研究者業績
基本情報
- 所属
- 藤田医科大学 岡崎医療センター 医学部・内科学 准教授
- 学位
- 博士(医学)(藤田保健衛生大学)
- J-GLOBAL ID
- 201501008162133427
- researchmap会員ID
- 7000012808
研究分野
1論文
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Parkinsonism & related disorders 131 107251-107251 2025年2月INTRODUCTION: Progressive supranuclear palsy (PSP) involves midbrain structures, including the red nucleus (RN), an iron-rich region that appears as a high-contrast area on quantitative susceptibility mapping (QSM). RN may serve as a promising biomarker for differentiating parkinsonism. However, RN deformation in PSP remains elusive. This study aimed to evaluate RN deformation in PSP using coronal QSM images and compare them with those of Parkinson's disease (PD) and healthy controls (HC). METHODS: We evaluated the QSM images of 22 patients with PSP, 37 patients with PD, and 43 HC. We developed a grading system to assess RN deformation on coronal QSM images and classified them into three grades. The midbrain and RN volumes were extracted using distinct approaches, and their relationship with grading was investigated. For validation, coronal QSM images of 16 PSP patients from a different institution were assessed. RESULTS: In PSP, 59 % of the patients displayed a flattened RN of grade 3, which we termed a Rice-Grain Appearance. The volume reductions in midbrain and RN were associated with deformation. Differentiation based on the presence of this appearance yielded a specificity of 1.000 (CI: 1.000-1.000) and sensitivity of 0.591 (0.385-0.796) for distinguishing PSP from others. Secondary dataset also showed that 56 % of patients with PSP were classified as grade 3. CONCLUSION: In coronal QSM images, the flattened RN shape appears to be specific to PSP compared to PD and HC and may serve as a marker to help differentiate PSP in future clinical settings.
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Pediatrics international : official journal of the Japan Pediatric Society 67(1) e15865 2025年
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Emerging Infectious Diseases 30(12) 2024年12月
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Journal of Parkinson's disease 14(8) 1533-1542 2024年11月BACKGROUND: Recent evidence suggests a link between glycoprotein non-metastatic melanoma protein B (GPNMB) and Parkinson's disease (PD) pathogenesis. Although elevated plasma GPNMB levels associated with disease severity have been reported in PD, cerebrospinal fluid (CSF) alterations remain elusive. OBJECTIVE: To explore CSF GPNMB alterations and its clinical significance in PD. METHODS: This study enrolled 118 sporadic PD patients and 40 controls. We examined the potential associations between CSF GPNMB levels and the clinical characteristics or biomarkers of neurodegenerative pathogenesis. RESULTS: PD patients had higher CSF GPNMB levels than controls (p = 0.0159). In the PD group, CSF GPNMB levels correlated with age (age at examination: rs = 0.2511, p = 0.0061; age at onset: rs = 0.2800, p = 0.0021) and the severity of motor and cognitive dysfunction (MDS-UPDRS III score: rs = 0.1998, p = 0.0347; Mini-Mental State Examination score: rs = -0.1922, p = 0.0370). After correcting for multiple comparisons, the correlation with age at onset remained significant. CSF GPNMB levels were also positively correlated with CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) levels in both the PD (rs = 0.3582, p < 0.0001) and control (rs = 0.4743, p = 0.0023) groups. Furthermore, multiple regression analysis revealed CSF sTREM2 level as the strongest determinant of CSF GPNMB levels in the PD group (t-value = 3.49, p = 0.0007). CONCLUSIONS: Elevated CSF GPNMB levels, linked with age and microglial activation, may be a valuable marker for understanding the interplay between aging, neuroinflammation, and PD pathology.
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NPJ Parkinson's disease 10(1) 170-170 2024年9月9日The relationship between reduced serum uric acid (UA) levels and Parkinson's disease (PD), particularly purine metabolic pathways, is not fully understood. Our study compared serum and cerebrospinal fluid (CSF) levels of inosine, hypoxanthine, xanthine, and UA in PD patients and healthy controls. We analyzed 132 samples (serum, 45 PD, and 29 age- and sex-matched healthy controls; CSF, 39 PD, and 19 age- and sex-matched healthy controls) using liquid chromatography-tandem mass spectrometry. Results showed significantly lower serum and CSF UA levels in PD patients than in controls (p < 0.0001; effect size r = 0.5007 in serum, p = 0.0046; r = 0.3720 in CSF). Decreased serum hypoxanthine levels were observed (p = 0.0002; r = 0.4338) in PD patients compared to controls with decreased CSF inosine and hypoxanthine levels (p < 0.0001, r = 0.5396: p = 0.0276, r = 0.2893). A general linear model analysis indicated that the reduced UA levels were mainly due to external factors such as sex and weight in serum and age and weight in CSF unrelated to the purine metabolic pathway. Our findings highlight that decreased UA levels in PD are influenced by factors beyond purine metabolism, including external factors such as sex, weight, and age, emphasizing the need for further research into the underlying mechanisms and potential therapeutic approaches.
