研究者詳細 - 小野寺　理

論文 - 小野寺　理

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Concurrent Alzheimer's disease pathologies in Lewy body diseases affect cognition and glucose metabolism in the posterior cingulate gyrus: A multimodal PET study. 国際誌

Kosei Nakamura, Kenji Tagai, Hitoshi Shinotoh, Shigeki Hirano, Soichiro Kitamura, Hironobu Endo, Keisuke Takahata, Yuhei Takado, Ming-Rong Zhang, Kazunori Kawamura, Osamu Onodera, Makoto Higuchi, Hitoshi Shimada

Journal of Alzheimer's disease : JAD 106 ( 3 ) 1074 - 1086 2025年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

BackgroundLewy body disease (LBD) is a neurodegenerative disease characterized by Lewy bodies, and it clinically presents dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Alzheimer's disease (AD) pathologies frequently coexist with LBD, complicating the clinical manifestation.ObjectiveWe evaluated the impact of AD pathologies, including amyloid-β and tau depositions, on cognitive dysfunction and glucose metabolism in LBD using multiple positron emission tomography scans.MethodsOur study cohort consisted of 14 patients diagnosed with LBD, including five from the PD spectrum and nine from the DLB spectrum. In addition, 12 amyloid-negative cognitively healthy controls (HCs) and 13 amyloid-positive AD-spectrum patients were included. We subsequently explored the influence of amyloid and tau deposition on cognitive dysfunction and glucose metabolism among the LBD patients.ResultsIn the LBD group, 44.4% of the DLB patients were amyloid-positive, and all PD patients were amyloid-negative. While tau accumulation was lower than in AD and similar to HCs at the group level, tau accumulation in the AD signature region was correlated with cognitive dysfunction. Among the changes in glucose metabolism, the cingulate island sign (CIS) index was elevated compared to AD. However, as cognitive impairment progressed, the CIS index decreased, reflecting reduced metabolism in the posterior cingulate gyrus, which was closely associated with tau accumulation in the same region.ConclusionsOur findings indicate that AD pathologies, and particularly tau accumulation, significantly impact both cognitive dysfunction and glucose metabolism in LBD. This underscores the importance of addressing AD-related changes in the clinical management of LBD patients.

DOI： 10.1177/13872877251351220

TDP-43 mutants with different aggregation properties exhibit distinct toxicity, axonal transport, and secretion for disease progression in a mouse ALS/FTLD model. 国際誌

Hideki Mori, Tokiharu Sato, Shintaro Tsuboguchi, Masahiko Takahashi, Yuka Nakamura, Kana Hoshina, Taisuke Kato, Masahiro Fujii, Osamu Onodera, Masaki Ueno

Neurobiology of disease 212 106988 - 106988 2025年8月

記述言語：英語掲載種別：研究論文（学術雑誌）

TDP-43 accumulates and forms inclusions in neurons in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) and is assumed to cause neurodegenerative processes. The morphologies and cellular and areal distributions of accumulated TDP-43 inclusions are pathologically diverse among ALS/FTLD patients; however, whether and how different types of TDP-43 affect the process and severity of disease progression are not fully understood. Here, we compared the pathological events evoked by TDP-43 mutations, which have different aggregation properties, in cultured neurons and the cerebral cortex in mice. We selected TDP-43C173/175S and TDP-43G298S as aggregation-prone and nonprone mutants, respectively. Cytoplasmically expressed TDP-43C173/175S induced insoluble inclusions more robustly than TDP-43G298S did. In contrast, TDP-43G298S induced cell death more severely than TDP-43C173/175S. TDP-43G298S was further found to be efficiently transported in axons and led to axon degeneration, while this effect was not obvious in TDP-43C173/175S. Instead, TDP-43C173/175S was frequently trapped in the axon initial segments. Finally, TDP-43G298S was secreted in exosomes and transferred to oligodendrocyte-lineage cells in vitro more efficiently than TDP-43C173/175S to induce cell death. The transfer further evoked cytokine responses in microglial cells. These data revealed that different aggregation properties of TDP-43 cause distinct pathological events. These findings may explain the differences in the neurodegenerative progression and distribution observed among patients with ALS and FTLD.

