Tsuyoshi Nakai

ABSTRACT 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.

Recombinant tissue-type plasminogen activators (rtPA) effectively dissolve blood clots and improve symptoms in patients with acute ischemic stroke and myocardial infraction. Although rtPA are used in patients taking antiplatelets or anticoagulants to improve clinical outcomes, combination therapy may increase the risk of hemorrhagic transformation (HT) and intracerebral hemorrhage (ICH). However, few studies have investigated the risk of HT and ICH associated with these combination therapies. This study aimed to investigate the adverse-event and drug-drug interaction signals for HT and ICH under combination therapy with alteplase and various antiplatelets or anticoagulants, using the Japanese Adverse Drug Event Report database. Adverse-event signals were evaluated using the reporting odds ratio and information components, and drug-drug interaction signals were studied using the Ω shrinkage measure, additive, multiplicative, and Chi-square statistics models. We also investigated predictors of HT and ICH, time-to-onset, and outcomes in patients receiving alteplase. HT and/or ICH signals were detected in patients receiving alteplase in combination with aspirin, P2Y₁₂ inhibitors, cilostazol, ozagrel sodium, direct oral anticoagulants, warfarin potassium, heparin group, or argatroban. Hypertension and diabetes mellitus were significant risk factors for alteplase-induced HT. Most HT and ICH events occurred within 1 day after alteplase administration, and more than 60% of affected patients were not in recovery. In conclusion, continued monitoring is required in patients receiving alteplase in combination with any of the eight types of antiplatelets or the aforementioned anticoagulants. Additionally, the occurrence of HT or ICH within 1 day post-alteplase administration should be considered in patients with hypertension or diabetes mellitus. The findings from this study may help in understanding the risk of HT and ICH induced by rtPA in patients taking antiplatelet or anticoagulant medications, as well as in promoting the appropriate use of rtPA. Further prospective observational studies and randomized controlled trials are needed to assess these finding.