanari Kitazono, Toru Iwaki, Association of adipocyte enhancer-binding protein 1 with Alzheimer's disease pathology in human hippocampi, Brain Pathology, 10.1111/bpa.12475, 28, 1, 58-71, Epub ahead of print, 2018.01.
48. Shinkichi Takamori, Gouji Toyokawa, Isamu Okamoto, Kazuki Takada, Fumihiko Kinoshita, Yuka Kozuma, Taichi Matsubara, Naoki Haratake, Takaki Akamine, Nobutaka Mukae, Fumihiko Hirai, Tetsuzo Tagawa, Yoshinao Oda, Toru Iwaki, Koji Iihara, Yoichi Nakanishi, Yoshihiko Maehara, Clinical significance of PD-L1 expression in brain metastases from non-small cell lung cancer, Anticancer Research, 10.21873/anticanres.12258, 38, 1, 553-557, 2018.01, Aim: To investigate the association between positivity for programmed cell death-ligand 1 (PD-L1) in brain metastases (BM) and the prognosis or clinical factors in patients with non-small cell lung cancer (NSCLC). Materials and Methods: Thirty-two patients with surgically resected brain-metastatic NSCLC were enrolled. The PD-L1 expression in BM was analyzed using the antibody against human PD-L1 (clone SP142). The PD-L1 positivity was defined as PD-L1 expression on brain-metastatic tumor cells of =5%. Results: Seven (21.9%) out of 32 patients showed PD-L1 positivity in BM. The PD-L1-positive BM group had a significantly shorter brain-specific disease-free survival than the PD-L1-negative BM group (p<
0.05). PD-L1 positivity in BM was significantly associated with a heavy smoking history and the administration of radiotherapy for BM before surgery (p<
0.05 and p<
0.05, respectively). Conclusion: The PD-L1 expression in BM from NSCLC may be associated with local recurrence following surgery, and the smoking- or radiotherapy-derived effects..
49. Osamu Togao, Hiwatashi Akio, Koji Yamashita, Kazufumi Kikuchi, Daichi Momosaka, Koji Yoshimoto, Daisuke Kuga, Masahiro Mizoguchi, Satoshi Suzuki, Toru Iwaki, Marc Van Cauteren, Koji Iihara, Hiroshi Honda, Measurement of the perfusion fraction in brain tumors with intravoxel incoherent motion MR imaging Validation with histopathological vascular density in meningiomas, British Journal of Radiology, 10.1259/bjr.20170912, 91, 1085, 2018.01, Objective: To evaluate the quantification performance of the perfusion fraction (f) measured with intravoxel incoherent motion (IVIM) MR imaging in a comparison with the histological vascular density in meningiomas. Methods: 29 consecutive patients with meningioma (59.0 ± 16.8 years old, 8 males and 21 females) who underwent a subsequent surgical resection were examined with both IVIM imaging and a histopathological analysis. IVIM imaging was conducted using a singleshot SE-EPI sequence with 13 b-factors (0, 10, 20, 30, 50, 80, 100, 200, 300, 400, 600, 800, 1000 s mm-2) at 3T. The perfusion fraction (f) was calculated by fitting the IVIM bi-exponential model. The 90-percentile f-value in the tumor region-of-interest (ROI) was defined as the maximum f-value (f-max). Histopathological vascular density (%Vessel) was measured on CD31-immunostainted histopathological specimens. The correlation and agreement between the f-values and %Vessel was assessed. Results: The f-max (15.5 ± 5.5%) showed excellent agreement [intraclass correlation coefficient (ICC) = 0.754] and a significant correlation (r = 0.69, p < 0.0001) with the %Vessel (12.9 ± 9.4%) of the tumors. The Bland- Altman plot analysis showed excellent agreement between the f-max and %Vessel (bias, -2.6%; 95% limits of agreement, from -16.0 to 10.8%). The f-max was not significantly different among the histological subtypes of meningioma. Conclusion: An excellent agreement and a significant correlation were observed between the f-values and %Vessel. The f-value can be used as a noninvasive quantitative imaging measure to directly assess the vascular volume fraction in brain tumors. Advances in knowledge: The f-value measured by IVIM imaging showed a significant correlation and an excellent agreement with the histological vascular density in the meningiomas. The f-value can be used as a noninvasive and quantitative imaging measure to directly assess the volume fraction of capillaries in brain tumors..
50. Yuhei Sangatsuda, Nobuhiro Hata, Satoshi Suzuki, Yojiro Akagi, Ryusuke Hatae, Daisuke Kuga, Koji Yoshimoto, Seiya Momosaki, Toru Iwaki, Koji Iihara, An elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component in the cerebellar hemisphere, Neuropathology, 10.1111/neup.12478, 2018.01, Pilocytic astrocytoma is a less aggressive form of glial tumor that commonly occurs in the pediatric population, and its malignant transformation is extremely rare. Here, we report an elderly case of malignant small cell glioma with hemorrhage coexistent with a calcified pilocytic astrocytoma component. An 80-year-old male was found to have a right cerebellar non-enhanced tumor with hematoma adjoining a calcified nodule. The lesion was surgically removed, and a histological examination verified that the tumor was a malignant small cell glioma with hemorrhagic change and the calcified nodule showed features of pilocytic astrocytoma. Genetic analyses revealed no glioma-relevant genetic alterations such as IDH and BRAF mutations. Although calcification is generally observed in slowly growing gliomas, the aggressive clinical course of calcified cerebellar pilocytic astrocytoma has been previously reported. Our extremely rare case shows that careful follow-up is necessary even for calcified pilocytic astrocytomas..
51. Kazufumi Kikuchi, Akio Hiwatashi, Osamu Togao, Koji Yamashita, Koji Yoshimoto, Masahiro Mizoguchi, Satoshi O. Suzuki, Toru Iwaki, Yuriko Suzuki, Hiroshi Honda, Correlation between arterial spin-labeling perfusion and histopathological vascular density of pediatric intracranial tumors, Journal of Neuro-Oncology, 10.1007/s11060-017-2604-8, 135, 3, 561-569, Epub ahead of print, 2017.12, Traditional MRI methods for estimation of blood flow in brain tumors require high-flow injection of contrast agents through large-bore intravenous access, which limits their pediatric utility. In contrast, arterial spin-labeling (ASL) can be used without contrast media. This study aimed to evaluate the relationship between tumor blood flow (TBF) measured by ASL and histopathological vascular density in pediatric brain tumors. Nineteen consecutive children were evaluated (10 boys, 9 girls
median age: 6 years
8 high-grade and 11 low-grade tumors). ASL was performed with a pseudocontinuous labeling time of 1650 ms and post-labeling delay of 1525 ms. The maximal absolute (aTBF) and relative (rTBF) tumor blood flows were measured. To evaluate the relative vascular area (%Vessel), the total stained vascular area was divided by the whole tissue area. Spearman’s rank-order correlation, the Mann–Whitney U test, and receiver operating characteristic analysis were used for statistical analysis. The absolute and relative TBF rates were 4.9–92.9 mL/100 g/min and 0.17–3.59 mL/100 g/min, respectively. The %Vessel was 0.6–30.2%. The %Vessel showed a significant positive correlation with TBF (aTBF: r = 0.87, P <
0.0001
rTBF: r = 0.89, P <
0.0001). The TBF rate of high-grade tumors was significantly higher than that of low-grade tumors (aTBF: P = 0.0050, rTBF: P = 0.0036). The rTBF had the best diagnostic performance (area under the curve: 0.89). ASL perfusion imaging without contrast material can be used for accurate evaluation of histopathological vascular density and may be helpful for tumor grading in children..
52. Comparative profiling of cortical gene expression in Alzheimer's disease patients and mouse models demonstrates a link between amyloidosis and neuroinflammation..
53. Hiroyuki Honda, Kensuke Sasaki, Hiroshi Takashima, Daisuke Mori, Sachiko Koyama, Satoshi O. Suzuki, Toru Iwaki, Different Complicated Brain Pathologies in Monozygotic Twins With Gerstmann-Straussler-Scheinker Disease, JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY, 10.1093/jnen/nlx068, 76, 10, 854-863, 2017.10, Gerstmann-Straussler-Scheinker disease (GSS) is an autosomal, dominantly inherited prion disease. In this study, we present different complicated brain pathologies determined postmortem of monozygotic GSS twin sisters. Case 1 showed cerebellar ataxia at the age of 58 years, and died at 66 years. Case 2 became symptomatic at the age of 75 years, and died at 79 years. There was a 17-year difference in the age of onset between the twins. Postmortem examination revealed numerous prion protein (PrP) plaques in the brains of both cases. The spongiform change and brain atrophy in case 1 were more severe compared with those in case 2. Western-blot analysis identified proteinase-resistant PrP (PrPres) at the molecular weight of 21-30 kDa and 8 kDa in the twins. Gel filtration revealed that PrPres was mainly composed of PrP oligomer. PrPres signal patterns were similar between the twins. Additionally, case 1 showed alpha-synuclein-opathy and case 2 showed Alzheimer disease pathology. These different proteinopathies were involved in the amyloid plaque formations of both cases. The degree of GSS pathology was mainly related to disease duration. The amyloid plaque formations could be decorated by concomitant neuropathological changes such as alpha-synuclein-opathy and tauopathy..
54. Koji Yoshimoto, Ryusuke Hatae, Satoshi O Suzuki, Nobuhiro Hata, Daisuke Kuga, Yojiro Akagi, Takeo Amemiya, Yuhei Sangatsuda, Nobutaka Mukae, Masahiro Mizoguchi, Koji Yamashita, Toru Iwaki, Koji Iihara, High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas, Neuropathology, 10.1111/neup.12408, 38, 1, 3-10, 2017.08, Craniopharyngioma consists of adamantinomatous and papillary subtypes. Recent genetic analysis has demonstrated that the two subtypes are different, not only in clinicopathological features, but also in molecular oncogenesis. Papillary craniopharyngioma (pCP) is characterized by a BRAF mutation, the V600E (Val 600 Glu) mutation. Adamantinomatous craniopharyngioma (aCP) can be distinguished by frequent β-catenin gene (CTNNB1) mutations. Although these genetic alterations can be a diagnostic molecular marker, the precise frequency of these mutations in clinical specimens remains unknown. In this study, we first evaluated BRAF V600E and CTNNB1 mutations in four and 14 cases of pCP and aCP, respectively, using high-resolution melting analysis followed by Sanger sequencing. The results showed that 100% (4/4) of pCP cases had BRAF V600E mutations, while 78% (11/14) of the aCP cases had CTNNB1 mutations, with these genetic alterations being subtype-specific and mutually exclusive. Second, we evaluated BRAF V600E and CTNNB1 mutations by immunohistochemical analysis (IHC). All pCP cases showed positive cytoplasmic staining with the BRAF V600E-mutant antibody (VE-1), whereas 86% (12/14) of aCP cases showed positive cytoplasmic and nuclear staining for CTNNB1, suggesting a CTNNB1 mutation. Only one case of wild-type CTNNB1 on the DNA analysis showed immunopositivity on IHC. We did not detect a coexistence of BRAF V600E and CTNNB1 mutations in any single tumor, which indicated that these genetic alterations were mutually exclusive. We also report our modified IHC protocol for VE-1 staining, and present the possibility that BRAF V600E mutations can be used as a diagnostic marker of pCP in the differentiation of Rathke cleft cyst with squamous metaplasia..
55. Daichi Momosaka, Osamu Togao, Akio Hiwatashi, Koji Yamashita, Koji Yoshimoto, Megumu Mori, Toru Iwaki, Hiroshi Honda, Spindle cell/sclerosing rhabdomyosarcoma with intracranial invasion without destroying the bone of the skull base: a case report and literature review., Acta Radiol Open., 10.1177/2058460117727316, 6, 8, 2058460117727316, 2017.08, Spindle cell/sclerosing rhabdomyosarcoma (ssRMS) is a new subtype of rhabdomyosarcoma included in the World Health Organization soft tissue and bone tumor classification in 2013. Despite the increasing number of reported cases of ssRMS, the imaging characteristics of ssRMS are not established. Herein, we present the case of an elderly Japanese woman with ssRMS of the masticator space with intracranial invasion without destruction of the adjacent bone. Attention should be paid to the presence of intracranial infiltration that may indicate a worse prognosis. Tumor growth without bone destruction could be a key finding to differentiate ssRMSs from conventional subtypes of rhabdomyosarcoma..
56. Shinkichi Takamori, Gouji Toyokawa, Isamu Okamoto, Kazuki Takada, Yuka Kozuma, Taichi Matsubara, Naoki Haratake, Takaki Akamine, Masakazu Katsura, Nobutaka Mukae, Fumihiro Shoji, Tatsuro Okamoto, Yoshinao Oda, Toru Iwaki, Koji Iihara, Yoichi Nakanishi, Yoshihiko Maehara, Discrepancy in programmed cell death-ligand 1 between primary and metastatic non-small cell lung cancer, Anticancer Research, 10.21873/anticanres.11813, 37, 8, 4223-4228, 2017.08, Aim: To investigate the discordance in the programmed cell death-ligand 1 (PD-L1) expression between primary and metastatic tumors and analyze the association between the discordance and the clinical factors in non-small cell lung cancer (NSCLC) patients. Patients and Methods: Twenty-one NSCLC patients who underwent surgery or biopsy for paired primary and metastatic lesions at our Institution from 2005 to 2016 were analyzed. Lesions with the PD-L1 expression being 5% were considered PD-L1-positive. Results: The metastatic sites included the brain (n=16), adrenal gland (n=3), spleen (n=1) and jejunum (n=1). Negative conversion of the primary PD-L1-positive NSCLC and positive conversion of the primary PD-L1-negative NSCLC were observed in 3 (14%) and 2 (10%) cases, respectively. Radiotherapy for the metastatic brain lesion before its resection showed a significant relationship with the positive conversion of the primary PD-L1-negative NSCLC (p=0.048). Conclusion: Radiotherapy-derived effects may contribute to the positive conversion of the primary PD-L1-negative NSCLC..
57. Ryusuke Hatae, Nobuhiro Hata, Satoshi O. Suzuki, Koji Yoshimoto, Daisuke Kuga, Hideki Murata, Yojiro Akagi, Yuhei Sangatsuda, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology, NEUROPATHOLOGY, 10.1111/neup.12347, 37, 3, 191-199, Epub 2016 Oct 28, 2017.06, Brain tumors harbor various BRAF alterations, the vast majority of which are the BRAF kinase-activating V600E mutation. BRAF mutations are most frequently detected in certain subtypes of low-grade glioma, such as pilocytic astrocytoma (PA), pleomorphic xanthoastrocytoma (PXA), ganglioglioma (GG) and dysembryoplastic neuroepithelial tumor (DNT). However, it is unclear whether gliomas harboring BRAF mutations can be invariably regarded as these glioma subtypes or their derivatives. To address this question, we analyzed 274 gliomas in our institutional case series. We performed high-resolution melting analyses and subsequent direct Sanger sequencing on DNA isolated from snap-frozen tumor tissues. As expected, BRAF mutations were detected in the aforementioned low-grade gliomas: in 4/27 PAs,2/3 PXAs, 4/8 GGs, and 1/6 DNTs. In addition to these gliomas, 1/2 astroblastomas (ABs) and 2/122 glioblastomas (GBs) harbored BRAF mutations. Pathological investigation of the two GBs revealed that one was a GB displaying epithelial features that presumably arose from a precedent GG, whereas the other GB, which harbored a rare G596 A mutation, showed marked epithelial features, including astroblastic rosettes. Our results indicate that in addition to being present in established BRAF-associated gliomas, BRAF mutations might be associated with epithelial features in high-grade gliomas, including sheet-like arrangement of polygonal tumor cells with a plump cytoplasm and astroblastic rosettes, and thus could potentially serve as a genetic marker for these features..
58. Masahiro Shijo, Hiroyuki Honda, Sachiko Koyama, Koji Ishitsuka, Koichiro Maeda, Junya Kuroda, Mitsugu Tanii, Takanari Kitazono, Toru Iwaki, Dura mater graft-associated Creutzfeldt-Jakob disease with 30-year incubation period, NEUROPATHOLOGY, 10.1111/neup.12359, 37, 3, 275-281, Epub 2016 Dec 7, 2017.06, Over 60% of all patients with dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) have been diagnosed in Japan. The incubation period has ranged from 1 to 30 years and the age at onset from 15 to 80 years. Here, we report a 77-year-old male Japanese autopsied dCJD case with the longest incubation period so far in Japan. He received a cadaveric dural graft at the right cranial convexity following a craniotomy for meningioma at the age of 46. At 30 years post-dural graft placement, disorientation was observed as an initial symptom of dCJD. He rapidly began to present with inconsistent speech, cognitive impairment and tremor of the left upper extremity. Occasional myoclonic jerks were predominantly observed on the left side. Brain MRI presented hyperintense signals on diffusion-weighted and T2-weighted images, at the right cerebral cortex. The most hyperintense lesion was located at the right parietal lobe, where the dura mater graft had been transplanted. Single-photon emission CT scan showed markedly decreased cerebral blood flow at the right parietal lobe. EEG revealed diffuse and slow activities with periodic sharp-wave complex discharges seen in the right parietal, temporal and occipital lobes. He died of pneumonia 9 months after onset. Brain pathology revealed non-plaque-type dCJD. Laterality of neuropathological changes, including spongiform change, neuronal loss, gliosis or PrP deposits, was not evident. Western blot analysis showed type 1 PrPCJD. Alzheimer-type pathology and PSP-like pathology were also observed..
59. Nobuhiro Hata, Ryusuke Hatae, Koji Yoshimoto, Hideki Murata, Daisuke Kuga, Yojiro Akagi, Yuhei Sangatsuda, Satoshi O. Suzuki, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, Insular primary glioblastomas with IDH mutations: Clinical and biological specificities, NEUROPATHOLOGY, 10.1111/neup.12362, 37, 3, 200-206, Epub 2017 Jan 24, 2017.06, Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower-grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH-wildtype (IDH-wt) pGBMs. IDH-mutant (IDH-mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH-mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH-wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long-surviving case, but genetic alterations in the astrocyte-sGBM pathway were generally prevalent in IDH-mut pGBMs. Our results present a unique phenotype of IDH-mut pGBMs arising frominsular cortex region, themolecular backgrounds of which are similar to sGBMs..
60. Shotaro Hayashida, Katsuhisa Masaki, Tomomi Yonekawa, Satoshi O. Suzuki, Akio Hiwatashi, Takuya Matsushita, Mitsuru Watanabe, Ryo Yamasaki, Toshihiko Suenaga, Toru Iwaki, Hiroyuki Murai, Jun-ichi Kira, Early and extensive spinal white matter involvement in neuromyelitis optica, Brain Pathology, 10.1111/bpa.12386, 27, 3, 249-265, 2017.05.
61. Trends in dementia prevalence, incidence, and survival rate in a Japanese community..
62. Naoki Fujii, Akihiro Watanabe, Hajime Arahata, Yuuji Kawano, Naokazu Sasagasako, Toru Iwaki, Report on an 11-year analysis of neurology autopsy cases Focusing on neurodegenerative diseases, IRYO - Japanese Journal of National Medical Services, 71, 5, 199-203, 2017.05.
63. A Case of Suprasellar Ganglioglioma arising from the Genu-Rostrum of the Corpus Callosum composed of Tumor Cells in Various Stages of Neuronal Differentiation.
64. Koji Yoshimoto, Ryusuke Hatae, Yuhei Sangatsuda, Satoshi O Suzuki, Nobuhiro Hata, Yojiro Akagi, Hideki Murata, Daisuke Kuga, Koji Yamashita, Osamu Togao, Hiwatashi Akio, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara, Prevalence and clinicopathological features of H3.3 G34-mutant high-grade gliomas: a retrospective study of 411 consecutive glioma cases in a single institution, Brain Tumor Pathol., 10.1007/s10014-017-0287-7, Epub ahead of print, 2017.04, A recurrent glycine-to-arginine/valine alteration at codon 34 (G34R/V) within H3F3A, a gene that encodes the replication-independent histone variant H3.3, reportedly occurs exclusively in pediatric glioblastomas. However, the clinicopathological and biological significances of this mutation have not been completely elucidated; especially, no such data exist for tumor samples from Japanese patients. We analyzed 411 consecutive glioma cases representing patients of all ages. Our results demonstrated that 14 patients (3.4%) harbored H3F3A mutations, of which four had G34R mutations and 10 had K27M mutations. G34R-mutant tumors were located in the parietal region in two patients and the basal ganglia in one patient. One patient showed multi-lobular extension similar to the pattern observed in gliomatosis cerebri. Regarding neuroradiological features, intratumoral calcification was evident in two cases and all cases showed no or scarce contrast enhancement on MRI. Histopathologically, the four G34R-mutant cases included three glioblastomas and one astroblastoma. We have also investigated alterations in histone methylation including H3K27me3, H3K9me3, and H3K4me3 in G34R-mutant samples by immunohistochemistry. These results indicate that G34R-mutant tumors are likely to show extensive infiltration and alterations in global histone trimethylation might also play an important role in G34R mutant tumors..
65. Osamu Togao, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Jochen Keupp, Koji Yoshimoto, Daisuke Kuga, Masami Yoneyama, Satoshi O. Suzuki, Toru Iwaki, Masaya Takahashi, Koji Iihara, Hiroshi Honda, Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging: comparisons with diffusion- and perfusion-weighted imaging, European Radiology, 10.1007/s00330-016-4328-0, 27, 2, 578-588, in press, 2017.02, Objectives: To investigate whether amide proton transfer (APT) MR imaging can differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) among gliomas without intense contrast enhancement (CE). Methods: This retrospective study evaluated 34 patients (22 males, 12 females
age 36.0 ± 11.3 years) including 20 with LGGs and 14 with HGGs, all scanned on a 3T MR scanner. Only tumours without intense CE were included. Two neuroradiologists independently performed histogram analyses to measure the 90th-percentile (APT90) and mean (APTmean) of the tumours’ APT signals. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were also measured. The parameters were compared between the groups with Student’s t-test. Diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis. Results: The APT90 (2.80 ± 0.59 % in LGGs, 3.72 ± 0.89 in HGGs, P = 0.001) and APTmean (1.87 ± 0.49 % in LGGs, 2.70 ± 0.58 in HGGs, P = 0.0001) were significantly larger in the HGGs compared to the LGGs. The ADC and rCBV values were not significantly different between the groups. Both the APT90 and APTmean showed medium diagnostic performance in this discrimination. Conclusions: APT imaging is useful in discriminating HGGs from LGGs among diffuse gliomas without intense CE. Key Points: • Amide proton transfer (APT) imaging helps in grading non-enhancing gliomas • High-grade gliomas showed higher APT signal than low-grade gliomas • APT imaging showed better diagnostic performance than diffusion- and perfusion-weighted imaging.
66. Osamu Togao, Hiwatashi Akio, Koji Yamashita, Kazufumi Kikuchi, Jochen Keupp, Koji Yoshimoto, Daisuke Kuga, Masami Yoneyama, Satoshi Suzuki, Toru Iwaki, Masaya Takahashi, Koji Iihara, Hiroshi Honda, Grading diffuse gliomas without intense contrast enhancement by amide proton transfer MR imaging
comparisons with diffusion- and perfusion-weighted imaging, European Radiology, 10.1007/s00330-016-4328-0, 27, 2, 578-588, 2017.02, Objectives: To investigate whether amide proton transfer (APT) MR imaging can differentiate high-grade gliomas (HGGs) from low-grade gliomas (LGGs) among gliomas without intense contrast enhancement (CE). Methods: This retrospective study evaluated 34 patients (22 males, 12 females; age 36.0 ± 11.3 years) including 20 with LGGs and 14 with HGGs, all scanned on a 3T MR scanner. Only tumours without intense CE were included. Two neuroradiologists independently performed histogram analyses to measure the 90th-percentile (APT90) and mean (APTmean) of the tumours’ APT signals. The apparent diffusion coefficient (ADC) and relative cerebral blood volume (rCBV) were also measured. The parameters were compared between the groups with Student’s t-test. Diagnostic performance was evaluated with receiver operating characteristic (ROC) analysis. Results: The APT90 (2.80 ± 0.59 % in LGGs, 3.72 ± 0.89 in HGGs, P = 0.001) and APTmean (1.87 ± 0.49 % in LGGs, 2.70 ± 0.58 in HGGs, P = 0.0001) were significantly larger in the HGGs compared to the LGGs. The ADC and rCBV values were not significantly different between the groups. Both the APT90 and APTmean showed medium diagnostic performance in this discrimination. Conclusions: APT imaging is useful in discriminating HGGs from LGGs among diffuse gliomas without intense CE. Key Points: • Amide proton transfer (APT) imaging helps in grading non-enhancing gliomas • High-grade gliomas showed higher APT signal than low-grade gliomas • APT imaging showed better diagnostic performance than diffusion- and perfusion-weighted imaging.
67. Nona Abolhassani, Julio Leon, Zijing Sheng, Sugako Oka, Hideomi Hamasaki, Toru Iwaki, Yusaku Nakabeppu, Molecular pathophysiology of impaired glucose metabolism, mitochondrial dysfunction, and oxidative DNA damage in Alzheimer's disease brain., Mechanisms of ageing and development, 10.1016/j.mad.2016.05.005, 161, Pt A, 95-104, 2017.01, 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..
68. 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, Journal of Alzheimer's Disease, 10.3233/jad-160521, 55, 2, 613-624, 2016.11.
69. Nobuhiro Hata, Koji Yoshimoto, Ryusuke Hatae, Daisuke Kuga, Yojiro Akagi, Satoshi Suzuki, Toru Iwaki, Tadahisa Shono, Masahiro Mizoguchi, Koji Iihara, Deferred radiotherapy and upfront procarbazine–ACNU–vincristine administration for 1p19q codeleted oligodendroglial tumors are associated with favorable outcome without compromising patient performance, regardless of WHO grade, OncoTargets and Therapy, 10.2147/ott.s115911, Volume 9, 7123-7131, 2016.11.
70. Koji Yamashita, Akio Hiwatashi, Osamu Togao, Kazufumi Kikuchi, Yoshiyuki Kitamura, Masahiro Mizoguchi, Koji Yoshimoto, Daisuke Kuga, Satoshi O. Suzuki, Shingo Baba, Takuro Isoda, Toru Iwaki, Koji Iihara, Hiroshi Honda, Diagnostic utility of intravoxel incoherent motion mr imaging in differentiating primary central nervous system lymphoma from glioblastoma multiforme, Journal of Magnetic Resonance Imaging, 10.1002/jmri.25261, 44, 5, 1256-1261, 2016.11, Purpose: To evaluate the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating primary central nervous system lymphoma (PCNSL) from glioblastoma multiforme (GBM). Materials and Methods: Fifty patients, 17 with PCNSL and 33 with GBM, were retrospectively studied. From the 3 Tesla IVIM data, the perfusion fraction (f) and diffusion coefficient (D) were obtained. In addition, the maximum standard uptake value (SUVmax) was obtained from the FDG-PET data. Each of the three parameters was compared between PCNSL and GBM using Mann-Whitney U-test. The performance in discriminating between PCNSL and GBM was evaluated using receiver-operating characteristics analysis and area-under-the-curve (AUC) values for the three parameters. Results: The fmax and Dmin values were significantly higher in GBM than in PCNSL (P <
0.01 and P <
0.0001, respectively). In addition, the SUVmax value was significantly lower in GBM than in PCNSL (P <
0.0005). The AUC values for fmax, Dmin, and SUVmax were 0.756, 0.905, and 0.857, respectively. The combination of the fmax and Dmin increased the diagnostic performance (AUC = 0.936) of fmax (P <
0.05), but this value was not significantly different from the values for Dmin (P = 0.30). Conclusion: IVIM-MR imaging noninvasively provides useful quantitative information in distinguishing between PCNSL and GBM. J. Magn. Reson. Imaging 2016
44:1256–1261..
