Authors:
Petar Podlesniy [PhD], Joana Figueiro-Silva [MS], Albert Llado [MD, PhD], Anna Antonell [PhD], Raquel Sanchez-Valle [MD, PhD], Daniel Alcolea [MD], Alberto Lleo [MD, PhD], Jose Luis Molinuevo [MD, PhD], Nuria Serra [BS], & Ramon Trullas [PhD]
Summary:
Objective - To identify a novel biochemical marker that precedes clinical symptoms of Alzheimer's disease (AD).
Methods - Using quantitative PCR techniques, we measured circulating cell free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) from study participants, selected from a cohort of 282 subjects, that were classified, according to their concentrations of Aβ1-42, t-tau and p-tau and by the presence or absence of dementia, in: asymptomatic subjects at risk of AD, symptomatic patients diagnosed with sporadic AD, pre-symptomatic subjects carrying pathogenic PSEN1 mutations and patients diagnosed with Fronto-temporal Lobar Degeneration (FTLD). We performed equivalent studies in a separate validation cohort of sporadic AD and FTLD patients. In addition, we measured mtDNA copy number in cultured cortical neurons from mutant Amyloid Precursor Protein/Presenilin1 (APP/PS1) transgenic mice.
Results - Asymptomatic patients at risk of AD, and symptomatic AD patients, but not FTLD patients, exhibit a significant decrease in circulating cell free mtDNA in the CSF. These observations were confirmed in the validation cohort. In addition, pre-symptomatic subjects carrying pathogenic PSEN1 gene mutations show low mtDNA content in CSF before the appearance of AD related biomarkers in CSF. Moreover, mtDNA content in CSF classifies with high sensitivity and specificity AD patients against either controls or patients with FTLD. Furthermore, cultured cortical neurons from APP/PS1 transgenic mice have less mtDNA copies, before the appearance of altered synaptic markers.
Interpretation - Low content of mtDNA in CSF may be a novel biomarker for the early detection of preclinical AD. These findings support the hypothesis that mtDNA depletion is a characteristic pathophysiological factor of neurodegeneration in AD.
Source:
Annals of Neurology; (06/22/13)