Mitochondrial DNA (mtDNA) as fluid biomarker in neurodegenerative disorders: A systematic review

Several studies evaluated peripheral and cerebrospinal fluid (CSF) mtDNA as a putative biomarker in neurodegenerative diseases, often yielding inconsistent findings. We systematically reviewed the current evidence assessing blood and CSF mtDNA levels and variant burden in Parkinson's disease (PD), Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Multiple sclerosis (MS) was also included as a paradigm of chronic neuroinflammation-driven neurodegeneration.

Medline, Embase, Scopus and Web of Science were searched for articles published from inception until October 2023. Studies focused on mtDNA haplogroups or hereditary pathogenic variants were excluded. Critical appraisal was performed using the Quality Assessment for Diagnostic Accuracy Studies criteria.

Fifty-nine original studies met our a priori-defined inclusion criteria. The majority of CSF-focused studies showed (i) decreased mtDNA levels in PD and AD; (ii) increased levels in MS compared to controls. No studies evaluated CSF mtDNA in ALS. Results focused on blood cell-free and intracellular mtDNA were contradictory, even within studies evaluating the same disease. This poor reproducibility is likely due to the lack of consideration of the many factors known to affect mtDNA levels. mtDNA damage and methylation levels were increased and reduced in patients compared to controls, respectively. A few studies investigated the correlation between mtDNA and disease severity, with conflicting results.

Additional well-designed studies are needed to evaluate CSF and blood mtDNA profiles as putative biomarkers in neurodegenerative diseases. The identification of "mitochondrial subtypes" of disease may enable novel precision medicine strategies to counteract neurodegeneration.