title: Neuronal injury biomarkers and prognosis in ADNI subjects with normal cognition.
abstract: BACKGROUND
  Based on previous studies, a preclinical classification for Alzheimer's disease (AD) has been proposed. However, 1) specificity of the different neuronal injury (NI) biomarkers has not been studied, 2) subjects with subtle cognitive impairment but normal NI biomarkers (SCINIB) have not been included in the analyses and 3) progression to mild cognitive impairment (MCI) or dementia of the AD type (DAT), referred to here as MCI/DAT, varies between studies. Therefore, we analyzed data from 486 cognitively normal (CN) and 327 DAT subjects in the AD Neuroimaging Initiative (ADNI)-1/GO/2 cohorts.
  
  
  RESULTS
  In the ADNI-1 cohort (median follow-up of 6 years), 6.3% and 17.0% of the CN subjects developed MCI/DAT after 3 and 5 years follow-up, respectively. NI biomarker cutoffs [structural magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG-PET) and cerebrospinal fluid (CSF) tau] were established in DAT patients and memory composite scores were calculated in CN subjects in a cross-sectional sample (n = 160). In the complete longitudinally followed CN ADNI cohort (n = 326, median follow-up of 2 years), CSF and MRI values predicted an increased conversion to MCI/DAT. Different NI biomarkers showed important disagreements for classifying subjects as abnormal NI [kappa = (-0.05)-(0.33)] and into AD preclinical groups. SCINIB subjects (5.0%) were more prevalent than AD preclinical stage 3 subjects (3.4%) and showed a trend for increased progression to MCI/DAT.
  
  
  CONCLUSIONS
  Different NI biomarkers lead to different classifications of ADNI subjects, while structural MRI and CSF tau measures showed the strongest predictive value for progression to MCI/DAT. The newly defined SCINIB category of ADNI subjects is more prevalent than AD preclinical stage individuals.
authors.forename: Jon B
authors.initials: JB
authors.lastname: Toledo
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: David A
authors.initials: DA
authors.lastname: Wolk
authors.forename: Xiao
authors.initials: X
authors.lastname: Da
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.forename: Steven E
authors.initials: SE
authors.lastname: Arnold
authors.forename: William
authors.initials: W
authors.lastname: Jagust
authors.forename: Clifford
authors.initials: C
authors.lastname: Jack
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
authors.forename: Christos
authors.initials: C
authors.lastname: Davatzikos
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Shaw
authors.affiliation: Department of Pathology & Laboratory Medicine, Institute on Aging, Center for Neurodegenerative Disease Research, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. trojanow@mail.med.upenn.edu.
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D003071:Cognition / Q000502:physiology*; D060825:Cognitive Dysfunction / Q000175:diagnosis; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D016208:Databases, Factual / Q000706:statistics & numerical data; D018450:Disease Progression; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D011569:Psychiatric Status Rating Scales; D011877:Radionuclide Imaging; D013997:Time Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D019788:Fluorodeoxyglucose F18