TY - JOUR
T1 - Identifying amyloid pathology-related cerebrospinal fluid biomarkers for Alzheimer's disease in a multicohort study
AU - Alzheimer's Disease Neuroimaging Initiative
AU - Leung, Yuk Yee
AU - Toledo, Jon B.
AU - Nefedov, Alexey
AU - Polikar, Robi
AU - Raghavan, Nandini
AU - Xie, Sharon X.
AU - Farnum, Michael
AU - Schultz, Tim
AU - Baek, Young
AU - Deerlin, Vivianna V.
AU - Hu, William T.
AU - Holtzman, David M.
AU - Fagan, Anne M.
AU - Perrin, Richard J.
AU - Grossman, Murray
AU - Soares, Holly D.
AU - Kling, Mitchel A.
AU - Mailman, Matthew
AU - Arnold, Steven E.
AU - Narayan, Vaibhav A.
AU - Lee, Virginia M.Y.
AU - Shaw, Leslie M.
AU - Baker, David
AU - Wittenberg, Gayle M.
AU - Trojanowski, John Q.
AU - Wang, Li San
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of apolipoprotein E (. APOE) e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Results: Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Discussion: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, other's roles in symptomatic AD samples worth further explorations.
AB - Introduction: The dynamic range of cerebrospinal fluid (CSF) amyloid β (Aβ1-42) measurement does not parallel to cognitive changes in Alzheimer's disease (AD) and cognitively normal (CN) subjects across different studies. Therefore, identifying novel proteins to characterize symptomatic AD samples is important. Methods: Proteins were profiled using a multianalyte platform by Rules Based Medicine (MAP-RBM). Due to underlying heterogeneity and unbalanced sample size, we combined subjects (344 AD and 325 CN) from three cohorts: Alzheimer's Disease Neuroimaging Initiative, Penn Center for Neurodegenerative Disease Research of the University of Pennsylvania, and Knight Alzheimer's Disease Research Center at Washington University in St. Louis. We focused on samples whose cognitive and amyloid status was consistent. We performed linear regression (accounted for age, gender, number of apolipoprotein E (. APOE) e4 alleles, and cohort variable) to identify amyloid-related proteins for symptomatic AD subjects in this largest ever CSF-based MAP-RBM study. ANOVA and Tukey's test were used to evaluate if these proteins were related to cognitive impairment changes as measured by mini-mental state examination (MMSE). Results: Seven proteins were significantly associated with Aβ1-42 levels in the combined cohort (false discovery rate adjusted P < .05), of which lipoprotein a (Lp(a)), prolactin (PRL), resistin, and vascular endothelial growth factor (VEGF) have consistent direction of associations across every individual cohort. VEGF was strongly associated with MMSE scores, followed by pancreatic polypeptide and immunoglobulin A (IgA), suggesting they may be related to staging of AD. Discussion: Lp(a), PRL, IgA, and tissue factor/thromboplastin have never been reported for AD diagnosis in previous individual CSF-based MAP-RBM studies. Although some of our reported analytes are related to AD pathophysiology, other's roles in symptomatic AD samples worth further explorations.
KW - Alzheimer's disease
KW - Amyloid beta
KW - Biomarkers
KW - Cerebrospinal fluid
KW - Cognitive impairment
KW - Dementia
UR - http://www.scopus.com/inward/record.url?scp=84940181687&partnerID=8YFLogxK
U2 - 10.1016/j.dadm.2015.06.008
DO - 10.1016/j.dadm.2015.06.008
M3 - Article
C2 - 26693175
AN - SCOPUS:84940181687
SN - 2352-8729
VL - 1
SP - 339
EP - 348
JO - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
JF - Alzheimer's and Dementia: Diagnosis, Assessment and Disease Monitoring
IS - 3
ER -