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Journal of medical virology 96(8) e29850 2024年8月Herpes simplex encephalitis (HSE) is an acute form of encephalitis that can lead to poor neurological outcomes. Although the exact pathogenesis of HSE remains elusive, recent reports suggest a significant role for postinfectious immune-inflammatory processes in the central nervous system (CNS). This study aimed to clarify the association between CNS autoimmune responses and clinical presentation in patients with HSE, focusing on cerebrospinal fluid (CSF) characteristics, particularly the IgG index. We retrospectively analyzed 176 consecutive patients suspected of having aseptic meningitis /encephalitis for chronological changes in CSF findings and clinical presentations. These patients underwent PCR screening for herpesviruses (HV) in their CSF. We identified seven patients positive for herpes simplex virus type 1 (HSV-1), 20 patients positive for varicella-zoster virus, and 17 patients who met the criteria for aseptic meningitis but were PCR-negative for HV. Patients in the HSV-1-positive group exhibited a significant increase in the IgG index at the time of PCR-negative conversion compared with on admission (p = 0.0156), while such a change was not observed in the other two groups. Additionally, all patients in the HSV-1-positive group tested negative for anti-neural autoantibodies in CSF and serum samples collected approximately 3 weeks after onset. This study, therefore, highlights that CSF IgG index elevation occurs even after PCR-confirmed HSV-1 clearance, which might indicate immunopathogenesis that is independent of antibody-mediated mechanisms.
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パーキンソン病・運動障害疾患コングレスプログラム・抄録集 18回 73-73 2024年7月
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パーキンソン病・運動障害疾患コングレスプログラム・抄録集 18回 86-86 2024年7月
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European journal of neurology 31(3) e16158 2024年3月BACKGROUND AND PURPOSE: Multiple system atrophy (MSA) is a neurodegenerative disease with characteristic motor and autonomic symptoms. Impaired brain serotonergic innervation can be associated with various clinical indices of MSA; however, the relationship between clinical symptoms and cerebrospinal fluid (CSF) levels of 5-hydroxyindole acetic acid (5-HIAA), a main serotonin metabolite, has not been fully elucidated. METHODS: To compare CSF 5-HIAA levels between patients with MSA and healthy controls, we included 33 controls and 69 MSA patients with either predominant parkinsonian or cerebellar ataxia subtypes. CSF 5-HIAA levels were measured using high-performance liquid chromatography. Additionally, we investigated correlations between CSF 5-HIAA and various clinical indices in 34 MSA patients. RESULTS: CSF 5-HIAA levels were significantly lower in MSA patients than in controls (p < 0.0001). Probable MSA patients had lower CSF 5-HIAA levels than possible MSA patients (p < 0.001). In MSA patients, CSF 5-HIAA levels were inversely correlated with scores in Parts 1, 2, and 4 of the Unified Multiple System Atrophy Rating Scale, and with systolic and diastolic blood pressure in Part 3. Structural equation modeling revealed significant paths between serotonin and clinical symptoms, and significance was highest for activities of daily living, walking, and body sway. CONCLUSIONS: Serotonin dysfunction, as assessed by CSF 5-HIAA levels, may implicate greater MSA severity.
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Frontiers in molecular neuroscience 17 1507033-1507033 2024年Parkinson's disease (PD) involves the disruption of brain energy homeostasis. This encompasses broad-impact factors such as mitochondrial dysfunction, impaired glycolysis, and other metabolic disturbances, like disruptions in the pentose phosphate pathway and purine metabolism. Cortical hubs, which are highly connected regions essential for coordinating multiple brain functions, require significant energy due to their dense synaptic activity and long-range connections. Deficits in ATP production in PD can severely impair these hubs. The energy imbalance also affects subcortical regions, including the massive axonal arbors in the striatum of substantia nigra pars compacta neurons, due to their high metabolic demand. This ATP decline may result in α-synuclein accumulation, autophagy-lysosomal system impairment, neuronal network breakdown and accelerated neurodegeneration. We propose an "ATP Supply-Demand Mismatch Model" to help explain the pathogenesis of PD. This model emphasizes how ATP deficits drive pathological protein aggregation, impaired autophagy, and the degeneration of key brain networks, contributing to both motor and non-motor symptoms.
