長尾 龍之介

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.

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.