71. Hiroyuki Honda, Kosuke Matsuzono, Soichiro Fushimi, Kota Sato, Satoshi O Suzuki, Koji Abe, 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., Journal of neuropathology and experimental neurology, 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..
72. 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, 2010 Jul 9. [Epub ahead of print], 2016.08.
73. Trends in autopsy-verified dementia prevalence over 29 years of the Hisayama study..
74. Atsushi Kobayashi, Yuichi Matsuura, Toru Iwaki, Yasushi Iwasaki, Mari Yoshida, Hitoshi Takahashi, Shigeo Murayama, Masaki Takao, Shinsuke Kato, Masahito Yamada, Shirou Mohri, Tetsuyuki Kitamoto, Sporadic Creutzfeldt-Jakob Disease MM1+2C and MM1 are Identical in Transmission Properties, Brain Pathology, 10.1111/bpa.12264, 26, 1, 95-101, Epub ahead of print, 2016.01, The genotype (methionine, M or valine, V) at polymorphic codon 129 of the PRNP gene and the type (1 or 2) of abnormal prion protein in the brain are the major determinants of the clinicopathological features of sporadic Creutzfeldt-Jakob disease (CJD), thus providing molecular basis for classification of sporadic CJD, that is, MM1, MM2, MV1, MV2, VV1 or VV2. In addition to these "pure" cases, "mixed" cases presenting mixed neuropathological and biochemical features have also been recognized. The most frequently observed mixed form is the co-occurrence of MM1 and MM2, namely MM1+2. However, it has remained elusive whether MM1+2 could be a causative origin of dura mater graft-associated CJD (dCJD), one of the largest subgroups of iatrogenic CJD. To test this possibility, we performed transmission experiments of MM1+2 prions and a systematic neuropathological examination of dCJD patients in the present study. The transmission properties of the MM1+2 prions were identical to those of MM1 prions because MM2 prions lacked transmissibility. In addition, the neuropathological characteristics of MM2 were totally absent in dCJD patients examined. These results suggest that MM1+2 can be a causative origin of dCJD and causes neuropathological phenotype similar to that of MM1..
75. Matsuzono K, Hiroyuki Honda, Sato K, Morihara R, Hishikawa N, Yamashita T, Kono S, Ohta Y, Toru Iwaki, Abe K, 'PrP systemic deposition disease': clinical and pathological characteristics of novel familial prion disease with 2-bp deletion in codon 178, Eur J Neurol., 10.1111/ene.12905., 23, 1, 196-200, 2016.01, BACKGROUND AND PURPOSE: A novel TYPE of prion disease associated mainly with autonomic-sensory polyneuropathy was reported by us previously.
METHODS: Here the autopsy pathology for patient 1 (the sister) and the clinical characteristics of her younger brother (patient 2) are newly reported. Polymerase chain reaction based restriction fragment length polymorphism analysis of the prion protein gene (PRNP) was performed on both patients and their father (normal control).
RESULTS: Polymerase chain reaction based restriction fragment length polymorphism analysis revealed a 2-bp deletion (CT) in codon 178 that causes an additional variable 25 amino acids at the C terminal, from the mutation site to the premature stop codon at codon 203, in both patients 1 and 2 but not in their father. The autopsy of patient 1 showed remarkable prion protein (PrP) deposits in the sympathetic ganglion and peripheral nerves, correlated to her severe autonomic sensory failure. PrP deposits were also found in the central nervous system and peripheral organs such as the heart, lung, stomach, jejunum, ileum, colon, urinary bladder and adrenal gland. The symptoms and biopsy findings of patient 2 were nearly the same as those reported previously for patient 1. His cognitive function was well preserved, but autonomic functions were severely impaired. His biopsied samples showed PrP deposits in the sural nerve and nerve plexuses of the stomach and colon.
CONCLUSION: The present unique 2-bp deletion (CT) in codon 178 induced a 'PrP systemic deposition disease' such as pan-autonomic failure, sensory neuropathy and mild cognitive impairment with a specific pathology..
76. Osamu Togao, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Masahiro Mizoguchi, Koji Yoshimoto, Satoshi O. Suzuki, Toru Iwaki, Makoto Obara, Marc Van Cauteren, Hiroshi Honda, Differentiation of high-grade and low-grade diffuse gliomas by intravoxel incoherent motion MR imaging, Neuro-Oncology, 10.1093/neuonc/nov147, 18, 1, 132-141, 2016.01, Background Our aim was to assess the diagnostic performance of intravoxel incoherent motion (IVIM) MR imaging for differentiating high-grade gliomas (HGGs) from low-grade gliomas (LGGs). Methods Forty-five patients with diffuse glioma (age 50.9 ± 20.4 y
26 males, 19 females) were assessed with IVIM imaging using 13 b-values (0-1000 s/mm2) at 3T. The perfusion fraction (f), true diffusion coefficient (D), and pseudo-diffusion coefficient (D∗) were calculated by fitting the bi-exponential model. The apparent diffusion coefficient (ADC) was obtained with 2 b-values (0 and 1000 s/mm2). Relative cerebral blood volume was measured by the dynamic susceptibility contrast method. Two observers independently measured D, ADC, D∗, and f, and these measurements were compared between the LGG group (n = 16) and the HGG group (n = 29). Results Both D (1.26 ± 0.37 mm2/s in LGG, 0.94 ± 0.19 mm2/s in HGG
P <
. 001) and ADC (1.28 ± 0.35 mm2/s in LGG, 1.03 ± 0.19 mm2/s in HGG
P <
. 01) were lower in the HGG group. D was lower than ADC in the LGG (P <
. 05) and HGG groups (P <
. 0001). D∗ was not different between the groups. The f-values were significantly larger in HGG (17.5 ± 6.3%) than in LGG (5.8 ± 3.8%
P <
. 0001) and correlated with relative cerebral blood volume (r = 0.85
P <
. 0001). Receiver operating characteristic analyses showed areas under curve of 0.95 with f, 0.78 with D, 0.73 with ADC, and 0.60 with D∗. Conclusion IVIM imaging is useful in differentiating HGGs from LGGs..
77. Midlife and Late-Life Smoking and Risk of Dementia in the Community: The Hisayama Study..
78. Multiphasic acute disseminated encephalomyelitis associated with atypical rubella virus infection - response to the letter from Wu et al..
79. Akira Maekawa, Kenichi Kohashi, Yuichi Yamada, Akira Nakamizo, Koji Yoshimoto, Masahiro Mizoguchi, Toru Iwaki, Yoshinao Oda, A case of intracranial solitary fibrous tumor/hemangiopericytoma with dedifferentiated component, Neuropathology, 10.1111/neup.12181, 35, 3, 260-265, 2015.06, We report the case of a 51-year-old Japanese man with an intracranial dedifferentiated solitary fibrous tumor/hemangiopericytoma (SFT/HPC) identified morphologically and immunohistochemically, comprised of a typical SFT/HPC with a high-grade pleomorphic component. NAB2-STAT6 fusion transcripts were detected by reverse transcriptase polymerase chain reaction in both the conventional and high-grade components. The tumor cells in both components showed the nuclear expression of STAT6 protein, indicating the diagnostic value of these examinations. Intracranial dedifferentiated SFT/HPC is a very rare but important differential diagnosis in intracranial pleomorphic tumors..
80. Multiphasic acute disseminated encephalomyelitis associated with atypical rubella virus infection..
81. 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..
82. 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 cancers, including gliomas. Acetyl-CoA carboxylase (ACC) catalyzes the carboxylation of acetyl-CoA to malonylCoA, 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 (21 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..
83. Altered expression of diabetes-related genes in Alzheimer's disease brains: the Hisayama study..
84. 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 : official journal of the Japanese Society of Neuropathology, 10.1111/neup.12095, 34, 3, 284-90, 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 component-dependent 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..
85. Osamu Togao, Takashi Yoshiura, Jochen Keupp, Akio Hiwatashi, Koji Yamashita, Kazufumi Kikuchi, Yuriko Suzuki, Satoshi O. Suzuki, Toru Iwaki, Nobuhiro Hata, Masahiro Mizoguchi, Koji Yoshimoto, Koji Sagiyama, Masaya Takahashi, Hiroshi Honda, Amide proton transfer imaging of adult diffuse gliomas: correlation with histopathological grades, NEURO-ONCOLOGY, 10.1093/neuonc/not158, 16, 3, 441-448, Epub 2013 Dec 4., 2014.03, Background. Amide proton transfer (APT) imaging is a novel molecular MRI technique to detect endogenous mobile proteins and peptides through chemical exchange saturation transfer. We prospectively assessed the usefulness of APT imaging in predicting the histological grade of adult diffuse gliomas.
Methods. Thirty-six consecutive patients with histopathologically proven diffuse glioma (48.1 +/- 14.7 y old, 16 males and 20 females) were included in the study. APT MRI was conducted on a 3T clinical scanner and was obtained with 2 s saturation at 25 saturation frequency offsets omega = -6 to + 6 ppm (step 0.5 ppm). delta B-0 maps were acquired separately for a point-by-point delta B-0 correction. APT signal intensity (SI) was defined as magnetization transfer asymmetry at 3.5 ppm: magnetization transfer ratio (MTR)(asym) = (S[-3.5 ppm] -S[+ 3.5 ppm])/S-0. Regions of interest were carefully placed by 2 neuroradiologists in solid parts within brain tumors. The APT SI was compared with World Health Organization grade, Ki-67 labeling index (LI), and cell density.
Results. The mean APT SI values were 2.1 +/- 0.4% in grade II gliomas (n = 8), 3.2 +/- 0.9% in grade III gliomas (n = 10), and 4.1 +/- 1.0% in grade IV gliomas (n = 18). Significant differences in APT intensity were observed between grades II and III (P < .05) and grades III and IV (P < .05), as well as between grades II and IV (P < .001). There were positive correlations between APT SI and Ki-67 LI (P = .01, R = 0.43) and between APT SI and cell density (P < .05, R = 0.38). The gliomas with microscopic necrosis showed higher APT SI than those without necrosis (P < .001).
Conclusions. APT imaging can predict the histopathological grades of adult diffuse gliomas..
86. Masahiro Mizoguchi, Nobuhiro Hata, Satoshi O. Suzuki, Yutaka Fujioka, Hideki Murata, Toshiyuki Amano, Akira Nakamizo, Koji Yoshimoto, Toru Iwaki, Tomio Sasaki, Pediatric glioblastoma with oligodendroglioma component: Aggressive clinical phenotype with distinct molecular characteristics, NEUROPATHOLOGY, 10.1111/neup.12029, 33, 6, 652-657, 2013 Mar 27. [Epub ahead of print], 2013.12, The 2007 World Health Organization classification defined a new variant of glioblastoma (GBM) containing oligodendroglioma foci as GBM with an oligodendroglioma component (GBMO), which shows a favorable clinical outcome compared with classic GBM. However, all of the reported cases of GBMO have been adult cases, with no previous reports of pediatric cases. In this report, we demonstrated molecular characteristics of a pediatric GBMO case, showing aggressive clinical behavior with 8-month overall survival. The case showed neither isocitrate dehydrogenase 1/2 genes (IDH1/2) mutation nor 1p/19q co-deletion, a hallmark of oligodendroglioal tumors. In addition, microsatellite instability, leading to the putative mechanism of temozolomide (TMZ) resistance, was frequently detected. Molecular genetic analysis may provide critical prognostic and therapeutic insights, especially for the pediatric glioma containing oligodendroglioma components..
87. An autopsy case of Alzheimer’s disease presenting with corticobasal syndrome.
88. A case of hereditary diffuse leukoencephalopathy with axonal spheroids caused by a de novo mutation in CSF1R masquerading as primary progressive multiple sclerosis..
89. TAR DNA-binding protein 43 pathology in a case clinically diagnosed with facial-onset sensory and motor neuronopathy syndrome: an autopsied case report and a review of the literature..
90. Impaired cytoplasmic-nuclear transport of hypoxia-inducible factor-1α in amyotrophic lateral sclerosis..
91. Katsuhisa Masaki, Satoshi O. Suzuki, Takuya Matsushita, Takeshi Matsuoka, Shihoko Imamura, Ryo Yamasaki, Makiko Suzuki, Toshihiko Suenaga, Toru Iwaki, Jun-Ichi Kira, Connexin 43 Astrocytopathy Linked to Rapidly Progressive Multiple Sclerosis and Neuromyelitis Optica, PLoS ONE, 10.1371/journal.pone.0072919, 8, 8, e72919-e72919, 2013.08.
92. Toshiyuki Amano, Satoshi O. Suzuki, Masahiro Mizoguchi, Koji Yoshimoto, Akira Nakamizo, Hideki Murata, Toru Iwaki, Tomio Sasaki, A fibrotic nodule arising from the cerebellopontine angle, Brain Tumor Pathology, 10.1007/s10014-012-0105-1, 30, 2, 122-127, Published online: 08 June 2012, 2013.04, The authors present an extremely rare case of a fibrotic nodule arising from the cerebellopontine (CP) angle. A 57-year-old male had suffered from hearing disturbance and tinnitus for several years. Computed tomography revealed a high-density mass in the left CP angle with little enhancement after intravenous administration of contrast media. Magnetic resonance imaging (MRI) showed a very hypointense mass on T2-weighted imaging. T1-weighted MRI with gadolinium revealed very faint, delayed enhancement of the tumor. The patient underwent surgical resection of the tumor. Histopathologically the lesion comprised entirely fibrotic tissue consisting of thick collagenous fibers and sclerosing blood vessels with a few intervening viable cells with, partly, the immunophenotype of arachnoid cells. Intracranial fibrotic nodules are extremely rare. This tumor, however, had some radiological features similar to those of other, more common, tumors for example meningiomas or solitary fibrous tumors
it was, therefore, difficult to distinguish it from the others. It is believed that intracranial fibrotic nodules usually have benign, non-neoplastic characteristics, although their natural history is not yet fully understood. It is, therefore, necessary to be able to perform a differential diagnosis that will distinguish this rare condition from other intracranial fibrous neoplasms that occasionally have malignant features. © The Japan Society of Brain Tumor Pathology 2012..
93. Toru Iwaki, The 102nd Neuropathological Meeting of Kyushu District 3 November 2012, Neuropathology, 10.1111/neup.12001, 33, 2, 219-219, 2013.04.
94. HIROYUKI HONDA, Ryotaro Ishii, Ai Hamano, Kyoko Itoh, Satoshi O Suzuki, Shinji Fushiki, Masanori Nakagawa, Toru Iwaki, Microsphere formation in a subtype of Creutzfeldt-Jakob disease with a V180I mutation and codon 129 MM polymorphism., Neuropathol Appl Neurobiol., 10.1111/nan.12047., 2013 Mar 26.[Epub ahead of print], 2013.03, Creutzfeldt-Jakob disease (CJD) with a point mutation of valine to isoleucine at codon 180 in the gene for PrP (V180I CJD) is genetic form of CJD found most frequently in Japan [1]. There are several reports of autopsied V180I CJD cases [2, 3], in which the examples with methionine and valine heterozygosity at the polymorphic codon 129 were found at a higher rate compared to the normal population in Japan [4]. Here, we report a patient with numerous amyloid microsphere formations in an unusual subtype of CJD with a V180I MM mutation who underwent a continuous intraventricular infusion of pentosan polysulfate (PPS). Western blot analysis for protease-resistant PrP (PrPres ) revealed the characteristic two bands devoid of a diglycoform. Size exclusion gel chromatography showed that diglycoform PrPs were present mainly in a monomeric state, and less in an oligomeric state, and that the diglycoform PrPs were completely degraded by proteinase K (PK) treatment. These PrP-positive structures and PrP molecular species were unique to genetic CJD with V180I and 129MM..
95. Koji Yamashita, Takashi Yoshiura, Akio Hiwatashi, Osamu Togao, Koji Yoshimoto, Satoshi O. Suzuki, Koichiro Abe, Kazufumi Kikuchi, Yasuhiro Maruoka, Masahiro Mizoguchi, Toru Iwaki, Hiroshi Honda, Differentiating primary CNS lymphoma from glioblastoma multiforme: Assessment using arterial spin labeling, diffusion-weighted imaging, and 18F-fluorodeoxyglucose positron emission tomography, Neuroradiology, 10.1007/s00234-012-1089-6, 55, 2, 135-143, 2012 Sep 9. [Epub ahead of print], 2013.02, Introduction: Our purpose was to evaluate the diagnostic performance of arterial spin labeling (ASL) perfusion imaging, diffusion-weighted imaging (DWI), and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in differentiating primary central nervous system lymphomas (PCNSLs) from glioblastoma multiformes (GBMs). Methods: Fifty-six patients including 19 with PCNSL and 37 with GBM were retrospectively studied. From the ASL data, an absolute tumor blood flow (aTBF) and a relative tumor blood flow (rTBF) were obtained within the enhancing portion of each tumor. In addition, the minimum apparent diffusion coefficient (ADCmin) and the maximum standard uptake value (SUVmax) were obtained from DWI and FDG-PET data, respectively. Each of the four parameters was compared between PCNSLs and GBMs using Kruskal-Wallis test. The performance in discriminating between PCNSLs and GBMs was evaluated using the receiver-operating characteristics analysis. Area-under-the-curve (AUC) values were compared among the four parameters using a nonparametric method. Results: The aTBF, rTBF, and ADCmin were significantly higher in GBMs (mean aTBF ± SD = 91.6 ± 56.0 mL/100 g/min, mean rTBF ± SD = 2.61 ± 1.61, mean ADCmin ± SD = 0.78 ± 0.19 × 10-3 mm2/s) than in PCNSLs (mean aTBF ± SD = 37.3 ± 10.5 mL/100 g/min, mean rTBF ± SD = 1.24 ± 0.37, mean ADCmin ± SD = 0.61 ± 0.13 × 10-3 mm2/s) (p <
0.005, respectively). In addition, SUVmax was significantly lower in GBMs (mean ± SD = 13.1 ± 6.34) than in PCNSLs (mean ± SD = 22.5 ± 7.83) (p <
0.005). The AUC for aTBF (0.888) was higher than those for rTBF (0.810), ADCmin (0.768), and SUVmax (0.848), although their difference was not statistically significant. Conclusion: ASL perfusion imaging is useful for differentiating PCNSLs from GBMs as well as DWI and FDG-PET. © 2012 Springer-Verlag..
96. Satoko Shibano, Kensuke Sasaki, Satoru Kidoaki, Toru Iwaki, 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. © 2012 Japanese Society of Neuropathology..
97. Intracellular accumulation of toxic turn amyloid-β is associated with endoplasmic reticulum stress in Alzheimer's disease..
98. Nobuya Murakami, Takato Morioka, Satoshi O. Suzuki, Kimiaki Hashiguchi, Toshiyuki Amano, Ayumi Sakata, Toru Iwaki, Tomio Sasaki, Focal cortical dysplasia type IIa underlying epileptogenesis in patients with epilepsy associated with Sturge-Weber syndrome, EPILEPSIA, 10.1111/j.1528-1167.2012.03628.x, 53, 11, e184-e188, 2012 Aug 20. [Epub ahead of print], 2012.11, In patients with epilepsy associated with Sturge-Weber syndrome (SWS), epileptogenesis has been suggested to be caused by chronic ischemia in cortical areas affected by leptomeningeal angiomatosis or by ischemia-related cortical malformations. However, this has not been fully verified electrophysiologically. We herein present two cases of SWS with medically intractable epilepsy in which the epileptogenic area involved focal cortical dysplasia (FCD) type IIa near the region of leptomeningeal angiomatosis. In both cases, the ictal-onset zones were identified by chronic subdural electrodes, and the presence of FCD type IIa was shown histopathologically. In SWS, especially in association with focal leptomeningeal angiomatosis, FCD may thus play a major role in epileptogenesis. FCD should therefore be demonstrated by the collective findings of perioperative neurophysiologic examination, anatomic and functional neuroimaging, and histopathologic examination..
99. Koji Yamashita, Takashi Yoshiura, Akio Hiwatashi, Osamu Togao, Koji Yoshimoto, Satoshi O. Suzuki, Kazufumi Kikuchi, Masahiro Mizoguchi, Toru Iwaki, Hiroshi Honda, Arterial spin labeling of hemangioblastoma: Differentiation from metastatic brain tumors based on quantitative blood flow measurement, Neuroradiology, 10.1007/s00234-011-0977-5, 54, 8, 809-813, 2011 Nov 10. [Epub ahead of print], 2012.08, Introduction Hemangioblastoma and metastatic tumors are the major differential diagnoses for the posterior fossa tumors in adults. Our purpose was to evaluate the efficacy of ASL in differentiating hemangioblastomas from metastatic brain tumors. Methods A total of 19 patients including 5 with a hemangioblastomas and 14 with metastatic tumors (7 from lung cancer, 4 frombreast cancer, 1 fromRCC, 1 from gastric cancer, and 1 from unknown origin) were enrolled in this study. ASL was performed using a pulsed ASL method at a 3-T unit. aTBF was measured as a mean absolute blood flow value within a region of interest drawn in the tumor. In addition, rTBF was obtained by normalizing the aTBF by a blood flow measured in the normal-appearing cortical gray matter. The aTBF and rTBF values were compared between hemangioblastomas and metastatic tumors using Student's t test. Results Both the aTBF and rTBF values were significantly higher in hemangioblastomas (mean aTBF±SD=437± 274 mL/100 g/min, mean rTBF±SD=7.96±3.12) in comparison with metastatic brain tumors (mean aTBF±SD= 125±134 mL/100 g/min, mean rTBF±SD=2.98±3.91
P<
0.05, respectively). However, a metastasis from RCC showed very high aTBF (559 mL/100 g/min) and rTBF (16.2). Conclusion Our results demonstrated that ASL provides useful information to differentiate between hemangioblastomas and metastatic brain tumors. Metastasis from RCC may mimic hemangioblastoma on ASL blood flow measurement. © 2011 Springer-Verlag..
100. Masahiro Mizoguchi, Koji Yoshimoto, Xinlong Ma, Yanlei Guan, Nobuhiro Hata, Toshiyuki Amano, Akira Nakamizo, Satoshi O. Suzuki, Toru Iwaki, Tomio Sasaki, Molecular characteristics of glioblastoma with 1p/19q co-deletion, BRAIN TUMOR PATHOLOGY, 10.1007/s10014-012-0107-z, 29, 3, 148-153, 2012 Jun 27. [Epub ahead of print], 2012.07, Recent developments in molecular analysis have revealed genetic alterations in human gliomas. Loss of heterozygosity (LOH) is a critical molecular marker for classification of human glioma, and is useful for predicting outcome. Our previous LOH study identified a small subgroup of glioblastoma (GBM), with 1p/19q co-deletion, with a favorable clinical outcome. In this study, we investigated molecular pathological features of eight GBM with 1p/19q co-deletion compared with "classic" GBM and anaplastic oligodendroglioma (AO). We estimated EGFR gene amplification, EGFRvIII expression, CDKN2A (p16) homozygous deletion, and isocitrate dehydrogenase 1/2 (IDH1/2) gene mutations. We also conducted an analysis of the expression of proneural genes (DLL3, OLIG2, SOX2). On histopathological review, only one GBM was diagnosed as glioblastoma with oligodendroglioma component (GBMO). Loss of chromosomes 10 and 17p is common, and neither IDH1/2 mutations nor EGFRvIII expression were detected in GBM with 1p/19q co-deletion. The expression profile revealed high expression of the OLIG2 gene in this subgroup. High expression of proneural gene OLIG2 without EGFRvIII expression may be associated with a favorable clinical outcome; however, IDH1/2 gene status and the extent of LOH regions may indicate that this small subgroup of GBM is a distinct genetic subgroup from oligodendroglial tumors..
101. Extensive loss of connexins in Baló's disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocyte/myelin interaction..
102. 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.
103. Differential activation of proapoptotic molecules between mouse and rat models of distal motor trigeminal denervation..
104. Omoto M, Suzuki SO, Ikeuchi T, Ishihara T, Kobayashi T, Tsuboi Y, Ogasawara J, Koga M, Kawai M, Iwaki T, Kanda T, Autosomal dominant tauopathy with parkinsonism and central hypoventilation, Neurology, 78, 10, 762-764, Epub 2012 Feb 22, 2012.03.
105. M. Omoto, S. Suzuki, T. Ikeuchi, T. Ishihara, T. Kobayashi, Y. Tsuboi, J. Ogasawara, M. Koga, M. Kawai, T. Iwaki, T. Kanda, Clinical/Scientific notes, Neurology, 10.1212/WNL.0b013e318248e531, 78, 10, 762-764, 2012.03.
106. Kenta Masui, Yukako Nakata, Naoki Fujii, Toru Iwaki, Extensive distribution of glial cytoplasmic inclusions in an autopsied case of multiple system atrophy with a prolonged 18-year clinical course, Neuropathology, 10.1111/j.1440-1789.2011.01222.x, 32, 1, 69-76, Epub 2011 May 26, 2012.02, We describe herein an autopsied case of multiple system atrophy (MSA) with prolonged clinical course of 18 years, and evaluate the extent of neurodegeneration and glial cytoplasmic inclusions (GCIs) in the entire brain of this rare case. A 64-year-old woman presented with typical neurological symptoms and imaging features of MSA. Thereafter, she became bedridden, and breathing was assisted through a tracheostomy for 12 years. She died at the age of 82 after 18 years from the initial symptom. Post mortem examination revealed severe neurodegeneration in the inferior olive, pontine nuclei, substantia nigra, locus ceruleus, putamen and cerebellum. Notably, phosphorylated α-synuclein (p-α-syn)-positive GCIs were found in these areas, but their number was very low. In contrast, the density of GCIs was much higher in such regions as the tectum/tegmentum of the brainstem, pyramidal tracts, neocortices and limbic system, which usually contain a small number of GCIs. Another constituent of GCIs, ubiquitin (Ub) and Ub-associated autophagy substrate p62, were also positive in some GCIs, and distribution of Ub/p62 immunoreactivity was proportionate to that of p-α-syn+ GCIs despite the very long duration of the disease. Furthermore, this case had complicated hypoxic encephalopathy, but p-α-syn+ GCIs were also found in the damaged white matter, indicating the contribution of α-syncleinopathy as well as hypoxic effect to the secondary myelin and axonal loss in the white matter. Together, this rare case suggests the contribution of the disease duration to the prevalence of GCIs, and the possible involvement of the limbic system in extensive-stage disease. © 2011 Japanese Society of Neuropathology..