DOI： 10.1016/j.nbd.2025.106988

Specific Contribution of the Cerebellar Inferior Posterior Lobe to Motor Learning in Degenerative Cerebellar Ataxia. 国際誌

Kyota Bando, Takeru Honda, Kinya Ishikawa, Shinichi Shirai, Ichiro Yabe, Tomohiko Ishihara, Osamu Onodera, Yuichi Higashiyama, Fumiaki Tanaka, Yoshiyuki Kishimoto, Masahisa Katsuno, Takahiro Shimizu, Ritsuko Hanajima, Takumi Kanata, Yuji Takahashi, Hidehiro MizusawaMD

Cerebellum (London, England) 24 ( 5 ) 132 - 132 2025年7月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVE: Degenerative cerebellar ataxia, a group of progressive neurodegenerative disorders, is characterised by cerebellar atrophy and impaired motor learning. Using CerebNet, a deep learning algorithm for cerebellar segmentation, this study investigated the relationship between cerebellar subregion volumes and motor learning ability. METHODS: We analysed data from 37 patients with degenerative cerebellar ataxia and 18 healthy controls. Using CerebNet, we segmented four cerebellar subregions: the anterior lobe, superior posterior lobe, inferior posterior lobe, and vermis. Regression analyses examined the associations between cerebellar volumes and motor learning performance (adaptation index [AI]) and ataxia severity (Scale for Assessment and Rating of Ataxia [SARA]). RESULTS: The inferior posterior lobe volume showed a significant positive association with AI in both single (B = 0.09; 95% CI: [0.03, 0.16]) and multiple linear regression analyses (B = 0.11; 95% CI: [0.008, 0.20]), an association that was particularly evident in the pure cerebellar ataxia subgroup. SARA scores correlated with anterior lobe, superior posterior lobe, and vermis volumes in single linear regression analyses, but these associations were not maintained in multiple linear regression analyses. This selective association suggests a specialised role for the inferior posterior lobe in motor learning processes. CONCLUSION: This study reveals the inferior posterior lobe's distinct role in motor learning in patients with degenerative cerebellar ataxia, advancing our understanding of cerebellar function and potentially informing targeted rehabilitation approaches. Our findings highlight the value of advanced imaging technologies in understanding structure-function relationships in cerebellar disorders.

DOI： 10.1007/s12311-025-01887-y

[Hereditary Leukoencephalopathy: Overview to Definition, Diagnosis and Treatment].

Shin Koide, Shoichiro Ando, Osamu Onodera

Brain and nerve = Shinkei kenkyu no shinpo 77 ( 5 ) 561 - 568 2025年5月

記述言語：日本語掲載種別：研究論文（学術雑誌）

Hereditary leukoencephalopathies represent a heterogeneous group of inherited disorders characterized by abnormalities in the white matter of the brain. Recent advances in neuroimaging and genetic analyses have deepened our understanding of the underlying pathologies, leading to refined classification and diagnostic frameworks. Although many have no curative therapy, new treatments, such as hematopoietic stem cell transplantation, offer promising prospects for some of these diseases. Early and accurate diagnosis is critically important as it may improve management strategies and ultimately enhance patient outcomes.

DOI： 10.11477/mf.188160960770050561

Long-Term Clinical Landscapes of Spinal Hypertrophic Pachymeningitis With Anti-Neutrophil Cytoplasmic Antibody–Associated Vasculitis 国際誌

Akihiro Nakajima, Mariko Hokari, Fumihiro Yanagimura, Etsuji Saji, Hiroshi Shimizu, Yasuko Toyoshima, Kaori Yanagawa, Musashi Arakawa, Akiko Yokoseki, Takahiro Wakasugi, Kouichirou Okamoto, Kei Watanabe, Keitaro Minato, Yutaka Otsu, Yukiko Nozawa, Daisuke Kobayashi, Kazuhiro Sanpei, Hirotoshi Kikuchi, Shunsei Hirohata, Kazuaki Awamori, Aya Nawata, Mitsunori Yamada, Hitoshi Takahashi, Masatoyo Nishizawa, Hironaka Igarashi, Noboru Sato, Akiyoshi Kakita, Osamu Onodera, Izumi Kawachi

Neurology 104 ( 8 ) e213420 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

