Hippocampal disconnection contributes to memory dysfunction in individuals at risk for Alzheimer's disease

Abstract

The concept of amnestic mild cognitive impairment (MCI) describes older people who show a decline predominantly in memory function, but who do not meet criteria for dementia. Because such individuals are at high risk for developing Alzheimer's disease, they are of great interest for understanding the prodromal stages of the disease process. The mechanism underlying memory dysfunction in people with MCI is not fully understood. The present study uses quantitative, high-resolution structural MRI techniques to investigate, in vivo, the anatomical substrate of memory dysfunction associated with MCI. Changes in brain structures were assessed with two imaging techniques: (i) whole-brain, voxel-based morphometry to determine regions of reduced white matter volume and (ii) sensitive volumetric segmentation of the entorhinal cortex and hippocampus, gray matter regions that are critically important for memory function. In participants with amnestic MCI, compared with age-matched controls, results showed a significant decrease in white matter volume in the region of the parahippocampal gyrus that includes the perforant path. There was also significant atrophy in both the entorhinal cortex and the hippocampus. Regression models demonstrated that both hippocampal volume and parahippocampal white matter volume were significant predictors of declarative memory performance. These results suggest that, in addition to hippocampal atrophy, disruption of parahippocampal white matter fibers contributes to memory decline in elderly individuals with MCI by partially disconnecting the hippocampus from incoming sensory information.

Fig. 1.

Color map showing significant (P = 0.001) voxels of decreased white matter density in participants with amnestic MCI compared with controls, superimposed on coronal and sagittal slices of an average template based on data for all subjects. The image is masked to include only white matter regions. The colors correspond to the t values shown on the color bar. Note the bilaterality of significant differences in the white matter of the parahippocampal gyrus.

Fig. 2.

A coronal slice illustrating the segmentation of the entorhinal cortex (outlined, right side) and the hippocampus (outlined, left side).

Fig. 3.

Mean normalized entorhinal (A) and hippocampal (B) volumes in participants with amnestic MCI and healthy age-matched controls. Volumes are shown for each hemisphere separately. Vertical bars represent the standard error of the mean. ∗, significantly different from controls (P < 0.001).