Mitochondrial DNA deletions in the cerebrospinal fl uid of patients with idiopathic REM sleep behaviour disorder

Background Idiopathic rapid eye movement (REM) sleep behaviour disorder (IRBD) represents the prodromal stage of Lewy body disorders (Parkinson ' s disease (PD) and dementia with Lewy bodies (DLB)) which are linked to variations in circulating cell -free mitochondrial DNA (cf-mtDNA). Here, we assessed whether altered cf-mtDNA release and integrity are already present in IRBD. Methods We used multiplex digital PCR (dPCR) to quantify cf-mtDNA copies and deletion ratio in cerebrospinal fl uid (CSF) and serum in a cohort of 71 participants, including 1) 17 patients with IRBD who remained disease -free (nonconverters), 2) 34 patients initially diagnosed with IRBD who later developed either PD or DLB (converters), and 3) 20 age -matched controls without IRBD or Parkinsonism. In addition, we investigated whether CD9-positive extracellular vesicles (CD9-EVs) from CSF and serum samples contained cf-mtDNA. Findings Patients with IRBD, both converters and non -converters, exhibited more cf-mtDNA with deletions in the CSF than controls. This fi nding was con fi rmed in CD9-EVs. The high levels of deleted cf-mtDNA in CSF corresponded to a signi fi cant decrease in cf-mtDNA copies in CD9-EVs in both IRBD non -converters and converters. Conversely, a signi fi cant increase in cf-mtDNA copies was found in serum and CD9-EVs from the serum of patients with IRBD who later converted to a Lewy body disorder. Interpretation Alterations in cf-mtDNA copy number and deletion ratio known to occur in Lewy body disorders are already present in IRBD and are not a consequence of Lewy body disease conversion. This suggests that mtDNA dysfunction is a primary molecular mechanism of the pathophysiological cascade that precedes the full clinical motor and cognitive manifestation of Lewy body disorders.