Hirohisa Watanabe

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.

Amyotrophic lateral sclerosis (ALS) exhibits considerable clinical variability, such as differences in age at onset (AAO). Multiple factors, including genetic factors, may underlie this variability; however, the specific determinants remain unclear. To identify genes affecting AAO, we have conducted a genome-wide association study in Japanese patients with ALS (discovery cohort: n = 1808; replication cohort: n = 207). Here, we show that the minor A allele of rs113161727 at the ADAM29-GPM6A locus is associated with a younger AAO in the discovery cohort (effect, -4.27 years; p = 4.60 × 10^-8); this finding has been confirmed in the replication cohort (p = 0.0068) and meta-analysis (p = 1.08 × 10^-9). Among 65 ALS patients with a SOD1 mutation, the AAO has been found to be 10.2 years younger in those with the A allele than in those without it (p = 0.002). This variant correlates with GPM6A upregulation in iPSC-derived motor neurons, suggesting GPM6A as a candidate AAO modifier. Overall, our study highlights the impact of genetic modifiers on ALS heterogeneity and provides a potential target for delaying disease onset.

<jats:title>ABSTRACT</jats:title> <jats:sec> <jats:title>Objective</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> CSF mt64‐ND1 and mt96‐ND5 levels were lower in PD patients than controls ( <jats:italic>p</jats:italic>  = 0.002, <jats:italic>p</jats:italic>  = 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Interpretation</jats:title> <jats:p>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.</jats:p> </jats:sec>