107. Yuichiro Kikkawa, Akira Nakamizo, Satoshi O. Suzuki, Shunya Tanaka, Ryosuke Tsuchimochi, Toshiyuki Amano, Koji Yoshimoto, Masahiro Mizoguchi, Toru Iwaki, Tomio Sasaki, Spinal endodermal cyst resembling an arachnoid cyst in appearance: Pitfalls in intraoperative diagnosis of cystic lesions, Surgical Neurology International, 10.4103/2152-7806.98518, 3, 1, 78, Available FREE in open access from: http://www.surgicalneurologyint.com/text.asp?2012/3/1/78/98518, 2012.01, Background: Surgical treatment of endodermal cysts requires total removal of the cyst wall during the first operation to prevent recurrence. Therefore, intraoperative pathological diagnosis plays an important role in determining the optimal surgical strategy. We present a rare case of a spinal endodermal cyst and discuss its diagnostic difficulty during the intraoperative pathological examination. Case Description: An 18-year-old male presented with progressive paraparesis and precordial oppression. Magnetic resonance (MR) imaging revealed an intradural extramedullary cystic mass having the same signal intensity as cerebrospinal fluid (CSF) without gadolinium enhancement at the T1-T2 level. The preoperative diagnosis was an endodermal or arachnoid cyst. The patient underwent surgery. An intraoperative frozen section showed a cyst wall consisting of loose, thin, fibrous tissue intermittently covered by flattened epithelium. The diagnosis was an arachnoid cyst. Accordingly, partial resection of the cyst wall was performed to create CSF communication between the cyst and subarachnoid space. However, the postoperative pathological diagnosis from permanent sections was an endodermal cyst, which was lined with ciliated columnar epithelium that was immunopositive for cytokeratin and epithelial membrane antigen. Subsequent paraffin embedding and immunostaining of the intraoperative frozen sample also confirmed patchy cytokeratin expression by all flattened epithelial cells. The patient's cyst had refilled 10 months after surgery, and he subsequently underwent fenestration of the cyst wall and placement of a cyst-subarachnoid shunt. Conclusion: Examination of multiple samples from multiple sites or intraoperative immunostaining of frozen sections is recommended for accurate intraoperative diagnosis of endodermal cysts. Copyright © 2012 Kikkawa Y..
108. Satoshi O. Suzuki, Toru Iwaki, Kenji Arakawa, Hirokazu Furuya, Naoki Fujii, Akiko Iwaki, 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 NEUROPATHOLOGICA, 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..
109. [Astrocytopathy in neuromyelitis optica, multiple sclerosis and Baló's disease]..
110. 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, 77, 12, 1126-1134, 2011.09.
111. T. Matsuzaki, K. Sasaki, J. Hata, Y. Hirakawa, K. Fujimi, T. Ninomiya, S. O. Suzuki, S. Kanba, Y. Kiyohara, T. Iwaki, Association of Alzheimer 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 epsilon 4 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. Neurology (R) 2011; 77: 1068-1075.
112. Reappraisal of aquaporin-4 astrocytopathy in Asian neuromyelitis optica and multiple sclerosis patients..
113. Kenta Masui, Satoshi O. Suzuki, Kimiaki Hashiguchi, Takato Morioka, Takashi Yoshiura, Tomio Sasaki, Toru Iwaki, Focal cortical dysplasia coexisting with diffuse astrocytoma in childhood: A case report and reappraisal of the glial component in archival FCD cases, NEUROPATHOLOGY, 10.1111/j.1440-1789.2010.01173.x, 31, 4, 433-439, 2011.08, We report a rare case of focal cortical dysplasia (FCD) concurring with diffuse astrocytoma and arachnoid cyst, and also re-evaluate the glial component in archival FCD cases for the differential diagnosis of diffuse gliomas. A 7-year-old boy with a 9-month history of psychomotor seizures disclosed a hyperintense area accompanied by a cystic lesion in the left temporal lobe on MRI. The surgical specimen displayed dyslamination of the cortices and ectopic neurons in the white matter, associated with dysmorphic neurons, indicating FCD type IIA. Additionally, the lesion showed diffuse proliferation and infiltration of glial cells, immunopositive for infiltrating glioma markers (nestin, doublecortin, MAP-2e) and p53, and MIB-1 index was 2.0%. These findings indicated coexisting diffuse astrocytoma. Coexistence of diffuse glioma with FCD is unusual, but we often notice increased population of small glial cells in FCD lesions. Re-evaluation of archival FCD cases with diverse markers revealed that reactive microglia significantly proliferate in the white matter lesions. Therefore, a careful pathological assessment has to be made to define a rare case of diffuse glioma occurring in FCD..
114. Midlife and late-life blood pressure and dementia in Japanese elderly: the Hisayama study..
115. Yoshihiro Seki, Satoshi O. Suzuki, Kenta Masui, Shiori Harada, Seiji Nakamura, Shigenobu Kanba, Toru Iwaki, 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, Microglia are implicated in both neuroprotection and neurodegeneration, and are a key area of interest with respect to various CNS diseases. Until now, primary microglia prepared by various isolation methods have been widely used to investigate their role in CNS diseases. However, there are some problems with the current isolation methods, such as the numbers of animals required in order to obtain sufficient numbers of microglial cells due to low yields, and also the long periods of culture required. We herein describe a simple, high-yield method for isolating not only primary microglia, but also immortalized microglial cells. Our method allows for the isolation of an almost pure population of microglia with only two steps. First, a primary mixed neural culture was prepared from the brains of 3-day-old postnatal rats. Next, primary microglia were collected for 2 h by adhesion to Aclar plastic film. The average yield by this method was approximately 50 times higher than that of the conventional shaking method. Immortalized microglial cells could also be prepared based on this procedure. A plasmid vector encoding the SV40 large T antigen was transfected into the mixed neural culture using a calcium phosphate precipitation method. Then, proliferating immortalized microglia were collected after several weeks in a similar fashion. Several clones were obtained by limited dilution and one of the immortalized cell lines was designated SMK. The SMK cells exhibited markers specific for the microglia lineage, including Iba-1, CD11b, CD45, CD68, major histocompatibility complex (MHC) class I and MHC class II, but not for the astrocyte-specific markers, GFAP and glutamate aspartate transporter. SMK also showed phagocytic activity. In conclusion, this method resulted in a high-yield preparation of microglial cultures with ease and reproducibility..
116. Apolipoprotein genotype for prediction of Alzheimer's disease in older Japanese: the Hisayama Study..
117. Akira Nakamizo, Yojiro Akagi, Toshiyuki Amano, Satoshi O Suzuki, Rie Otsuka, Yasunobu Abe, Koji Yoshimoto, Toru Iwaki, Tomio Sasaki, Donor-derived adult T-cell leukaemia, The Lancet, 10.1016/S0140-6736(11)60315-2, 377, 9771, 1124, 2011.03.
118. Yukie Araki, Masahiro Mizoguchi, Koji Yoshimoto, Tadahisa Shono, Toshiyuki Amano, Akira Nakamizo, Satoshi O. Suzuki, Toru Iwaki, Tomio Sasaki, Quantitative digital assessment of MGMT immunohistochemical expression in glioblastoma tissue, BRAIN TUMOR PATHOLOGY, 10.1007/s10014-010-0004-2, 28, 1, 25-31, 2011.02, Recent reports have suggested an important clinical role for hypermethylation of the O(6)-methylguanine-DNA-methyltransferase (MGMT) promoter in patients with glioblastomas. Whether MGMT protein expression is correlated with promoter hypermethylation and patient outcomes, however, has not been elucidated. Here we describe a quantitative digital method for assessment of MGMT-specific immunostaining, and analyze the relationship between expression levels and methylation status of the MGMT promoter. We investigated 46 tumors from patients who received a diagnosis of glioblastoma or gliosarcoma. Immunohistochemistry with anti-MGMT antibody and methylation-specific PCR using bisulfite-modified tumor DNA were performed. The digital assessment method used image-analysis software to determine a digital MGMT staining index, and the results were compared with those obtained via conventional visual assessments. The digital staining index clearly correlated with the methylation status of MGMT promoter. In addition, the index correlated with our observational results when nuclear and cytoplasmic staining were assessed in three different fields. Our digital assessment method enabled us to assess uncertain immunopositive samples objectively and quantitatively, which is an important consideration when examining heterogeneous cellular staining. We expect that this method will be useful for assessment of heterogeneous staining with any antibodies..
119. Takeshi Matsuoka, Naoki Fujii, Akira Kondo, Akiko Iwaki, Toshihiro Hokonohara, Hiroyuki Honda, Kensuke Sasaki, Satoshi O. Suzuki, Toru Iwaki, An autopsied case of sporadic adult-onset amyotrophic lateral sclerosis with FUS-positive basophilic inclusions, NEUROPATHOLOGY, 10.1111/j.1440-1789.2010.01129.x, 31, 1, 71-76, 2011.02, Basophilic inclusions (BIs), which are characterized by their staining properties of being weakly argyrophilic, reactive with Nissl staining, and immunohistochemically negative for tau and transactive response (TAR) DNA-binding protein 43 (TDP-43), have been identified in patients with juvenile-onset amyotrophic lateral sclerosis (ALS) and adult-onset atypical ALS with ophthalmoplegia, autonomic dysfunction, cerebellar ataxia, or a frontal lobe syndrome. Mutations in the fused in sarcoma gene (FUS) have been reported in cases of familial and sporadic ALS, and FUS immunoreactivity has been demonstrated in basophilic inclusion body disease (BIBD), neuronal intermediate filament inclusion disease (NIFID), and atypical frontotemporal lobar degeneration with ubiquitin-positive and tau-negative inclusions (aFTLD-U). In the present study, we immunohistochemically and ultrastructurally studied an autopsy case of sporadic adult-onset ALS with numerous BIs. The patient presented with the classical clinical course of ALS since 75 years of age and died at age 79. Postmortem examination revealed that both Betz cells in the motor cortex and motor neurons in the spinal cord were affected. The substantia nigra was spared. Notably, BIs were frequently observed in the motor neurons of the anterior horns, the inferior olivary nuclei, and the basal nuclei of Meynert. BIs were immunopositive for p62, LC3, and FUS, but immunonegative for tau, TDP-43, and neurofilament. Ultrastructurally, BIs consisted of filamentous or granular structures associated with degenerated organelles with no limiting membrane. There were no Bunina bodies, skein-like inclusions, or Lewy-like inclusions. All exons and exon/intron boundaries of the FUS gene were sequenced but no mutations were identified..
120. Rina Torisu, Satoshi O. Suzuki, Kenta Masui, Koji Yoshimoto, Masahiro Mizoguchi, Makoto Hashizume, Peter Canoll, James E. Goldman, Tomio Sasaki, Toru Iwaki, 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 PATHOLOGY, 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..
121. Masafumi Sanefuji, Ryutaro Kira, Kenichi Matsumoto, Kenjiro Gondo, Hiroyuki Torisu, Hideshi Kawakami, Toru Iwaki, Toshiro Hara, Autopsy Case of Later-Onset Pontocerebellar Hypoplasia Type 1: Pontine Atrophy and Pyramidal Tract Involvement, JOURNAL OF CHILD NEUROLOGY, 10.1177/0883073810372991, 25, 11, 1429-1434, 2010.11, The combination of pontocerebellar hypoplasia and anterior horn cell degeneration is classified as pontocerebellar hypoplasia type 1. Although most cases exhibit severe muscle weakness and hypotonia neonatally with short life spans, some cases exhibit a later onset with a longer life span and show cerebellar atrophy without pontine involvement. We present a child who exhibited neurological deterioration and progressive atrophy of the cerebellum and pons, with onset of symptoms at 20 months and death at 15 years of age. The pathological findings disclosed anterior horn cell degeneration and pyramidal tract involvement in addition to pontocerebellar atrophy, leading to the diagnosis of pontocerebellar hypoplasia type 1. The present case suggests that the degenerative pattern of later-onset pontocerebellar hypoplasia type 1 is similar to that of prenatal-onset cases. Further reports of later-onset cases with histopathological examination are required to elucidate the nosology and etiology of the disorder..
122. Aquaporin-4 astrocytopathy in Baló's disease..
123. 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
目的:我々は、糖尿病がAlzheimer病(AD)の病理学的過程にどのように影響を与えるのかについて評価するために、糖尿病関連因子とAD病理との関連について検討を行った。
方法:この研究では、福岡県久山町の住民のうち、1998年から2003年までに死亡し、かつ1988年の検診にて75g経口血糖負荷試験を施行された連続剖検135名(男性74名、女性61名)の検体を用いた。我々は、1988年の検診において、糖尿病関連因子として、空腹時血糖、糖負荷2時間後血糖、空腹時インスリン、インスリン抵抗性評価尺度(HOMA-IR)を測定した。脳内の老人斑についてはCERADガイドライン、神経原線維変化についてはBraakステージ分類に基づいて評価した。各因子とAD病理との関連についての解析は、共分散分析とロジスティック解析を行った。
結果:解析にて、性、年齢、収縮期血圧、総コレステロール、BMI、喫煙、運動、脳血管障害で調整すると、糖負荷2時間後血糖、空腹時インスリン、HOMA-IRの高値が、老人斑のリスクの上昇と関連した。しかし、糖尿病関連因子と神経原線維変化については、有意な関連を認めなかった。AD病理のリスクに関して、アポリポ蛋白E(APOE)の遺伝子型を考慮すると、高血糖とAPOEε4が共存すると、老人斑形成のリスクが上がった。同様の傾向は、高インスリン血症やHOMA-IR高値でも認められた。
結論:この研究から、インスリン抵抗性によって引き起こされる高インスリン血症、高血糖が、APOEε4とともに、老人斑形成を加速させることが示唆された。
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..
124. Kenta Masui, Satoshi O. Suzuki, Rina Torisu, James E. Goldman, Peter Canoll, Toru Iwaki, 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. (C) 2010 Wiley-Liss, Inc..
125. Shinya Yamaguchi, Satoshi O. Suzuki, Yoshihiro Matsuo, Toshio Uesaka, Koichiro Matsukado, Kenta Masui, Toru Iwaki, Large hypothalamic hamartoma with calcification and cystic components in an adult, Neurologia Medico-Chirurgica, 10.2176/nmc.50.495, 50, 6, 495-498, 2010.06, A 24-year-old female presented with an unusual case of hypothalamic hamartoma manifesting as seizure. Neuroimaging findings were atypical, showing the large tumor (maximum diameter, 50 mm) with a cystic component and calcification. Surgery was performed and histological examination demonstrated heterotopia. Hamartoma should be considered in the differential diagnosis of a suprasellar, non-enhanced mass attached to the hypothalamus. Excessive unnecessary surgery should be avoided, and intraoperative pathological examination may lead to enhanced assessment and better outcomes..
126. Takahisa Tateishi, Toshihiro Hokonohara, Ryo Yamasaki, Shiro Miura, Hitoshi Kikuchi, Akiko Iwaki, Hiroshi Tashiro, Hirokazu Furuya, Yuko Nagara, Yasumasa Ohyagi, Nobuyuki Nukina, Toru Iwaki, Yasuyuki Fukumaki, Jun-ichi Kira, Multiple system degeneration with basophilic inclusions in Japanese ALS patients with FUS mutation, ACTA NEUROPATHOLOGICA, 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..
127. Kenta Masui, Satoshi O. Suzuki, Akira Kondo, Toru Iwaki, A 6-YEAR-OLD GIRL WITH AN EXTRA-AXIAL MASS IN THE MIDDLE CRANIAL FOSSA, BRAIN PATHOLOGY, 10.1111/j.1750-3639.2009.00348.x, 20, 1, 269-272, 20(1): 269-272, 2010.01.
128. Yoshito Mizoguchi, Akira Monji, Takahiro Kato, Yoshihiro Seki, Leo Gotoh, Hideki Horikawa, Satoshi O. Suzuki, Toru Iwaki, Miyuki Yonaha, Sadayuki Hashioka, Shigenobu Kanba, Brain-Derived Neurotrophic Factor Induces Sustained Elevation of Intracellular Ca2+ in Rodent Microglia, JOURNAL OF IMMUNOLOGY, 10.4049/jimmunol.0901326, 183, 12, 7778-7786, 2009.12, Microglia are intrinsic immune cells that release factors, including proinflammatory cytokines, NO, and neurotrophins, following activation after disturbance in the brain. Elevation of intracellular Ca2+ concentration ([Ca2+](i)) is important for microglial functions, such as the release of cytokines and NO from activated microglia. There is increasing evidence suggesting that pathophysiology of neuropsychiatric disorders is related to the inflammatory responses mediated by microglia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin well known for its roles in the activation of microglia as well as in pathophysiology and/or treatment of neuropsychiatric disorders. In this study, we observed that BDNF induced a sustained increase in [Ca2+]i through binding with the truncated tropomyosin-related kinase B receptor, resulting in activation of the PLC pathway and store-operated calcium entry in rodent microglial cells. RT-PCR and immunocytochemical techniques revealed that truncated tropomyosin-related kinase B-T1 receptors were highly expressed in rodent microglial cells. Sustained activation of store-operated calcium entry occurred after brief BDNF application and contributed to the maintenance of sustained [Ca2+]i elevation. Pretreatment with. BDNF significantly suppressed the release of NO from activated microglia. Additionally, pretreatment of BDNF suppressed the IIFN-gamma-induced increase in [Ca2+]i, along with a rise in basal levels of [Ca2+]i in rodent microglial cells. We show direct evidence that rodent microglial cells are able to respond to BDNF, which may be important for the regulation of inflammatory responses, and may also be involved in the pathophysiology and/or the treatment of neuropsychiatric disorders. The Journal of Immunology, 2009, 183: 7778-7786..
129. Degenerative and protective reactions of the rat trigeminal motor nucleus after removal of the masseter and temporal muscles..
130. Haruhiko Minaki, Kensuke Sasaki, Hiroyuki Honda, Toru Iwaki, Prion protein oligomers in Creutzfeldt-Jakob disease detected by gel-filtration centrifuge columns, NEUROPATHOLOGY, 10.1111/j.1440-1789.2009.01007.x, 29, 5, 536-542, 29(5): 536-542, 2009.10, Prion diseases are diagnosed by the detection of accumulation of abnormal prion protein (PrP) using immunohistochemistry or the detection of protease-resistant abnormal PrP (PrPres). Although the abnormal PrP is neurotoxic by forming aggregates, recent studies suggest that the most infectious units are smaller than the amyloid fibrils. In the present study, we developed a simplified method by applying size-exclusion gel-filtration chromatography to examine PrP oligomers without proteinase K digestion in Creutzfeldt-Jakob disease (CJD) samples, and evaluated the correlation between disease severity and the polymerization degree of PrP. Brain homogenates of human CJD and non-CJD cases were applied to the gel-filtration spin columns, and fractionated PrP molecules in each fraction were detected by western blot. We observed that PrP oligomers could be detected by the simple gel-filtration method and distinctly separated from monomeric cellular PrP (PrPc). PrP oligomers were increased according to the disease severity, accompanied by the depletion of PrPc. The separated PrP oligomers were already protease-resistant in the case with short disease duration. In the cases with quite severe pathology the oligomeric PrP reached a plateau, which may indicate that PrP molecules could mostly develop into amyloid fibrils in the advanced stages. The increase of PrP oligomers correlated with the degree of histopathological changes such as spongiosis and gliosis. The decrease of monomeric PrPc was unexpectedly obvious in the diseased cases. Dynamic changes of both oligomerization of the human PrP and depletion of normal PrPc require further elucidation to develop a greater understanding of the pathogenesis of human prion diseases..
131. Kensuke Sasaki, Haruhiko Minaki, Toru Iwaki, Development of oligomeric prion-protein aggregates in a mouse model of prion disease, Journal of Pathology, 10.1002/path.2576, 219, 1, 123-130, 219(1): 123-130, 2009.09, In prion diseases the normal cellular isoform of prion protein (PrP), denoted PrPC, is converted into an abnormal, pathogenic isoform of PrP (PrPSc). Diagnostic tools for prion diseases are conventionally based on the detection of protease-resistant PrP (PrPres) after proteinase K digestion. However, recent studies have revealed that protease-sensitive abnormal PrP (sPrPSc) also exists in significant amounts in brains suffering from prion diseases. Here, we designed a simplified size-exclusion gel chromatography assay, using disposable spin columns to examine PrP aggregates in the course of the disease, without proteinase K digestion. Brain homogenates of NZW mice, inoculated intracranially with Fukuoka-1 strain, and which died at around 120 days post-inoculation, were assayed by this gel-fractionation method and eluted PrP molecules in each fraction were detected by western blot analysis. Oligomeric PrP molecules were well separated from monomers, as predicted. A conventional protease-digestion assay was also performed to detect PrPres and revealed that the ratio of PrPres to total PrP increased drastically from 105 days. However, the increase of PrP oligomers became significant from 90 days. These PrP oligomers in the early disease stage would, therefore, be sPrPSc molecules that might affect the disease pathology, such as spongiform change and abnormal PrP deposition. We also observed that the resistance of PrP oligomers to proteinase K and insolubility in phosphotungstic acid precipitation increased with disease progression, which suggests that PrP oligomers are not clearly distinguished from cellular PrP or PrPres but may overlap in a continuous spectrum. Our study casts light on the ambiguity of the definition of PrPSc and indicates that the abnormality of PrP molecules should be determined from various perspectives, more than protease resistance. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley &
Sons, Ltd..
132. Takashi Shichita, Yuki Sugiyama, Hiroaki Ooboshi, Hiroshi Sugimori, Ryusuke Nakagawa, Ichiro Takada, Toru Iwaki, Yasunori Okada, Mitsuo Iida, Daniel J. Cua, Yoichiro Iwakura, Akihiko Yoshimura, Pivotal role of cerebral interleukin-17-producing T cells in the delayed phase of ischemic brain injury, Nature Medicine, 10.1038/nm.1999, 15, 8, 946-950, 15(8): 946-950, 2009.08, Lymphocyte recruitment and activation have been implicated in the progression of cerebral ischemia-reperfusion (I/R) injury, but the roles of specific lymphocyte subpopulations and cytokines during stroke remain to be clarified. Here we demonstrate that the infiltration of T cells into the brain, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles in the evolution of brain infarction and accompanying neurological deficits. Blockade of T cell infiltration into the brain by the immunosuppressant FTY720 reduced I/R-induced brain damage. The expression of IL-23, which was derived mostly from infiltrated macrophages, increased on day 1 after I/R, whereas IL-17 levels were elevated after day 3, and this induction of IL-17 was dependent on IL-23. These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 functions in the immediate stage of I/R brain injury, whereas IL-17 has an important role in the delayed phase of I/R injury during which apoptotic neuronal death occurs in the penumbra. Intracellular cytokine staining revealed that T lymphocytes, but not CD4 + helper T cells, were a major source of IL-17. Moreover, depletion of T lymphocytes ameliorated the I/R injury. We propose that T lymphocytes, including T lymphocytes, could be a therapeutic target for mitigating the inflammatory events that amplify the initial damage in cerebral ischemia..
133. Highly selective leptomeningeal amyloidosis with transthyretin variant Ala25Thr., [URL].
134. [Solitary neurofibroma presenting as a tender soft-to-firm tumor at the temporal head region masquerading as temporal arteritis]..
135. Hironori Kamano, Tomoyuki Noguchi, Takashi Yoshiura, Futoshi Mihara, Osamu Togao, Tadahisa Shono, Toru Iwaki, Tomio Sasaki, Hiroshi Honda, Intraorbital lobular capillary hemangioma (pyogenic granuloma), Radiation Medicine - Medical Imaging and Radiation Oncology, 10.1007/s11604-008-0280-5, 26, 10, 609-612, 26(10): 609-612, 2008.12, [URL], A 44-year-old man with a history of a foreign body in his right eye visited our hospital. On computed tomography a well-enhanced mass with low attenuation septal walls and a capsule was detected in the right orbit. On magnetic resonance imaging the mass showed inhomogenous high intensity on T2-weighted images and low intensity on diffusion-weighted images. The mass was histopathologically diagnosed as a lobular capillary hemangioma. This is the first report about image findings of lobular capillary hemangioma in the orbit. © 2008 Japan Radiological Society..
136. Tadahisa Shono, Nobuhiko Yokoyama, Toshio Uesaka, Junya Kuroda, Ryu Takeya, Tomoko Yamasaki, Toshiyuki Amano, Masahiro Mizoguchi, Satoshi O. Suzuki, Hiroaki Niiro, Kyoko Miyamoto, Koichi Akashi, Toru Iwaki, Hideki Sumimoto, Tomio Sasaki, Enhanced expression of NADPH oxidase Nox4 in human gliomas and its roles in cell proliferation and survival, INTERNATIONAL JOURNAL OF CANCER, 10.1002/ijc.23569, 123, 4, 787-792, 123(4): 787-792, 2008.08, [URL], Reactive oxygen species (ROS) have been attracting attention as mediators of various cell-signaling pathways. Nox-family NADPH oxidases have proven to be a major source of ROS production in various cell types and have crucial roles in various physiological and pathological processes. In this study, we show that Nox4, a member of Nox family, is prominently expressed in various neuroepithelial tumors by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemical studies. We quantified Nox4 mRNA expression by real-time PCR in tumor specimens from 58 patients with astrocytomas and found that the expression levels of Nox4 mRNA in glioblastomas (WHO grade IV) were significantly higher than those in other astrocytomas (WHO grade II and III). In addition, we show that specific knockdown of Nox4 expression by RNA interference results in cell-growth inhibition and enhances induction of apoptosis by chemotherapeutic agents, such as cisplatin, in cultured glioma cell lines. Based on these observations, enhanced expression of Nox4 appears to be involved in cell proliferation and survival in glioma cells. (c) 2008 Wiley-Liss, Inc..
137. *Autopsy of a suspected venous circulatory disturbance localized in the medulla oblongata and upper cervical cord accompanied with an aneurysm.
