Sexual Dimorphism and Hemispheric Asymmetry of Hippocampal Volumetric Integrity in Normal Aging and Alzheimer Disease

Abstract

Background and purpose: Asymmetric atrophy of the hippocampus is an important clinical finding in normal aging and Alzheimer disease. In this study, we investigate the associations between the magnitude and asymmetry of hippocampal volumetric integrity and age, sex, and dementia severity.

Materials and methods: We have recently developed a rapid fully automatic algorithm to measure the hippocampal parenchymal fraction, an index of hippocampal volumetric integrity on structural MR imaging of the brain. We applied this algorithm to measure the hippocampal parenchymal fraction bilaterally on 775 MR imaging volumes scanned from 198 volunteers in a publicly available data base. All subjects were right-handed and older than 60 years of age. Subjects were categorized as cognitively healthy (n = 98), with mild cognitive impairment (n = 70), or with mild/moderate Alzheimer disease (n = 30). We used linear mixed-effects models to analyze the hippocampal parenchymal fraction and its asymmetry with respect to age, sex, dementia severity, and intracranial volume.

Results: After controlling for age, sex, and intracranial volume, we found that the magnitude of the hippocampal parenchymal fraction decreased and its asymmetry increased significantly with dementia severity. Also, hippocampal parenchymal fraction asymmetry was significantly higher in men after controlling for all other variables, but there was no sex effect on hippocampal parenchymal fraction magnitude. The magnitude of the hippocampal parenchymal fraction decreased and its asymmetry increased significantly with age in subjects who were cognitively healthy, but associations with age were different in nature in the mild cognitive impairment and Alzheimer disease groups.

Conclusions: Hippocampal atrophy progresses asymmetrically with age in cognitively healthy subjects. Hippocampal parenchymal fraction asymmetry is significantly higher in men than women and in mild cognitive impairment/Alzheimer disease relative to cognitively healthy individuals.

Fig 1.

Axial (left), coronal (middle), and sagittal (right) slices through a 3D structural MR imaging scan of a subject. The right hippocampus probabilistic VOI is superimposed on the image in native space.

Fig 2.

Histogram of the voxels with nonzero probabilities on the VOI in Fig 1 (thin line) along with a fitted Gaussian mixture model (thick line) using the expectation-maximization algorithm. The automatically determined CSF threshold is shown as a vertical line approximately located at the intensity value of 70. The HPF is defined as the fraction of voxels in the VOI whose intensities are greater than the CSF threshold.

Fig 3.

Predicted marginal means of the asymmetry index in different diagnostic groups. AI was found to be significantly different between the CN versus MCI (P < .001), CN versus AD (P < .001), and MCI versus AD (P = .03) groups. AI increased with increasing dementia severity. Error bars indicate 95% CI.

Fig 4.

Predicted marginal means of the asymmetry index in men and women. The AI was found to be significantly higher in men (P < .01) after controlling for age, intracranial volume, and diagnostic group. Error bars indicate 95% CI.

Fig 5.

Predicted marginal means of the HPF (averaged across hemispheres) in different diagnostic groups. The HPF was found to be significantly different between the CN versus MCI (P < .001), CN versus AD (P < .001), and MCI versus AD (P < .001) groups. The HPF decreased with increasing dementia severity. Error bars indicate 95% CI.