title: Baseline CSF p-tau levels independently predict progression of hippocampal atrophy in Alzheimer disease.
abstract: OBJECTIVE
  To investigate whether baseline CSF biomarkers are associated with hippocampal atrophy rate as a measure of disease progression in patients with Alzheimer disease (AD), patients with mild cognitive impairment (MCI), and controls, controlling for baseline neuropsychological and MRI findings.
  
  
  METHODS
  We assessed data from 31 patients with AD, 25 patients with MCI, and 19 controls (mean age 68 +/- 8 years; 39 [52%] female) who visited our memory clinic and had received serial MRI scanning (scan interval 1.7 +/- 0.7 years). At baseline, CSF biomarkers (amyloid beta 1-42, tau, and tau phosphorylated at threonine 181 [p-tau]) were obtained, as well as neuropsychological data. Baseline MRI scans were assessed using visual rating scales for medial temporal lobe atrophy (MTA), global cortical atrophy, and white matter hyperintensities. Hippocampal atrophy rates were estimated using regional nonlinear "fluid" registration of follow-up scan to baseline scan.
  
  
  RESULTS
  Stepwise multiple linear regression, adjusted for age and sex, showed that increased CSF p-tau levels (beta [standard error]: -0.79 [0.35]) at baseline was independently associated with higher subsequent hippocampal atrophy rates (p < 0.05), together with poorer memory performance (0.09 [0.04]) and more severe MTA (-0.60 [0.21]). The association of memory function with hippocampal atrophy rate was explained by the link with diagnosis, because it disappeared from the model after we additionally corrected for diagnosis.
  
  
  CONCLUSIONS
  Baseline CSF levels of tau phosphorylated at threonine 181 are independently associated with subsequent disease progression, as reflected by hippocampal atrophy rate. This effect is independent of baseline neuropsychological and MRI predictors. Our results imply that predicting disease progression can best be achieved by combining information from different modalities.
authors.affiliation: Department of Radiology and Alzheimer Center, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. w.henneman@vumc.nl
authors.forename: W J P
authors.initials: WJ
authors.lastname: Henneman
authors.forename: H
authors.initials: H
authors.lastname: Vrenken
authors.forename: J
authors.initials: J
authors.lastname: Barnes
authors.forename: I C
authors.initials: IC
authors.lastname: Sluimer
authors.forename: N A
authors.initials: NA
authors.lastname: Verwey
authors.forename: M A
authors.initials: MA
authors.lastname: Blankenstein
authors.forename: M
authors.initials: M
authors.lastname: Klein
authors.forename: N C
authors.initials: NC
authors.lastname: Fox
authors.forename: P
authors.initials: P
authors.lastname: Scheltens
authors.forename: F
authors.initials: F
authors.lastname: Barkhof
authors.forename: W M
authors.initials: WM
authors.lastname: van der Flier
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology* / Q000503:physiopathology; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000134:cerebrospinal fluid; D001284:Atrophy / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D015415:Biomarkers / Q000032:analysis / Q000134:cerebrospinal fluid; D018450:Disease Progression; D005260:Female; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000175:diagnosis / Q000209:etiology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010766:Phosphorylation; D011237:Predictive Value of Tests; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013912:Threonine / Q000737:chemistry / Q000378:metabolism; D016875:tau Proteins / Q000032:analysis / Q000134:cerebrospinal fluid*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D016875:tau Proteins; D013912:Threonine