138. Takahiro Kato, Yoshito Mizoguchi, Akira Monji, Hideki Horikawa, Satoshi O. Suzuki, Yoshihiro Seki, Toru Iwaki, Sadayuki Hashioka, Shigenobu Kanba, Inhibitory effects of aripiprazole on interferon-γ-induced microglial activation via intracellular Ca2+ regulation in vitro, Journal of Neurochemistry, 10.1111/j.1471-4159.2008.05435.x, 106, 2, 815-825, 106(2): 815-825, 2008.07, The activation of the inflammatory/immunological response system is suggested to be related to the pathophysiology of schizophrenia. Aripiprazole is a novel atypical antipsychotic, which is a high-affinity dopamine D2 receptor partial agonist. Atypical antipsychotics, all of which have dopamine D2 receptor antagonism, have recently reported to have significantly inhibitory effects on interferon (IFN)-γ-induced microglial activation in vitro. In the present study, we investigated whether or not aripiprazole also has anti-inflammatory effect on IFN-γ-induced microglial activation. Not quinpirole, dopamine D2 full agonist, but aripiprazole significantly inhibited the generation of nitric oxide (NO) and tumor necrosis factor (TNF)-α from IFN-γ-activated microglia and suppressed the IFN-γ-induced elevation of intracellular Ca2+ concentrations ([Ca2+]i) in murine microglial cells. Increased [Ca2+]i has been reported to be required, but by itself not sufficient, for the release of NO and certain cytokines. As a result, we can speculate that aripiprazole may inhibit IFN-γ-induced microglial activation through the suppression of IFN-γ-induced elevation of [Ca2+]i in microglia. Our results demonstrated that not only antipsychotics which have dopamine D2 receptor antagonism but also aripiprazole have anti-inflammatory effects via the inhibition of microglial activation. Antipsychotics may therefore have a potentially useful therapeutic effect on patients with schizophrenia by reducing the microglial inflammatory reactions. © 2008 International Society for Neurochemistry,..
139. , [URL].
140. An autopsy case of amyotrophic lateral sclerosis with ampulla cardiomyopathy, [URL].
141. Guan Y, Hata N, Kuga D, Yoshimoto K, Mizoguchi M, Shono T, Suzuki SO, Tahira T, Kukita Y, Higasa K, Yokoyama N, Nagata S, Iwaki T, Sasaki T, Hayashi K., Narrowing of the regions of allelic losses of chromosome 1p36 in meningioma tissues by an improved SSCP analysis., Int. J. Cancer, 122, 8, 1820-1826, 122(8): 1820-1826, 2008.04, [URL].
142. Noguchi T, Yoshiura T, Hiwatashi A, Togao O, Yamashita K, Shono S, Mizoguchi M, Sasaki T, Suzuki SO, Iwaki T, Kobayashi K, Mihara F, Honda H., Perfusion imaging of brain tumors using arterial spin-labeling: correlation with histopathologic vascular density., Am. J. Neuroradiol., 29, 4, 688-693, 29(4): 688-693, 2008.04.
143. , [URL].
144. [An autopsy case of amyotrophic lateral sclerosis with ampulla cardiomyopathy]..
145. Hata N, Shono T, Mizoguchi M, Matsumoto K, Guan Y, Nagata S, Hayashi K, Iwaki T, Sasaki T, Loss of heterozygosity analysis in an anaplastic oligodendroglioma arising after radiation therapy, Neurol Res, 29: 723-726, 2007.10.
146. Tadahisa Shono, Yoshihiro Natori, Takato Morioka, Rina Torisu, Masahiro Mizoguchi, Shinji Nagata, Satoshi O. Suzuki, Toru Iwaki, Takanori Inamura, Masashi Fukui, Kazunari Oka, Tomio Sasaki, Results of a long-term follow-up after neuroendoscopic biopsy procedure and third ventriculostomy in patients with intracranial germinomas, JOURNAL OF NEUROSURGERY, 10.3171/PED-07/09/193, 107, 3, 193-198, 107(3): 193-198, 2007.09, Object. The authors report the results of long-term follow-ups in 12 patients with intracranial germinomas who underwent neuroendoscopic procedures before chemotherapy and radiotherapy, and discuss the usefulness and safety of these procedures.
Methods. Between January 1996 and December 2005 at Kyushu University Hospital, 12 patients with intracranial germinomas underwent neuroendoscopic biopsy procedures involving a flexible fiberscope. Eight patients simultaneously underwent endoscopic third ventriculostomy (ETV) for existing obstructive hydrocephalus. All patients received chemotherapy and radiotherapy postoperatively, according to the regimen promulgated by the Japanese Pediatric Brain Tumor Study Group. The patients were followed for an average of 78.6 months (range 15-134 months), and a retrospective study was conducted.
Results. Germinomas were histologically verified in all patients. No postoperative deaths or permanent morbidity was related to the neuroendoscopic procedures. No other cerebrospinal fluid diversion, such as that achieved with a ventriculoperitoneal shunt, was needed for the management of hydrocephalus. A complete response to postoperative chemotherapy and radiotherapy was achieved in all cases. Only one patient had a recurrent lesion in the spinal cord 6 years after the initial treatment; however, this patient had undergone only the neuroendoscopic biopsy procedure without ETV.
Conclusions. Neuroendoscopic procedures can permit a precise histological diagnosis of intracranial germinomas and are safe and effective in the management of hydrocephalus associated with these tumors. The risk of tumor dissemination due to the neuroendoscopic procedures appears to be minimal when the appropriate chemotherapy and radiotherapy are provided postoperatively..
147. Toshio Uesaka, Tadahisa Shono, Daisuke Kuga, Satoshi O. Suzuki, Hiroaki Niiro, Kyoko Miyamoto, Kenichi Matsumoto, Masahiro Mizoguchi, Masaru Ohta, Toru Iwaki, Tomio Sasaki, Enhanced expression of DNA topoisomerase II genes in human medulloblastoma and its possible association with etoposide sensitivity, JOURNAL OF NEURO-ONCOLOGY, 10.1007/s11060-007-9360-0, 84, 2, 119-129, 84: 119-129, 2007.09, Medulloblastoma (MB) is the most common malignant neuroepithelial tumor of childhood. The DNA topoisomerase II (Topo II) inhibitor etoposide has been widely used for the treatment of MBs; however, it remains unknown whether MB cells are more sensitive to etoposide than other malignant neuroepithelial tumor cells. In this study, we tested the chemosensitivities of malignant neuroepithelial tumors (26 glioblastomas, 9 anaplastic astrocytomas, and 5 MBs) to etoposide and vincristine using the succinate dehydrogenase inhibition test and found that MB cells are more sensitive to etoposide and more resistant to vincristine than other tumor cells. We performed quantitative reverse-transcription polymerase chain reaction to evaluate the expression of genes related to etoposide sensitivity, and found co-overexpression of DNA topoisomerase II (Topo II) alpha and beta mRNA in MBs. In addition, the levels of Topo II alpha and beta mRNA in these tumors correlated with etoposide sensitivity. Immunohistochemical studies using surgical samples of these tumors demonstrated that the percentages of Topo II alpha immunopositive cells (Topo II alpha labeling index) correlated with those of Ki-67 immunopositive cells (MIB-1 labeling index); however, neither the Topo II alpha nor the MIB-1 labeling index correlated with the levels of Topo II alpha mRNA or etoposide sensitivity. Based on these observations, Topo II alpha and beta mRNA expression, but not the Topo II alpha labeling index, might be a useful marker for sensitivity to etoposide in human malignant neuroepithelial tumors..
148. Tadahisa Shono, Masahiko Tosaka, Kenichi Matsumoto, Sadao Onaka, Shinya Yamaguchi, Masahiro Mizoguchi, Toru Iwaki, Yoichi Nakazato, Tomio Sasaki, Ganglioglioma in the third ventricle: Report on two cases, Neurosurgical Review, 10.1007/s10143-007-0090-8, 30, 3, 253-258, 30: 253-258, 2007.07, Gangliogliomas are uncommon central nervous system (CNS) tumors composed of a mixture of glial and neuronal elements. Although these tumors can occur in any portion of the central nervous system, involvement of the ventricular system is rare. We herein report on two cases of gangliogliomas in the third ventricle in a 34-year-old woman and in a 52-year-old man. One patient presented only with headaches, and the other presented symptoms associated with panhypopituitarism and diabetes insipidus. In the first case the tumor in the middle portion of the third ventricle was successfully removed by a transcallosal subchoroidal approach. In the second case the hemorrhagic tumor was located in the anterior floor of the third ventricle and was removed by an anterior inter-hemispheric trans-lamina terminalis approach. To date, follow-ups of both patients have involved no adjuvant therapy, and there have been no signs of tumor recurrence on magnetic resonance images. The nature, radiological findings, and treatments of these tumors are discussed. © 2007 Springer-Verlag..
149. Toshio Uesaka, Tadahisa Shono, Satoshi O. Suzuki, Akira Nakamizo, Hiroaki Niiro, Masahiro Mizoguchi, Toru Iwaki, Tomio Sasaki, Expression of VEGF and its receptor genes in intracranial schwannomas, JOURNAL OF NEURO-ONCOLOGY, 10.1007/s11060-007-9336-0, 83, 3, 259-266, 83:259-266, 2007.07, Vascular endothelial growth factor (VEGF) is considered to be a major regulator of angiogenesis in various brain tumors. In this study, we determined the expression levels of VEGF, and vascular endothelial growth factor receptor (VEGFR)-1 and -2 mRNA in 46 intracranial schwannomas by quantitative real-time PCR, and correlated these with various clinical factors or other molecular markers. We found that these tumors expressed significant amounts of VEGF mRNA in comparison with other brain tumors, including malignant gliomas and meningiomas. In addition, we performed immunohistochemical studies for VEGF and VEGFR-1, and confirmed that these tumors prominently express these proteins. The expression levels of VEGF and VEGFR-1 mRNA in recurrent tumors were higher than those in primary tumors. When we divided patients into two groups according to VEGF mRNA expression in the tumor, there was no significant difference in patient age, gender, or cranial nerves of origin between groups; however, the tumor volume tended to be larger in the high VEGF group than in the low VEGF group. The levels of VEGFR-1 mRNA and neurofibromatosis-2 mRNA in the high VEGF group were significantly greater than those in the low VEGF group. Levels of VEGFR-2 mRNA and DNA topoisomerase II alpha mRNA, and the MIB-1 labeling index in the high VEGF group were slightly higher than those in the low VEGF group; however, the difference was not statistically significant. Based on these observations, the significance of VEGF and its receptor genes in intracranial schwannomas is discussed..
150. Kouhei Fujimi, Kazuhito Noda, Kensuke Sasaki, Yoshinobu Wakisaka, Yumihiro Tanizaki, Mitsuo Iida, Yutaka Kiyohara, Shigenobu Kanba, Toru Iwaki, Altered Expression of COX-2 in Subdivisions of the Hippocampus during Aging and in Alzheimer’s Disease: The Hisayama Study, Dementia and Geriatric Cognitive Disorders, 10.1159/000101957, 23, 6, 423-431, 2007.05.
151. Satoshi O. Suzuki, Richard J. McKenney, Shin-ya Mawatari, Masashi Mizuguchi, Atsushi Mikami, Toru Iwaki, James E. Goldman, Peter Canoll, Richard B. Vallee, Expression patterns of LIS1, dynein and their interaction partners dynactin, NudE, NudEL and NudC in human gliomas suggest roles in invasion and proliferation, ACTA NEUROPATHOLOGICA, 10.1007/s00401-006-0180-7, 113, 5, 591-599, 2007.05, Diffusely infiltrating gliomas are the most common type of primary intracranial neoplasm in humans. One of the major obstacles to the effective treatment of these tumors is their highly infiltrative growth. However, mechanisms controlling their migration and proliferation are poorly understood. Glioma cells resemble neural progenitors, and we hypothesize that gliomas recapitulate the capacity of migration and proliferation of progenitors that takes place during brain development. Based on recent evidence implicating cytoplasmic dynein and its regulatory proteins in neural progenitor migration and division, we conducted immunohistochemical evaluation of surgically resected human glioma samples for the presence and distribution of these proteins. We examined expression of LIS1, the gene responsible for type I lissencephaly, cytoplasmic dynein and the dynein- and LIS1-interacting factors dynactin, NudE/NudEL and NudC, which play significant roles in neural progenitor cell behavior. We found that each of these proteins is expressed in all histological types and grades of human neuroectodermal tumors examined. Immunohistochemical analysis revealed that the levels of expression varied from cell to cell within each tumor, ranging from very high to undetectable. This stands in contrast to the low levels of diffuse staining seen in non-neoplastic brain tissue. Of particular interest, we noted tumor cells infiltrating the white matter and tumor cells undergoing cell division amongst the cells with notably high expression levels. These findings are compatible with the idea that LIS1 and its interacting proteins play a role in glioma migration and proliferation analogous to their role during brain development..
152. Intraneuronal amyloid beta42 enhanced by heating but counteracted by formic acid..
153. Yasushi Miyagi, Yoshihiro Natori, Satoshi O. Suzuki, Toru Iwaki, Takato Morioka, Koichi Arimura, Yoshihisa Maeda, Tadahisa Shono, Koichiro Matsukado, Tomio Sasaki, Purely cystic form of choroid plexus papilloma with acute hydrocephalus in an infant: Case report, Journal of Neurosurgery, 105, 6, 480-484, 105:480-484, 2006.12, Infants with acute hydrocephalus often present with nonspecific neurological signs, and cystic choroid plexus papilloma (CPP) is a very rare cause of acute obstructive hydrocephalus. The authors present the case of a 1-year-old girl who became irritable, started vomiting, and became comatose within a day. Magnetic resonance (MR) imaging revealed a cystic lesion in the third ventricle as well as hydrocephalus. Although the aqueduct appeared to be patent, phase-contrast MR imaging showed no pulsatile flow of cerebrospinal fluid in the ventricles. An emergent endoscopic third ventriculostomy was performed. Endoscopic examination revealed a highly mobile cyst attached by a pedicle to the choroid plexus adjacent to the Monro foramen in the lateral ventricle. The cyst was totally excised during the endoscopic procedure and was subsequently diagnosed as a CPP on the basis of histopathological findings. Purely cystic CPP is a very rare pathological entity
however, when it does occur, it can cause obstructive hydrocephalus which, without rapid diagnosis and surgical intervention, could lead to sudden death..
154. Kazuhito Noda, Kensuke Sasaki, Kohei Fujimi, Yoshinobu Wakisaka, Yumihiro Tanizaki, Yoshiyuki Wakugawa, Yutaka Kiyohara, Mitsuo Iida, Hisamiti Aizawa, Toru Iwaki, 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.
155. Styrylbenzoazole derivatives for imaging of prion plaques and treatment of transmissible spongiform encephalopathies..
156. Hiroyuki Murai, Hideaki Tokunaga, Ikuko Kubo, Masakazu Kawajiri, Toru Iwaki, Takayuki Taniwaki, Jun-ichi Kira, Myeloradiculitis caused by Cyptococcus neoformans infection in a patient with ulcerative colitis: A neuropathological study, JOURNAL OF THE NEUROLOGICAL SCIENCES, 10.1016/j.jns.2006.05.050, 247, 2, 236-238, 247:236-238, 2006.09, Meningitis is the most common feature of cryptococcal infection of the nervous system. We herein describe the case of a 48-year-old man with fulminant cryptococcal myeloradiculitis, whose initial symptoms were impotence, dysuria and weakness of the lower extremities. He had been administered prednisolone and azathioprine for 7 years for ulcerative colitis before onset of myeloradiculitis. He finally developed meningoencephalitis and died 2 months after onset despite treatment with amphotericin B and flucytosine. Post-mortem examination revealed numerous infiltrations of cryptococci in the spinal roots as well as in the meninges and subarachnoid space. Inflammatory cells and cryptococci had infiltrated the vessel walls in the spinal cord, and this was accompanied by necrotizing myelopathy. Myeloradiculitis is rare in cryptococcal infection, and this is the first case report to demonstrate direct cryptococcal infection in the spinal roots. Cryptococcal infection should be considered while managing myeloradiculopathy of unknown etiology, especially in immunocompromised patients. (c) 2006 Elsevier B.V. All rights reserved..
157. 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.
158. Takuya Matsushita, Hiroyuki Murai, Masakazu Kawajiri, Hiroshi Muratani, Toru Iwaki, Takayuki Taniwaki, Jun-ichi Kira, Character changes from idiopathic cranial pachymeningoencephalitis, Journal of the Neurological Sciences, 10.1016/j.jns.2006.01.008, 244, 1-2, 163-166, 244(1-2): 163-166, 2006.05, A 66-year-old man with idiopathic cranial pachymeningoencephalitis was described. He suffered from left orbital pain, and character changes. He became short tempered, and was very attached to trifles. Two years prior to these symptoms, he had developed transient left abducent nerve palsy. Head MRI showed a thickening and enhancement of the dura mater on gadolinium-enhanced T1-weighted images, and high signal intensity lesions at bilateral frontal lobes predominantly in the white matter on T2-weighted images. Biopsies revealed microglial proliferation in the cerebral parenchyma, and mild lymphocytic perivascular infiltration. No evidence of intracranial infection was detected. We therefore treated him with methylprednisolone pulse therapy followed by oral prednisolone. His character became gradually normalized, and bilateral frontal lobe lesions seen on MRI disappeared. This is the first case to describe recurrent pachymeningoencephalitis with character changes, and symptoms were probably due to frontal lobe dysfunction. © 2006 Elsevier B.V. All rights reserved..
159. Satoshi Kawatake, Yuki Nishimura, Suehiro Sakaguchi, Toru Iwaki, Katsumi Doh-ura, Surface plasmon resonance analysis for the screening of ant-prion compounds., Biological & Pharmaceutical Bulletin, 10.1248/bpb.29.927, Vol.29, No.5, 927-932, 2006.05, The interaction of anti-prion compounds and amyloid binding dyes with a carboxy-terminal domain of prion protein (PrP121-231) was examined using surface plasmon resonance (SPR) and compared with inhibition activities of abnormal PrP formation in scrapie-infected cells. Most examined compounds had affinities for PrP121-231: antimalarials had low affinities, whereas Congo red, phthalocyanine and thioflavin S had high affinities. The SPR binding response correlated with the inhibition activity of abnormal PrP formation. Several drugs were screened using SPR to verify the findings: propranolol was identified as a new anti-prion compound. This fact indicates that drug screenings by this assay are useful..
160. Wakisaka Yoshinobu, Santa Naohiko, Doh-ura Katsumi, Kitamoto Tetsuyuki, Ibayashi Setsuro, Iida Mitsuo, Iwaki Toru, Increased asymmetric pulvinar magnetic resonance imaging signals in Creutzfeldt-Jakob disease with florid plaques following a cadaveric dura mater graft., Neuropathology, 10.1111/j.1440-1789.2006.00638.x, 26, 1, 82-88, 2006.02.
161. Hata N. Shono T. Yoshimoto K. Mizoguchi M. Kawamura T. Nagata S. Matsumoto K. Hayashi K. Iwaki T. Sasaki T., An astroblastoma case associated with loss of heterozygosity on chromosome 9p., J Neurooncol, 80:69-73, 2006.01.
162. Hata N. Yoshimoto K. Yokoyama N. Mizoguchi M. Shono T. Guan Y. Tahira T. Kukita Y. Higasa K. Nagata S. Iwaki T. Sasaki T. Hayashi K., Allelic losses of chromosome 10 in glioma tissues detected by quantitative single-strand conformation polymorphisum analysis., Clin Chem, 52:370-378, 2006.01.
163. Yasushi Nakagawa, Toshiro Kawashima, Tomomi Yamada, Mutsuo Harano, Akira Monji, Takefumi Yuzuriha, Toru Iwaki, Aluminum chloride does not facilitate deposition of human synthetic amyloid β1-42 peptide in the rat ventricular system of a short-term infusion model, Neuropathology, 10.1111/j.1440-1789.2005.00630.x, 25, 3, 195-200, 25:195-200, 2005.09, Recent data have demonstrated that a 39-43 amino acid peptide called β-amyloid peptide (Aβ), which predominantly contains 42 residues (Aβ1-42), has a strong tendency to form insoluble aggregates and that the toxic effects of Aβ are based on its aggregation. In a previous study, we reported that infusion of 100 μg of human synthetic Aβ1-42 (sAβ1-42), which is a main component of diffuse plaques, into the lateral ventricle of the rat brain of a short-term infusion model resulted in almost complete disappearance of sAβ1-42 aggregates from the ventricles by 28 days. In addition, aluminum is considered a potential etiological factor in Alzheimer's disease (AD). Neurotoxicity from excess brain exposure to aluminum has been documented from both clinical observations and animal experiments, although a direct relationship between aluminum and AD has yet to be clearly established. We therefore investigated the effects of sAβ1-42 aggregates with aluminum chloride (AlCl3) in the ventricular system of the rat brain of a short-term infusion model. At either 2 or 7 days following infusion, sAβ1-42 formed aggregates with AlCl3 that spread throughout the entire ventricular system. However, sAβ1-42 aggregates with AlCl 3 had almost disappeared from the ventricles by 28 days, resulting in similarities with respect to the time-course and the neuropathological changes observed in sAβ1-42 aggregation without AlCl3. We herein report for the first time that considerable amounts of sAβ1-42 aggregates with AlCl3 almost disappear from the rat ventricular system by 28 days post-infusion..
164. Satoshi O. Suzuki, Toru Iwaki, Dynamic analysis of glioma cells: Looking into "movement phenotypes", Neuropathology, 10.1111/j.1440-1789.2005.00626.x, 25, 3, 254-262, 2005.09, One of the major obstacles to the successful treatment of diffuse gliomas is their highly infiltrative property. It is one of the important therapeutic strategies to inhibit infiltration of glioma cells and make it possible to locally control a lesion. To achieve this, we first need to observe and describe detailed movement profiles of glioma cells in the brain tissue at the cellular level. Then we further need to determine extra and intracellular molecules that play a key role in glioma cell invasion. Live cell imaging is a powerful technique to investigate the basic movement pattern of glioma cells as well as the effects of therapeutic interventions on their migration. In this review, we describe a technical aspect of live cell imaging with special regard to time-lapse video imaging and discuss the relevance of the methods to glioma studies..
165. Akiko Furuta, Sachio Takashima, Hideaki Yokoo, Jeffrey D. Rothstein, Keiji Wada, Toru Iwaki, Expression of glutamate transporter subtypes during normal human corticogenesis and type II lissencephaly, Developmental Brain Research, 10.1016/j.devbrainres.2005.01.005, 155, 2, 155-164, 155:155-164, 2005.03, Glutamate transporters are thought to have an important role in central nervous system (CNS) development. We investigated the expression of the sodium-dependent high-affinity glutamate transporters EAAT1, EAAT2, and EAAT3 in 11 human autopsied cases without neurological disorders and in four cases with type II lissencephaly including Walker Warburg's syndrome (WWS) and Fukuyama-type congenital muscular dystrophy (FCMD), both of which are classified as migration disorders of the human brain. Expression of glutamate transporter subtypes was differentially regulated during normal human corticogenesis. Although EAAT1 and EAAT2 were mainly localized to the cortical astrocytes in the postnatal brain, EAAT1 was enriched in the proliferative zones and radial glia from 13 gestational weeks (GW) to 20 GW. EAAT2 was abundant in the intermediate zone until 23 GW, and transiently expressed in the radial fibers of the transitional form of radial glia into mature astrocytes as well as partly in the corticofugal axonal bundles. EAAT3 immunoreactivity was robust in the apical dendrites of the pyramidal neurons in the marginal zone and cortical plate during corticogenesis, and decreased postnatally. In the individuals with type II lissencephaly, glutamate transporters were expressed in the extrusion of neuroglial tissue. Bundles of EAAT2-immunoreactive radial fibers were prominent in the specimens at 20 GW. Thus, glutamate transporters are differentially regulated during normal and impaired corticogenesis. Altered glutamate transporter expression in type II lissencephaly suggests that glutamate metabolism is involved in the formation of the normal cortex and contributes to the disorganized cortex seen in migration disorders. © 2005 Elsevier B.V. All rights reserved..
166. Hiroshi Nomura, Akiko Furuta, Yoshitaka Tanaka, Toru Iwaki, Forced retraction of spinal root injury enhances activation of p38 MAPK cascade in infiltrating macrophages, Neuropathology, 10.1111/j.1440-1789.2004.00584.x, 25, 1, 37-47, 2005.03, Root-rupture injury is a type of preganglionic brachial plexus injury resulting from traction force, where a small section of the spinal root is usually left behind. We have established experimental models of both root-rupture injury with traction force and rhizotomy without traction force in rats and we examined the activation of microglia/macrophages in both conditions. LGP107 and LGP96, which are rat homologs of lysosome-associated membrane proteins, were most useful as immunohistochemical markers of mononuclear phagocytes. The metabolic activation of macrophages was analyzed by immunohistochemistry with a series of antibodies against tumor necrosis factor-alpha (TNF-alpha), cathepsin B, p38 mitogen-activated protein kinase (MAPK), and mitogen-activated kinase kinase 3 (MKK3). Both root-rupture injury and rhizotomy rapidly induced the aggregation of numerous macrophages from the injured dorsal root to the dorsal funiculus and TNF-alpha was highly expressed by the macrophages in the injured dorsal root at 48 h. Activation of p38 MAPK was preferentially observed in the macrophages at the ruptured dorsal root
however, only slight activation of p38 MAPK was observed at the rhizotomized dorsal root. These findings suggest that traction injury of the spinal root might induce activation of the p38 MAPK cascade and production of TNF-alpha in the infiltrating macrophages, both of which might participate in aggravation of the root injury..
167. Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease..
168. 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.
169. Yasushi Nakagawa, Takefumi Yuzuriha, Toru Iwaki, Active clearance of human amyloid β 1-42 peptide aggregates from the rat ventricular system, Neuropathology, 10.1111/j.1440-1789.2004.00549.x, 24, 3, 194-200, 2004.09, A major constituent of SP in the brains of Alzheimer's disease is 39-43 amino acid peptide called β-amyloid peptide (Aβ). Recent data have demonstrated that Aβ has a strong tendency to form insoluble aggregates and that toxic effects of Aβ is based on its aggregation. In the current study, 100 μg of human synthetic Aβ 1-42 (sAβ 1-42) was infused into the lateral ventricle of rat brain using a short-term infusion model. At 2 or 7 days following the infusion, sAβ 1-42 was found to form insoluble aggregates, scattering throughout the entire ventricular systems. The sAβ 1-42 aggregates were partially engulfed by phagocytic cells and deposited at the meningeal vessels or the choroid plexuses. However, these deposits mostly disappeared from the ventricles by 28 days post-infusion. Here, it is reported for the first time that considerable amounts of sAβ 1-42 are almost cleared from the rat ventricular system by the mononuclear phagocytic system..
170. Eduardo Gámez, Yoshinobu Goto, Kengo Nagata, Toru Iwaki, Tomio Sasaki, Takehisa Matsuda, Photofabricated Gelatin-Based Nerve Conduits: Nerve Tissue Regeneration Potentials, Cell Transplantation, 10.3727/000000004783983639, 13, 5, 549-564, 13: 549-564, 2004.07.
171. Furukawa Hisako, Doh-ura Katsumi, Sasaki Kensuke, Iwaki Toru, Accumulation of prion protein in muscle fibers of experimental chloroquine myopathy: in vivo model for deposition of prion protein in non-neuronal tissues., Lab Invest, 10.1038/labinvest.3700111, 84, 7, 828-835, 2004.07.
