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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.

Studies have demonstrated loss of serotonergic neurons in the brainstems of patients with multiple-system atrophy (MSA). This study aimed to semiquantitatively investigate the status of serotonin transporter (SERT) distribution in the brainstem of individuals with MSA-parkinsonian type (MSA-P) via 123I-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-FP-CIT) SPECT and compare it with pathologic findings in some cases. Methods: We administered 123I-FP-CIT intravenously to 19 patients with MSA-P and 17 healthy controls (HCs) and performed SPECT and MRI scans. Specific binding ratio (SBR) images were generated, and summed voxel-based SBRs for the midbrain, pons, and entire brainstem were quantified. The Mann-Whitney U test was used to compare the MSA-P and HC groups, and receiver operating characteristic curves were used to analyze the midbrain-to-pons ratio of the summed voxel-based SBR. Further, we assessed postmortem SERT immunohistochemistry pathology in the brainstems of representative MSA-P cases and HCs to compare the distribution and density of SERT with SPECT findings. Results: 123I-FP-CIT SPECT results revealed a significant summed voxel-based SBR decrease in the midbrain and an increase in the pons in the MSA-P group, although the brainstem summed voxel-based SBRs did not differ significantly (P < 0.05). The use of the midbrain-to-pons ratio for differentiation generated an area under the curve of 0.93. SERT immunostaining pathology, consistent with the 123I-FP-CIT SPECT findings, demonstrated a significant decrease in SERT expression in the substantia nigra and a significant increase in the pontine raphe nucleus in patients with MSA-P. Conclusion: Our results indicate differences in SERT distribution in the brainstems of patients with MSA-P and HCs.

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.