Longitudinal changes in white matter disease and cognition in the first year of the Alzheimer disease neuroimaging initiative

Abstract

Objective: To evaluate relationships between magnetic resonance imaging (MRI)-based measures of white matter hyperintensities (WMHs), measured at baseline and longitudinally, and 1-year cognitive decline using a large convenience sample in a clinical trial design with a relatively mild profile of cardiovascular risk factors.

Design: Convenience sample in a clinical trial design.

Subjects: A total of 804 participants in the Alzheimer Disease Neuroimaging Initiative who received MRI scans, cognitive testing, and clinical evaluations at baseline, 6-month follow-up, and 12-month follow-up visits. For each scan, WMHs were detected automatically on coregistered sets of T1, proton density, and T2 MRI images using a validated method. Mixed-effects regression models evaluated relationships between risk factors for WMHs, WMH volume, and change in outcome measures including Mini-Mental State Examination (MMSE), Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and Clinical Dementia Rating Scale sum of boxes scores. Covariates in these models included race, sex, years of education, age, apolipoprotein E genotype, baseline clinical diagnosis (cognitively normal, mild cognitive impairment, or Alzheimer disease), cardiovascular risk score, and MRI-based hippocampal and brain volumes.

Results: Higher baseline WMH volume was associated with greater subsequent 1-year increase in ADAS-Cog and decrease in MMSE scores. Greater WMH volume at follow-up was associated with greater ADAS-Cog and lower MMSE scores at follow-up. Higher baseline age and cardiovascular risk score and more impaired baseline clinical diagnosis were associated with higher baseline WMH volume.

Conclusions: White matter hyperintensity volume predicts 1-year cognitive decline in a relatively healthy convenience sample that was similar to clinical trial samples, and therefore should be considered as a covariate of interest at baseline and longitudinally in future AD treatment trials.

Figure 1

Example white matter hyperintensity (WMH) detection results for 3 individuals whose WMH distributions are representative of the broader sample. Detected WMHs are overlaid in white on slices of T1-weighted images. Each row shows a set of 3 slices for a given individual. Each column shows detection at an analogous slice across all 3 individuals. The 3 individuals differ in their WMH distribution: they possess very mild periventricular capping (A), pronounced periventricular caps and confluent WMHs (B), and punctate WMHs scattered throughout the brain (C).

Figure 2

Mini-Mental State Examination (MMSE) trajectories by baseline diagnostic group. Longitudinal measurements of MMSE in 90 randomly selected subjects from the Alzheimer’s Disease Neuroimaging Initiative, including 30 each from groups that were cognitively normal at baseline (cognitively normal), had mild cognitive impairment (MCI) at baseline, and had Alzheimer disease (AD) at baseline, are shown as dots. Trajectories in these measurements predicted by the mixed effects statistical models are shown as lines. The models used factors measured at baseline to predict the baseline and slope of the trajectory. Note that the y-axes for the 3 subplots are scaled differently to account for broad differences in MMSE trajectory across groups.

Figure 3

Alzheimer Disease Assessment Scale–Cognitive Subscale (ADAS-Cog) trajectories by baseline diagnostic group. Longitudinal measurements of ADAS-Cog in 90 randomly selected subjects from the Alzheimer’s Disease Neuroimaging Initiative including 30 each from groups that were cognitively normal at baseline (cognitively normal), had mild cognitive impairment (MCI) at baseline, and had Alzheimer disease (AD) at baseline, are shown as dots. Trajectories in these measurements predicted by the mixed effects statistical models are shown as lines. The models used factors measured at baseline to predict the baseline and slope of the trajectory. Note that the y-axes for the 3 subplots are scaled differently to account for broad differences in ADAS-Cog trajectory across groups.