172. Kenichi Matsumoto, Satoshi O. Suzuki, Masashi Fukui, Toru Iwaki, Accumulation of MDM2 in pleomorphic xanthoastrocytomas, Pathology International, 10.1111/j.1440-1827.2004.01637.x, 54, 6, 387-391, 2004.06, The molecular genetic basis and the tumorigenic mechanism of pleomorphic xanthoastrocytoma (PXA) still remain to be elucidated. The amplification of the mdm2 gene and accumulation of the MDM2 protein, which is considered to be one of the major cellular regulators of p53-mediated cell growth control, were studied in eight specimens of PXA obtained from five patients. All of the PXA samples showed at least focal immunopositivity for MDM2. However, none of the samples showed mdm2 gene amplification. These results suggest that accumulation of MDM2 without gene amplification may be one of the major molecular events occurring in the tumorigenesis of PXA..
173. Takashi Iida, Akiko Furuta, Yusaku Nakabeppu, Toru Iwaki, Defense mechanism to oxidative DNA damage in glial cells., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1111/j.1440-1789.2003.00540.x, 24, 2, 125-30, 2004.06, Astrocytosis is a sequential morphological change of astrocytic reaction to tissue damage, and is associated with regulation of antioxidant defense mechanisms to reduce oxidative damage. The repair enzymes to oxidative DNA damage, oxidized purine-nucleoside triphosphatase (hMTH1) and a mitochondrial type of 8-oxoguanine DNA glycosylase (hOGG1-2a) in brain tumors and neurons of Alzheimer's disease, were previously reported. In the present study, glial expression of these repair enzymes under such pathological conditions as cerebrovascular diseases and metastatic brain tumors, were investigated. Furthermore, an in-vitro experiment using a glioma cell-line under oxidative stress was performed to verify the immunohistochemical results of post-mortem materials. As a result, hOGG1-2a immunoreactivities in reactive astrocytes were more intense than those to hMTH1. Oligodendrocytes of acute or subacute stage of brain infarction were strongly immunoreactive to both repair enzymes. In-vitro study revealed that, hOGG1-2a is constitutively expressed in both untreated glioma cells and the glioma cells under oxidative stress. However, although no immunoreactivity to hMTH1 was found in the control cells, accumulation of hMTH1 was rapidly induced by oxidative stress. These results indicate that the two repair enzymes to oxidative DNA damage are differentially regulated in glial cells, and that there is a difference in the expression of the repair enzymes between reactive astrocytes and oligodendrocytes..
174. Kensuke Ishikawa, Katsumi Doh-ura, Yukitsuka Kudo, Noriyuki Nishida, Ikuko Murakami-Kubo, Yukio Ando, Tohru Sawada, Toru Iwaki, Amyloid imaging probes are useful for detection of prion plaques and treatment of transmissible spongiform encephalopathies, Journal of General Virology, 10.1099/vir.0.19754-0, 85, 6, 1785-1790, 2004.06, Diagnostic imaging probes have been developed to monitor cerebral amyloid lesions in patients with neurodegenerative disorders. A thioflavin derivative, 2-[4′-(methylamino)phenyl] benzothiazole (BTA-1) and a Congo red derivative, (trans, trans),-1-bromo-2,5-bis-(3-hydroxycarbonyl-4-hydroxy)styrylbenzene (BSB) are representative chemicals of these probes. In this report, the two chemicals were studied in transmissible spongiform encephalopathies (TSE). Both BTA-1 and BSB selectively bound to compact plaques of prion protein (PrP), not only in the brain specimens of certain types of human TSE, but also in the brains of TSE-infected mice when the probes were injected intravenously. The chemicals bound to plaques in the brains were stable and could be detected for more than 42 h post-injection. In addition, the chemicals inhibited abnormal PrP formation in a cellular model of TSE with IC50 values of 4 nM for BTA-1 and 1·4 μM for BSB. In an experimental mouse model, the intravenous injection of 1 mg BSB prolonged the incubation period by 14 %. This efficacy was only observed against the RML strain and not the other strains examined. These observations suggest that these chemicals bind directly to PrP aggregates and inhibit new formation of abnormal PrP in a strain-dependent manner. Both BTA-1 and BSB can be expected to be lead chemicals not only for imaging probes but also for therapeutic drugs for TSEs caused by certain strains..
175. Doh-ura Katsumi, Ishikawa Kensuke, Murakami-Kubo Ikuko, Sasaki Kensuke, Mohri Shirou, Race Richard, Iwaki Toru, Treatment of transmissible spongiform encephalopathy by intraventricular drug infusion in animal models., J Virol, 10.1128/JVI.78.10.4999-5006.2004, 78, 10, 4999-5006, 2004.05.
176. Ijichi, N, Tsujimoto, N, Iwaki, T, Fukumaki, Y, Iwaki A, Distal sox binding elements of the αB-crystallin gene show lens enhancer activity in transgenic mouse embryos., J. Biochem., 10.1093/jb/mvh049, 135, 3, 413-20, 2004.03.
177. Quinoline derivatives are therapeutic candidates for transmissible spongiform encephalopathies..
178. Yoshinobu Wakisaka, Akiko Furuta, Katsuaki Masuda, Wataru Morikawa, Michihiko Kuwano, Toru Iwaki, Cellular Distribution of NDRG1 Protein in the Rat Kidney and Brain During Normal Postnatal Development, Journal of Histochemistry & Cytochemistry, 10.1177/002215540305101111, 51, 11, 1515-1525, 2003.11.
179. Yoshinobu Wakisaka, Akiko Furuta, Yumihiro Tanizaki, Yutaka Kiyohara, Mitsuo Iida, Toru Iwaki, Age-associated prevalence and risk factors of Lewy body pathology in a general population: the Hisayama study, Acta Neuropathologica, 10.1007/s00401-003-0750-x, 106, 4, 374-382, 2003.10.
180. Qingguo Yuan, Kenichi Matsumoto, Yusaku Nakabeppu, Toru Iwaki, A comparative immunohistochemistry of O6-methylguanine-DNA methyltransferase and p53 in diffusely infiltrating astrocytomas., Neuropathology : official journal of the Japanese Society of Neuropathology, 10.1046/j.1440-1789.2003.00504.x, 23, 3, 203-9, 2003.09, The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6 position of guanine, thereby protecting the genome against guanine : cytosine to adenine : thymine transition and, meanwhile, conferring tumor resistance to many anti-cancer alkylating agents commonly used in the treatment of malignant gliomas. Studies on the involvement of p53 protein in expression of the MGMT gene have provided conflicting results regarding the relation between p53 protein and MGMT gene expression. To examine the potential immunostaining pattern of MGMT expression and to evaluate the possible relationship between p53 and MGMT regulation, we assessed MGMT and p53 accumulation on 35 cases of diffusely infiltrating astrocytomas. With a few cases showing cytoplasmic staining, MGMT accumulation was mainly nuclear. The percentage of labeled tumor cells was lower in high-grade astrocytomas than in low-grade astrocytomas (P < 0.05). Additionally, p53-immunopositive tumor cells were usually immunonegative to MGMT. Thus, it is suggested that MGMT expression is reduced during malignant transformation of diffusely infiltrating astrocytomas, and that mutant p53 protein might be associated with down regulation of the MGMT expression..
181. Akiko Furuta, Mami Noda, Satoshi O. Suzuki, Yoshinobu Goto, Yoshiko Kanahori, Jeffrey D. Rothstein, Toru Iwaki, Translocation of glutamate transporter subtype excitatory amino acid carrier 1 protein in kainic acid-induced rat epilepsy, American Journal of Pathology, 10.1016/S0002-9440(10)63705-4, 163, 2, 779-787, 2003.08, Glutamate excitotoxicity has been implicated in the pathophysiology of epilepsy. Systemic injection of kainic acid (KA) in the rat produces an animal model of human temporal lobe epilepsy. We examined the temporal expression of the sodium-dependent neuronal glutamate transporter, excitatory amino acid carrier 1 (EAAC1), in KA-induced rat epilepsy. As an early alteration, perinuclear deposits of EAAC1 protein were found mainly in the large pyramidal neurons at the hippocampus, neocortex, piriform cortex, and amygdala with the reduction of neuropil staining 6 hours after KA injection. Immunoelectron microscopic study revealed that the perinuclear EAAC1 immunoreactivity corresponded to the translocation to the Golgi complex. At this time point, EAAC1 mRNA was down-regulated. The intracellular aggregation of EAAC1 primarily disappeared by 24 hours. In vitro studies indicated that internalization of EAAC1 from the plasma membrane to the intracellular compartment by KA treatment was associated with the reduction of electrogenic transporter currents. Our results suggest that the transient EAAC1 internalization participates in the modulation of the transporter function preventing excessive glutamate uptake to pyramidal neurons during the early stage of epilepsy..
182. Sasaki Kensuke, Doh-ura Katsumi, Furuta Akiko, Nakashima Sachi, Morisada Yumi, Tateishi Jun, Iwaki Toru, Neuropathological features of a case with schizophrenia and prion protein gene P102L mutation before onset of Gerstmann-Straussler-Scheinker disease., Acta Neuropathol (Berl), 10.1007/s00401-003-0697-y, 106, 1, 92-96, 2003.07.
183. Involvement of cathepsin B in the motor neuron degeneration of amyotrophic lateral sclerosis..
184. M Osoegawa, H Ochi, H Kikuchi, S Shirabe, T Nagashima, T Tsumoto, Y Tamura, K Yamabe, H Takahashi, T Iwaki, J Kira, 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, Histologically proven eosinophilic myelitis has rarely been reported except in connection with parasitism. To clarify its clinicopathological features, we conducted a nationwide survey of biopsy-proven eosinophilic myelitis of unknown cause throughout Japan. Six such cases were collected and studied immunologically and pathologically. All were young to middle-aged men. All showed a protracted and fluctuating course with mild disability for 3-25 (mean 12.5) months before biopsy. Magnetic resonance imaging revealed localized lesions of T2-high and T1-iso signal intensity with a partial gadolinium enhancement in all cases. Cerebrospinal fluid (CSF) examinations were completely normal except for modest pleocytosis in two cases. Eosinophilia was present in the peripheral blood in two cases but was absent from the CSF of all cases. In spite of the chronic nature of the disease, spinal cord pathology revealed very active lesions with marked cell infiltration consisting mainly of CD8(+) T cells and varying numbers of eosinophils in the perivascular areas and the parenchyma. Both the myelin and axons were severely disrupted in all cases. Moreover, cosinophil cationic protein (ECP), an activated eosinophil product, was heavily deposited in the tissues. All but one case had hyperIgEemia and mite antigen-specific IgE in the sera, and two had accompanying atopic disorders. The present study thus revealed idiopathic eosinophilic myelitis to be a localized and persistent inflammation of the spinal cord. with distinct clinicopathological features, that has a possible link to atopic diathesis..
185. 異常型プリオン蛋白産生を阻害するキレート剤の探索.
186. 表面プラズモン共鳴法を用いたプリオン病治療薬の開発.
187. Toshiro Katsuta, Tooru Inoue, Hiroyuki Nakagaki, Morishige Takeshita, Ken Morimoto, Toru Iwaki, Distinctions between pituicytoma and ordinary pilocytic astrocytoma: Case report, Journal of Neurosurgery, 10.3171/jns.2003.98.2.0404, 98, 2, 404-406, 98(2):404-406, 2003.02, The authors present a rare case of pituicytoma. A dynamic magnetic resonance study performed after Gd injection revealed a markedly, homogeneously enhanced, early-phase pituitary lesion in a 32-year-old woman with a 1-year history of amenorrhea. The tumor bled easily during transsphenoidal resection. The lesion consisted of plump spindle cells and lacked Rosenthal fibers and granular bodies, and thus was different from ordinary pilocytic astrocytoma or any other form of this tumor. Although pituicytoma is often confused with pilocytic astrocytoma when it appears in the sellar region, these two kinds of gliomas should be distinguished on the basis of histological differences..
188. Katsumi Harimaya, Keiichiro Shiba, Hiroshi Nomura, Toru Iwaki, Yoshiharu Takemitsu, Ossification of the posterior atlantoaxial membrane: Case report, Journal of Neurosurgery, 98, 1, 77-79, 2003.01, The authors report a case of ossification of the posterior atlantoaxial membrane that led to the development of cervical myelopathy. Computerized tomography and magnetic resonance imaging were helpful in establishing the diagnosis, and decompressive laminectomy may be an appropriate intervention..
189. Hata N, Inoue T, Katsuta T, Iwaki T., Ectopic pituitary adenoma in the cavernous sinus causing oculomotor nerve paresis., Neurol Med Chir, 10.2176/nmc.43.399, 43, 8, 399-403, 43:399-403, 2003.01.
190. Toshio Uesaka, Toshiyuki Amano, Takanori Inamura, Kiyonobu Ikezaki, Satoshi Inoha, Miki Takamatsu, Toru Iwaki, Masashi Fukui, Intradural, extramedullary spinal Ewing’s sarcoma in childhood, Journal of Clinical Neuroscience, 10.1016/s0967-5868(02)00279-5, 10, 1, 122-125, 10:121-126, 2003.01.
191. Toru Iwaki, Hiroki Sawa, Jun Tateishi, Sixty-one-year-old woman presenting with deep coma during treatment for adrenal insufficiency, Neuropathology, 10.1046/j.1440-1789.2002.00465.x, 22, 4, 353-355, 2002.12.
192. Kenichi Matsumoto, Yoshihiro Natori, Eiko Hirokawa, Toru Iwaki, Bernard George, Griffith R. Harsh IV, Jack P. Rock, Andrew H. Kaye, Hypertrophic pachymeningitis as a result of a retropharyngeal inflammatory pseudotumor: Case report, Neurosurgery, 10.1097/00006123-200210000-00037, 51, 4, 1061-1065, 51(4):1061-1064, 2002.10, OBJECTIVE AND IMPORTANCE: An extremely rare case of a patient with hypertrophic pachymeningitis that resulted from an inflammatory pseudotumor of retropharynx is described. CLINICAL PRESENTATION: A 59-year-old man with a 9-year history of retropharyngeal inflammatory pseudotumor sought care for severe headache and multiple cranial nerve palsies. Magnetic resonance imaging and computed tomographic scans revealed pachymeningeal enhancement and obstructive hydrocephalus attributable to marked dural thickening around the foramen magnum. INTERVENTION: Decompression of the foramen magnum, C1 laminectomy, and meningeal biopsy were performed. The histological examination of the biopsy specimen revealed chronic inflammatory infiltrate in the hypertrophic dura mater. Corticosteroid pulse therapy was subsequently completed. Clinical and neuroradiological findings improved remarkably. CONCLUSION: A new case of hypertrophic pachymeningitis as a result of a retropharyngeal inflammatory pseudotumor is presented. We review and discuss the clinical features and the pathogenic mechanisms of hypertrophic pachymeningitis..
193. Hiroshi Nomura, Katsumi Harimaya, Hisaya Orii, Keiichiro Shiba, Takayoshi Ueta, Toru Iwaki, Traumatic neuroma of the anterior cervical nerve root with no subjective episode of trauma. Report of four cases, Journal of Neurosurgery, 97, 3, 393-396, 2002.10, The authors report four cases of traumatic neuroma in the cervical nerve root in patients with no history of trauma. In one case the patient presented with intractable pain in the left upper extremity and motor paresis of the left shoulder, and in another case the patient suffered neuropathic pain in the left forearm. In both cases, magnetic resonance (MR) imaging revealed an intradural extramedullary mass lesion in the ipsilateral cervical nerve root
these MR imaging signals were similar to the intensity of the spinal cord. Intraoperatively, fusiform enlargement of the anterior cervical nerve root was detected in the subarachnoid space. Histological examination showed a meandering change of axons accompanied by mild axonal swelling and a thin myelin sheath, which are consistent with the typical pathological features of traumatic neuroma. Postoperatively, pain resolved in both cases. The authors also investigated two traumatic neuromas of the anterior cervical nerve root in autopsy cases in which there was no history of trauma and no significant neurological signs suggestive of traumatic neuroma. The authors conclude that traumatic neuroma of the anterior cervical nerve root may develop following an unnoticed minor brachial plexus injury at birth or a forgotten traction injury of the upper extremity in childhood, and the lesion may be accompanied by various case-specific clinical features..
194. Kawashima Masatou, Doh-ura Katsumi, Mekada Eisuke, Fukui Masashi, Iwaki Toru, CD9 expression in solid non-neuroepithelial tumors and infiltrative astrocytic tumors., J Histochem Cytochem, 50, 9, 1195-1203, 50(9):1195-1203, 2002.09.
195. Hiroshi Nomura, Akiko Furuta, Toru Iwaki, 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, Preganglionic brachial plexus injuries fall into two categories according to the lesion site, root avulsion injury and root rupture injury. The latter type of injury involves part of the peripheral nervous system (PNS) component at the injured spinal cord surface. Previous investigators have used rhizotomy of experimental animals as a model for dorsal root rupture injury. However, the effect on the central nervous system (CNS)-PNS junction accompanied by the mechanical stress from traction force is hard to estimate in this model. The current study aimed to demonstrate temporal molecular alterations from the CNS-PNS junction to the ruptured dorsal root after traction injury by immunohistochemical procedures. At 28 days after dorsal rupture injury, GFAP-positive structures could be clearly identified showing rather straight lines from the centro-peripheral junction toward the peripheral stump in the ruptured dorsal root. Immunoelectron microscopy for GFAP verified GFAP IR within the astrocytic processes at the injured dorsal root at 28 days after dorsal rupture injury. Glial cell line-derived neurotrophic factor immunoreactivity (GDNF IR) was slightly upregulated within the Schwann cell bodies on the injured dorsal root at 24-48 h after rupture injury. However, GDNF IR had appeared showing a process-like profile on the ruptured dorsal root by 28 days, and it was closely related with GFAP-positive structures. In contrast, a small increase in GFAP IR was only detected on the proximal side on the rhizotomized dorsal root at 28 days after rhizotomy. A marked decrease in NF IR and S-100 IR was observed at the ruptured dorsal root from 7 days. On the other hand, laminin IR was strongly upregulated on the ruptured dorsal root from 48 h to 7 days, and was still evident at 28 days. We therefore conclude that the astrocytes show a unique ability to extend their processes toward the stump. This ability may provide a new medium for the study of axonal regeneration in future clinical experiments. © 2002 Elsevier Science B.V. All rights reserved..
196. Sasaki Kensuke, Doh-ura Katsumi, Wakisaka Yoshinobu, Iwaki Toru, Clusterin/apolipoprotein J is associated with cortical Lewy bodies: immunohistochemical study in cases with alpha-synucleinopathies., Acta Neuropathol (Berl), 10.1007/s00401-002-0546-4, 104, 3, 225-230, 104(3):225-230, 2002.09.
197. Takekazu Ohi, Kazuko Saita, Shinji Takechi, Kazuki Nabesima, Hirofumi Tashiro, Kazutaka Shiomi, Seiichiro Sugimoto, Tomotoshi Akematsu, Tatsuo Nakayama, Toru Iwaki, Shigeru Matsukura, Erratum: Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with a His46Arg mutation in Cu/Zn superoxide dismutase (Journal of the Neurological Sciences (2002) 197 (73-78) PII: S0022510X02000540), Journal of the Neurological Sciences, 10.1016/S0022-510X(02)00205-8, 201, 1-2, 93, 2002.09.
198. Junichi Nabekura, Tsuyoshi Ueno, Akihiko Okabe, Akiko Furuta, Toru Iwaki, Chigusa Shimizu-Okabe, Atsuo Fukuda, Norio Akaike, Reduction of KCC2 Expression and GABAA Receptor-Mediated Excitation after In Vivo Axonal Injury, Journal of Neuroscience, 22, 11, 4412-4417, 22: 4412-4417, 2002.06, After axotomy, application of muscimol, a GABAA receptor agonist, induced an increase in intracellular Ca2+ ([Ca 2+]i) in dorsal motor neurons of the vagus (DMV neurons). Elevation of [Ca2+]i by muscimol was blocked by bicuculline, tetrodotoxin, and Ni2+. In axotomized DMV neurons measured with gramicidin perforated-patch recordings, reversal potentials of the GABAA receptor-mediated response, presumably equal to the equilibrium potential of Cl-, were more depolarized than that in intact neurons. Thus, GABAA receptor-mediated excitation is suggested to be attributable to Cl- efflux out of the cell because of increased intracellular Cl- concentration ([Cl-] i) in axotomized neurons. Regulation of [Cl-]i in both control and injured neurons was disturbed by furosemide and bumetanide and by manipulating cation balance across the membrane, suggesting that functional alteration of furosemide-sensitive cation-Cl- cotransporters is responsible for the increase of [Cl-]i after axotomy. In situ hybridization revealed that neuron-specific K +-Cl- cotransporter (KCC2) mRNA was significantly reduced in the DMV after axotomy compared with that in control neurons. Similar expression of Na+, K+-Cl- cotransporter mRNA was observed between axotomized and control DMV neurons. Thus, axotomy led to disruption of [Cl-]i regulation attributable to a decrease of KCC2 expression, elevation of intracellular Cl-, and an excitatory response to GABA. A switch of GABA action from inhibitory to excitatory might be a mechanism contributing to excitotoxicity in injured neurons..
199. Takekazu Ohi, Kyoko Saita, Shinji Takechi, Kazuki Nabesima, Hirofumi Tashiro, Kazutaka Shiomi, Seiichiro Sugimoto, Tomotoshi Akematsu, Tatsuo Nakayama, Toru Iwaki, Shigeru Matsukura, Clinical features and neuropathological findings of familial amyotrophic lateral sclerosis with a His46Arg mutation in Cu/Zn superoxide dismutase, Journal of the Neurological Sciences, 10.1016/S0022-510X(02)00054-0, 197, 1-2, 73-78, 197:73-78, 2002.05, We examined the characteristic clinical features of one family of familial amyotrophic lateral sclerosis (FALS) with a His46Arg mutation in the enzyme Cu/Zn superoxide dismutase-1 (SOD1). The disease duration for this family was 18.1±13.2 (mean±S.D.) years, with the age at onset being 39.7±10.5 years old (mean±S.D.). The initial sign was distal weakness of the unilateral lower limb, extending to the lower limb of the other side. A wheel chair became necessary at 9.8±3.2 years after the onset. Upper limb weakness started at 15.5±8.9 years following from the onset. An autopsy was performed on a 71-year-old woman of the family with the mutation. Her disease duration was 47 years, and she died of pneumonia. She had no clear upper motor neuron involvement. Bulbar sign and respiratory muscle weakness had developed 2 years before her death. Neuropathological findings showed degeneration of corticospinal tracts, anterior/posterior spinocerebellar tracts, posterior columns, and Clarke's columns. There were few anterior horn cells in the lumbar spinal cord and no Lewy body-like hyaline inclusion bodies in these remaining anterior horn neurons. This is the first autopsy report of FALS with a His46Arg mutation in the SOD1 enzyme. © 2002 Elsevier Science B.V. All rights reserved..
200. Hitoshi Kikuchi, Akiko Furuta, Ken-ichi Nishioka, Satoshi O Suzuki, Yusaku Nakabeppu, Toru Iwaki, Impairment of mitochondrial DNA repair enzymes against accumulation of 8-oxo-guanine in the spinal motor neurons of amyotrophic lateral sclerosis., Acta neuropathologica, 10.1007/s00401-001-0480-x, 103, 4, 408-14, 408:408-414, 2002.04, Oxidative stress plays an important role in the pathogenesis of amyotrophic lateral sclerosis (ALS). In the present study, we investigated the expression of two major human enzymes that prevent errors caused by 8-oxoguanine (8-oxoG), a mitochondrial form of 8-oxoG DNA glycosylase (hOGG1) and oxidized purine nucleoside triphosphatase (hMTH1). We also investigated the relationship between their expression and the 8-oxoG accumulation observed in the large motor neurons of the lumbar spinal cord in seven cases of adult onset sporadic ALS, four cases of subarachnoid hemorrhage (SAH) and four control cases. 8-oxoG immunoreactivity increased in most large motor neurons in both the ALS and SAH cases. However, the large motor neurons in the control cases often lacked hOGG1 immunoreactivity, although some neurons expressed hOGG1 in either homogeneous or fine granular patterns. In SAH cases, most large motor neurons showed a fine granular pattern proportional to the increased 8-oxoG immunoreactivity. However, only half of the remaining motor neurons in ALS expressed hOGG1 in the fine granular pattern, and the rest did not show any immunoreactivity. In addition, small aggregates of hMTH1 in the nuclei of the anterior horn cells were present in several ALS cases. Our results indicate that the oxidative damage accumulates in the mitochondria of motor neurons in ALS, and that hOGG1 does not repair the damage efficiently, which may lead to a loss of motor neurons in ALS..
201. Sasaki Kensuke, Doh-ura Katsumi, Ironside James W, Iwaki Toru, Increased clusterin (apolipoprotein J) expression in human and mouse brains infected with transmissible spongiform encephalopathies., Acta Neuropathol (Berl), 10.1007/s004010100456, 103, 3, 199-208, 103:199-208, 2002.03.
202. Tsuneaki Takao, Toru Iwaki, 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, 2002.02, Study Design. The lumbar intervertebral discs of 135 subjects after autopsy were immunostained with antihuman heat shock protein 27 (HSP27) monoclonal antibody and antihuman heat shock protein 72 (HSP72) polyclonal antibody. Objectives. To present the data on metabolic changes that occurred in the chondrocytes of intervertebral discs during development and aging. Summary of Background Data. Heat shock proteins have been implicated in the progressive degeneration of articular cartilage in joint disease, such as rheumatoid arthritis and osteoarthritis. However, the role and expression of heat shock proteins in human intervertebral discs have received little study. Methods. One hundred thirty-five specimens of human intervertebral discs were stained with hematoxylin and eosin, alcian blue, and Masson's trichrome and were immunostained with HSP27 and HSP72 by an indirect immunoperoxidase method. The relative amounts of HSP27 and HSP72 deposition were graded according to a semiquantitative scoring system. Results. Heat shock protein 72 accumulated in the cytoplasm of the chondrocytes of both endplate cartilage and nucleus pulposus during gestation and thereafter decreased with aging (age, ≤60 years), and HSP72 immunoreactivity increased in the chondrocytes of degenerative discs. In addition, HSP72 was located in the nuclei of certain chondrocytes of the degenerated nucleus pulposus and anulus fibrosus, was highly expressed in the chondrocytes of endplate cartilage during gestation and childhood, and thereafter decreased with aging. Furthermore, with the progressive degeneration of the endplate cartilage, HSP27 immunoreactivity increased. The degree of HSP27 immunoreactivity did not change significantly according to age in either the nucleus pulposus or the anulus fibrosus. Conclusions. Heat shock protein 27 and HSP72 are thus considered to be useful molecular indicators for degenerative change in intervertebral discs. Both HSP27 and HSP72 are presumed to play a role in cell protection from stress that is induced by mechanical and biologic factors causing intervertebral disc degeneration..
