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

即使在考虑了长寿因素后，女性患阿尔茨海默氏症和相关痴呆的风险也更高 (AD/ADRD)，疾病进展和潜在的分子机制因性别而异。新陈代谢 生殖暴露是性别差异的一个潜在的生物驱动因素。怀孕有很强的影响 关于新陈代谢：高胎率与晚年糖尿病风险有关，可能是由于 葡萄糖动态平衡和活动，而母乳喂养是对代谢风险的保护。因为胰岛素 抵抗力和2型糖尿病是AD的危险因素，这些与生殖有关的因素似乎是合理的 代谢暴露会增加女性患AD的风险。然而，目前尚不清楚这些暴露是否 是认知衰退和阿尔茨海默病风险的重要预测或修饰者，以及这种认知变化 是由包括大脑淀粉样蛋白在内的AD相关神经生物学底物驱动的。博加卢萨心脏研究是一项 在一个混血儿(65%白人，35%黑人)队列中，从童年开始的心血管健康研究。子研究 包括Bogalusa Baby，它采访了1803名妇女的生育史，以及正在进行的 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，我们建立在这个方案的基础上，提供了950名认知障碍女性的组合样本。 其中450人接受核磁共振检查，275人接受正电子发射计算机断层扫描。总体目标是评估两国之间的关系 生育史，终生代谢暴露，以及中年认知和大脑功能，由 与广告相关的仪器和标记。总体假设是与怀孕相关的代谢暴露 即使在对孕前代谢暴露(葡萄糖)进行控制后，仍与晚年的大脑健康有关 和胰岛素抵抗)，这些影响将部分地通过后代谢暴露来调节。 怀孕了。这一假设将通过以下具体目的进行检验：1)检查生育史 作为中年认知和认知衰退的预测者；2)检查生育史作为大脑的预测者 结构和功能结果；以及3)检查生育史作为AD的预测因素-以及新陈代谢- 认知的相关分子底物。初步数据显示，认知能力较差与无胎相关， 没有母乳喂养史，早期血糖水平较差，特别是在女性中。因此， 假设无胎、较短/无哺乳史、较高的出生体重和较高的妊娠体重。 收益将与标准化神经认知电池的较差分数和较高的认知能力相关 下降；3T脑MRI灰质体积减少，白质高信号体积增大； 功能磁共振成像对Stroop任务的激活；脑淀粉样蛋白对18F-florbetapir PET和大脑的更高负荷 ~(18)F-脱氧葡萄糖PET中葡萄糖高代谢的研究这项研究的独特之处在于提供关键的 新的信息，可以帮助确定治疗和干预可能阻断代谢或 对大脑的内分泌功能障碍，并增加动力，以改善成年早期的健康，以预防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.