Reproductive history and later-life brain health: The Bogalusa Heart Study

即使考虑到长寿因素，女性患阿尔茨海默病和相关痴呆症的风险也更高 (AD/ADRD），疾病进展和潜在的分子机制因性别而异。代谢 生殖暴露是性别差异的一个潜在生物驱动因素。怀孕有强烈的影响 高产次与晚年糖尿病风险相关，可能是由于代谢的持续改变， 母乳喂养有助于维持体内葡萄糖的平衡和活性，而母乳喂养则可预防代谢风险。因为胰岛素 抵抗和2型糖尿病是AD的危险因素，这些生殖相关的 代谢暴露有助于女性患AD的风险。然而，目前尚不清楚这些暴露是否 是认知能力下降和AD风险的重要预测因子或修饰因子， 是由AD相关的神经生物学底物包括大脑淀粉样蛋白驱动的。博加卢萨心脏研究是一项 在一个出生婴儿（65%白色，35%黑人）队列中开始的心血管健康研究。子研究 包括《博加卢萨婴儿》，它采访了1803名妇女关于她们生育史， 儿童和成年早期血糖控制与中年认知、脑结构和脑的研究 功能在这个项目中，我们建立在这个协议，提供了一个合并样本的950名妇女与认知 450例采用MRI，275例采用PET扫描。总体目标是评估以下方面的关系： 生殖史、终生代谢暴露以及中年认知和脑功能， AD相关工具和标记。总的假设是，妊娠相关的代谢暴露 即使在控制了孕前代谢暴露（葡萄糖）之后， 和胰岛素抵抗），并且这些效应将部分由后代谢暴露介导。 怀孕该假设将通过以下具体目标进行检验：1）检查生殖史 作为中年认知和认知下降的预测因素; 2）检查生殖史作为大脑的预测因素 结构和功能结果;和3）检查生殖史作为AD和代谢的预测因子- 与认知相关的分子基质。初步数据显示，未经产的婴儿认知能力较差， 缺乏母乳喂养史，早期血糖水平更差，尤其是女性。因此 假设是未产、哺乳期较短/无哺乳史、出生体重较高和妊娠期体重较高 增益将与标准化神经认知成套测验的更差分数和更高的认知能力相关。 下降; 3T脑MRI上灰质体积较低，白色高信号体积较大， Stroop任务的fMRI激活;以及18F-florbetapir PET和脑内淀粉样蛋白的较高负荷 18F-氟脱氧葡萄糖PET显示葡萄糖高代谢。这项研究是独特的，提供关键的 新的信息，可以帮助确定治疗和干预，可能阻止代谢或 内分泌失调对大脑的影响，并增加动力，以改善健康在成年早期，以防止AD。

Even after accounting for longevity, women are at higher risk for Alzheimer's Disease and Related Dementias (AD/ADRD), and disease progression and underlying molecular mechanisms differ by sex. The metabolic exposures of reproduction are one potential biological driver of sex differences. Pregnancy has strong effects on metabolism: high parity is associated with later-life diabetes risk, due possibly to persistent alterations in glucose homeostasis and activity, while breastfeeding is protective against metabolic risk. Because insulin resistance and type 2 diabetes mellitus are risk factors for AD, it is plausible that these reproduction-related metabolic exposures contribute to AD risk among women. However, it is unknown whether these exposures are important predicters or modifiers of risk of cognitive decline and AD and whether such cognitive changes are driven by AD-related neurobiological substrates including cerebral amyloid. The Bogalusa Heart Study is a study of cardiovascular health starting in childhood in a biracial (65% white, 35% black) cohort. Substudies include Bogalusa Babies, which interviewed 1803 women about their reproductive histories, and an ongoing study of childhood and early adulthood glycemic control and midlife cognition, brain structure, and brain function. In this project, we build on this protocol, providing a combined sample of 950 women with cognitive measures, 450 with MRI and 275 with PET scans. The overall objective is to assess the relationship among reproductive history, lifetime metabolic exposures, and midlife cognition and brain function, as measured by AD-relevant instruments and markers. The overall hypothesis is that pregnancy-related metabolic exposures will be associated with later-life brain health even after control for pre-pregnancy metabolic exposures (glucose and insulin resistance), and that these effects will be partially mediated by metabolic exposures post- pregnancy. The hypothesis will be tested through the following specific aims: 1) Examine reproductive history as a predictor of midlife cognition and cognitive decline; 2) Examine reproductive history as a predictor of brain structural and functional outcomes; and 3) Examine reproductive history as a predictor of AD- and metabolism- related molecular substrates of cognition. Preliminary data showed worse cognition associated with nulliparity, lack of history of breastfeeding, and worse early-life glucose levels, especially among women. Therefore, the hypotheses are that nulliparity, shorter/no history of lactation, higher birthweight, and higher gestational weight gain will be associated with worse scores on a standardized neurocognitive battery and greater cognitive decline; lower gray matter volume and greater white matter hyperintensity volume on 3T brain MRI, and lower fMRI activation to a Stroop task; and higher burden of cerebral amyloid on 18F-florbetapir PET and cerebral glucose hypermetabolism on 18F-fluorodeoxyglucose PET. This study is uniquely situated to provide critical new information that could help identify treatments and interventions that may block the effects of metabolic or endocrine dysfunction on the brain, and add impetus to improving health in early adulthood to prevent AD.