203. Uesaka T, Miyazono M, Nishio S, Iwaki T., Astrocytoma of the pituitary gland(pituicytoma): case report., Neuroradiology, 10.1007/s002340100654, 44, 2, 123-125, 44:123-125, 2002.01.
204. Increased expression of manganese superoxide dismutase is associated with that of nitrotyrosine in myopathies with rimmed vacuoles..
205. Takashi Iida, Akiko Furuta, Kenichi Nishioka, Yusaku Nakabeppu, Toru Iwaki, Expression of 8-oxoguanine DNA glycosylase is reduced and associated with neurofibrillary tangles in Alzheimer's disease brain., Acta neuropathologica, 10.1007/s004010100418, 103, 1, 20-5, 2002.01, Recent studies have confirmed the role of reactive oxygen species in the pathogenesis of Alzheimer's disease (AD). 8-Oxo-2'-deoxyguanosine accumulation in AD brain has been discussed, but few studies of DNA repair enzymes in AD brain have been done. Further, a relationship between mitochondrial function and oxidative stress has been noticed. In this study, to evaluate the repair mechanism for oxidative DNA damage in AD brain, we investigated brain tissues from autopsy cases of AD and control cases using an antibody against the mitochondrial form of 8-oxoguanine DNA glycosylase (hOGG1-2a), an enzyme that repairs 8-oxo-2'-deoxyguanosine. hOGGI-2a is expressed mainly in the neuronal cytoplasm in both AD and control cases in regionally different manners. Expression of hOGG1-2a is decreased in the orbitofrontal gyrus and entorhinal cortex in AD compared to that in control cases. Immunoreactivity to hOGG1-2a is associated with neurofibrillary tangles, dystrophic neurites and reactive astrocytes in AD. Our results indicate that the repair enzyme for oxidative damage in mitochondrial DNA may not function appropriately in AD, and thus oxidative DNA damage in mitochondria may be involved in the pathomechanism of AD..
206. Shigeru Fukamachi, Akiko Furuta, Tomoaki Ikeda, Tsuyomu Ikenoue, Tsuyoshi Kaneoka, Jeffery D Rothstein, Toru Iwaki, Altered expressions of glutamate transporter subtypes in rat model of neonatal cerebral hypoxia-ischemia, Developmental Brain Research, 10.1016/S0165-3806(01)00303-0, 132, 2, 131-139, 132:131-139, 2001.12, Glutamate transporters are essential for maintaining the extracellular levels of glutamate at synaptic clefts and are regulated developmentally in a subtype-specific manner. We investigated chronological changes of immunoreactivities for glial glutamate transporters GLAST and GLT-1 and a neuronal glutamate transporter, EAAC1, in postnatal 7-day-old rat neocortices and hippocampi at 12, 24, 48 and 72 h after hypoxia-ischemia. Glutamate transporter subtypes are differentially expressed in the ischemic core and the boundary area of the neonatal rat brain with hypoxia-ischemia. Expressions of these glutamate transporters decreased in the ischemic core at 12 h, then immunoreactivities for GLAST and GLT-1 were recovered at the hippocampus. This was accompanied by a GFAP-positive gliosis at 72 h, whereas these immunoreactivities were reduced at the neocortex in the ischemic core. Glial glutamate transporters, especially GLAST, were noted in some astrocytes appearing as apoptosis as well as shrunken pyramidal neurons mainly in the boundary area of the neocortex. Increased perikaryal expression of EAAC1 was associated with that of MAP2 at the border of the boundary area. These temporal and regional expressions of glutamate transporters may contribute towards understanding the excitotoxic cell death mechanism in hypoxic-ischemic encephalopathy during the perinatal period. © 2001 Elsevier Science B.V. All rights reserved..
207. Iida T, Doh-ura K, Kawashima T, Abe H, Iwaki T, An atypical case of sporadic Creutzfeldt-Jakob disease with Parkinson's disease., Neuropathology, 10.1046/j.1440-1789.2001.00407.x, 21, 4, 294-297, 21:294-297, 2001.12.
208. Hata N, Inamura T, Imayama S, Morioka T, Nishio S, Miyazono M, Fukui M, Iwaki T., Multiple palisading granulomas in the scalp of an infant: A case report, Surg. Neurol., 10.1016/S0090-3019(01)00632-2, 56, 6, 396-399, 2001.12.
209. Kawashima T, Doh-ura K, Kikuchi H, Iwaki T, Cognitive dysfunction in patients with amyotrophic lateral sclerosis is associated with spherical or crescent-shaped ubiquitinated intraneuronal inclusions in the parahippocampal gyrus and amygdala, but not in the neostriatum., Acta Neuropathol (Berl), 102, 5, 467-472, 102: 467-472, 2001.11.
210. Midori Nakagawa, Naomi Tsujimoto, Hiroyuki Nakagawa, Toru Iwaki, Yasuyuki Fukumaki, Akiko Iwaki, Association of HSPB2, a Member of the Small Heat Shock Protein Family, with Mitochondria, Experimental Cell Research, 10.1006/excr.2001.5362, 271, 1, 161-168, 271:161-168, 2001.11.
211. Higashino T, Inamura T, Kawashima M, Ikezaki K, Miyazono M, Yoshimura T, Iwaki T, Fukui M., A lateral ventricular gliosarcoma arising in an ependymoma., Clin. Neuropathol., 20, 5, 219-223, 20:219-223, 2001.10.
212. Expression of hMTHI in the hippocampi of control and Alzheimer's disease
The oxidized purine nucleoside triphosphatase, hMTHI, has a critical role towards preventing errors caused by oxidized purine nucleoside triphosphates such as 8-oxo-dGTP and 2-hydroxy-dATP. We investigated the immunohistochemical expression of hMTHI in human hippocampal postmortem tissues representing non-neurological disease and Alzheimer's disease (AD). In the non-neurological subjects the hMTHI protein was enriched in the stratum lucidum at CA3 corresponding to mossy fiber synapses. In AD subjects, the synaptic immunoreactivities at CA3 were significantly decreased, whereas they tended to be increased at the entorhinal cortex. We suggest that the expression of hMTHI indicates indirect evidence of oxidative stress and its regulation is regionally differentiated in AD. © 2001 Lippincott Williams & Wilkins..
213. [An autopsy case of dementia with motor neuron disease accompanying Alzheimer's disease lesion]..
214. A patient with vitamin E deficient, myopathy presenting with amyotrophy.
215. Hiroshi Nomura, Akiko Furuta, Satoshi O. Suzuki, Toru Iwaki, Erratum: Dorsal horn lesion resulting from spinal root avulsion leads to the accumulation of stress-responsive proteins (Brain Research (2001) 893 (84-94) PII: S0006899300032911), Brain Research, 10.1016/S0006-8993(01)02676-2, 908, 1, 106, 2001.07.
216. [A patient with vitamin E deficient, myopathy presenting with amyotrophy]..
217. Expression of the lysosome-associated membrane proteins in myopathies with rimmed vacuoles..
218. [A case of Gerstmann-Sträussler-Scheinker syndrome (GSS) with late onset--a haplotype analysis of Glu219Lys polymorphism in PrP gene]..
219. Kawashima T, Doh-ura K, Ogomori K, Iwaki T, Apoptotic bodies in the cerebellum of Japanese patients with Creutzfeldt-Jakob disease., Pathol Int, 10.1046/j.1440-1827.2001.01181.x, 51, 3, 140-144, 51:140-144, 2001.03.
220. Hiroshi Nomura, Akiko Furuta, Satoshi O Suzuki, Toru Iwaki, Dorsal horn lesion resulting from spinal root avulsion leads to the accumulation of stress-responsive proteins, Brain Research, 10.1016/S0006-8993(00)03291-1, 893, 1-2, 84-94, 893:84-94, 2001.03, The aim of this study was to demonstrate acute to subacute molecular episodes in the dorsal horn following root avulsion using immunohistochemical methods with the markers for synapses, astrocytes and such stress-responsive molecules as heat shock proteins (Hsps) and p38 MAP kinase (p38). Among them, Hsp27 was accumulated selectively in the injured substantia gelatinosa 24 h after avulsion injury. The localization of Hsp27 in astrocytes within the substantia gelatinosa was confirmed by the double immunofluorescence method using anti-Hsp27 antibody and either anti-synaptophysin antibody or anti-glutamine synthetase antibody and by immunoelectron microscopy for Hsp27. The pattern of Hsp27 expression subsequently changed from glial pattern to punctate pattern by 7 days. Immunoelectron microscopy revealed that the punctate pattern in the subacute stage corresponded to distal parts of the astrocytic processes. Hsp27 immunoreaction was decreased 21 days after root avulsion. In the distal axotomy model, Hsp27 was accumulated later in the ipsilateral dorsal horn in a punctate pattern from 7 days after the axotomy. Phosphorylation of p38 was detected in microglia in the dorsal horn following both avulsion and axotomy. Substance P was slightly decreased in the injured substantia gelatinosa in both the avulsion and axotomy models around 14-21 days. We conclude that Hsp27 is a useful marker for demonstrating dorsal horn lesions following avulsion injury and that avulsion injury may induce Hsp27 in the dorsal horn more rapidly than distal axotomy. © 2001 Elsevier Science B.V..
221. 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.
222. Iwaki T., Hypothalamic mass in a 28-year-old man with diabetes insipidus, ataxia, nystagmus and dysarthria, Neuropathology, 10.1046/j.1440-1789.2001.00370.x, 21, 1, 99-100, 21:99-100, 2001.01.
223. Accumulation of 8-oxo-2'-deoxyguanosine and increased expression of hMTH1 protein in brain tumors.
Oxidative DNA damage generated by an attack of reactive oxygen species causes mutation or cell death that may lead to various diseases and may be related to initiation or progression of carcinogenesis. 8-Oxo-2′-deoxyguanosine (8-oxo-dG) is a major oxidative DNA damage product that can result in mutation, and hMTH1, human MutT homolog protein 1, has been identified as an enzyme that hydrolyzes 8-oxo-dGTP to the monophosphate, thus preventing accumulation of 8-oxo-dG in DNA. With immunohistochemical approaches, we investigated accumulation of 8-oxo-dG and expression of hMTH1 in brain tumor tissues obtained from surgical and autopsy cases, including 42 neuroepithelial tumors, 5 meningiomas, 2 metastatic brain tumors, and 1 schwannoma. 8-Oxo-dG accumulation and hMTH1 expression were increased in various brain tumors. Nuclei of brain tumor cells were immunoreactive for 8-oxo-dG in all cases. In most cases, both nuclei and cytoplasm of the tumor cells were immunoreactive for hMTH1. Both 8-oxo-dG accumulation and hMTH1 expression were most evident in high-grade gliomas, indicating that oxidative stress was high in these gliomas. Thus, the defense mechanism against such oxidative stress may be enhanced as well. These results suggest that oxidative stress may play a role in tumor progression..
224. Spinal cord lesions of myelitis with hyperIgEemia and mite antigen specific IgE (atopic myelitis) manifest eosinophilic inflammation
We report the neuropathological findings of spinal cord specimens obtained from two patients who had localized myelitis with hyperIgEemia and mite antigen specific IgE (atopic myelitis). Both cases showed mild spinal cord dysfunction, and the gadolinium-enhanced area of the isolated spinal cord lesion observed on MRI was biopsied, respectively. Neuropathologically, both cases showed many perivascular lymphocyte cuffings associated with disrupted vessels, and the infiltration of eosinophils in the spinal cord lesions. Both myelin and axons were lost in the lesions, which were associated with astrogliosis. These findings suggest that an allergic mechanism may play a role in this condition. Copyright © 2001 Elsevier Science B.V..
225. Kawashima M, Suzuki OS, Ikezaki K, Matsushima T, Fukui M, Iwaki T., Different responses of benign and atypical meningiomas to gamma-knife radiosurgery: report of two cases with immunohistochemical analysis., Brain Tumor Pathol, 18:61-66, 2001.01.
226. H Furukawa, K Doh-ura, K Sasaki, J Tateishi, T Iwaki, Abnormal prion protein isoforms in Japanese Creutzfeldt-Jakob disease, BRAIN PATHOLOGY, 10, 4, 665-666, 2000.09.
227. Tsuneaki Takao, Toru Iwaki, Jun Kondo, Yuji Hiraki, Immunohistochemistry of chondromodulin-I in the human intervertebral discs with special reference to the degenerative changes, Histochemical Journal, 10.1023/A:1004150211097, 32, 9, 545-550, 2000.09, The expression of the matrix protein chondromodulin-I has been studied in human intervertebral discs of 101 people using immunohistochemical analyses. The purpose of this report is to present data on the metabolic changes that were found to occur in the chondrocytes of intervertebral discs during development and aging. Chondromodulin-I was highly expressed during the gestational period and gradually decreased after maturation. It was detected in both the extracellular matrix and chondrocytes in the zone of hypertrophic cartilage, the zone of proliferative cartilage and the zone of resting cartilage in fetal discs. It was also present in the annulus fibrosus, nucleus pulposus and end-plate cartilage in mature discs. In degenerative discs, chondromodulin-I immunoreactivity tended to be elevated in the remaining chondrocytes. Our findings suggest that the expression of the protein is developmentally regulated and upregulated through a defense mechanism against the degenerative processes of the aged intervertebral disc..
228. T Kawashima, A Furuta, K Doh-ura, H Kikuchi, T Iwaki, Ubiquitin-immunoreactive skein-like inclusions in the neostriatum are not restricted to amyotrophic lateral sclerosis, but are rather aging-related structures, ACTA NEUROPATHOLOGICA, 100, 1, 43-49, 100: 43-49, 2000.07, We examined the presence of ubiquitin-immunoreactive skein-like inclusions (SLI) in the neostriatum and spinal cord in normal individuals and patients with different neurodegenerative diseases. Ubiquitin-immunoreactive SLI in the neostriatum were observed both in the normal individuals and in the patients with a variety of neurodegenerative diseases. In particular, SLI were frequently seen in normal aged subjects and certain neurodegenerative diseases, such as progressive supranuclear palsy and myotonic dystrophy. In contrast, the occurrence rate of SLI in cases with Pick's disease and multiple system atrophy tended to decrease. On the other hand, SLI in the spinal anterior horn were detected in cases of amyotrophic lateral sclerosis, but not in any cases with other neurodegenerative diseases. SLI in the neostriatum were also identifiable using phosphotungstic acid-hematoxylin and Gomori trichrome staining. Ubiquitin immunoelectron microscopy demonstrated that the SLI in the neostriatum corresponded to bundles of filaments. These features of SLI in the neostriatum were quite similar to those of intracytoplasmic rod-like inclusions (RLI) in the large neurons of caudate nucleus, which were first described by Kojima and Ogawa in 1974. Our findings indicate that SLI in the neostriatum are ubiquitin-related structures whose occurrence increases by aging, and less frequently accompany several neurodegenerative diseases, and are identical to at least some RLI..
229. K Doh-Ura, T Iwaki, B Caughey, Lysosomotropic agents and cysteine protease inhibitors inhibit scrapie-associated prion protein accumulation, JOURNAL OF VIROLOGY, 74, 10, 4894-4897, 74: 4894-4897, 2000.05, We report that lysosomotropic agents and cysteine protease inhibitors inhibited protease resistant prion protein accumulation in scrapie-infected neuroblastoma cells. The inhibition occurred without either apparent effects on normal prion protein biosynthesis or turnover or direct interactions with prion protein molecules. The findings introduce two new classes of inhibitors of the formation of protease-resistant prion protein..
230. Ko Ishihara, Naoya Hatano, Hiroyasu Furuumi, Reiko Kato, Toru Iwaki, Kiyonori Miura, Yoshihiro Jinno, Hiroyuki Sasaki, Comparative genomic sequencing identifies novel tissue-specific enhancers and sequence elements for methylation-sensitive factors implicated in Igf2/H19 imprinting, Genome Research, 10.1101/gr.10.5.664, 10, 5, 664-671, 2000.05, A differentially methylated region (DMR) and endoderm-specific enhancers, located upstream and downstream of the mouse H19 gene, respectively, are known to be essential for the reciprocal imprinting of Igf2 and H19. To explain the same imprinting patterns in non-endodermal tissues, additional enhancers have been hypothesized. We determined and compared the sequences of human and mouse H19 over 40 kb and identified 10 evolutionarily conserved downstream segments, 2 of which were coincident with the known enhancers. Reporter assays in transgenic mice showed that 5 of the other 8 segments functioned as enhancers in specific mesodermal and/or ectodermal tissues. We also identified a conserved 39-bp element that appeared repeatedly within the DMR and formed complexes with specific nuclear factors. Binding of one of the factors was inhibited when the target sequence contained methylated CpGs. These complexes may contribute to the presumed boundary function of the unmethylated DMR, which is proposed to insulate maternal Igf2 from the enhancers. Our results demonstrate that comparative genomic sequencing is highly efficient in identifying regulatory elements..
231. Anti-Ri-associated paraneoplastic cerebellar degeneration without opsoclonus in a patient with a neuroendocrine carcinoma of the stomach..
232. Familial Creutzfeldt-Jakob disease with D178N-129M mutation of PRNP presenting as cerebellar ataxia without insomnia..
233. Takashi Suzuki, Kazutoshi Nishiyama, Ayako Yamamoto, Jyoji Inazawa, Toru Iwaki, Takeshi Yamada, Ichiro Kanazawa, Yoshiyuki Sakaki, 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, Expression profiles of thousands of genes (cDNAs) were analyzed in sporadic Alzheimer disease (AD)-affected brains in comparison with normal subjects by using the high-density cDNA filter method and differential display analysis. Among 31 differentially expressed genes, one gene was found to be markedly depressed in AD-affected brains. A full-length (or nearly full-length) cDNA of the gene was isolated and sequenced. The cDNA turned out to be an orthologue of rat Nap1. The gene was thus designated human Nap1 (HGMW-approved symbol NCKAP1) and was mapped to human chromosome 2q32 by fluorescence in situ hybridization. Northern blotting and in situ hybridization studies showed that in brain, the gene is predominantly expressed in neuronal cells. Antisense oligo DNA of human Nap1 transcripts was found to induce apoptosis of neuronal cells. Based on these results, the possible role of human Nap1 in AD is discussed. (C) 2000 Academic Press..
234. Miyagi Y., Suzuki O.S., Iwaki T., Ishido K., Araki T., Kamikaseda K, Magnetic resonance appearance of multiple intracranial epidermoid cysts: intrathecal seeding of the cysts? Case report, J. Neurosurg., 92:711-714, 2000.01.
235. T. Kawashima, T. Adachi, Y. Tokunaga, A. Furuta, S. O. Suzuki, K. Doh-Ura, T. Iwaki, Immunohistochemical analysis in a case of idiopathic Lennox-Gastaut syndrome, Clinical Neuropathology, 18, 6, 286-292, 18: 286-292, 1999.11, We herein report a neuropathological and immunohistochemical analysis of a brain from a 25-year-old male with idiopathic type of Lennox-Gastaut syndrome (LGS). The clinical pictures, such as seizure type and progressive mental deterioration with an initial normal psychomotor and mental development in a man were typical of LGS. A routine neuropathological examination showed no pronounced changes, such as neuronal loss, morphologically abnormal neurons, inflammation, vascular changes, Lafora bodies and tumor cells, except that mild gliosis was seen only in CA4 of the hippocampus. Numerous corpora amylacea were observed throughout the cerebral cortices subjacent to the pia mater. An immunohistochemical analysis showed no marked findings for such proteins as glutamate transporters, glutamate decarboxylase, glutamine synthetase, neuronal cytoskeleton proteins and heat- shock proteins. However, intense ubiquitin-immunostained neurons were only found in CA4 of the hippocampus, whereas numerous astrocytes showed a strong immunoreaction for glial fibrillary acidic protein, but showed an exclusively reduced immunoreactivity for metallothionein-I/II, zinc-chelating protein. Our findings thus suggest that the pathology in the hippocampus is either causally or consequentially associated with the seizures occurring in LGS..
236. [A case of congenital non-progressive cerebellar ataxia with pigmentary retinal degeneration, fiber type disproportion and hypercreatine kinasemia]..
237. H. Tashiro, S. O. Suzuki, T. Hitotsumatsu, T. Iwaki, An autopsy case of spinocerebellar ataxia type 6 with mental symptoms of schizophrenia and dementia, Clinical Neuropathology, 18, 4, 198-204, 18: 198-204, 1999.08, We herein report the findings of an autopsy case of spinocerebellar ataxia type 6 (SCA6) which revealed a mild CAG-repeat expansion in the cola voltage-dependent calcium channel (CACNL1A4) gene on chromosome 19p13. A 39- year-old man who showed slowly progressive mental disorders and gait ataxia was clinically diagnosed to have cortical cerebellar atrophy (CCA) and schizophrenia. None of his relatives revealed any symptoms such as spinocerebellar disease, however, his younger brother had shown some mental disorders. The patient eventually died at 52 years of age, and an autopsy was thus performed. The main histopathological findings included a severe neuronal cell loss of Purkinje cells and inferior olivary nuclei. The number of Purkinje cells in our case had decreased severely in comparison to that in either OPCA or age-matched control cases, and the Purkinje cells in the cerebellar hemisphere were more affected than those in the cerebellar vermis. The neurons of the dentate nucleus and pontine nuclei were well-preserved, and no pathological changes were seen in cerebral cortices or basal ganglia. The clinicopathological findings were similar to those of late cortical cerebellar atrophy (LCCA), Holmes' cortical cerebellar atrophy (Holmes type) or SCA6 cases reported previously. Using genomic DNA extracted from archival paraffin-embedded sections in the frontal lobe, cerebral basal ganglia and cerebellum, the identical mild CAG-repeat expansions in the CACNL1A4/SCA6 gene were revealed in all samples examined. These findings suggest that in cases with LCCA or Holmes type atrophy, we should thus examine the CAG- repeat expansions in the SCA6 gene, and the genomic DNA extracted from paraffin-embedded sections was thus found to be useful in diagnosing SCA6 retrospectively..
238. Wipawan Thangnipon, Masahiro Mizoguchi, Yoji Kukita, Masakazu Inazuka, Toru Iwaki, Masashi Fukui, Kenshi Hayashi, Distinct pattern of PCR-SSCP analysis of p53 mutations in human astrocytomas, Cancer Letters, 10.1016/S0304-3835(99)00101-9, 141, 1-2, 195-201, 141: 195-201, 1999.07, Clarification of somatic mutations during the progression of human astrocytomas is important in order to understand the mechanisms underlying the development of these tumors. We analyzed surgical specimens of human astrocytomas for mutations in the p53 gene using single-strand conformation polymorphism analysis of polymerase chain reaction product (PCR-SSCP analysis) at a low pH. Klenow fragment treatment after PCR amplification was an effective means to get rid of some extra bands on the SSCP gel. Five mutations in three of 24 astrocytomas were identified by this improved SSCP method. The frequency of p53 gene mutations in astrocytomas examined was 12.5%. Further examination by direct sequencing showed that all five mutants had single-base substitutions resulting in missense mutations. The present studies revealed a loss of heterozygosity and two point mutations on the remaining allele in one of the fibrillary astrocytomas. Finally, the improvement of PCR-SSCP analysis using Klenow treatment and low pH showed a distinct electrophoresis gel pattern and could be relevant for the prognosis of human astrocytomas. Copyright (C) 1999 Elsevier Science Ireland Ltd..
239. Doh-ura K, Mohri S, Tashiro H, Kawashima T, Kikuchi H, Iwaki T, Brain injury does not modify transmissible spongiform encephalopathy caused by intraperitoneal inoculation with Fukuoka-1 strain., J Gen Virol, 80 ( Pt 6), 1551-1556, 80: 1551-1556, 1999.06.
240. H. Kikuchi, Katsumi Doh-ura, Jun-ichi Kira, Toru Iwaki, Preferential neurodegeneration in the cervical spinal cord of progressive supranuclear palsy, Acta Neuropathologica, 10.1007/s004010051033, 97, 6, 577-584, 97: 577-584, 1999.06.
241. Akihiro Nishie, Mayumi Ono, Tadahisa Shono, Junichi Fukushi, Michihiro Otsubo, Hitoshi Onoue, Yushi Ito, Takanori Inamura, Kiyonobu Ikezaki, Masashi Fukui, Toru Iwaki, Michihiko Kuwano, Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas, Clinical Cancer Research, 5, 5, 1107-1113, 5: 1107-1113, 1999.05, Macrophages are key participants in angiogenesis. In this study on human brain tumors, we first investigated whether macrophage infiltration is associated with angiogenesis and malignant histological appearance. Immunostaining of macrophages and small vessels in resected glioma specimens indicated that numbers of infiltrating macrophages and small vessel density were higher in glioblastomas than in astrocytomas or anaplastic astrocytomas. Macrophage infiltration was closely correlated with vascular density in human gliomas. Heme oxygenase-1 (HO-1), which is the rate-limiting enzyme in heme catabolism, was also associated with activated macrophages. Expression of mRNA encoding HO-1 was correlated with macrophage infiltration and vascular density in human glioma samples. Infiltrating macrophages were positively stained with anti-HO-1 antibody by immunohistochemical analysis, and in situ hybridization for HO-1 indicated that HO-1 was expressed in infiltrating macrophages in gliomas. HO-1 gene may be a useful marker for macrophage infiltration as well as neovascularization in human gliomas..
242. Kawashima T, Doh-ura K, Iwaki T, Argyrophilic grains in late-onset Creutzfeldt-Jakob diseased brain., Pathol Int, 10.1046/j.1440-1827.1999.00883.x, 49, 5, 369-373, 49: 369-373, 1999.05.
243. [An autopsy case with lower motor neuron disease showing a transient-appearance of anti-GM1 antibody and an improvement of conduction block after gamma-globulin administration]..
244. SO Suzuki, T Iwaki, Non-isotopic in situ hybridization of CD44 transcript in formalin-fixed paraffin-embedded sections, BRAIN RESEARCH PROTOCOLS, 10.1016/S1385-299X(98)00058-0, 4, 1, 29-35, 4: 29-35, 1999.04, We established a protocol for the non-isotopic in situ detection of adhesion molecule CD44 messenger RNA (mRNA) in archival formalin-fixed paraffin-embedded sections of human surgical materials. Four brain tumor samples with different histopathologies (a metastatic adenocarcinoma, a metastatic squamous carcinoma, a glioblastoma and a craniopharyngioma) were thus studied using a 157 nt digoxigenin-labeled RNA probe complementary to the common mRNA region to all the CD44 isoforms. The CD44 transcript was detected in the cytoplasm of glioma and such epithelial tumor cells as metastatic carcinoma and craniopharyngioma. A competitive hybridization study confirmed the specificity of the CD44 probe. The optimization of critical conditions are also discussed. This protocol should therefore be useful in making an accurate evaluation of mRNA localization and may also facilitate the successful completion of extensive retrospective studies on a large number of archival samples. (C) 1999 Elsevier Science B.V. All rights reserved..
