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

先兆子痫和大脑：中年早期的小血管疾病和认知功能

• 批准号: 10370575
• 负责人: Janet M Catov
• 金额: $ 95.35万
• 依托单位: MAGEE-WOMEN'S RES INST AND FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370575
• 关键词: Acute; Affect; Age; Alzheimer' s Disease; Apolipoprotein E; Area; Beds; Benefits and Risks; Bioinformatics; Biological Markers; Blood; Blood Vessels; Blood flow; Brain; Cardiac; Cardiovascular system; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrum; Chronic; Clinical Trials; Cognition; Cognitive; Data; Dementia; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Disease Progression; Early Intervention; Endoglin; Enrollment; Epidemiology; Etiology; Exposure to; Future; Genotype; Health; Hypertension; Hypoxia; Impaired cognition; Inflammation; Life; Life Style; Machine Learning; Measures; Microvascular Dysfunction; Monitor; Neurocognitive; Neurologic; Outcome; Parietal; Pathology; Patient Self-Report; Phenotype; Pilot Projects; Placenta; Positioning Attribute; Pre-Eclampsia; Pregnancy; Pregnancy Outcome; Prevention; Probability; Process; Protocols documentation; Race; Recording of previous events; Reperfusion Injury; Rest; Risk; Risk Factors; Risk Management; Spiral Artery of the Endometrium; Standardization; Techniques; Testing; Time; White Matter Hyperintensity; Woman; angiogenesis; base; blood-based biomarker; cardiometabolism; cardiovascular risk factor; cerebrovascular; circulating biomarkers; cognitive function; cognitive performance; cohort; dementia risk; executive function; gray matter; high risk population; information processing; middle age; multidisciplinary; multimodal neuroimaging; neuroimaging; older women; primary outcome; processing speed; racial diversity; relating to nervous system; risk stratification; sex; statistics; vascular bed; vascular cognitive impairment and dementia; young woman

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.

脑小血管疾病（cSVD）容易导致血管性认知障碍和痴呆，包括 阿尔茨海默病。先兆子痫（PE），一种妊娠特异性疾病，伴有急性高血压和胎盘 SVD 正在成为晚年痴呆症的一种性别特异性风险因素。 PE如何与病因学相关 痴呆症尚不清楚。患有 PE 的女性在其他血管床（包括大脑）中也会出现 SVD。 怀孕并随着年龄的增长而恶化，这表明这个过程随着时间的推移而演变。然而，SVD 的研究 人到中年就稀疏了。中年是评估这种风险的理想时机，因为认知方面的 PE 差异已经显现出来。 可以检测到，但仍有时间减缓痴呆症的进展。中年时的脑 SVD (cSVD) 可能会持续 了解 PE 如何与认知障碍相关的关键。 胎盘 SVD，即母体血管灌注不良 (MVM)，可预测短期妊娠情况更糟 结果。我们发现 MVM 和 PE 相结合可预测长期较差的母体血管健康状况：心脏、 舌下床和脑床。在我们的试点研究 (n=24) 中，MVM 和 PE 结合预测较低 脑血管反应性（CVR，cSVD 的早期阶段），尤其是额顶叶区域；反过来，CVR 也会降低 这些区域与体育相关的较差认知能力相关，并且似乎可以解释这一现象。 重要的是，这些 研究结果与高血压无关，表明 PE 对血管有直接和持久的影响 。聚乙烯和 MVM 可能是未来脑血管表型的早期指标，在中年时表现为较低的 CVR，并且 可以解释体育运动如何影响认知。我们建议对患有或未患有体育锻炼的中年女性进行研究，以：1) 描述 PE 相关认知能力较差的神经基础，2) 评估是否存在胎盘 SVD (MVM) 预测 SVD 和认知，以及 3) 探索舌下 SVD 和 SVD 的循环标志物是否存在 是 CSVD 和认知的标志。 我们提出了一项神经认知研究，以捕捉不同种族人群中 cSVD 的早期阶段和认知状态 队列的 450 来自我们正在进行的 WINDOWS 研究的女性（1:1 PE 和非 PE），平均年龄 = 45，15 年后 妊娠，30% 黑人，现有妊娠 10 年后 PE、MVM 和舌下 SVD 数据。我们将 使用我们先进的多模式神经影像方案来量化 cSVD（包括 CVR、血流量、 连接性）、用于测量认知的标准化验证协议以及 SVD 的非侵入性标记 （舌下 SVD，以及 循环生物标志物概况） 。我们的项目具有独特的定位，可以识别以前的 可以通过胎盘病理学在分娩时识别出的隐匿高危人群，并且可以从风险中受益 对痴呆症进行分层，以减轻或延缓疾病进展。