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Annals of clinical and translational neurology 2023年7月26日OBJECTIVE: Recent studies have revealed an association between Parkinson's disease (PD) and Fabry disease, a lysosomal storage disorder; however, the underlying mechanisms remain to be elucidated. This study aimed to investigate the enzymatic properties of serum alpha-galactosidase A (GLA) and compared them with the clinical parameters of PD. METHODS: The study participants consisted of 66 sporadic PD patients and 52 controls. We measured serum GLA activity and calculated the apparent Michaelis constant (Km ) and maximal velocity (Vmax ) by Lineweaver-Burk plot analysis. Serum GLA protein concentration was measured by enzyme-linked immunosorbent assay. We examined the potential correlations between serum GLA activity and GLA protein concentration and clinical features and the plasma neurofilament light chain (NfL) level. RESULTS: Compared to controls, PD patients showed significantly lower serum GLA activity (P < 0.0001) and apparent Vmax (P = 0.0131), but no change in the apparent Km value. Serum GLA protein concentration was lower in the PD group (P = 0.0168) and was positively associated with GLA activity. Serum GLA activity and GLA protein concentration in the PD group showed a negative correlation with age. Additionally, serum GLA activity was negatively correlated with the motor severity score and the level of plasma NfL, and was positively correlated with the score of frontal assessment battery. INTERPRETATION: This study highlights that the lower serum GLA activity in PD is the result of a quantitative decrement of GLA protein in the serum and that it may serve as a biomarker of disease severity.
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Associations of Alzheimer's-related plasma biomarkers with cognitive decline in Parkinson's disease.Journal of neurology 2023年7月22日BACKGROUND: Parkinson's disease (PD) is associated with cognitive decline through multiple mechanisms, including Alzheimer's disease (AD) pathology and cortical Lewy body involvement. However, its underlying mechanisms remain unclear. Recently, AD-related plasma biomarkers have emerged as potential tools for predicting abnormal pathological protein accumulation. We aimed to investigate the association between AD-related plasma biomarkers and cognitive decline in PD patients. METHODS: Plasma biomarkers were measured in 70 PD patients (49 with nondemented Parkinson's disease (PDND) and 21 with Parkinson's disease dementia (PDD)) and 38 healthy controls (HCs) using a single-molecule array. The study evaluated (1) the correlation between plasma biomarkers and clinical parameters, (2) receiver operating characteristic curves and areas under the curve to evaluate the discrimination capacity of plasma biomarkers among groups, and (3) a generalized linear model to analyze associations with Addenbrooke's Cognitive Examination-Revised and Montreal Cognitive Assessment-Japanese version scores. RESULTS: Plasma glial fibrillary acidic protein significantly correlated with cognitive function tests, including all subdomains, with a notable increase in the PDD group compared with the HC and PDND groups, while plasma neurofilament light chain captured both cognitive decline and disease severity in the PDND and PDD groups. Plasma beta-amyloid 42/40 and pholphorylated-tau181 indicated AD pathology in the PDD group, but plasma beta-amyloid 42/40 was increased in the PDND group compared with HCs and decreased in the PDD group compared with the PDND group. CONCLUSIONS: AD-related plasma biomarkers may predict cognitive decline in PD and uncover underlying mechanisms suggesting astrocytic pathologies related to cognitive decline in PD.
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パーキンソン病・運動障害疾患コングレスプログラム・抄録集 17回 109-109 2023年7月
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FEBS open bio 2023年2月21日Accumulating evidence suggests that various sphingolipids and glycosphingolipids can act as mediators for inflammation or signaling molecules in the nervous system. In this article, we explore the molecular basis of a new neuroinflammatory disorder called encephalomyeloradiculoneuropathy (EMRN), which affects the brain, spinal cord, and peripheral nerves; in particular, we discuss whether glycolipid and sphingolipid dysmetabolism is present in patients with this disorder. This review will focus on the pathognomonic significance of sphingolipid and glycolipid dysmetabolism for the development of EMRN and the possible involvement of inflammation in the nervous system.
MISC
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画像診断 42(2) 145-155 2022年1月25日<文献概要>TDP-43は主に核内に存在し,RNAの生合成をはじめ様々なプロセスに関与する.TDP-43の核内局在の喪失と異常な翻訳後修飾を受けた不溶化TDP-43の存在を特徴とする一群は,TDP-43proteinopathyと呼ばれ,筋萎縮性側索硬化症と前頭側頭葉変性症が代表的な疾患である.
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画像診断 41(14) 1470-1481 2021年11月25日<文献概要>認知症の診断は,適切な病歴聴取,神経学的診察,高次脳機能評価,脳画像を評価することで行われる.最近は,血液や髄液のバイオマーカー開発も目覚ましい.脳画像を解釈する上で,認知症の臨床像の特徴,診断基準,臨床病型の多様性,高次脳機能検査結果の解釈方法などを整理することは有益である.
講演・口頭発表等
164共同研究・競争的資金等の研究課題
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日本学術振興会 科学研究費助成事業 2021年4月 - 2024年3月
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日本学術振興会 科学研究費助成事業 2018年4月 - 2021年3月
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日本学術振興会 科学研究費助成事業 2015年4月 - 2018年3月
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日本学術振興会 科学研究費助成事業 2012年4月 - 2015年3月