title: CSF biomarker changes precede symptom onset of mild cognitive impairment.
abstract: OBJECTIVE
  This study evaluated longitudinal CSF biomarker measures collected when participants were cognitively normal to determine the magnitude and time course of biomarker changes before the onset of clinical symptoms in subjects with mild cognitive impairment (MCI).
  
  
  METHODS
  Longitudinal CSF collection and cognitive assessments were performed on a cohort of 265 participants who were cognitively normal at their baseline assessment and subsequently developed MCI or dementia. CSF β-amyloid 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) were determined longitudinally. Consensus diagnoses were completed annually. Cox regression analyses were performed, with baseline CSF values and time-dependent rate of change in CSF values as covariates (adjusted by baseline age, race, and education), in relation to time to onset of mild cognitive symptoms.
  
  
  RESULTS
  The mean time from baseline to onset of mild cognitive symptoms was 5.41 years. Increased risk of progressing from normal cognition to onset of clinical symptoms was associated with baseline values of Aβ1-42, p-tau, and the ratios of p-tau/Aβ1-42 and t-tau/Aβ1-42 (p < 0.002). Additionally, the rate of change in the ratios of t-tau/Aβ1-42 (p < 0.004) and p-tau/Aβ1-42 (p < 0.02) was greater among participants who were subsequently diagnosed with MCI.
  
  
  CONCLUSIONS
  Baseline differences in CSF values were predictive of clinical symptoms that were a harbinger of a diagnosis of MCI more than 5 years before symptom onset, and continue to show longitudinal changes as cognitive symptoms develop, demonstrating that baseline and longitudinal changes in CSF biomarkers are evident during the preclinical phase of Alzheimer disease.
authors.affiliation: From the Department of Neurology (A.M., M.L., M.A., R.O.), The Johns Hopkins University School of Medicine, Baltimore; and Department of Biostatistics (S.L., Y.L., M.-C.W.), Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
authors.forename: Abhay
authors.initials: A
authors.lastname: Moghekar
authors.forename: Shanshan
authors.initials: S
authors.lastname: Li
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.forename: Mei-Cheng
authors.initials: MC
authors.lastname: Wang
authors.forename: Marilyn
authors.initials: M
authors.lastname: Albert
authors.forename: Richard
authors.initials: R
authors.lastname: O'Brien
mesh_terms: D000368:Aged; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid*; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D016016:Proportional Hazards Models; D016019:Survival Analysis; 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