R01AG072646

Preeclampsia and the Brain: Small Vessel Disease and Cognitive Function in Early Midlife

Cerebral small vessel disease (CSVD) predisposes to vascular cognitive impairment and dementia, including Alzheimer's disease. Preeclampsia (PE), a pregnancy-specific disorder with acute hypertension and placental SVD, is emerging as a sex-specific risk factor for dementia later in life. How PE is implicated in the etiology of dementia is not known. Women with PE have SVD also in other vascular beds, including the brain, after pregnancy and worsening with older age, suggesting this process evolves over time. However, studies on SVD in midlife are sparse.

Midlife is an ideal time to assess this risk as PE differences in cognition are already detectable, and yet there is time to mitigate progression to dementia. Cerebral SVD (CSVD) in midlife may hold the key to understanding how PE is implicated in cognitive impairment. Placental SVD, known as maternal vascular malperfusion (MVM), predicts worse short-term pregnancy outcomes. We find MVM and PE combined predict long-term worse maternal vascular health in cardiac, sublingual, and cerebral beds.

In our pilot study (N=24), MVM and PE combined predicted lower cerebrovascular reactivity (CVR, an early stage of CSVD), especially in fronto-parietal areas; in turn, lower CVR in these regions was associated with, and appeared to explain, PE-related worse cognition. Importantly, these findings were independent of hypertension, suggesting PE has direct and lasting vascular effects. PE and MVM may be early indicators of a future cerebrovascular phenotype, manifesting in midlife as lower CVR, and may explain how PE affects cognition.

We propose to study midlife women with and without prior PE to:

1) Characterize the neural basis of PE-related poorer cognitive performance,
2) Assess whether placental SVD (MVM) predicts CSVD and cognition, and
3) Explore whether sublingual SVD and circulating markers of SVD are markers of CSVD and cognition.

We propose a neurocognitive study to capture early stages of CSVD and cognitive status in a racially diverse cohort of 450 women (1:1 PE and non-PE) from our ongoing WINDOWS study, mean age=45, 15 years post-pregnancy, 30% black, with existing data on PE, MVM, and sublingual SVD 10 years after pregnancy. We will use our advanced multimodal neuroimaging protocols to quantify CSVD (including CVR, blood flow, connectivity), standardized validated protocols to measure cognition, and non-invasive markers of SVD (sublingual SVD and circulating biomarker profiles).

Our project is uniquely positioned to identify a previously occult high-risk group that can be identified at delivery by placental pathology, and who may benefit from risk-stratification for dementia, to mitigate or delay disease progression.

Magee-Womens Research Institute And Foundation

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Pennsylvania United States

State-Wide

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 315% from $953,540 to $3,960,160.