Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 74, Issue 7, Pages 672-687Publisher
OXFORD UNIV PRESS INC
DOI: 10.1097/NEN.0000000000000207
Keywords
Alzheimer disease; Biomarkers; Cerebrospinal fluid; Cognitive impairment; Neurodegenerative disease; Parkinson disease
Categories
Funding
- Department of Veterans Affairs [P50 AG05136, P50 NS62684, P50 AG05131]
- Nancy and Buster Alvord Endowment
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Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ-, and amyloid (A) (42)-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE epsilon 4/epsilon 4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level versus those in APOE epsilon 3/epsilon 3 or APOE epsilon 3/epsilon 4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. Cerebrospinal fluid apoE-positive and -amyloid (A(42))-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients versus age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring.
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