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 ϭ 98), with mild cognitive impairment (n ϭ 70), or with mild/moderate Alzheimer disease (n ϭ 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. ABBREVIATIONS: AD ϭ Alzheimer disease; AI ϭ asymmetry index; ART ϭ Automatic Registration Toolbox; CN ϭ cognitively normal; DX ϭ diagnostic group factor; ICV ϭ intracranial volume; HPF ϭ hippocampal parenchymal fraction; LHPF ϭ left HPF; MCI ϭ mild cognitive impairment; RHPF ϭ right HPF A lzheimer disease (AD) is the most common form of demen-

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