Title:Cerebrospinal Fluid proNGF: A Putative Biomarker for Early Alzheimer’s Disease
Volume: 13
Issue: 7
Author(s): Scott E. Counts, Bin He, John G. Prout, Bernadeta Michalski, Lucia Farotti, Margaret Fahnestock and Elliott J. Mufson
Affiliation:
Keywords:
Alzheimer's disease, amyloid, biomarker, cerebrospinal fluid, mild cognitive impairment, proNGF, tau.
Abstract: The discovery of biomarkers for the onset of Alzheimer’s disease (AD) is essential for disease modification
strategies. To date, AD biomarker studies have focused on brain imaging and cerebrospinal fluid (CSF) changes in amyloid-
β (Aβ) peptide and tau proteins. While reliable to an extent, this panel could be improved by the inclusion of novel
biomarkers that optimize sensitivity and specificity. In this study, we determined whether CSF levels of the nerve growth
factor (NGF) precursor protein, proNGF, increased during the progression of AD, mirroring its up regulation in postmortem
brain samples of people who died with a clinical diagnosis of mild cognitive impairment (MCI) or AD. Immunoblot
analysis was performed on ventricular CSF harvested from participants in the Rush Religious Orders Study with an antemortem
clinical diagnosis of no cognitive impairment (NCI), amnestic MCI (aMCI, a putative prodromal AD stage), or
mild/moderate AD. ProNGF levels were increased 55% in aMCI and 70% in AD compared to NCI. Increasing CSF
proNGF levels correlated with impairment on cognitive test scores. In a complementary study, we found that proNGF was
significantly increased by 30% in lumbar CSF samples derived from patients with a clinical dementia rating (CDR) of 0.5
or 1 compared to those with a CDR = 0. Notably, proNGF/Aβ1-42 levels were 50% higher in CDR 0.5 and CDR 1 compared
to CDR 0 controls. By contrast, ELISA measurements of CSF brain-derived neurotrophic factor (BDNF) did not
distinguish aMCI from NCI. Taken together, these results suggest that proNGF protein levels may augment the diagnostic
accuracy of currently used CSF biomarker panels.