BACKGROUND AND OBJECTIVES: Spinal hypertrophic pachymeningitis (HP) is an extremely rare disorder characterized by the thickening of the spinal dura mater, which harbors distinct repertoires of immune cells due to the unique partitioning of the arachnoid blood-CSF barrier. The objectives were to identify the pathogenesis and therapeutic strategies for spinal HP. METHODS: This retrospective cohort study analyzed the clinical and pathologic profiles of patients with idiopathic/immune-mediated HP including spinal HP. RESULTS: Among 61 patients with idiopathic/immune-mediated HP, all 6 Japanese patients with spinal HP, with a median observation period of 88.8 months, were myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA)-seropositive. The MPO-ANCA+ spinal HP cohort had the following characteristics: (1) a predominance of older women; (2) all patients were classified as having microscopic polyangiitis based on the 2022 American College of Rheumatology/European League Against Rheumatism criteria; (3) 83% of patients developed subacute/chronic myelopathy due to extramedullary spinal cord compression; (4) 50% of patients had lesion extension to the epidural compartment and vertebral column; (5) 50% of patients presented with chronic sinusitis, otitis media, or mastoiditis; (6) 33% of patients had involvement of the lower airways or kidneys; (7) a higher disease activity of the nervous system was noted based on the Birmingham Vasculitis Activity Score (BVAS), in contrast to MPO-ANCA+ cranial HP; (8) granulomatous inflammation with myofibroblasts, immune cells including granulocytes, and B-cell follicle-like structures were observed in the thickened dura mater; (9) immunotherapies (with or without surgical decompression) were effective in reducing the modified Rankin Scale score and reduced BVAS during the first active insults; (10) combined immunotherapies with glucocorticoids and cyclophosphamide/rituximab helped in reducing relapses in the long term; and (11) surgical decompression, including laminectomy and duraplasty, was necessary for compressive myelopathy. These data suggest that MPO-ANCA+ spinal HP shares common features with MPO-ANCA+ cranial HP (1, 2, 6, 8, 9, and 10), but also has unique clinical features (3, 4, 5, 7, and 11). DISCUSSION: Our findings highlight the significant pathogenic role of ANCA in spinal HP. MPO-ANCA+ spinal HP, as an organ-threatening disease, should be positioned as having unique characteristics, whether limited to the CNS or as part of a generalized form in ANCA-associated vasculitis.

DOI： 10.1212/wnl.0000000000213420

Utility of Cerebrospinal Fluid Transferrin Receptor per Ferritin Ratio in Progressive Supranuclear Palsy 国際誌

Natsuki Akiyama, Masato Kanazawa, Kensaku Kasuga, Masahiro Hatakeyama, Takeshi Ikeuchi, Osamu Onodera

Movement Disorders Clinical Practice 12 ( 4 ) 446 - 452 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Progressive supranuclear palsy (PSP) is a major atypical parkinsonism. Because diagnosis based on the cardinal clinical features is often difficult, misdiagnosis with Parkinson's disease (PD) and multiple system atrophy (MSA) is common in PSP patients. Iron metabolism genes are reportedly involved in tau-accumulating neuronal cell death and ferroptosis in PSP, which is more severe than PD and MSA. The validity of transferrin receptor (TfR) expression as a biomarker of ferroptosis was also demonstrated. OBJECTIVE: We investigated whether TfR and the TfR to ferritin ratio in the cerebrospinal fluid (CSF) is a diagnostic biomarker of PSP. METHODS: This study included 2 independent retrospective CSF cohorts comprising patients, respectively, from Niigata University and a multicenter memory clinic, consisting of patients with PSP, PD, and MSA. All patients were classified as clinically probable or higher based on the Society of Movement Disorders Criteria. TfR and ferritin levels in the CSF were measured using Luminex assay. RESULTS: The levels of TfR in patients with PSP were higher than those in patients with PD and MSA in cohort 1 (PSP: N = 16, PD: N = 13, MSA: N = 20). The TfR to ferritin ratio in patients with PSP was significantly higher than that in patients with MSA. Subsequently, we validated these results in cohort 2 (PSP: N = 23, MSA: N = 6). The TfR to ferritin ratio was significantly higher in patients with PSP than in those with MSA. CONCLUSIONS: The CSF TfR to transferrin ratio was elevated in patients with PSP. These results should be validated in a larger cohort of patients.

DOI： 10.1002/mdc3.14313

Redefining the Pathogenic CAG Repeat Units Threshold in CACNA1A for Spinocerebellar Ataxia Type 6 国際誌

Yuya Hatano, Tomohiko Ishihara, Sachiko Hirokawa, Hidetoshi Date, Yuji Takahashi, Hidehiro Mizusawa, Osamu Onodera

