Preeclampsia and the Brain: Small vessel disease and cognitive function in early midlife

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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 understand 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.