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Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease

Authors

  • Petar Podlesniy PhD,

    1. Neurobiology Unit, Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, CSIC, Barcelona, Spain
    2. Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
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  • Joana Figueiro-Silva MS,

    1. Neurobiology Unit, Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, CSIC, Barcelona, Spain
    2. Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
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  • Albert Llado MD, PhD,

    1. Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomediques August Pi i Sunyer, IDIBAPS, Barcelona, Spain
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  • Anna Antonell PhD,

    1. Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomediques August Pi i Sunyer, IDIBAPS, Barcelona, Spain
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  • Raquel Sanchez-Valle MD, PhD,

    1. Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomediques August Pi i Sunyer, IDIBAPS, Barcelona, Spain
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  • Daniel Alcolea MD,

    1. Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
    2. Neurology Department, Hospital de Sant Pau, Barcelona, Spain
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  • Alberto Lleo MD, PhD,

    1. Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
    2. Neurology Department, Hospital de Sant Pau, Barcelona, Spain
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  • Jose Luis Molinuevo MD, PhD,

    1. Neurology Service, Hospital Clinic de Barcelona, Barcelona, Spain
    2. Institut d'Investigacions Biomediques August Pi i Sunyer, IDIBAPS, Barcelona, Spain
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  • Nuria Serra BS,

    1. Neurobiology Unit, Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, CSIC, Barcelona, Spain
    2. Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
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  • Ramon Trullas PhD

    Corresponding author
    1. Neurobiology Unit, Instituto de Investigaciones Biomedicas de Barcelona, Consejo Superior de Investigaciones Cientificas, CSIC, Barcelona, Spain
    2. Centro de Investigacion Biomedica en Red de Enfermedades Neurodegenerativas, CIBERNED, Madrid, Spain
    3. Institut d'Investigacions Biomediques August Pi i Sunyer, IDIBAPS, Barcelona, Spain
    • Address correspondence to Dr Trullas, Neurobiology Unit, IIBB/CSIC, IDIBAPS, CIBERNED, Rosselló 161, sexta planta, 08036 Barcelona, Spain. E-mail: ramon.trullas@iibb.csic.es

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Abstract

Objective

To identify a novel biochemical marker that precedes clinical symptoms in Alzheimer disease (AD).

Methods

Using quantitative polymerase chain reaction techniques, we measured circulating cell-free mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) from study participants, selected from a cohort of 282 subjects, who were classified according to their concentrations of amyloid β1–42, total tau, and phosphorylated tau and by the presence or absence of dementia, into asymptomatic subjects at risk of AD, symptomatic patients diagnosed with sporadic AD, presymptomatic subjects carrying pathogenic PSEN1 mutations, and patients diagnosed with frontotemporal 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, presymptomatic 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 discriminates with high sensitivity and specificity AD patients from either controls or patients with FTLD. Furthermore, cultured cortical neurons from APP/PS1 transgenic mice have fewer 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. Ann Neurol 2013;74:655–668

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