Neurology Genetics 11 ( 2 ) e200245 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND AND OBJECTIVES: Spinocerebellar ataxia type 6 (SCA6) is caused by expansion of CAG repeat units (RUs) in CACNA1A. While the pathologic threshold has been considered to be 20 or 21 RUs, the lower limit remains controversial. This study aimed to clarify the pathologic significance of RUs in SCA6, including the role of opposite alleles (OAs). METHODS: This was an observational study of patients with suspected spinocerebellar ataxia who underwent SCA6 genetic testing. We analyzed the relationship between CACNA1A RUs and age at onset (AAO). Family history positivity rates were examined for different RUs of the expanded allele (EA). Regression analyses were performed for AAO estimation based on the EA RUs. The influence of OAs on AAO was investigated, particularly in cases with 21-22 EA RUs. RESULTS: In total, 2,768 participants were enrolled. Family history positivity rates increased progressively above 19 RUs and plateaued at ≥23 RUs. Regression analysis of cases with ≥23 RUs showed that 96.20% of cases with ≥23 RUs, 90.67% of cases with 22 RUs, 91.15% of cases with 21 RUs, 61.54% of cases with 20 RUs, and 33.33% of cases with 19 RUs fell within the 95% prediction interval for AAO. However, no patients with ≤18 RUs were included. In the 21-22 RU group, OAs significantly influenced AAO, and ≥17 RUs had a significant effect. For ≥23 RUs, no significant OA effect was observed. Cases with 19-20 RUs showed a higher prevalence of OA with ≥19 RUs compared with cases with ≥23 RUs. DISCUSSION: Our findings suggest that clinical manifestation within a typical lifespan likely requires at least 19 RUs. The 19-20 RU range represents an intermediate zone where OA may influence disease likelihood. For 21-22 RUs, OA significantly affects AAO, indicating a complex interplay between EA and OA. ≥23 RUs seem sufficient to cause disease onset within a typical lifespan, regardless of OA. These results provide a new paradigm for SCA6 diagnosis and genetic counseling, emphasizing the need for cautious interpretation of the intermediate RU range and consideration of OA.

DOI： 10.1212/NXG.0000000000200245

“Chocolate Chip Sign” on Susceptibility-Weighted Imaging 国際誌

Shoichiro Ando, Rie Saito, Sho Kitahara, Masahiro Uemura, Yuya Hatano, Masaki Watanabe, Taisuke Kato, Yosuke Ito, Atchayaram Nalini, Tomohiko Ishihara, Shigeo Murayama, Hironaka Igarashi, Akiyoshi Kakita, Osamu Onodera

Neurology Genetics 11 ( 2 ) e200237 2025年4月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Ovid Technologies (Wolters Kluwer Health)

BACKGROUND AND OBJECTIVES: HTRA1-related cerebral small vessel disease (HRSVD) is a rare hereditary form of cerebral small vessel disease (CSVD) caused by HTRA1 pathogenic variants. Diagnosing HRSVD without genetic testing is challenging because of the lack of distinctive imaging features and clinical symptoms, and even family history can be unclear in some cases with HRSVD. This study investigates whether susceptibility-weighted imaging (SWI) can identify useful diagnostic findings for HRSVD. METHODS: This retrospective study included 8 patients with HRSVD, 12 with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 14 with sporadic CSVD (sCSVD). Two neurologists blinded to clinical data counted the number of hypointense dots around the midbrain on SWI. Receiver operating characteristic curve analysis evaluated the optimal threshold of the number that can distinguish HRSVD and CADASIL or sCSVD. In addition, histopathologic analysis including measurement of leptomeningeal vessel diameter and type III collagen deposition was performed on autopsied brains from 3 cases each of HRSVD, CADASIL, and sCSVD and control participants. RESULTS: Patients with HRSVD exhibited a significantly higher number of hypointense dots around the midbrain on SWI compared with CADASIL and sCSVD groups. A threshold of 5 or more dots, termed the "Chocolate Chip Sign," well distinguished HRSVD from CADASIL and sCSVD (area under the curve: 0.817, 95% confidence interval: 0.624-1.00). Three-dimensional SWI reconstruction and 7T MRI confirmed these dots as dilated extraparenchymal vessels. Histopathologic analysis revealed pronounced dilation of leptomeningeal veins with type III collagen accumulation specifically, in HRSVD brains. DISCUSSION: The Chocolate Chip Sign on SWI represents a novel and promising neuroimaging biomarker for HRSVD. This finding holds significant potential for facilitating early diagnosis, prompting timely genetic testing, and appropriate family screening for this rare genetic disorder.

DOI： 10.1212/nxg.0000000000200237

Oxygen–glucose-deprived peripheral blood mononuclear cells act on hypoxic lesions after ischemia-reperfusion injury 国際誌

Takeshi Kanayama, Masahiro Hatakeyama, Natsuki Akiyama, Yutaka Otsu, Osamu Onodera, Takayoshi Shimohata, Masato Kanazawa

Experimental Neurology 385 115121 - 115121 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

