Donepezil treatment and changes in hippocampal structure in very mild Alzheimer disease

Abstract

Objective: To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia.

Design: MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields.

Setting: A dementia clinic at Washington University School of Medicine.

Patients or other participants: Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician.

Main outcome measures: Hippocampal volume loss and surface deformation.

Results: There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations.

Conclusions: Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.

Figure 1. Visualization of the pattern of longitudinal change on the hippocampal surfaces in nondemented subjects and subjects with very mild DAT, either treated with donepezil or untreated

Top panels show the left and right hippocampi viewed from the top (dorsal surface), while bottom panels shows the left and right hippocampi viewed from the bottom (ventral surface). Baseline-to-follow-up changes for the nondemented subject, untreated subjects and treated subjects are shown in the left, middle and right columns, respectively. Boundaries between the three zones of the hippocampal surface (i.e., lateral, superior and inferior-medial) are drawn in black and all three zones are labeled (CA1 = CA1, SUB = Subiculum, REM = Remainder, which is comprised of CA2–4 plus the dendate gyrus). Rates of change (slopes) of inward variation of the hippocampal surface is represented by cooler flame colors (i.e., blue to purple), while slopes of outward variation is represented by warmer colors (i.e., orange to red).

Figure 2. Comparison of the patterns of longitudinal change on the hippocampal surfaces in subjects among very mild DAT treated with donepezil, untreated DAT subjects and nondemented subjects

Top panels show the left and right hippocampi viewed from the top (dorsal surface), while bottom panels shows the left and right hippocampi viewed from the bottom (ventral surface). Comparisons (difference in the mean, unadjusted for covariates) between treated and nondemented subjects are shown in the left column. Comparisons between untreated and nondemented subjects are shown in the middle column. Comparisons between treated and untreated subjects are shown in the right column. Boundaries between the three zones of the hippocampal surface (i.e., lateral, superior and inferior-medial) are drawn in black and all three zones are labeled (CA1 = CA1, SUB = Subiculum, REM = Remainder). Rates of change (slopes) of hippocampal surface variation are compared. Surface locations showing significant differences (p<0.05, uncorrected for multiple comparisons) are visualized with blue to purple colors (for inward) and orange to red colors (for outward).