Hippocampal hyperactivation in presymptomatic familial Alzheimer's disease

Abstract

Objective: The examination of individuals who carry fully penetrant genetic alterations that result in familial Alzheimer's disease (FAD) provides a unique model for studying the early presymptomatic disease stages. In AD, deficits in episodic and associative memory have been linked to structural and functional changes within the hippocampal system. This study used functional MRI (fMRI) to examine hippocampal function in a group of healthy, young, cognitively-intact presymptomatic individuals (average age 33.7 years) who carry the E280A presenilin-1 (PS1) genetic mutation for FAD. These PS1 subjects will go on to develop the first symptoms of the disease around the age of 45 years. Our objective was to examine hippocampal function years before the onset of clinical symptoms.

Methods: Twenty carriers of the Alzheimer's-associated E280A PS1 mutation and 19 PS1-negative control subjects participated. Both groups were matched for age, sex, education level, and neuropsychological test performance. All participants performed a face-name associative encoding task while in a Phillips 1.5T fMRI scanner. Analysis focused on the hippocampal system.

Results: Despite identical behavioral performance, presymptomatic PS1 mutation carriers exhibited increased activation of the right anterior hippocampus during encoding of novel face-name associations compared to matched controls.

Interpretation: Our results demonstrate that functional changes within the hippocampal memory system occur years before cognitive decline in FAD. These presymptomatic changes in hippocampal physiology in FAD suggest that hippocampal fMRI patterns during associative encoding may also provide a preclinical biomarker in sporadic AD.

FIGURE 1

Carriers show greater right anterior hippocampus activity during encoding of face-name associations. (A) Statistical Parametric Maps (SPMs) for the comparison PS1 mutation carriers vs controls for the contrast novel face-name pairs vs repeated face-name pairs are displayed on anatomical images derived from an average obtained from the normalized structural images of all subjects using an anatomical mask of the combined right and left hippocampus with a statistical threshold of p < 0.005 uncorrected (extent threshold 5 voxels). PS1 mutation carriers (n = 20) demonstrate increased intensity changes in the right hippocampus when compared to controls (n = 19). MNI coordinates for peak activated voxel: [x,y,z][27, −24, −12]. Color bar represents t values for all activated voxels within the anatomical mask. (B) Parameter estimates extracted as a sphere with a radius of 5mm and centered at the coordinate [24, −30, −15; MNI] from the right hippocampus for the novel face pairs and the repeated face-name pairs for controls and PS1 mutation carriers. For the novel condition, the mean parameter estimates were 0.19 (SD 0.33) for the controls, and 0.45 (SD 0.34) for PS1 carriers. For the repeated condition, the mean parameter estimates were −0.009 (SD 0.41) for the controls, and −0.008 (SD 0.36) for PS1 carriers. The data in A and B suggest hyperactivation in the right hippocampus as an early functional change during associative memory encoding in presymptomatic FAD. MNI 5 Montreal Neurological Institute.

FIGURE 2

Whole brain exploratory analyses. Statistical parametric maps (SPMs) for both groups, controls and PS1 mutation carriers, for the contrast novel face-name pairs vs repeated face-name pairs are displayed on anatomical images derived from an average obtained from the normalized structural images of all subjects with a statistical threshold of p < 0.005 uncorrected (extent threshold = 20 voxels). (A) Within-group analysis: both groups showed an increase in the fMRI signal response of association areas in the frontal and parietal lobes and in the hippocampal formation to novel vs repeated stimuli. (B) Between-group analysis: controls showed greater activity in frontal and parietal regions whereas carriers exhibited greater activity in the right cingulate gyrus and the right anterior hippocampus to novel vs repeated stimuli. Color bar represents t values for all activated voxels in the whole brain.