BACKGROUND: Despite advances in reperfusion therapies, ischemic stroke remains a major cause of long-term disability due to residual hypoxic lesions persisting after macrovascular reperfusion. These residual hypoxic lesions, caused by microvascular dysfunction, represent an important therapeutic target. We previously demonstrated that oxygen-glucose-deprived peripheral blood mononuclear cells (OGD-PBMCs) migrate to ischemic brain regions and promote functional recovery after stroke. This recovery occurs through mechanisms involving hypoxia-inducible factor-1α, exosomal miR-155-5p, and vascular endothelial growth factor (VEGF). However, it remains unclear whether OGD-PBMCs target hypoxic regions. METHODS: We evaluated cerebral blood flow using a laser speckle flow imaging system. Next, we utilized pimonidazole to investigate the presence of hypoxic lesions after ischemia-reperfusion injury in a rat suture occlusion model in immunohistochemical analyses. We also compared levels of a cell surface receptor in human PBMCs by flow cytometric analysis under normoxic and OGD conditions. RESULTS: We found persistent pimonidazole-positive hypoxic lesions at 10- and 28-days post-reperfusion despite restored gross cerebral perfusion. Treatment with the C-X-C motif chemokine receptor 4 (CXCR4) inhibitor AMD3100 before and after OGD-PBMCs administration reduced the number of OGD-PBMCs in the brain parenchyma compared to the control group (P = 0.018). Administered OGD-PBMCs localized within these hypoxic regions via the stromal cell-derived factor-1/CXCR4 chemotactic axis. OGD-PBMCs enhanced VEGF expression, specifically within hypoxic lesions, compared to the phosphate-buffered saline group (P < 0.01). Furthermore, OGD-PBMCs reduced the number of pimonidazole-positive hypoxic cells in the ischemic core on 28 days. These findings demonstrate that OGD-PBMCs selectively migrate to and modulate the microenvironment of hypoxic lesions following cerebral ischemia-reperfusion injury. CONCLUSION: Targeting these residual hypoxic regions may underline the therapeutic effects of OGD-PBMC treatment and represent a promising strategy for improving stroke recovery despite successful recanalization.

DOI： 10.1016/j.expneurol.2024.115121

Frequency of FGF14 intronic GAA repeat expansion in patients with multiple system atrophy and undiagnosed ataxia in the Japanese population 国際誌

Toshiyuki Kakumoto, Kenta Orimo, Takashi Matsukawa, Jun Mitsui, Tomohiko Ishihara, Osamu Onodera, Yuta Suzuki, Shinichi Morishita, Ayaka Chikada, Kenta Orimo, Takashi Matsukawa, Tatsushi Toda, Jun Mitsui, Hiroyufki Ishiura, Koji Abe, Toru Yamashita, Hidehiro Mizusawa, Yuji Takahashi, Masahisa Katsuno, Kazuhiro Hara, Osamu Onodera, Tomohiko Ishihara, Masayoshi Tada, Satoshi Kuwabara, Atsuhiko Sugiyama, Yoshitaka Yamanaka, Ryosuke Takahashi, Yusuke Sakato, Tomoyuki Ishimoto, Nobukatsu Sawamoto, Ritsuko Hanajima, Yasuhiro Watanabe, Hiroshi Takigawa, Tadashi Adachi, Hiroshi Takashima, Keiko Higashi, Junichi Kira, Ichiro Yabe, Masaaki Matsushima, Katsuhisa Ogata, Kinya Ishikawa, Yoichiro Nishida, Taro Ishiguro, Kokoro Ozaki, Tetsuya Nagata, Shoji Tsuji, Tatsushi Toda, Shoji Tsuji

European Journal of Human Genetics 33 ( 3 ) 325 - 333 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by autonomic nervous system dysfunction and cerebellar ataxia or parkinsonism. Recently, expanded GAA repeats (≥250 repeat units) in intron 1 of FGF14 have been shown to be responsible for spinocerebellar ataxia type 27B (SCA27B), a late-onset ataxia with an autosomal dominant inheritance. Patients with SCA27B may also exhibit autonomic nervous system dysfunction, potentially overlapping with the clinical presentations of MSA patients. In this study, to explore the possible involvement of expanded GAA repeats in MSA, we investigated the frequencies of expanded GAA repeats in FGF14 in 548 patients with MSA, 476 patients with undiagnosed ataxia, and 455 healthy individuals. To fully characterize the structures of the expanded GAA repeats, long-range PCR products suggesting the expansion of GAA repeats were further analyzed using a long-read sequencer. Of the 548 Japanese MSA patients, we identified one MSA patient (0.2%) carrying an expanded repeat with (GAA)≥250. Among the 476 individuals with undiagnosed ataxia, (GAA)≥250 was observed in six (1.3%); this frequency was higher than that in healthy individuals (0.2%). The clinical characteristics of the MSA patient with (GAA)≥250 were consistent with those of MSA, but not with SCA27B. Further research is warranted to explore the possibility of the potential association of expanded GAA repeats in FGF14 with MSA.

