title: Test-retest reliability of memory task functional magnetic resonance imaging in Alzheimer disease clinical trials.
abstract: OBJECTIVE
  To examine the feasibility and test-retest reliability of encoding-task functional magnetic resonance imaging (fMRI) in mild Alzheimer disease (AD).
  
  
  METHODS
  Randomized, double-blind, placebo-controlled study.
  
  
  METHODS
  Memory clinical trials unit.
  
  
  METHODS
  We studied 12 patients with mild AD (mean [SEM] Mini-Mental State Examination score, 24.0 [0.7]; mean Clinical Dementia Rating score, 1.0) who had been taking donepezil hydrochloride for more than 6 months from the placebo arm of a larger 24-week study (n = 24, 4 scans on weeks 0, 6, 12, and 24, respectively).
  
  
  METHODS
  Placebo and 3 face-name, paired-associate encoding, block-design blood oxygenation level-dependent fMRI scans in 12 weeks.
  
  
  METHODS
  We performed whole-brain t maps (P < .001, 5 contiguous voxels) and hippocampal regions-of-interest analyses of extent (percentage of active voxels) and magnitude (percentage of signal change) for novel-greater-than-repeated face-name contrasts. We also calculated intraclass correlation coefficients and power estimates for hippocampal regions of interest.
  
  
  RESULTS
  Task tolerability and data yield were high (95 of 96 scans yielded favorable-quality data). Whole-brain maps were stable. Right and left hippocampal regions-of-interest intraclass correlation coefficients were 0.59 to 0.87 and 0.67 to 0.74, respectively. To detect 25.0% to 50.0% changes in week-0 to week-12 hippocampal activity using left-right extent or right magnitude with 80.0% power (2-sided α = .05) requires 14 to 51 patients. Using left magnitude requires 125 patients because of relatively small signal to variance ratios.
  
  
  CONCLUSIONS
  Encoding-task fMRI was successfully implemented in a single-site, 24-week, AD randomized controlled trial. Week 0 to 12 whole-brain t maps were stable, and test-retest reliability of hippocampal fMRI measures ranged from moderate to substantial. Right hippocampal magnitude may be the most promising of these candidate measures in a leveraged context. These initial estimates of test-retest reliability and power justify evaluation of encoding-task fMRI as a potential biomarker for signal of effect in exploratory and proof-of-concept trials in mild AD. Validation of these results with larger sample sizes and assessment in multisite studies is warranted.
authors.affiliation: Memory Disorders Unit, Massachusetts General Hospital, 15 Parkman Street, Wang Ambulatory Care Center 715, Boston, MA 02114, USA. atri@nmr.mgh.harvard.edu
authors.forename: Alireza
authors.initials: A
authors.lastname: Atri
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: O'Brien
authors.forename: Aishwarya
authors.initials: A
authors.lastname: Sreenivasan
authors.forename: Sarah
authors.initials: S
authors.lastname: Rastegar
authors.forename: Sibyl
authors.initials: S
authors.lastname: Salisbury
authors.forename: Amy N
authors.initials: AN
authors.lastname: DeLuca
authors.forename: Kelly M
authors.initials: KM
authors.lastname: O'Keefe
authors.forename: Peter S
authors.initials: PS
authors.lastname: LaViolette
authors.forename: Dorene M
authors.initials: DM
authors.lastname: Rentz
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Locascio
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D003072:Cognition Disorders / Q000473:pathology / Q000503:physiopathology; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008568:Memory; D008569:Memory Disorders / Q000473:pathology / Q000503:physiopathology; D008875:Middle Aged; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D018579:Patient Selection; D015203:Reproducibility of Results
chemical_list: D010100:Oxygen