Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects |
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| Authors: | Leslie M Shaw PhD Hugo Vanderstichele PhD Malgorzata Knapik‐Czajka PhD Christopher M Clark MD Paul S Aisen MD Ronald C Petersen MD Kaj Blennow MD PhD Holly Soares PhD Adam Simon PhD Piotr Lewczuk MD PhD Robert Dean MD Eric Siemers MD William Potter MD Virginia M‐Y Lee PhD John Q Trojanowski MD PhD Alzheimer's Disease Neuroimaging Initiative |
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| Institution: | 1. Department of Pathology and Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA;2. Department of Diagnostic Development, Innogenetics NV, Gent, Belgium;3. Department of Neurology, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA;4. University of California San Diego, San Diego, CA;5. Mayo Clinic College of Medicine, Rochester, MN;6. Department of Psychiatry and Neurochemistry, Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at G?teborg University, M?lndal, Sweden;7. Pfizer Global Research and Development, Groton, CT;8. Merck Research Laboratories, West Point, PA;9. Department of Psychiatry and Psychotherapy, University of Erlangen‐Nuremberg, Erlangen, Germany;10. Eli Lilly & Company, Indianapolis, IN |
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| Abstract: | Objective Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects. Methods Amyloid‐β 1 to 42 peptide (Aβ1–42), total tau (t‐tau), and tau phosphorylated at the threonine 181 were measured in (1) cerebrospinal fluid (CSF) samples obtained during baseline evaluation of 100 mild AD, 196 mild cognitive impairment, and 114 elderly cognitively normal (NC) subjects in ADNI; and (2) independent 56 autopsy‐confirmed AD cases and 52 age‐matched elderly NCs using a multiplex immunoassay. Detection of an AD CSF profile for t‐tau and Aβ1–42 in ADNI subjects was achieved using receiver operating characteristic cut points and logistic regression models derived from the autopsy‐confirmed CSF data. Results CSF Aβ1–42 was the most sensitive biomarker for AD in the autopsy cohort of CSF samples: receiver operating characteristic area under the curve of 0.913 and sensitivity for AD detection of 96.4%. In the ADNI cohort, a logistic regression model for Aβ1–42, t‐tau, and APOε4 allele count provided the best assessment delineation of mild AD. An AD‐like baseline CSF profile for t‐tau/Aβ1–42 was detected in 33 of 37 ADNI mild cognitive impairment subjects who converted to probable AD during the first year of the study. Interpretation The CSF biomarker signature of AD defined by Aβ1–42 and t‐tau in the autopsy‐confirmed AD cohort and confirmed in the cohort followed in ADNI for 12 months detects mild AD in a large, multisite, prospective clinical investigation, and this signature appears to predict conversion from mild cognitive impairment to AD. Ann Neurol 2009 |
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