ArticlesSex differences in prefrontal volume with aging and Alzheimer’s disease☆
Introduction
Understanding sex differences in neurodegeneration with Alzheimer’s disease (AD) is important because sex differences have been reported in epidemiological and cognitive studies of AD. Increasing age is a risk factor for AD, and the higher life expectancy of women leads to a larger population of women with AD than men with AD [13]. There are additional gender related differences beyond life expectancy as women have a higher prevalence of AD when age is removed as a factor [13]. Thus, both sex and age are risk factors that contribute to the development of AD. Additionally, sex differences in the performance of cognitive [2] and behavioral [18] measures exist in AD. Examination of patterns of neural degeneration between men and women with AD could be useful in understanding the etiology of these differences.
Volumetric sex differences have been reported for a variety of neural regions across the lifespan [3], [4], [10], [23], [25]. Sex differences in frontal lobe volume are particularly interesting because the frontal lobe may be highly sensitive to degeneration with healthy aging [4], [21]. This structure shows sex differences in morphology both early [20], [25] and later [4] in life. Men and women show differential age-related decline of frontal lobe volume, with men showing a greater decline than women [17]. Sex differences in frontal lobe measures have also been reported with the disease-related degeneration in AD [14]. Differences in frontal lobe volume could be related to differential patterns of degenerative changes in the brains of men and women. Few studies have directly examined whether volumetric sex differences in the frontal lobe are altered with neurodegeneration in AD.
Healthy aging or progression to dementia may selectively affect one tissue type or another and the atrophy of particular tissue types may differ across the lifespan. For example, there is a preferential loss of prefrontal gray matter in subjects 18 to 78 years of age [21], whereas there is a selective decline in white matter of the prefrontal cortex in the oldest old (≥85 years of age) [24]. Additionally, changes in tissue volume could be specific to one sex. For example, there is a decline in gray matter volume and not white matter volume in women aged 16 to 65 but not men [1]. It is not known if alteration of a particular tissue differs between men and women with AD.
Although many studies show that the prefrontal cortex degenerates with both healthy aging and AD [5], [6], [15], [19], [20], [22] it is unknown how sex contributes to AD degeneration. We used quantitative volumetric MRI to directly compare the sex differences in total prefrontal and prefrontal white and gray matter volumes in healthy older subjects to those with AD in order to understand how degenerative changes may differ in men and women.
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Subjects
Healthy aged men (HM; n = 17) and women (HW; n = 17) and men (AM; n = 16) and women (AW; n = 14) with Alzheimer’s disease were examined for the present study. Scans for HM and HW were collected as part of the Oregon Brain Aging Study (OBAS), a longitudinal study of brain aging and cognition at Oregon Health Sciences University (OHSU) and the Veterans Affairs Medical Center in Portland, Oregon. Scans for AM and AW were collected as part of the Oregon Alzheimer’s Disease Center (OADC) clinical
Subject characteristics
Clinical and demographic characteristics of the subjects are described in Table 1. There were no differences by group or sex in age, education, or socioeconomic status. Healthy men and women did not differ in general knowledge as assessed by the WAIS-R vocabulary score. There was a significant difference in MMSE scores between the healthy and AD subjects (F(1,59) = 70.1, p = <0.01). Alzheimer’s patients had lower MMSE scores than healthy elderly, but disease severity as indicated by the MMSE
Discussion
The present study found that there is a sex difference in prefrontal tissue volume with aged men having greater volume than aged women. The individual group analyses suggest this sex difference is lost in AD. Sex differences in prefrontal volume were not specific to gray or white matter. Additionally, healthy men and women were matched for general knowledge as assessed by WAIS-R vocabulary, and men and women with AD were matched for disease severity as assessed by the MMSE; and thus sex
Acknowledgements
The authors thank Milar Moore, Tamara Karnos, and Dave Kerr for technical assistance with this study.
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This work was supported by NIH AG12611 and a National Alzheimer’s Disease Association Grant to JSJ; NIH AG0817 and a VA Merit Grant to JAK; and NIMH MH11855 to DHS.