Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease

Richard J. Perrin, Rebecca Craig-Schapiro, James P. Malone, Aarti R. Shah, Petra Gilmore, Alan E. Davis, Catherine M. Roe, Elaine R. Peskind, Ge Li, Douglas R. Galasko, Christopher M. Clark, Joseph Quinn, Jeffrey Kaye, John C. Morris, David M. Holtzman, Reid Townsend, Anne M. Fagan

Research output: Contribution to journalArticle

123 Citations (Scopus)

Abstract

Background: Ideally, disease modifying therapies for Alzheimer disease (AD) will be applied during the 'preclinical' stage (pathology present with cognition intact) before severe neuronal damage occurs, or upon recognizing very mild cognitive impairment. Developing and judiciously administering such therapies will require biomarker panels to identify early AD pathology, classify disease stage, monitor pathological progression, and predict cognitive decline. To discover such biomarkers, we measured AD-associated changes in the cerebrospinal fluid (CSF) proteome. Methods and Findings: CSF samples from individuals with mild AD (Clinical Dementia Rating [CDR] 1) (n = 24) and cognitively normal controls (CDR 0) (n = 24) were subjected to two-dimensional difference-in-gel electrophoresis. Within 119 differentially-abundant gel features, mass spectrometry (LC-MS/MS) identified 47 proteins. For validation, eleven proteins were re-evaluated by enzyme-linked immunosorbent assays (ELISA). Six of these assays (NrCAM, YKL-40, chromogranin A, carnosinase I, transthyretin, cystatin C) distinguished CDR 1 and CDR 0 groups and were subsequently applied (with tau, p-tau181 and Aβ42 ELISAs) to a larger independent cohort (n = 292) that included individuals with very mild dementia (CDR 0.5). Receiver-operating characteristic curve analyses using stepwise logistic regression yielded optimal biomarker combinations to distinguish CDR 0 from CDR>0 (tau, YKL-40, NrCAM) and CDR 1 from CDR

Original languageEnglish (US)
Article numbere16032
JournalPLoS One
Volume6
Issue number1
StatePublished - 2011

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Cerebrospinal fluid
dementia
Biomarkers
cerebrospinal fluid
Alzheimer disease
Cerebrospinal Fluid
Dementia
biomarkers
Alzheimer Disease
Pathology
Assays
Gels
Cystatin C
Chromogranin A
Immunosorbents
Prealbumin
Proteome
Electrophoresis
Enzyme-Linked Immunosorbent Assay
Mass spectrometry

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Perrin, R. J., Craig-Schapiro, R., Malone, J. P., Shah, A. R., Gilmore, P., Davis, A. E., ... Fagan, A. M. (2011). Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease. PLoS One, 6(1), [e16032].

Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease. / Perrin, Richard J.; Craig-Schapiro, Rebecca; Malone, James P.; Shah, Aarti R.; Gilmore, Petra; Davis, Alan E.; Roe, Catherine M.; Peskind, Elaine R.; Li, Ge; Galasko, Douglas R.; Clark, Christopher M.; Quinn, Joseph; Kaye, Jeffrey; Morris, John C.; Holtzman, David M.; Townsend, Reid; Fagan, Anne M.

In: PLoS One, Vol. 6, No. 1, e16032, 2011.

Research output: Contribution to journalArticle

Perrin, RJ, Craig-Schapiro, R, Malone, JP, Shah, AR, Gilmore, P, Davis, AE, Roe, CM, Peskind, ER, Li, G, Galasko, DR, Clark, CM, Quinn, J, Kaye, J, Morris, JC, Holtzman, DM, Townsend, R & Fagan, AM 2011, 'Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease', PLoS One, vol. 6, no. 1, e16032.
Perrin RJ, Craig-Schapiro R, Malone JP, Shah AR, Gilmore P, Davis AE et al. Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease. PLoS One. 2011;6(1). e16032.
Perrin, Richard J. ; Craig-Schapiro, Rebecca ; Malone, James P. ; Shah, Aarti R. ; Gilmore, Petra ; Davis, Alan E. ; Roe, Catherine M. ; Peskind, Elaine R. ; Li, Ge ; Galasko, Douglas R. ; Clark, Christopher M. ; Quinn, Joseph ; Kaye, Jeffrey ; Morris, John C. ; Holtzman, David M. ; Townsend, Reid ; Fagan, Anne M. / Identification and Validation of Novel Cerebrospinal Fluid Biomarkers for Staging Early Alzheimer's Disease. In: PLoS One. 2011 ; Vol. 6, No. 1.
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