245. Mizoguchi M., Inamura T., Ikezaki K., Iwaki T., Oda S., Maehara Y., Oki E., Terasaki M., Fukui M, Patient survival and microsatellite instability in gliomas by high-resolution fluorescent analysis, Oncology Report, 6, 4, 791-795, 6: 791-795, 1999.01.
246. Matsuishi T., Nagamitsu S., Shoji H., Itoh M., Takashima S., Iwaki T., Shida N., Yamashita Y., Sakai T., Kato H, Increased cerebrospinal fluid levels of substance P in patients with amyotrophic lateral sclerosis, J. Neural Transm., 10.1007/s007020050214, 106, 9-10, 943-948, 106: 943-948, 1999.01.
247. Takao T., Kaku S., Tashima T., Iwaki T, Cerebral B-cell lymphoma following treatment for Tolosa-Hunt syndrome, Clin. Neuropathol., 18, 2, 87-92, 18: 87-92, 1999.01.
248. Immunohistochemical analysis of spinal cord lesions in amyotrophic lateral sclerosis using microtubule-associated protein 2 (MAP2) antibodies..
249. Kawashima T, Kikuchi H, Takita M, Doh-ura K, Ogomori K, Oda M, Iwaki T, Skein-like inclusions in the neostriatum from a case of amyotrophic lateral sclerosis with dementia., Acta Neuropathol (Berl), 10.1007/s004010050932, 96, 5, 541-545, 96: 541-545, 1998.11.
250. [A case of subacute necrotizing lymphadenitis complicated with brachial plexus neuritis]..
251. Furukawa H, Doh-ura K, Kikuchi H, Tateishi J, Iwaki T, A comparative study of abnormal prion protein isoforms between Gerstmann-Straussler-Scheinker syndrome and Creutzfeldt-Jakob disease., J Neurol Sci, 10.1016/S0022-510X(98)00096-3, 158, 1, 71-75, 158: 71-75, 1998.06.
252. M. Mizoguchi, T. Iwaki, T. Morioka, M. Fukui, J. Tateishi, Abnormal cytoarchitecture of cortical dysplasia verified by immunohistochemistry, Clinical Neuropathology, 17, 2, 100-109, 17: 100-109, 1998.03, Cortical dysplasia is a broad category for an abnormal structure of the cerebrum due to a disorder of the normal developmental process for neocortex. We investigated the cortical dysplastic lesions which were surgically resected from 4 patients with intractable epilepsy. All cases showed a derangement of the cortical laminar structure and dysplastic changes in the neurons. In addition, 3 of them showed large round cells (balloon cells) in the deep cortex and subcortical white matter. Since each lesion showed slightly different features, we further examined the lesions immunohistochemically by using a panel of antibodies against cytoskeletal proteins to recognize and classify the cortical dysplastic lesions. An immunohistochemical study revealed marked abnormalities of the cytoskeletal structures of dysplastic neurons, bizarre glial cells and balloon cells. These cells showed an accumulation of either phosphorylated NF, MAP2 or GFAP in a distinct fashion. Ubiquitin immunoreactivity highlighted the extent of cortical dysplastic lesions. In a young patient, we also found the neuronal cytoplasmic lipofuscin deposition. It is thus considered that these diverse immunohistochemical appearances of cortical dysplasia may thus imply a different pathogenesis and they should therefore be classified based on the extent of histological abnormalities..
253. [An autopsy case of rhino-orbito-cerebral mucormycosis associated with multiple cranial nerve palsy and subsequent subarachnoid hemorrhage].
254. Satake M., Nakagawa Y., Yamashita S., Hashiguchi E., Fujii N., Yoshimura T., Iwaki T, Subacute autonomic and sensory ganglionopathy: a postmortem case, J. Neurol. Neurosurg. Psychiatry, 10.1136/jnnp.64.4.561, 64, 4, 561-561, 64: 561, 1998.01.
255. Yamada T, Yoshiyama Y, Kawaguchi N, Ichinose A, Iwaki T, Hirose S, Jefferies WA, Possible roles of transglutaminases in Alzheimer's disease, Dement. Geriatr. Cogn. Disord., 10.1159/000017031, 9, 2, 103-110, 9: 103-110, 1998.01.
256. Hamada Y., Mizoguchi M., Suzuki S.O., Iwaki T, Accumulation of class I mutant p53 and apoptosis induced by carboplatin in a human glioma cell line, Brain Tumor Pathol., 15: 77-82, 1998.01.
257. Toru Iwaki, Koji Ogomori, Naoyuki Tomokane, Akira Kondo, Jun Tateishi, Rosenthal fibers and glial filaments associated with hemidesmosome-like structures in perivascular astrocytes in a juvenile form of Alexander's disease, Neuropathology, 10.1111/j.1440-1789.1997.tb00063.x, 17, 4, 340-343, 17: 340-343, 1997.12.
258. Iwaki A, Nagano T, Nakagawa M, Iwaki T, Fukumaki Y, Identification and Characterization of the Gene Encoding a New Member of the α-Crystallin/Small hsp Family, Closely Linked to the αB-Crystallin Gene in a Head-to-Head Manner, Genomics, 10.1006/geno.1997.4956, 45, 2, 386-394, 45: 386-394, 1997.10, Iwaki, A, Nagano, T, Nakagawa, M, Iwaki, T & Fukumaki, Y, 1997, 'Identification and Characterization of the Gene Encoding a New Member of the α-Crystallin/Small hsp Family, Closely Linked to the αB-Crystallin Gene in a Head-to-Head Manner', Genomics, vol. 1263, no. 2, pp. 105-394..
259. Yasuhiro Hamada, Toru Iwaki, Masashi Fukui, Jun Tateishi, A comparative study of embedded nerve tissue in six NF2-associated schwannomas and 17 nonassociated NF2 schwannomas, Surgical Neurology, 10.1016/S0090-3019(96)00487-9, 48, 4, 395-400, 48: 395-400, 1997.10, BACKGROUND: Neurofibromatosis-2 (NF2) is an autosomal dominant disorder in which patients typically show bilateral acoustic tumors, and they are usually diagnosed histopathologically as schwannomas. The nerve of origin of a schwannoma is often demonstrated on the periphery along the capsule but not penetrating the substance of the tumor. However, there is a possibility that NF2 schwannomas and solitary schwannomas differ from participation in nerve components. METHODS: In this study, the authors noted the relationship between the tumor and the original nerves. To detect whether there were embedded nerves in the tumor, immunohistologic staining using neurofilament and myelin basic protein antibodies was performed on 6 NF2 schwannomas and 17 non-NF2 schwannomas. RESULTS: Four of five NF2 schwannomas had embedded nerves and one of four, which was considered to be the early stage of the tumor occurrence, remarkably embedded original nerves. On the other hand, embedded nerves were not seen in non-NF2 schwannomas. CONCLUSIONS: The authors concluded that the NF2 schwannomas tend have original nerves embedded in the tumor substance, which may be based on the difference of the motility of tumor cells, and the authors believe that it is difficult to remove NF2 schwannomas while preserving the original nerve..
260. Kawashima T, Furukawa H, Doh-ura K, Iwaki T, Diagnosis of new variant Creutzfeldt-Jakob disease by tonsil biopsy., Lancet, 350, 9070, 68-69, 350: 68-69, 1997.07.
261. Yasuhiro Hamada, Katsuya Goto, Tooru Inoue, Toru Iwaki, Haruo Matsuno, Satoshi Suzuki, Toshio Matsushima, Masashi Fukui, Etsuo Miyake, Histopathological aspects of dural arteriovenous fistulas in the transverse-sigmoid sinus region in nine patients, Neurosurgery, 10.1097/00006123-199703000-00005, 40, 3, 452-458, 40: 452-458, 1997.03, OBJECTIVE: In recent years, dural arteriovenous fistulas (DAVFs) have been primarily thought to be acquired lesions, formed after sinus thrombosis. The pathogenesis of DAVF, however, is still controversial. We have studied histopathological aspects of DAVFs in resected specimens obtained from nine patients, to obtain clues to the pathogenesis of DAVFs. METHODS: Histological comparison was made among nine DAVF cases and five control cases without venous sinus disease. In addition, the relationship between the clinical course and histological aspects was investigated. RESULTS: The essential abnormality found was a connection between the dural arteries and the dural veins within the venous sinus wall, through small vessels averaging approximately 30 μm in diameter. By using several staining methods, we confirmed that the vessels were part of the venous system
we named these dilated venules 'crack-like vessels.' CONCLUSION: The development of abnormal communications between dural arteries and dural veins (crack-like vessels) is regarded as the essential part of the pathogenesis of DAVFs, and sinus thrombus is not thought to be an essential lesion of DAVEs. It might be postulated that sinus hypertension caused by stenocclusive disease of the venous sinuses triggers the development of fistulous connections between arteries and veins in the dural wall, which may result in increasingly dilated venules and the formation of DAVFs..
262. Suzuki SO, Mizoguchi M, Iwaki T, Detection of SV40 T antigen genome in human gliomas., Brain Tumor Pathol., 14: 125-129, 1997.01.
263. KB Kegel, A Iwaki, T Iwaki, JE Goldman, alpha B-crystallin protects glial cells from hypertonic stress, AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 270, 3, C903-C909, 39(3): C903-C909, 1996.03, alpha B-crystallin and the small stress protein, heat shock protein of 27 kDa (HSP27), share structural similarities and are coordinately induced by classical stress stimuli. We have recently observed that hypertonic stress produced by high NaCl concentrations selectively induces alpha B-crystallin in glial cells. To examine divergence of the functional properties of these two related proteins, we have constructed stable, alpha B-crystallin-expressing glial cell lines from the U-251 MCT glioma cells, which are normally deficient in alpha B-crystallin expression but constitutively express HSP27. These transfected cells lines are more resistant to acute hypertonic stress than the parental line from which they were derived. Moreover, the parental line acclimates to stepwise increases in hypertonicity and upregulates endogenous alpha B-crystallin in the process but not HSP27. The overexpression of HSP27 and alpha B-crystallin in NIH/3T3 fibroblasts, a cell line that normally expresses little alpha B-crystallin and no HSP27, does not result in increased survival. This suggests that alpha B-crystallin interacts with cell-type specific mechanisms to aid in protection from hypertonic stress..
264. 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.
265. 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.
266. Kondo A, Baba S, Iwaki T, Harai H, Koga H, Kimura T, Takamatsu J, Hyperbaric oxygenation prevents delayed neuronal death following transient ischaemia in the gerbil hippocampus., Neuropathol. Applied Neurobiol., 10.1111/j.1365-2990.1996.tb01114.x, 22, 4, 350-360, 22: 350-360, 1996.01.
267. Y Hamada, T Iwaki, M Fukui, J Tateishi, Proliferative activity and apoptosis of Langerhans histiocytes in eosinophilic granulomas as evaluated by MIB-1 and TUNEL methods, Clinical Molecular Pathology, 10.1136/mp.48.5.m251, 48, 5, M251-M255, 48: M251-M255, 1995.10.
268. Y HIGUCHI, T IWAKI, J TATEISHI, NEURODEGENERATION IN THE LIMBIC AND PARALIMBIC SYSTEM IN PROGRESSIVE SUPRANUCLEAR PALSY, NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, 21, 3, 246-254, 21: 246-254, 1995.06, Progressive supranuclear palsy is neuropathologically characterized by neuronal degeneration of the basal ganglia, brain stem, and cerebellum. In addition, cortical neuronal degeneration associated with neurofibrillary tangles formation has been identified over wide areas of the brain in patients with progressive supranuclear palsy. We studied the distribution of alpha B-crystallin-positive degenerating neurons in cases with progressive supranuclear palsy, and compared them with those in Pick's disease, Alzheimer's disease, senile dementia of Alzheimer type, and normal aged individuals. A large number of alpha B-crystallin-positive neurons was found in the cerebral cortices of four out of nine patients with progressive supranuclear palsy, In particular, alpha B-crystallin-positive ballooned neurons were frequently observed in deep cortical pyramidal cell layers of the limbic and paralimbic systems in these diseases. The involvement of the limbic and paralimbic systems may thus contribute to personality changes as well as to memory and cognitive impairment in some patients with progressive supranuclear palsy..
269. Munechika Enjoji, Toru Iwaki, Hajime Nawata, Takeshi Watanabe, IgH Intronic Enhancer Element HE2 (μB) Functions as a cis‐Activator in Choroid Plexus Cells at the Cellular Level as well as in Transgenic Mice, Journal of Neurochemistry, 10.1046/j.1471-4159.1995.64030961.x, 64, 3, 961-966, 64: 961-966, 1995.03, Abstract: Immunoglobulin heavy‐chain (IgH) gene expression is regulated largely by the IgH gene intronic enhancer (ENHiH), which is composed of multiple protein‐binding motifs. These motifs are DNA elements that are important for the regulation of IgH gene transcription. It has been reported that the HE2 (μB) and μA motifs within the ENHiH affect B cell‐specific gene expression. To examine the function of the HE2 and μA elements in vivo, we established transgenic mouse lines. A deletion mutant of the human ENHiH that contains the HE2 and μA motifs, but lacks the motifs corresponding to murine E5, E3, and octamer, functioned not only in B lymphocytes but also in choroid plexus cells, which secrete CSF. As a result, we obtained choroid plexus tumor‐bearing transgenic mice and could establish choroid plexus carcinoma cell lines. In addition, using the luciferase assay, we confirmed at the cellular level that the HE2 motif shows a fair degree of enhancer activity in cultured choroid plexus carcinoma cells. These results suggest that existence of a trans‐acting factor for the HE2 motif in choroid plexus cells. Actually, in this cultured cell line, the existence of a protein binding to the HE2 motif was demonstrated by a gel retardation assay. Due to the sequence homology between the HE2 motif and the Ets‐binding sites, an Ets‐related protein is a highly probable candidate for being the binding factor. Copyright © 1995, Wiley Blackwell. All rights reserved.
270. T IWAKI, A IWAKI, Y FUKUMAKI, J TATEISHI, ALPHA-B-CRYSTALLIN IN C6 GLIOMA-CELLS SUPPORTS THEIR SURVIVAL IN ELEVATED EXTRACELLULAR K+ - THE IMPLICATION OF A PROTECTIVE ROLE OF ALPHA-B-CRYSTALLIN ACCUMULATION IN REACTIVE GLIA, BRAIN RESEARCH, 10.1016/0006-8993(94)01393-V, 673, 1, 47-52, 673: 47-52, 1995.02, It has been shown by immunohistochemical studies that alpha B-crystallin accumulates in the reactive and neoplastic glial cells in a variety of pathologic situations. However, the molecular mechanism for the induction of alpha B-crystallin in diseased brains is still unknown. Since any destructive brain lesions cause an abnormal elevation in the potassium (K+) concentration of the extracellular space, which disturbs the regulatory mechanism of glial cell volume, we investigated the influence of elevated extracellular K+ on the expression of alpha B-crystallin in glial cells. The treatment of rat C6 glioma cells with augmented K+ in the culture media induced an accumulation of alpha B-crystallin mRNA in a dose-dependent manner and an accumulation of the alpha B-crystallin as well. Furthermore, an overexpression of alpha B-crystallin in the C6 transformant transfected with a rat alpha B-crystallin cDNA conferred a resistant phenotype against the insult of elevated extracellular K+ on the glioma cells. Thus, alpha B-crystallin may contribute to the survival of reactive glia in the presence of a high extracellular Kf concentration..
271. Masaru Ohta, Tom Iwaki, Tetsuyuki Kitamoto, Iwao Takeshita, Jun Tateishi, Masashi Fukui, MIB1 staining index and scoring of histologic features in meningioma. Indicators for the prediction of biologic potential and postoperative management, Cancer, 10.1002/1097-0142(19941215)74:12<3176::aid-cncr2820741217>3.0.co;2-n, 74, 12, 3176-3189, 74: 3176-3189, 1994.12.
272. Tsutomu Hitotsumatsu, Toru Iwaki, Masashi Fukui, Jun Tateishi, Cytoplasmic inclusions of astrocytic elements of glial tumors: special reference to round granulated body and eosinophilic hyaline droplets, Acta Neuropathologica, 10.1007/BF00296486, 88, 6, 501-510, 88: 501-510, 1994.12, Round granulated body (RGB) and eosinophilic hyaline droplets (EHDs) have been described as cytoplasmic inclusions of certain astrocytic tumors. In the previous literature, however, these inclusions have been described using various terms or regarded as nosologically the same entity. Light microscopically, RGB apeared as a round discrete body filled with fine uniform granules, while EHDs demonstrated a cluster of bright eosinophilic, round objects of various size. They could be clearly distinguished even by conventional histochemical staining such as the Masson trichrome stain and the phosphotungstic acid hematoxylin preparation. Both RGB and EHDs expressed positive immunoreactions for glial fibrillary acidic protein, several lysosomal markers, and some stress-response proteins. The ultrastructural appearances of these inclusions were distinct, however, one common feature was that they consisted of aggregations of numerous membrane-bound electron-dense bodies. Thus, both inclusions appear to be produced by neoplastic astrocytes and are possibly related to the lysosomal system. We examined the presence of RGB and EHDs in 138 astrocytic tumors. Both inclusions occurred most frequently in pleomorphic xanthoastrocytomas, followed by gangliogliomas and pilocytic astrocytomas. Subependymal giant cell astrocytomas exhibited only RGBs. RGBs and EHDs were not seen in any abundance in glioblastomas, gliosarcomas, fibrillary astrocytomas, protoplasmic astrocytomas, or oligo-astrocytomas. Some glioblastomas, however, showed only EHDs in small numbers. Several anaplastic astrocytomas were associated with a large number of RGBs and/or EHDs, and they revealed only rare mitosis despite marked cellular pleomorphism. Although RGB and EHDs have different morphological features, the presence of these inclusions in abundance may represent either a degenerative change, a long-standing lesion, or an indolent growth of the astrocytic tumors. © 1994 Springer-Verlag..
273. Toru Iwaki, Masayuki Miyazono, Tsutomu Hitotsumatsu, Jun Tateishi, An immunohistochemical study of tissue transglutaminase in gliomas with reference to their cell dying processes, American Journal of Pathology, 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 was not limited to apoptotic bodies but could also be detected in necrobiotic cell nests..
274. Hideo Hara, Mihoko Morita, Toru Iwaki, Tomoko Hatae, Yasuto Itoyarna, Tetuyuki Kitamoto, Shin-Ichirou Akizuki, Ikuo Goto, Takeshi Watanabe, Detection of human T lymphotrophic virus type I (HTLV-I) proviral DNA and analysis of T cell receptor Vβ CDR3 sequences in spinal cord lesions of HTLV-I-associated myelopathy/tropical spastic paraparesis, Journal of Experimental Medicine, 10.1084/jem.180.3.831, 180, 3, 831-839, 180: 831-839, 1994.09, Identification of the localization of human T lymphotrophic virus type I (HTLV-I) proviral DNA in the central nervous system (CNS) is crucial to the understanding of the pathogenesis of HTLVI- associated myelopathy (HAM)/tropical spastic paraparesis (TSP) pathogenesis. We have developed a sensitive detection method, called two-step polymerase chain reaction (PCR) in situ hybridization, which enabled us to detect the HTLV-I proviral DNA in paraffin-embedded spinal cord tissue sections from HAM/TSP patients. HTLV-I proviral DNA was detected only in the nucleus of lymphocytes that had infiltrated into the spinal cord. However, no proviral DNA was amplified in any neuronal cells, including neurons and glial cells. This indicates that the demyelination of the spinal cord by HTLV-I as a result of viral infection of oligodendrocytes or neuronal cells is unlikely. The T cell receptor Vβ gene sequence from lymphocytes in the spinal cord lesions taken from the same HAM/TSP autopsy cases revealed unique and restricted CDR3 motifs, CASSLXG(G) (one-letter amino acid. X is any amino acid), CASSPT(G), and CASSGRL which are similar to those described in T cells from brain lesions of multiple sclerosis (MS) and in a rat T cell clone derived from experimental allergic encephalomyelitis (EAE) lesions. The present results suggest that T cells containing restricted V3 CDK3 motifs, which are also found in MS and EAE, become activated upon HTLV-I infection and infiltrate into the spinal cord lesions of HAM/TSP patients. © 1994, Rockefeller University Press., All rights reserved..
275. T IWAKI, A IWAKI, J TATEISHI, JE GOLDMAN, SENSE AND ANTISENSE MODIFICATION OF GLIAL ALPHA-B-CRYSTALLIN PRODUCTION RESULTS IN ALTERATIONS OF STRESS FIBER FORMATION AND THERMORESISTANCE, JOURNAL OF CELL BIOLOGY, 125, 6, 1385-1393, 125:1385-1393, 1994.06, The phenotypic effects of selectively altering the levels of alpha B-crystallin in cultured glial cells were analyzed using sense and antisense approaches. Rat C6 glioma cells and human U-373MG glioma cells were transfected with a rat alpha B-crystallin sense cDNA or an antisense cDNA regulated by a Rous sarcoma virus promoter to alter cellular levels of alpha B-crystallin. The antisense strategy resulted in decreased alpha B-crystallin levels, as revealed by Western blot and immunocytochemical analyses. The reduced alpha B-crystallin expression was accompanied by alterations in cellular phenotype: (a) a reduction of cell size and/or a slender cell morphology; (b) a disorganized microfilament network; and (c) a reduction of cell adhesiveness. Like HSP27, the presence of additional alpha B-crystallin protein confers a thermoresistant phenotype to stable transfectants. Thus, alpha B-crystallin in glioma cells plays a role in their thermal resistance and may contribute to the stability of cytoskeletal organization..
276. Takuro Kobayashi, Takeshi Yamada, Taeko Yasutake, Nobue Shinnoh, Ikuo Goto, Toru Iwaki, Adrenoleukodystrophy gene encodes an 80 kDa membrane protein, Biochemical and Biophysical Research Communications, 10.1006/bbrc.1994.1805, 201, 2, 1029-1034, 201:1029-1034, 1994.06, An antibody against the synthetic C-terminal peptides deduced from the cDNA of the gene responsible for X-linked adrenoleukodystrophy (ALD) was produced to characterize the product of the ALD gene. The antibody reacted with the 80 kDa band protein in control fibroblasts, while no bands were detected in the fibroblasts from a patient with ALD (#163), in which mRNA of the ALD gene was undetectable based on Northern blot analysis. The 293T cells transfected with the full-coding cDNA inserted in the expression vector produced a new 80 kDa protein, as detected by Western blot. In an immunocytological study, the staining was in a punctate pattern, in the normal fibroblasts. However, there was no punctate staining in the #163 cells. These data thus indicate that the ALD gene encodes an 80 kDa membrane protein. © 1994 Academic Press, Inc..
277. Higuchi Masakazu, Ito Takashi, Imai Yoshinori, Iwaki Toru, Hattori Masahira, Kohsaka Shinichi, Niho Yoshiyuki, Sakaki Yoshiyuki, Expression of the α2-macroglobulin-encoding gene in rat brain and cultured astrocytes, Gene, 10.1016/0378-1119(94)90565-7, 141, 2, 155-162, 141:155-162, 1994.04, The α2-macroglobulin (α2M), a protease inhibitor, is a major acute-phase protein in rats, and is produced in the liver during acute inflammation. Recently, it has been demonstrated that α2M is also produced by cultured astrocytes from newborn rat brain and has neurite-promoting activity. Here, we found that the expression of the α 2M gene was significantly enhanced in the brain following intraperitoneal injection of the neurotoxicant, kainic acid (KA), suggesting that α2M acts as an acute-phase protein in the brain, as in the case of the liver, and may be involved in neural repair processes. Expression of α2M in cultured astrocytes was shown to be stimulated by interleukin-6 (IL-6) and/or leukemia inhibitory factor (LIF) in the presence of glucocorticoid. The amount of mRNAs for IL-6 and LIF increased in the brain of KA-injected rats prior to α2M induction. These results strongly suggested that IL-6 and LIF are involved in α2M induction in the brain, as in the case of the liver. Analysis of the cis-acting element(s) and the trans-acting factor(s) suggested that the regulatory mechanism for α2M expression in astrocytes was similar to that in inflamed liver. © 1994..
278. Tsutomu Hitotsumatsu, Tetsuyuki Kitamoto, Toru Iwaki, Masashi Fukui, Jun Tateishi, An exon 8-spliced out transcript of neurofibromatosis 2 gene is constitutively expressed in various human tissues, Journal of Biochemistry, 10.1093/oxfordjournals.jbchem.a124664, 116, 6, 1205-1207, 116: 1205-1207, 1994.01, We succeeded in cloning the exon 8-spliced out transcript of neurofibromatosis 2 (NF2) gene in human glioma cell lines. We then investigated the expression of the spliced out form in various human tissues by PCR analysis followed by Southern blot hybridization and sequencing to evaluate whether it was generated by normal alternative splicing or by a splicing mutation. The analysis revealed the splicing out of exon 8 in the various tissues, and the transcript missing exon 8 should thus be considered as a product of normal alternative splicing. Our results further support the possibility that the NF2 gene expresses multiple alternatively-spliced transcripts variantly in different tissue types. © 1994 BY The Journal of Biochemistry..
279. Masaru Ohta, Tetsuyuki Kitamoto, Toru Iwaki, Tetsuya Ohgami, Masashi Fukui, Jun Tateishi, Immunohistochemical distribution of amyloid precursor protein during normal rat development, Developmental Brain Research, 10.1016/0165-3806(93)90019-7, 75, 2, 151-161, 75: 151-161, 1993.10, This study focused on the immunohistochemical identification of the β/A4 amyloid precursor protein (APP) in various developmental stages of both the rat central nervous system (CNS) and the peripheral nervous system (PNS). A comparative study with myelin basic protein (MBP) and synaptophysin (SYP) facilitated the understanding of neuronal maturation and synaptogenesis on both prenatal and postnatal development. Our immunohistochemical study revealed APP to be widely distributed through the nervous system while existing mainly in the cytoplasm, dendrites and axons of the neurons. However, immunoreactivity was also observed in either the ependymal cells or the choroid plexus epithelial cells. Our immunostaining was carried out by the hydrated autoclaving method and revealed the expression of APP at embryonic day 15 in the neuron of the mesencephalic nucleus of the trigeminal nerve and the anterior horn of the spinal cord, trigeminal and spinal ganglion, ependymal cells and the choroid plexus. We thus observed dramatic changes of APP expression in the cerebellum from the embryonic stage. The maturation of synaptogenesis in the cerebellar molecular layer was parallel to the extension of the dendrites of Purkinje cells, which revealed immunoreactivity for APP. These findings suggested that APP played an important role in neuronal maturation and synaptogenesis. Thus, APP is considered to be a useful marker for neuronal development. © 1993..
