Hirohisa Watanabe

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>

<jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>Patients with PD had lower body weight (p=0.003), body mass index (BMI; p=0.001) and body fat mass (p&lt;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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>