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

脑小血管病（cSVD）易导致血管性认知障碍和痴呆，包括 老年痴呆症先兆子痫（PE）是一种妊娠特异性疾病，伴有急性高血压和胎盘 SVD正在成为老年痴呆症的性别特异性风险因素。PE是如何牵连到的病因 痴呆症是未知的。患有PE的女性在其他血管床也有SVD，包括大脑， 怀孕和随着年龄的增长而恶化，表明这一过程随着时间的推移而演变。然而，关于SVD的研究 在中年是稀疏的。中年是评估这种风险的理想时间，因为认知上的PE差异已经 可检测到，但仍有时间缓解进展为痴呆症。中年脑SVD（cSVD）可能 了解PE如何与认知障碍有关的关键。 胎盘SVD，称为母体血管灌注不良（MVM），预测短期妊娠更糟 结果。我们发现MVM和PE联合预测长期较差的母体心脏血管健康， 舌下和脑床。在我们的初步研究（n=24）中，MVM和PE联合预测较低 脑血管反应性（CVR，cSVD的早期阶段），特别是在额顶叶区域;反过来，降低CVR 在这些区域中，与PE相关的认知能力下降有关，并似乎可以解释这种现象。 重要的是这些 结果与高血压无关，表明PE具有直接和持久的血管效应 . PE和 MVM可能是未来脑血管表型的早期指标，在中年表现为较低的CVR， 可以解释体育如何影响认知。我们建议研究有和没有既往PE的中年女性：1） 表征PE相关认知能力较差的神经基础，2）评估胎盘SVD是否 (MVM)预测cSVD和认知，以及3）探索是否舌下SVD和SVD的循环标志物 是cSVD和认知的标志物。 我们提出了一项神经认知研究，以捕获cSVD的早期阶段和种族多样性的认知状态。 队列 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岁，术后15年， 妊娠，30%黑人，妊娠后10年PE、MVM和舌下SVD的现有数据。我们将 使用我们先进的多模式神经成像方案来量化cSVD（包括CVR，血流， 连接性）、测量认知的标准化验证方案以及SVD的非侵入性标志物 （舌下SVD，以及 循环生物标志物谱） .我们的项目定位独特， 在分娩时可通过胎盘病理学确定的隐性高危人群，以及可能从风险中获益的人群- 对痴呆进行分层，以减轻或延迟疾病进展。

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.