280. Masayuki Miyazono, Toru Iwaki, Tetsuyuki Kitamoto, Ryong-Woon Shin, Masashi Fukui, Jun Tateishi, Widespread distribution of tau in the astrocytic elements of glial tumors, Acta Neuropathologica, 10.1007/BF00304137, 86, 3, 236-241, 86: 236-241, 1993.08, Recently tau immunoreactivity has been observed in astrocytes in Alzheimer's disease and other neurological diseases. We examined the immunohistochemical localization of tau in 110 human brain tumors. Tau was widely distributed in the glial neoplastic cells and the reactive astrocytes in tumor tissues. In human surgical specimens positive immunostaining for tau was frequently observed in astrocytic tumors, oligodendroglial tumors, and glioblastoma, as well as neuronal tumors. The astrocytic neoplastic cells in medulloblastoma and other poorly differentiated tumors were also stained. In contrast, no immunoreactivity was observed in meningiomas and schwannomas. The expression of tau in brain tumors was mainly restricted to those cells with astrocytic features rather than small immature cells. The expression of tau mRNA was also demonstrated in astrocytic tumors. In conjunction with the findings of tau-positive astrocytes in some degenerative disorders, astrocytes are considered to have a potential to express tau through neoplastic transformation and reactive processes. © 1993 Springer-Verlag..
281. T IWAKI, A IWAKI, J TATEISHI, Y SAKAKI, JE GOLDMAN, ALPHA-B-CRYSTALLIN AND 27-KD HEAT-SHOCK PROTEIN ARE REGULATED BY STRESS CONDITIONS IN THE CENTRAL-NERVOUS-SYSTEM AND ACCUMULATE IN ROSENTHAL FIBERS, AMERICAN JOURNAL OF PATHOLOGY, 143, 2, 487-495, 1993.08, 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..
282. T IWAKI, A IWAKI, JE GOLDMAN, ALPHA-B-CRYSTALLIN IN OXIDATIVE MUSCLE-FIBERS AND ITS ACCUMULATION IN RAGGED-RED FIBERS - A COMPARATIVE IMMUNOHISTOCHEMICAL AND HISTOCHEMICAL-STUDY IN HUMAN SKELETAL-MUSCLE, ACTA NEUROPATHOLOGICA, 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..
283. N YOKOYAMA, T IWAKI, JE GOLDMAN, J TATEISHI, M FUKUI, SMALL HEAT-SHOCK PROTEIN IS EXPRESSED IN MENINGIOMAS AND IN GRANULOFILAMENTOUS INCLUSION-BODIES, ACTA NEUROPATHOLOGICA, 85, 3, 248-255, 85: 248-255, 1993.02, The cellular expression of estrogen receptor-related small heat-shock protein (HSP27) in meningiomas was investigated immunologically. A cytoplasmic distribution of HSP27 was demonstrated in surgical specimens of 22 of 26 cases with meningiomas and cultured meningioma cells derived from two individuals. By Western blotting, HSP27 was detected in every tissue homogenate of 17 cases studied. Thus, HSP27 appears to be constitutively expressed in most meningiomas. In anaplastic portions of one papillary meningioma, there were numerous granulofilamentous inclusion bodies [Goldman JE et al. (1980) Cancer 46:156-161]. The inclusion bodies were immunopositive for HSP27 despite the negativity of the tumor cytoplasms. Thus, HSP27 seems to participate in the formation of certain inclusion bodies in meningioma cells, like alphaB-crystallin which participates in the formation of Rosenthal fibers in astrocytes..
284. A IWAKI, T MURAMOTO, T IWAKI, H FURUMI, ML DARIODELEON, J TATEISHI, Y FUKUMAKI, A MISSENSE MUTATION IN THE PROTEOLIPID PROTEIN GENE RESPONSIBLE FOR PELIZAEUS-MERZBACHER DISEASE IN A JAPANESE FAMILY, HUMAN MOLECULAR GENETICS, 2, 1, 19-22, 2:19-22, 1993.01, We investigated the proteolipid protein (PLP) gene of two boys in a Japanese family with Pelizaeus - Merzbacher (PMD), an X-linked neurologic disorder characterized by dysmyelination in the central nervous system (CNS). The patients showed similar clinical signs from birth and autopsy on the elder brother confirmed a connatal type of PMD. Direct sequencing of the PLP gene and PLP mRNAs from the brain of the PMD patient revealed a G to T transition in exon V of the PLP gene, which leads to a glycine to cystein substitution at residue 220. Allele-specific oligonucleotide hybridization revealed that this mutation was also present in his brother, but was absent in 100 X chromosomes of normal Japanese individuals. Northern blot analysis showed that the mRNA levels of PLP and myelin basic protein, two major myelin proteins produced by oligodendrocytes, were much reduced in the PMD brain, hence, there was a specific loss of oligodendrocytes. It seems likely that the substitution is responsible for PMD (connatal type) in this particular family and causes oligodendrocytes death in the CNS..
285. M. Miyazono, T. Iwaki, J. Tateishi, M. Fukui, Anaplastic large cell ki-1 lymphoma in the central nervous system: Report of an autopsy case, Acta Neuropathologica, 10.1007/BF00304479, 84, 5, 577-580, 84: 577-580, 1992.10, A 45-year old immunocompetent man presented with multiple lesions in the brain. A histological examination of the tumors showed a diffuse infiltrate of lymphoid cells with cellular polymorphism and of multinucleated giant cells. These cells were immunolabeled with antibodies against B cell lineage and with a monoclonal antibody, Ber-H2 (CD30), which showed the presence of Ki-1 antigen. Recently, among systemic non-Hodgkin's lymphomas, attention has been given to Ki-1-positive lymphomas, which have been incorporated in the up-dated Kiel classification. We report here a case of Ki-1-positive lymphoma arising in the CNS and review previously reported cases. © 1992 Springer-Verlag..
286. M. Miyazono, T. Kitamoto, T. Iwaki, J. Tateishi, Colocalization of prion protein and β protein in the same amyloid plaques in patients with Gerstmann-Sträussler Syndrome, Acta Neuropathologica, 10.1007/BF00713522, 83, 4, 333-339, 83: 333-339, 1992.07, We examined paraffin-embedded brain sections from three patients with Creutzfeldt-Jakob disease (CJD) and four patients with Gerstmann-Sträussler syndrome (GSS) who also had β protein deposits in the brains. Immunostaining using anti-prion protein (PrP) and anti-β protein coupled with formic acid pretreatment, revealed PrP deposits and β protein deposits, respectively. In all four GSS patients examined, sequential double immunostaining and single immunostaining in serial sections or simultaneous double immunofluorescence revealed the colocalization of PrP and β protein in the same amyloid plaques. The plaques labeled with both antibodies were designated as β-PrP plaques. Small kuru plaques of less than 15 μm in diameter were rarely found to coexist with β deposits. The percentages of β-PrP plaques in larger kuru plaques were not constant among the four GSS patients. The colocalization patterns of both deposits were observed as being roughly of two types as follows: (1) diffuse β protein deposits located around the PrP core
and (2) a β protein core and PrP core simultaneously existing in one amyloid plaque. Under an electron microscope, we were able to confirm the presence of both β protein and PrP in a single plaque in four GSS patients older than 60 years old. In contrast, no colocalization of either deposits was seen in the amyloid plaque core fractions of a young GSS patient who had no β protein deposits, even at the electron microscopic level. Therefore, the colocalization of both proteins in a single plaque is believed to be age-related and incidental in GSS patients but suggests a similar morphogenesis of both amyloid deposits. © 1992 Springer-Verlag..
287. Akiko Iwaki, Toru Iwaki, James E. Goldman, Koji Ogomori, Jun Tateishi, Yoshiyuki Sakaki, Accumulation of αB-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, Neuroscience Letters, 10.1016/0304-3940(92)90689-5, 140, 1, 89-92, 140: 89-92, 1992.06.
288. Ryong-Woon Shin, Toru Iwaki, Tetsuyuki Kitamoto, Yuji Sato, Jun Tateishi, 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, American Journal of Pathology, 140, 4, 937-945, 140: 937-945, 1992.04, Using the hydrated autoclaving method, a new immunohistochemical procedure to enhance tau immunoreactivity in formalin-fixed brain tissue, the authors recently reported that tau protein is detected in neuronal cell bodies and proximal dendrites, gray matter neuropil, axons, and glial cells in normal human hippocampus and neocortex. In the this study, the authors performed a comparative study of the distribution of normal and modified forms of tau in Alzheimer's disease (AD) and control brains. In the cerebral cortex and white matter of AD brains, a massive accumulation of modified tau and/or severe depletion of normal tau were documented in all the tau compartments. In mild AD cases, gray matter neuropil, axons, and glial cells were less severely involved than neuronal perikarya. In the controls, neuronal perikarya were often involved by modified tau accumulation, but the other compartments showed normal distribution. These observations suggest that modifications of tau which lead to neurofibrillary lesions in AD may begin in neuronal perikarya and extend to the other tau compartments in advanced stages of the disease..
289. Miyazono M, Kitamoto T, Doh-ura K, Iwaki T, Tateishi J, Creutzfeldt-Jakob disease with codon 129 polymorphism (valine): a comparative study of patients with codon 102 point mutation or without mutations., Acta Neuropathol, 84, 4, 349-354, 1992.04.
290. 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.
291. Kaneko Y, Iwaki T, Fukui M, Lectin histochemistry of human fetal notochord, ecchordosis physaliphora, and chordomas., Arch. Pathol. Lab. Med., 116, 1, 60-64, 116: 60-64, 1992.01.
292. T IWAKI, J TATEISHI, IMMUNOHISTOCHEMICAL DEMONSTRATION OF ALPHAB-CRYSTALLIN IN HAMARTOMAS OF TUBEROUS SCLEROSIS, AMERICAN JOURNAL OF PATHOLOGY, 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..
293. T IWAKI, A IWAKI, M MIYAZONO, JE GOLDMAN, PREFERENTIAL EXPRESSION OF ALPHA-B-CRYSTALLIN IN ASTROCYTIC ELEMENTS OF NEUROECTODERMAL TUMORS, CANCER, 68, 10, 2230-2240, 68: 2230-2240, 1991.11, Recently the authors have identified a major component of Rosenthal fibers as alpha-B-crystallin, a major lens protein. In the current study the authors investigated the expression of alpha-B-crystallin in four cultured glioma cell lines and in 115 human neuroectodermal tumors. alpha-B-crystallin was expressed differentially by those glioma cell lines, but not by neuroblastoma cell lines. Northern blot analysis revealed two distinct messages for alpha-B-crystallin in C-6, whereas only a single message in U-373MG and G26-24. In human surgical specimens positive immunostaining was frequently observed in the following brain tumors: pilocytic astrocytoma of the juvenile type, anaplastic astrocytoma, glioblastoma multiforme, and subependymal giant cell astrocytoma. The astrocytic elements of mixed oligoastrocytomas, glioblastomas with sarcomatous components, and gangliogliomas were likewise strongly stained. In contrast, little immunoreactivity was observed in ependymal and choroid plexus tumors. Thus, alpha-B-crystallin is mainly expressed by astrocytic tumors among neuroectodermal neoplasms, without regard to the presence of Rosenthal fibers..
294. 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, 1991.09.
295. Y. Kaneko, T. Iwaki, T. Matsushima, M. Fukui, Comprehensive lectin histochemistry of normal and neoplastic human choroid plexus cells: alternation of lectin-binding patterns through neoplastic transformation, Acta Neuropathologica, 10.1007/BF00293955, 82, 2, 127-133, 82: 127-133, 1991.07, Lectin histochemistry of the normal and neoplastic human choroid plexus cells [six choroid plexus papillomas (CPPs) and three choroid plexus carcinomas (CPCs)] was performed using eight representative lectins to study the development of sugar chain structures and also to determine whether lectins were useful for a histopathological diagnosis of choroid plexus neoplasms (CPNs). The normal choroid plexus cells reacted with Ricinus communis (RCA-I), Canavalia ensiformis (Con A), Limax flavus (LFA) and Triticum vulgaris (WGA), while Arachis hypoaea (PNA) stained them only after the removal of sialic acid. Human fetal choroid plexus cells at 8 weeks gestation already showed the same lectin-binding patterns as adult ones. All CPNs were stained by RCA-I and Con A in a similar manner as the normal choroid plexus cells. Although seven CPNs were positive for LFA, two CPCs were not stained by LFA, which bound to sialic acid. Two LFA-positive CPPs were stained by PNA before the removal of sialic acid. Moreover, unlike the normal choroid plexus cells, Ulex europaeus-, Glycine maximus- and Dolichos biflorus- binding sites often appeared, and WGA-binding sites of three CPNs remained even after sialic acid removal. In conclusion, the glycosialylation in normal choroid plexus cells was completed during the early embryonic stage. The lectin-binding patterns of CPNs were heterogenous in each case. The alternation of the glycosialylation and/or acquisition of binding sites for some lectins was sometimes observed through a neoplastic transformation. © 1991 Springer-Verlag..
296. T IWAKI, A IWAKI, RKH LIEM, JE GOLDMAN, EXPRESSION OF ALPHA-B-CRYSTALLIN IN THE DEVELOPING RAT-KIDNEY, KIDNEY INTERNATIONAL, 40, 1, 52-56, 1991.07, The expression and cellular localization of alpha-B-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 alpha-B-crystallin rapidly increased after birth to reach adult levels by 20 days. At the same time, immunohistochemistry for alpha-B-crystallin demonstrated that the prominent elongation of Henle's loop during the first 10 days of life was accompanied by increased alpha-B-crystallin expression. Thus, the development of alpha-B-crystallin expression is correlated temporally with the acquisition of tubule function in early post-natal life..
297. R. W. Shin, T. Iwaki, T. Kitamoto, J. Tateishi, Hydrated autoclave pretreatment enhances tau immunoreactivity in formalin-fixed normal and Alzheimer's disease brain tissues, Laboratory Investigation, 64, 5, 693-702, 64: 693-702, 1991.05, We developed a new immunohistochemical method by which normal tau antigenicity can be visualized in paraffin sections of formalin-fixed brain tissue. This method consists of autoclave pretreatment of sections immersed into distilled water (hydrated autoclaving) before incubation with anti-tau antibodies. In normal human brain, immunoreactive tau was detected in neuronal cell bodies and dendrites, axon fibers, astroglia, oligodendroglia and gray matter neuropil. In previous studies on normal tau distribution, different optimized fixations that effectively preserve tau antigenicity were used but none of these revealed all of these compartments together. Our method is therefore considered to be more sensitive for detecting normal tau immunoreactivity. In addition, hydrated autoclaving had an enhancing effect on the abnormally phosphorylated (modified) tau immunoreactivity in formalin-fixed brains. In hydrated autoclaving of sections from patients with Alzheimer's disease, neuropil threads, senile plaques, extracellular and intracellular tangles were enhanced in quantity and in staining intensity. Therefore, modified tau appears to accumulate more densely than expected from conventional immunohistochemistry. Immunoblot analysis showed that normal or modified tau immunoreactivity was totally or partially eliminated on formalin treatment and could be revisualized by hydrated autoclaving, an event presumably related to recovering of formalin-masked tau antigens through denaturation by hydrated autoclaving..
298. N TOMOKANE, T IWAKI, J TATEISHI, A IWAKI, JE GOLDMAN, ROSENTHAL FIBERS SHARE EPITOPES WITH ALPHA-B-CRYSTALLIN, GLIAL FIBRILLARY ACIDIC PROTEIN, AND UBIQUITIN, BUT NOT WITH VIMENTIN - IMMUNOELECTRON MICROSCOPY WITH COLLOIDAL GOLD, AMERICAN JOURNAL OF PATHOLOGY, 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..
299. A IWAKI, T IWAKI, JE GOLDMAN, RKH LIEM, MULTIPLE MESSENGER-RNAS OF RAT-BRAIN ALPHA-CRYSTALLIN-B CHAIN RESULT FROM ALTERNATIVE TRANSCRIPTIONAL INITIATION, JOURNAL OF BIOLOGICAL CHEMISTRY, 265, 36, 22197-22203, 265 :22197-22203, 1990.12, Two major classes of mRNAs for the alpha-crystallin B chain (or alpha(B)crystallin), about 0.9 and 1.2 kilobases in length, are expressed in rat brain. To examine the structures of these mRNAs, we isolated cDNA clones from rat brain and genomic DNA from rat liver. Characterization of these clones as well as Northern blot analysis indicated that the various mRNAs differed in the lengths of their 5' leader sequences. RNase protection assays revealed that the gene for alpha-crystallin B chain contains multiple start sites. The transcriptional start sites of the longer mRNAs are preceded by a putative CAAT box and that of the shorter mRNA by a putative TATA box. The shorter mRNA encodes the alpha-crystallin B chain protein, whereas the longer mRNA contained three extra small open reading frames upstream of the AUG start codon for the protein. The shorter mRNA is abundant in lens, heart, muscle, and kidney, while the longer mRNAs are constitutively expressed at low levels in a wide variety of tissues. The shorter mRNA was increased by treatment with phorbol 12-myristate 13-acetate in rat C6 glioma cells. Since there is only a single copy of the alpha-crystallin B chain gene, our results indicate that the two classes of mRNAs are generated by alternative transcriptional initiation from different promoters and their expressions are regulated differentially..
300. Yoichi Kaneko, Iwao Takeshita, Toshio Matsushima, Toru Iwaki, Takatoshi Tashima, Masashi Fukui, Immunohistochemical study of ependymal neoplasms: histological subtypes and glial and epithelial characteristics, Virchows Archiv A Pathological Anatomy and Histopathology, 10.1007/BF02190526, 417, 2, 97-103, 417: 97-103, 1990.06, An immunohistochemical study on ependymal tumours was performed in order to determine what relationships exist between histological subtypes and epithelial or glial characteristics. Thirty-eight ependymal tumours were examined with antibodies to cytokeratin (CK), epithelial membrane antigen (EMA), transthyretin (TTR) and glial fibrillary acidic protein (GFAP) using the avidin-biotin-complex technique. They included 23 ependymomas, 13 anaplastic ependymomas, and 2 myxopapillary ependymomas. Only 3 of the 23 ependymomas were positive with EMA but 19 reacted with GFAP. None of them were positive with CK. Six of the 13 anaplastic ependymomas were positive with EMA, 3 with CK and 10 with GFAP. Five of the 6 anaplastic ependymomas which had epithelial marker proteins were either negative or weakly positive for GFAP. The present study demonstrates that most benign ependymomas exhibit GFAP positivity while the anaplastic ones tend to suppress their glial nature in favour of epithelial differrentiation. However, ependymal tumours showed few characteristics of choroid plexus cells
only one of the examined cases was positive for TTR. © 1990 Springer-Verlag..
301. T Iwaki, A Kume-Iwaki, J E Goldman, Cellular distribution of alpha B-crystallin in non-lenticular tissues., Journal of Histochemistry & Cytochemistry, 10.1177/38.1.2294148, 38, 1, 31-39, 1990.01.
302. Tashima T, Fukui M, Nishio S, Fujii K, Iwaki T, Radiation-induced meningiomas and their proliferative activity. Cytokinetic study using bromodeoxyuridine., Acta Neurochir., 10.1007/BF01402189, 102, 1-2, 69-72, 102: 69-72, 1990.01.
303. 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..
304. Toru Iwaki, Akiko Kume-Iwaki, Ronald K.H. Liem, James E. Goldman, αB-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.
305. T. Iwaki, M. Fukui, I. Takeshita, M. Tsuneyoshi, J. Tateishi, Hemangiopericytoma of the meninges: A clinicopathologic and immunohistochemical study, Clinical Neuropathology, 7, 3, 93-99, 1988.05.
306. T. Inoue, T. Tashima, S. Nishio, I. Takeshita, T. Iwaki, M. Fukui, Vascular permeability and cell kinetics of ethylnitrosourea (ENU)-induced rat brain tumours, Acta Neurochirurgica, 10.1007/BF01400531, 91, 1-2, 67-72, 91: 67-72, 1988.03, Vascular permeability and proliferative activity of ethylnitrosourea (ENU)-induced rat brain tumours were studied by intravenous injection of Evans blue dye (EB) and by bromodeoxyuridine (BrdU) uptake examinations. Tumours induced by ENU showed various histologial types, and they were oligodendrogliomas, mixed oligo-astrocytomas, mixed oligo-ependymomas, astrocytomas, anaplastic astrocytomas, polymorphic gliomas, and ependymomas. The labelling indexes (LIs: the ratio of BrdU-labelled cells to total cells) of tumour and vascular component cells in the tumour were high in anaplastic astrocytomas, polymorphic gliomas and ependymomas, but low in oligodendrogliomas. EB stained anaplastic astrocytomas, polymorphic gliomas and ependymomas deeply, but did not penetrate oligodendrogliomas. In mixed gliomas, EB staining and the LIs of tumour cells were not uniform. After intracarotid infusion of hyperosmolar mannitol into tumour-bearing rats, tumour staining with EB and the LIs of tumour cells were not increased, whereas the penetration of EB into the normal brain was drastically increased. Therefore it is not likely that the delivery of chemotherapeutic drugs to the tumour could be increased by intracarotid infusion of hyperosmolar manitol. Our data suggest that the vascular permeability of tumour vessels is highly correlated with the high proliferative activity of tumour and its vascular cells. © 1988 Springer-Verlag..
307. T. Iwaki, I. Takeshita, M. Fukui, K. Kitamura, Cell kinetics of the malignant evolution of meningothelial meningioma, Acta Neuropathologica, 10.1007/BF00688188, 74, 3, 243-247, 74: 243-247, 1987.09, A meningotheliomatous meningioma occurred in the right parietal parasagittal region of a 43-year-old woman. A total excision was carried out. Three years and 9 months later, one parasagittal and two falx tumours in close proximity recurred and were excised. The falx tumors showed the features of an anaplastic transitional meningioma with increased mitoses. The falx meningioma recurred locally and repeatedly, despite radiation therapy and chemoimmunotherapy. She died 7 years and 8 months after the onset. At autopsy, the tumor was found to have metastasized via the cerebrospinal fluid to the spinal cord and pituitary stalk. Extracranial metastases were not evident. At the fourth craniotomy, bromodeoxyuridine (BrdU) was administered intravenously to label tumor cells in the S phase of the cell cycle. The BrdU-labeled cells accounted for 9.0%
they are usually less than 1% in benign meningiomas. Meningothelial meningiomas with a high labeling index recur rapidly, even after Simpson's grade 2 removal, and treatment for a malignant meningioma should be instituted. © 1987 Springer-Verlag..
308. T. Iwaki, M. Fukui, A. Kondo, T. Matsushima, I. Takeshita, Epithelial properties of pleomorphic xanthoastrocytomas determined in ultrastructural and immunohistochemical studies, Acta Neuropathologica, 10.1007/BF00692844, 74, 2, 142-150, 1987.06, Three cases of pleomorphic xanthoastrocytoma (PXA), one of which showed anaplastic evolution, are described. In all three the PXA tumors were well circumscribed and could be totally removed. Light-microscopically, pleomorphic tumor cells clustered gregariously and often formed alveolar structures. Electron microscopy revealed various epithelial properties, such as junctions and interdigitations between apposing tumor cells, and prominent basal laminae surrounding tumor nests. The circumscribed growth of PXA, as contrasted with an infiltrative growth of usual astrocytoma, can be attributed to the cellular cohesion based on the epithelial properties of the tumor cells. In the third patient, tumor recurred 6 months postoperatively. Although the recurrent tumor retained the alveolar structures, pleomorphism and various degenerative features of the tumor cells diminished with advance in the proliferative activities. © 1987 Springer-Verlag..
309. T. Iwaki, A. Kondo, I. Takeshita, H. Nakagaki, K. Kitamura, J. Tateishi, Proliferating potential of folliculo-stellate cells in human pituitary adenomas - Immunohistochemical and electron microscopic analysis, Acta Neuropathologica, 10.1007/BF00688045, 71, 3-4, 233-242, 1986.09, 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 cell, 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, GFAP0-positive FS cells were numerous. In the pathological conditions FS cells may possess the potential of reactive proliferation. © 1986 Springer-Verlag..
310. H. Nagara, H. Doi, T. Iwaki, M. Kuramitsu, J. Tateishi, Intracytoplasmic inclusion of Hirano type in Purkinje cells, Clinical Neuropathology, 5, 3, 131-133, 5: 131-133, 1986.05, Intracytoplasmic, rod-shaped and eosinophilic inclusions were recognized only in Purkinje cells in a case of Crow-Fukase syndrome. The ultrastructure of the inclusions was similar to that of the Hirano body and was suspected to have some relation to neurofilaments..
311. Masaharu Kuramitsu, Hiroki Sawa, Iwao Takeshita, Toru Iwaki, Kanefusa Kato, Neuron-specific γ-enolase derived from human glioma, Neurochemical Pathology, 10.1007/BF03160188, 4, 2, 89-105, 4: 89-105, 1986.04, Neuron-specific γ-enolase in human neurogenic tumors, including gliomas, transplanted gliomas, and permanent human glioma cell lines, was studied quantitatively, using newly established enzyme immunoassay methods, together with immunostaining of the tissue and cell preparations. A significantly high level of γ-enolase was found in some glioblastomas, astrocytomas and oligodendrogliomas as well as medulloblastomas. Glioblastomas transplanted into mice and cultured cell lines derived from the same origins, as well as the permanent human glioma cell lines, also contained γ-enolase, although the contents were low compared with findings in the original tumor tissues. Immunohistochemically, γ-enolase stained intensely in the glioblastomatous cells. Serum γ-enolase concentrations in some patients with gliomas and those of all the transplanted mice were enhanced. The serum γ-enolase levels in the mice correlated well with size of the transplanted tumor tissues. These results indicate that neuron-specific γ-enolase is produced in some neurogenic tumors of nonneuronal origin, therefore, serum γ-enolase may be a useful biomarker for monitoring the extent of disease in patients with gliomas. © 1986 Humana Press Inc..
312. Fukui M, Iwaki T, Sawa H, Inoue T, Takeshita I, Kitamura K, Proliferative activity of meningiomas as evaluated by bromodeoxyuridine uptake examination., Acta Neurochir., 10.1007/BF01401236, 81, 3-4, 135-141, 1986.01, Proliferative activity of meningiomas was examined in 12 consecutive cases by administering bromodeoxyuridine (BrdU) before surgical removal and by immunohistochemical staining of the removed tumours using anti-BrdU monoclonal antibody (anti-BrdU MAb) to detect BrdU-labelled tumour cells. The 12 cases consisted of 6 with a primary tumour and 6 with a recurrent tumour. All of the tumours contained labelled cells and the labelling index (LI) was obtained in each tumour. The highest average LI was 13.6% and the second highest was 9.0% both in recurrent cases of histologically malignant meningothelial meningioma. The high LIs of both cases were thought to correspond well with the rapid recurrence of the tumour. The average LI of a case of recurrent haemangiopericytic tumour was 2.0%, and that of a case of meningioma associated with von Recklinghausen disease was 1.5%. The other 8 meningiomas showed the average LIs ranging from 0.1 to 0.9%, which were considered to be the LIs of usual benign meningiomas. The results of the BrdU uptake examination was considered to reflect well the clinical behaviour of meningiomas. The usefulness of the BrdU uptake examination in brain tumours, which can be employed in the clinical practice without any serious side-effects, is stressed..