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Recent studies led by Pitt Psychiatry investigators examine the associations between post-traumatic stress disorder and cardiovascular and brain health in women (JAMA Network Open), and sex-dependent alterations in the memory network (Alzheimer’s & Dementia).

Posttraumatic Stress Disorder Symptoms and Cardiovascular and Brain Health in Women

Most women in the United States will experience at least one major traumatic event in their life, and 10% will develop post-traumatic stress disorder (PTSD). PTSD is associated with a 50%-60% increased risk of cardiovascular disease, stroke, and dementia–major women’s health issues, with cardiovascular disease in particular as the leading cause of death among US women. Midlife, a critical time for women’s cardiovascular and brain health, includes menopause—a time of accelerating vascular risk, decreased memory performance, and potential biological vulnerability to earlier stress exposure.

Investigators including Rebecca Thurston, PhD (Pittsburgh Foundation Chair in Women's Health and Dementia and Professor of Psychiatry, Clinical and Translational Science, Epidemiology and Psychology); Karen Jakubowski, PhD (Assistant Professor of Psychiatry); Minjie Wu, PhD (Assistant Professor of Psychiatry); and Howard Aizenstein, MD, PhD (Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Professor of Bioengineering and Clinical and Translational Science), from Pitt Psychiatry, recruited 274 women (ages 45-67 years old), who underwent vascular imaging, neuroimaging, and a comprehensive neuropsychological battery. They tested whether higher PTSD symptoms are associated with higher carotid intima media thickness, greater brain white matter hyperintensity or volume, and poorer cognition. In addition, they tested a modifying role of the APOEε4 genotype, which is associated with dementia risk, particularly in women—hypothesizing that women who were APOEε4 carriers would be at elevated cardiovascular and neurocognitive risk with PTSD symptoms.

Results from the study were recently published in JAMA Network Open. The scientists found that among midlife women, higher PTSD symptoms were associated with greater carotid atherosclerosis. Among women who were APOEε4 carriers, PTSD symptoms were associated with greater white matter hyperintensity volume and poorer cognitive performance across multiple domains. 

“These findings underscore the importance of PTSD to women’s cardiovascular and brain health at midlife. Efforts to improve women’s cardiovascular and brain health at midlife and beyond need to consider women’s mental health, and particularly any symptoms from PTSD,” said Dr. Thurston, the study’s corresponding author.

Thurston RC, Jakubowski K, Chang Y, Wu M, Mitchell EB, Aizenstein H, Koenen KC, Maki PM.
JAMA Network Open. 2023;6(11):e2341388. doi:10.1001/jamanetworkopen.2023.41388

Sex-Dependent Alterations in Hippocampal Connectivity Are Linked to Cerebrovascular and Amyloid Pathologies in Normal Aging

The changes that occur in the brain during the years leading up to cognitive impairment in Alzheimer's disease are not well understood. Individuals with Alzheimer’s disease frequently have decreased hippocampal activation during memory functional magnetic resonance imaging (fMRI) tasks. However, increased hippocampal activation and functional connectivity have been observed in subjects who are at risk for Alzheimer's disease due to genetic predisposition or high amyloid β deposition. The increased activation/functional connectivity observed early in Alzheimer's disease progression may be the recruitment of extra neural resources to maintain normal cognition despite the neurotoxic effect of amyloid β deposition seen in Alzheimer's.

Sex is an important factor when studying Alzheimer's disease, as roughly two-thirds of individuals with the disease in the United States are female, and sex differences have been observed in the trajectories of cognitive decline and disease progression. Yet few studies have examined whether these sex-dependent differences in Alzheimer's disease progression are reflected by the fMRI biomarker of hippocampal activity/connectivity.

Investigators including Rebecca Thurston, PhD (Pittsburgh Foundation Chair in Women's Health and Dementia and Professor of Psychiatry, Clinical and Translational Science, Epidemiology and Psychology); William Klunk, MD, PhD (Distinguished Professor Emeritus of Psychiatry); Dana Tudorascu, PhD (Associate Professor of Psychiatry and Biostatistics); Ann Cohen, PhD (Associate Professor of Psychiatry); Victor Villemagne, MD (Professor of Psychiatry); Howard Aizenstein, MD, PhD (Charles F. Reynolds III and Ellen G. Detlefsen Endowed Chair in Geriatric Psychiatry and Professor of Bioengineering and Clinical and Translational Science); and Minjie Wu, PhD (Assistant Professor of Psychiatry), examined the neurobiological mechanisms driving different rates of Alzheimer's disease progression. They used fMRI to investigate sex differences in a two-year change in hippocampal functional connectivity during associative memory encoding in cognitively unimpaired adults ages 65-93 years old. They additionally examined whether sex-dependent changes in hippocampal functional connectivity are associated with amyloid β burden or white matter hyperintensity volume.

In a study published in Alzheimer’s & Dementia, the scientists reported that males had increased hippocampal-prefrontal connectivity over two years, associated with greater amyloid β burden. Females had increased bilateral hippocampal functional connectivity, associated with greater white matter hyperintensity volume.
“These findings suggest sex-dependent alterations in the memory network in the presence of cerebrovascular and Alzheimer's disease pathologies and highlight the role of cerebrovascular disease in women's risk for Alzheimer's disease, potentially explaining the accelerated trajectory of cognitive decline in women,” said Dr. Wu, the study’s corresponding author.

Schweitzer N, Li J, Thurston RC, Lopresti B, Klunk WE, Snitz B, Tudorascu D, Cohen A, Kamboh MI, Halligan-Eddy E, Iordanova B, Villemagne VL, Aizenstein H, Wu M.
Alzheimer's & Dementia. 2023; 1-11. https://doi.org/10.1002/alz.13503