DOI： 10.1038/s41431-024-01743-3

Early diagnosis of cryptococcal meningoencephalitis in HIV-negative patients: Integration of brain MRI and clinical findings. 国際誌

Kosei Nakamura, Masato Kanazawa, Yuka Koike, Takuya Konno, Osamu Onodera

eNeurologicalSci 38 100552 - 100552 2025年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Cryptococcal meningoencephalitis (CM) in human immunodeficiency virus (HIV)-negative patients are often diagnosed later than in HIV-infected patients, which increases mortality rates concerning the former. Consequently, early diagnosis and treatment are crucial for improving clinical prognosis in HIV-negative patients. This study investigated the utility of magnetic resonance imaging (MRI) in combination with clinical and laboratory findings for early diagnosis of CM in HIV-negative patients. METHODS: This retrospective cohort analysis included consecutive patients diagnosed with central nervous system (CNS) infections. Demographic profiles, laboratory findings, admission symptoms, and MRI findings were assessed. A comparative analysis between CM and other CNS infections was performed. RESULTS: Twelve HIV-negative patients were diagnosed with CM, while 38 exhibited other CNS infections (two fungal, 23 bacterial, 12 viral, one parasitic). Pseudocysts on MRI (p = 0.002), absence of fever (p = 0.001), headache (p = 0.005), and normal C-reactive protein (CRP) levels (p = 0.020) were specific findings in CM. By applying a cut-off value of one point in combination of pseudocysts, absence of fever, headache, and normal CRP levels in differentiating CM from other CNS infections, the sensitivity and specificity were calculated as 76.3 % and 91.7 %, respectively. CONCLUSION: Integrating pseudocysts, absence of fever, headache, and normal CRP levels predicts early CM diagnosis, potentially improving outcomes.

DOI： 10.1016/j.ensci.2025.100552

Novel Aspects of Hereditary Spastic Paraplegia: A Clinicopathologic and Biochemical Study of a Patient With a Heterozygous GCH1 Variant. 国際誌

Shoko Hongo, Tetsuhiko Ikeda, Mari Tada, Rina Aida, Tetsuo Ozawa, Norikazu Hara, Akinori Miyashita, Takashi Nakajima, Osamu Onodera, Takeshi Ikeuchi, Hiroshi Ichinose, Akiyoshi Kakita

Neuropathology and applied neurobiology 51 ( 1 ) e70006 2025年2月

Clinical utility of CSF Aβ38 in Japanese research and clinical cohorts. 国際誌

Tamao Tsukie, Kensaku Kasuga, Masataka Kikuchi, Takanobu Ishiguro, Akinori Miyashita, Osamu Onodera, Takeshi Iwatsubo, Takeshi Ikeuchi

Alzheimer's & dementia (Amsterdam, Netherlands) 17 ( 2 ) e70125 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

INTRODUCTION: Previous studies have reported that cerebrospinal fluid (CSF) amyloid beta (Aβ42/Aβ38) performs comparably to Aβ42/Aβ40 in predicting amyloid positron emission tomography (PET) positivity in White cohorts. However, this finding has not been validated in diverse populations. Moreover, the utility of CSF Aβ38 in diagnosing various neurological diseases has not been fully understood. METHODS: We analyzed CSF Aβ38, Aβ40, Aβ42, phosphorylated tau181, and neurofilament light chain in Japanese research and clinical cohorts with Alzheimer's clinical syndrome (ACS) or non-ACS. RESULTS: CSF Aβ42/Aβ38 predicted amyloid PET positivity comparably to Aβ42/Aβ40. The levels of CSF Aβ38 were significantly lower in patients with progressive supranuclear palsy (PSP) and idiopathic normal pressure hydrocephalus (iNPH) than in those with other diseases. DISCUSSION: We validated the high diagnostic performance of CSF Aβ42/Aβ38 in Japanese patients with AD. CSF Aβ38 reduction may be a characteristic feature of PSP and iNPH. HIGHLIGHTS: The diagnostic value of cerebrospinal fluid (CSF) amyloid beta (Aβ)38 was examined in Japanese research and clinical cohorts.CSF Aβ42/Aβ38 and Aβ42/Aβ40 showed comparable performance to detect brain Aβ deposition.CSF Aβ42/Aβ38 and Aβ42/Aβ40 discordant group showed a characteristic profile.CSF Aβ38 and Aβ40 were prominently decreased in progressive supranuclear palsy and idiopathic normal pressure hydrocephalus.

