島 さゆり

BACKGROUND: Alterations in tryptophan-kynurenine (TRP-KYN) metabolism, which is associated with neuroinflammation, remain unclear in multiple system atrophy (MSA). OBJECTIVE: The aim was to investigate cerebrospinal fluid (CSF) TRP metabolites in MSA and their associations with other biomarkers. METHODS: A total of 51 patients with MSA and 56 controls were included. CSF TRP metabolites, such as KYN, quinolinic acid (QA), and kynurenic acid (KA), along with neurofilament light chain (NfL), glycoprotein nonmetastatic melanoma protein B (GPNMB), and soluble triggering receptor expressed on myeloid cells 2 (sTREM2), were analyzed. RESULTS: Patients with MSA exhibited higher levels of QA, a neuroinflammatory marker, and lower levels of KA, a neuroprotective marker, yielding an elevated QA-to-KA ratio. Neither QA nor KA correlated with clinical scores. GPNMB, sTREM2, and NfL were increased; however, these markers were independent of KYN pathway metabolites. CONCLUSIONS: MSA exhibited a significant imbalance in KYN metabolism, suggesting a shift toward inflammatory processes distinct from classic neuroinflammatory markers. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

BACKGROUND: Weight loss is a substantial non-motor feature of Parkinson's disease (PD) associated with worse clinical outcomes, but the underlying mechanisms remain poorly understood. Thus, we investigated the mechanisms of PD-related weight loss by examining the correlation between body composition and various plasma metabolites. METHODS: We enrolled 91 patients with PD and 47 healthy controls between July 2021 and October 2023. Body composition was evaluated using bioelectrical impedance analysis. Plasma metabolite profiling was conducted via mass spectrometry, including short-chain and medium-chain fatty acids, Krebs cycle intermediates, ketone bodies and phospholipids. Subsequently, alterations in body composition in PD and their association with plasma metabolites were assessed. RESULTS: Patients with PD had lower body weight (p=0.003), body mass index (BMI; p=0.001) and body fat mass (p<0.001) compared with controls. Metabolomic analyses revealed that, in patients with PD, glycolysis and Krebs cycle markers (lactic acid and succinic acid) were reduced, while ketone bodies (acetoacetic acid and 3-hydroxybutyric acid), amino acid catabolism-related markers (2-hydroxybutyric acid and 2-oxobutyric acid) and acetic acid were elevated. Notably, in patients with PD, acetoacetic acid and 3-hydroxybutyric acid negatively correlated with BMI. Phosphatidylcholine (40:2) was also elevated in PD and showed higher levels in individuals at more advanced Hoehn and Yahr stages. CONCLUSIONS: PD-related fat loss was accompanied by a pattern of lower glycolytic activity and higher levels of lipid and amino acid metabolism-related metabolites, consistent with a potential shift in energy utilisation. These findings highlight metabolic pathways as potential targets for interventions to mitigate weight loss in PD.

BACKGROUND: Lysosomal dysfunction is recognized as a key pathological feature of Parkinson's disease (PD); however, its peripheral signatures remain unclear. METHODS: This study evaluated the peripheral profiles of lysosomal hydrolases and their regulation by transcription factor EB (TFEB), focusing on α-galactosidase A (GLA) and β-mannosidase in the peripheral blood mononuclear cells (PBMCs) of 63 PD patients and 44 healthy controls. Lysosomal enzyme activities in PBMC homogenates and serum were quantified using a fluorometric enzymatic assay with kinetic analysis. Protein concentrations were measured by ELISA, and TFEB activation status was evaluated by its phosphorylation level using western blotting. RESULTS: GLA activity and protein concentrations were higher in the PBMCs of patients, but not for β-mannosidase. TFEB protein concentrations were also elevated and showed positive correlations with lysosomal enzyme protein concentrations. TFEB phosphorylation status showed that the ratio of non-phosphorylated to total TFEB did not differ between PD and controls. However, within the PD group, this ratio negatively correlated with TFEB concentrations, suggesting a potential uncoupling between TFEB expression and its functional activation status. Furthermore, both serum-to-PBMC ratios of GLA activity and protein concentration were lower in PD and were associated with PBMC counts, indicating impaired enzyme release from PBMC. CONCLUSIONS: Elevated TFEB expression in PBMCs may reflect a compensatory response to PD-related cellular stress. However, this response may be functionally insufficient due to limited TFEB activity, potentially leading to reduced lysosomal enzyme release. Thus, peripheral TFEB-related lysosomal abnormalities may serve as indicators of systemic autophagy-lysosome dysregulation in PD.

