Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment.
Altered levels of cerebrospinal fluid (CSF) peptides related to Alzheimer's disease (AD) are associated with pathologic AD diagnosis, although cognitively normal subjects can also have abnormal levels of these AD biomarkers. To identify novel CSF biomarkers that distinguish pathologically confirmed AD from cognitively normal subjects and patients with other neurodegenerative disorders, we collected antemortem CSF samples from 66 AD patients and 25 patients with other neurodegenerative dementias followed longitudinally to neuropathologic confirmation, plus CSF from 33 cognitively normal subjects. We measured levels of 151 novel analytes via a targeted multiplex panel enriched in cytokines, chemokines and growth factors, as well as established AD CSF biomarkers (levels of Abeta42, tau and p-tau(181)). Two categories of biomarkers were identified: (1) analytes that specifically distinguished AD (especially CSF Abeta42 levels) from cognitively normal subjects and other disorders; and (2) analytes altered in multiple diseases (NrCAM, PDGF, C3, IL-1alpha), but not in cognitively normal subjects. A multi-prong analytical approach showed AD patients were best distinguished from non-AD cases (including cognitively normal subjects and patients with other neurodegenerative disorders) by a combination of traditional AD biomarkers and novel multiplex biomarkers. Six novel biomarkers (C3, CgA, IL-1alpha, I-309, NrCAM and VEGF) were correlated with the severity of cognitive impairment at CSF collection, and altered levels of IL-1alpha and TECK associated with subsequent cognitive decline in 38 longitudinally followed subjects with mild cognitive impairment. In summary, our targeted proteomic screen revealed novel CSF biomarkers that can improve the distinction between AD and non-AD cases by established biomarkers alone.
Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283, USA.
William T
WT
Hu
Alice
A
Chen-Plotkin
Steven E
SE
Arnold
Murray
M
Grossman
Christopher M
CM
Clark
Leslie M
LM
Shaw
Eve
E
Pickering
Max
M
Kuhn
Yu
Y
Chen
Leo
L
McCluskey
Lauren
L
Elman
Jason
J
Karlawish
Howard I
HI
Hurtig
Andrew
A
Siderowf
Virginia M-Y
VM
Lee
Holly
H
Soares
John Q
JQ
Trojanowski
D000367:Age Factors; D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D015415:Biomarkers / Q000134:cerebrospinal fluid; D016022:Case-Control Studies; D003072:Cognition Disorders / Q000134:cerebrospinal fluid* / Q000175:diagnosis; D003627:Data Interpretation, Statistical; D003704:Dementia / Q000134:cerebrospinal fluid / Q000175:diagnosis; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid / Q000175:diagnosis; D012680:Sensitivity and Specificity; D012737:Sex Factors
D015415:Biomarkers