DOI： 10.1002/dad2.70125

The analysis of schizophrenia-like psychosis in dentatorubral-pallidoluysian atrophy. 国際誌

Ichiko Ikegami, Yuka Mitsuhashi Koike, Hideki Hayashi, Sachiko Hirokawa, Shoichiro Ando, Tomohiko Ishihara, Osamu Onodera

Frontiers in neurology 16 1564856 - 1564856 2025年

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive neurodegenerative disorder caused by expanded CAG repeats in the ATN1 gene, characterized by cerebellar ataxia, seizures, tremors, and myoclonus. Although approximately 10% of patients with DRPLA reportedly develop schizophrenia-like psychosis (SLP), the distinct association between the clinical course of DRPLA and SLP remains unclear. This study aimed to elucidate the clinical features of SLP in patients with DRPLA. METHODS: We reviewed 22 cases of pathologically or genetically confirmed DRPLA with SLP, including 21 from the literature and one from our institution. Patient data, including clinical features, treatment information, and disease course, were extracted and analyzed. RESULTS: The age of onset was categorized as juvenile (n = 6), early adult (n = 8), and late adult (n = 8). Initially, 10 patients presented with motor symptoms, with six exhibiting psychiatric symptoms and six with both motor and psychiatric symptoms simultaneously. Furthermore, three patients were initially diagnosed with schizophrenia, while four experienced progressive worsening of psychiatric symptoms. The number of CAG repeats ranged from 57 to 76 (mean, 66.0) in the 10 patients with a genetic diagnosis. Summarily, 12 patients received psychotropic medications, with nine showing improvement in delusions and hallucinations. CONCLUSION: SLP can manifest across all DRPLA forms (juvenile-, early adult-, and late adult-onset) and may precede or follow motor symptoms. The clinical course and efficacy of psychotropic medications in patients with DRPLA and SLP suggest a shared pathogenesis between DRPLA and schizophrenia.

DOI： 10.3389/fneur.2025.1564856

A case of cerebral amyloid angiopathy with ipsilateral tau and contralateral amyloid PET uptake related to cadaveric dura mater implanted in childhood 国際誌

Yuki Hatakeyama, Atsushi Michael Kimura, Shintaro Tsuboguchi, Mikhail Ratanov, Kosei Nakamura, Masahiro Hatakeyama, Yukimi Nakamura, Masaki Watanabe, Yoshihiro Murakami, Yuko Saito, Shigeo Murayama, Kensaku Kasuga, Takeshi Ikeuchi, Hironaka Igarashi, Osamu Onodera, Hitoshi Shimada

European Journal of Nuclear Medicine and Molecular Imaging 52 ( 8 ) 2737 - 2739 2024年12月

Blood–brain barrier dysfunction in multiple system atrophy: A human postmortem study 国際誌

Ramil Gabdulkhaev, Hiroshi Shimizu, Masato Kanazawa, Yasuko Kuroha, Arika Hasegawa, Jiro Idezuka, Kazuki Tainaka, Osamu Onodera, Akiyoshi Kakita

Neuropathology 45 ( 3 ) 210 - 222 2024年12月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Wiley

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by an accumulation of phosphorylated α‐synuclein (p‐αsyn) in oligodendrocytes in the form of glial cytoplasmic inclusions (GCIs). In MSA, not only mature oligodendrocytes but also oligodendrocyte precursor cells (OPCs) are affected. The latter play an important role in remyelination by differentiating into mature oligodendrocytes, as well as maintaining the blood–brain barrier (BBB) by promoting the expression of tight junction proteins. We have hypothesized that in MSA, the BBB is impaired as a result of aberrant interactions between affected OPCs and the cerebral vasculature. To verify this hypothesis, we conducted a neuropathological examination of postmortem brains from MSA patients and control subjects, focusing on the primary motor area, one of the main regions affected in MSA. Using double immunofluorescence, we quantified the expression of tight junction protein claudin‐5 in capillary endothelial cells and found that it was significantly lower in MSA than in controls in both the gray matter and white matter. Furthermore, a significantly higher amount of fibrinogen was extravasated into the brain parenchyma in MSA patients than in controls. In addition, leakage of IgG was detected almost specifically in MSA brain parenchyma, as visualized in three dimensions by combining techniques of chemical tissue clearing and light sheet microscopy. Finally, we confirmed accumulation of p‐αsyn‐positive GCIs along the cerebral vasculature within OPCs. These results suggest that BBB dysfunction and associated fibrinogen extravasation are constant findings in MSA, presumably triggered by the deposition of p‐αsyn in perivascular OPCs.

