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. 2010 Jun;119(6):669-78.
doi: 10.1007/s00401-010-0667-0. Epub 2010 Mar 16.

Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment

William T Hu  1 , Alice Chen-Plotkin, Steven E Arnold, Murray Grossman, Christopher M Clark, Leslie M Shaw, Eve Pickering, Max Kuhn, Yu Chen, Leo McCluskey, Lauren Elman, Jason Karlawish, Howard I Hurtig, Andrew Siderowf, Virginia M-Y Lee, Holly Soares, John Q Trojanowski
Affiliations

Novel CSF biomarkers for Alzheimer's disease and mild cognitive impairment

William T Hu et al. Acta Neuropathol. 2010 Jun.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Boxplots showing median values, quartiles, and outliers (circles) of traditional (i.e. tau and Aβ42) and other candidate CSF biomarkers that differed in levels between subjects with normal cognition and AD. Values shown are normalized to mean values of cognitively normal subjects. a Analytes elevated in AD as compared to cognitively normal subjects. b Analytes decreased in AD as compared to cognitively normal subjects. Levels in patients with autopsy-confirmed non-AD neurodegeneration were also shown for comparison. White box cognitively normal subjects, blue box autopsy-confirmed cases of AD, red box autopsy-confirmed cases of non-AD neurodegenerative disorders. *I-309 was found to differ between AD and cognitively normal subjects by random forest and PAM, but not Mann–Whitney U test
Fig. 2
Fig. 2
AD biomarkers identified by each of the three analytical strategies (logistic regression, random forest, and PAM). a Biomarkers useful in distinguishing between subjects with AD and normal cognition. b Biomarkers useful in distinguishing between subjects with AD and other non-AD neurodegenerative disorders. Analytes in overlapping regions were identified by multiple strategies as important biomarkers
Fig. 3
Fig. 3
Boxplots showing median values, quartiles, and outliers (circles) of traditional and candidate biomarkers that differed in levels between AD and other non-AD neurodegenerative disorders. Values shown are normalized to mean values of cognitively normal subjects. White box cognitively normal subjects, blue box AD, yellow box FTLD-TDP, orange box FTLD-Tau, green box dementia with Lewy bodies
Fig. 4
Fig. 4
Partial residual plots of MAP analytes versus rates of subsequent cognitive decline in MCI. Linear fit and 95% confidence interval for fit are shown for each graph. The overall model includes age, gender, education, IL-1α level and TECK level
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