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).

Design: Randomized, double-blind, placebo-controlled study.

Setting: Memory clinical trials unit.

Participants: 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).

Interventions: Placebo and 3 face-name, paired-associate encoding, block-design blood oxygenation level-dependent fMRI scans in 12 weeks.

Main outcome measures: 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.

Figure 1

Stability of whole-brain SPM maps. N>R contrast maps (p<0.001, 5-voxel extent) for the same template coordinate (-24, -24, -9) for the placebo-arm (PLAC, n=12) at baseline (A), week 6 (T₂) (n=11) (B) and week 12 (T₃) (n=12) (C). Mapwise activity patterns are stable and consistent with patterns found in previous studies ^, . Difference maps with p<0.01, 5-voxel extent threshold (not shown) show no significant clusters (i.e. no significant differences between baseline, week 6 and week 12 scans).

Figure 2

Mean +/− SEM MAG (percent signal change, PSC) and EXT (percentage voxels active, PVA) of N>R contrast BOLD fMRI signal in the left and right Hippocampal ROIs across the three, T₁ (baseline, week 0), T₂ (week 6), and T₃ (week 12) scans. Hippocampal ROIs demonstrated similar EXT and MAG of activation at each fMRI session.