Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.
<h4>Background</h4>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 j...
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2011
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oai:doaj.org-article:14913627f3684daeb666751f635a0bc92021-11-18T07:00:33ZIdentification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease.1932-620310.1371/journal.pone.0016032https://doaj.org/article/14913627f3684daeb666751f635a0bc92011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21264269/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methods and findings</h4>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<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.<h4>Conclusions</h4>Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions.Richard J PerrinRebecca Craig-SchapiroJames P MaloneAarti R ShahPetra GilmoreAlan E DavisCatherine M RoeElaine R PeskindGe LiDouglas R GalaskoChristopher M ClarkJoseph F QuinnJeffrey A KayeJohn C MorrisDavid M HoltzmanR Reid TownsendAnne M FaganPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 1, p e16032 (2011) |
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| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 F Quinn Jeffrey A Kaye John C Morris David M Holtzman R Reid Townsend Anne M Fagan Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. |
| description |
<h4>Background</h4>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.<h4>Methods and findings</h4>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<1 (tau, chromogranin A, carnosinase I) with areas under the curve of 0.90 (0.85-0.94 95% confidence interval [CI]) and 0.88 (0.81-0.94 CI), respectively.<h4>Conclusions</h4>Four novel CSF biomarkers for AD (NrCAM, YKL-40, chromogranin A, carnosinase I) can improve the diagnostic accuracy of Aβ42 and tau. Together, these six markers describe six clinicopathological stages from cognitive normalcy to mild dementia, including stages defined by increased risk of cognitive decline. Such a panel might improve clinical trial efficiency by guiding subject enrollment and monitoring disease progression. Further studies will be required to validate this panel and evaluate its potential for distinguishing AD from other dementing conditions. |
| format |
article |
| author |
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 F Quinn Jeffrey A Kaye John C Morris David M Holtzman R Reid Townsend Anne M Fagan |
| author_facet |
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 F Quinn Jeffrey A Kaye John C Morris David M Holtzman R Reid Townsend Anne M Fagan |
| author_sort |
Richard J Perrin |
| title |
Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. |
| title_short |
Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. |
| title_full |
Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. |
| title_fullStr |
Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. |
| title_full_unstemmed |
Identification and validation of novel cerebrospinal fluid biomarkers for staging early Alzheimer's disease. |
| title_sort |
identification and validation of novel cerebrospinal fluid biomarkers for staging early alzheimer's disease. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/14913627f3684daeb666751f635a0bc9 |
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| _version_ |
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