DOI： 10.1111/neup.13021

SMN2 gene copy number affects the incidence and prognosis of motor neuron diseases in Japan

Tomohiko Ishihara, Akihide Koyama, Naoki Atsuta, Mari Tada, Saori Toyoda, Kenta Kashiwagi, Sachiko Hirokawa, Yuya Hatano, Akio Yokoseki, Ryoichi Nakamura, Genki Tohnai, Yuishin Izumi, Ryuji Kaji, Mitsuya Morita, Asako Tamura, Osamu Kano, Masashi Aoki, Satoshi Kuwabara, Akiyoshi Kakita, Gen Sobue, Osamu Onodera

BMC Medical Genomics 17 ( 1 ) 2024年11月

L-arginine in patients with spinocerebellar ataxia type 6: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial 国際誌

Tomohiko Ishihara, Masayoshi Tada, Yoshitomi Kanemitsu, Yuji Takahashi, Kinya Ishikawa, Kensuke Ikenaka, Makito Hirano, Takanori Yokota, Eiko N. Minakawa, Katsuhisa Saito, Yoshitaka Nagai, Osamu Onodera

eClinicalMedicine 78 102952 - 102952 2024年11月

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：Elsevier BV

BACKGROUND: Therapeutic advancements for the polyglutamine diseases, particularly spinocerebellar degeneration, are eagerly awaited. We evaluated the safety, tolerability, and therapeutic effects of L-arginine, which inhibits the conformational change and aggregation of polyglutamine proteins, in patients with spinocerebellar ataxia type 6 (SCA6). METHODS: A multicenter, randomized, double-blind, placebo-controlled phase 2 trial (clinical trial ID: AJA030-002, registration number: jRCT2031200135) was performed on 40 genetically confirmed SCA6 patients enrolled between September 1, 2020, and September 30, 2021. The main inclusion criteria were as follows: SCA6 diagnosed by genetic testing, 20 years of age or older, Scale for the Assessment and Rating of Ataxia (SARA) "walking" score of at least one point, and SARA "total" score of at least 10 points, and ability to walk 10 m or more with or without an assistive device. The investigational drug was administered orally at 0.50 g/kg/day (L-arginine group: L-arginine 0.38 g/kg/day; placebo group: L-arginine 0.0 g/kg/day) for 48 weeks. Subjects who consented to participate were assigned a subject identification code, and were allocated 1:1 to the L-arginine or the placebo group, according to a predetermined allocation chart. The primary efficacy endpoint was change in total Scale for the Assessment and Rating of Ataxia (SARA) score from baseline to 48 weeks. The secondary endpoints were 1) SARA walking + standing score, 2) each of the eight SARA scales at 0, 4, 8, 16, 24, 32, 40, and 48 weeks, and 3) TUGT, BDI-II, CGI, PGI-I, and SF-8. FINDINGS: Forty patients received the investigational drug, and 37 completed the study (L-arginine group: 18; placebo group: 19). The mean medication adherence rate was 97.2% in the l-arginine group. Regarding the primary endpoint, the difference between the L-arginine group and the placebo group was -1.52 (95% CI: -3.10 to 0.06, P = 0.0582). As the secondary endpoints, the change of SARA total score from baseline was greater in the L-arginine group than in the placebo group at all assessment time points, but the differences were not significant. Two serious (required hospitalization) adverse reactions occurred in the L-arginine group, including one case of pneumonia (severe, death) and one case of abnormal liver function (moderate, recovery). INTERPRETATION: L-arginine treatment resulted in an improvement tendency in SARA total score of SCA6 patients. Our results suggest that a phase 3 study of L-arginine for SCA6, with a 48-week observation period and change in total SARA score as the primary endpoint, may be feasible for further analyzing the therapeutic effect of L-arginine. However, careful consideration of statistical power and sample size is necessary. FUNDING: Japan Agency for Medical Research and Development and Health Labour Sciences Research Grant, Japan.

DOI： 10.1016/j.eclinm.2024.102952

A case of isolated dystextia due to subcortical infarction: a novel condition of digital device era

Masahiro Hatakeyama, Takeshi Kanayama, Saori Tokunaga, Toshiya Kizaki, Shintaro Tsuboguchi, Masato Kanazawa, Osamu Onodera

BMC Neurology 24 ( 1 ) 2024年10月

本邦における抗LGI1脳炎の特徴自己免疫介在性脳炎・脳症の全国疫学調査

河内泉, 佐治越爾, 佐藤泰憲, 飯塚高浩, 木村暁夫, 佐久間啓, 中嶋秀人, 大石真莉子, 中島章博, 神田隆, 高橋幸利, 渡邊修, 鵜沢顕之, 桑原聡, 小野寺理

臨床神経学 64 ( Suppl. ) S252 - S252 2024年10月

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