OBJECTIVE: Cerebrospinal fluid (CSF) cell-free mitochondrial DNA (cf-mtDNA) is a potential biomarker for Parkinson's disease (PD), but its clinical relevance remains unclear. We investigated associations between CSF cf-mtDNA levels, body composition, nutritional status, and metabolic biomarkers in PD. METHODS: CSF cf-mtDNA levels, defined as the copy numbers of two regions of the mtDNA circular molecule (mt64-ND1 and mt96-ND5), were quantified in 44 PD patients and 43 controls using multiplex digital PCR. The mt96-ND5/mt64-ND1 ratio was calculated to estimate mtDNA deletion burden. Associations with clinical features, body composition, serum nutritional markers, and plasma energy metabolism-related organic acids were examined. Generalized linear models (GLMs) were performed to adjust for confounders. RESULTS: CSF mt64-ND1 and mt96-ND5 levels were lower in PD patients than controls (p = 0.002, p = 0.001), while the mt96-ND5/mt64-ND1 ratio showed no group difference. GLM analysis identified body composition indices and serum albumin as key determinants of cf-mtDNA levels. Subgroup analysis showed lower cf-mtDNA levels in PD patients with preserved body composition and nutritional status. The mt96-ND5/mt64-ND1 ratio displayed a biphasic association with body composition and an inverse correlation with plasma 2-ketoglutaric acid, suggesting a link to energy metabolism. INTERPRETATION: CSF cf-mtDNA levels are reduced in PD and influenced by body composition and nutritional status, supporting their role as a metabolic biomarker. While the cf-mtDNA deletion ratio remained unchanged, its association with body composition suggests a complex interplay between mitochondrial integrity and metabolism. These findings highlight the relevance of cf-mtDNA in PD pathophysiology and the need for further study.

Objective The development of non-invasive clinical diagnostics is paramount for the early detection of Alzheimer’s disease (AD). Neurofibrillary tangles in AD originate from the entorhinal cortex, a cortical memory area that mediates navigation via path integration (PI). Here, we studied correlations between PI errors and levels of a range of AD biomarkers using a 3D virtual reality navigation system to explore PI as a non-invasive surrogate marker for early detection. Methods We examined 111 healthy adults for PI using a head-mounted 3D VR system, AD-related plasma biomarkers (GFAP, NfL, Aβ40, Aβ42, and p-tau181), Apolipoprotein E (ApoE) genotype, and demographic and cognitive assessments. Covariance of PI and AD biomarkers was assessed statistically, including tests for multivariate linear regression, logistic regression, and predictor importance ranking using machine learning, to identify predictive relationships for PI errors. Results We found significant positive correlations between PI errors with age and plasma GFAP, p-tau181, and NfL levels. Multivariate analysis identified significant correlations of plasma GFAP (t-value = 2.16, p = 0.0332) and p-tau181 (t-value = 2.53, p = 0.0128) with PI errors. Predictor importance ranking using machine learning and receiver operating characteristic curves identified plasma p-tau181 as the most significant predictor of PI. ApoE genotype and plasma p-tau181 showed positive and negative PI associations (ApoE: coefficient = 0.650, p = 0.037; p-tau181: coefficient = −0.899, p = 0.041). EC thickness exhibited negative correlations with age, mean PI errors, and GFAP, NfL, and p-tau181; however, none of these associations remained significant after adjusting for age in linear regression analyses. Conclusion These findings suggest that PI quantified by 3D VR navigation systems may be useful as a surrogate diagnostic tool for the detection of early AD pathophysiology. The hierarchical application of 3D VR PI and plasma p-tau181, in particular, may be an effective combinatorial biomarker for early AD neurodegeneration. These findings advance the application of non-invasive diagnostic tools for early testing and monitoring of AD, paving the way for timely therapeutic interventions and improved epidemiological patient outcomes.

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.

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.

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.

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.

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.

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.