Impact of Depression on Alzheimer's disease: Prenatal Immune Origins and Shared Impact of Sex

抑郁症对阿尔茨海默病的影响：产前免疫起源和性别的共同影响

• 批准号: 10408710
• 负责人: JILL M GOLDSTEIN
• 金额: $ 152.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10408710
• 关键词: 3-Dimensional; Adult; Adult Children; Age; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid deposition; Anisotropy; Biological Markers; Blood Vessels; Brain; Brain imaging; Choroid; Coupled; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Exhibits; Exposure to; Fascicle; Fetal Growth Retardation; Frequencies; Functional Magnetic Resonance Imaging; Functional disorder; Ganglion Cell Layer; Gene Expression; Genetic; Hippocampus (Brain); Human; Hyperactivity; Immune; Immune system; Immunologic Markers; Individual; Inferior; Inflammatory; Innate Immune System; Interleukin-1; Interleukin-10; Interleukin-6; Intervention; Link; Longevity; Major Depressive Disorder; Maps; Measures; Mediating; Mediation; Memory; Memory Loss; Mental Depression; Molecular; Moods; Multimodal Imaging; Onset of illness; Outcome; Parietal; Parietal Lobe; Pathology; Pathway interactions; Peripheral Blood Mononuclear Cell; Persons; Physiology; Population; Positron-Emission Tomography; Pre-Eclampsia; Pregnancy; Public Health; Recurrence; Rest; Risk; Sex Differences; Short-Term Memory; Siblings; Stress; Structure; TNF gene; Testing; Thick; Thinness; Third Pregnancy Trimester; Time; Verbal Learning; Water; White Matter Hyperintensity; Woman; adverse outcome; base; cerebrovascular; clinical diagnosis; cohort; density; extracellular; fetal; fetal programming; follow-up; health economics; high risk; human old age (65+); immune activation; immune system function; in utero; innovation; macula; memory encoding; men; middle age; neuroinflammation; neurovascular; novel; offspring; pre-clinical; predictive marker; prenatal; prenatal exposure; prenatal stress; prospective; retina blood vessel structure; retinal imaging; retinal nerve fiber layer; risk sharing; sex; therapeutic target; transcriptomics; white matter; β-amyloid burden

“Impact of Depression on Alzheimer's disease: Prenatal Immune Origins and Shared Impact of Sex” Project Summary With the substantial increase in aging of the population, early prevention of Alzheimer’s disease (AD) is one of the most important public health and economic challenges of our time. AD is associated with major depressive disorder (MDD), and both have twice the frequency in women than men. However, the shared pathophysiology that underlies MDD and AD is not well known. We will test the hypothesis that this shared risk has fetal origins that involve abnormalities in immune-stress and vascular pathways with sex-dependent consequences. We are uniquely poised to examine this for the first time in humans using our 60-year prospective prenatal cohort of adults, followed since 2nd/3rd trimesters of gestation and tested recently at ages 44-57 in MH090291. In that study, we investigated the fetal programming of sex differences in memory circuitry aging, following 212 discordant siblings (one exposed to preeclampsia (PE) or fetal growth restriction (FGR) and one unexposed) wherein we showed PE/FGR associated with maternal prenatal immune activation abnormalities in TNF-, IL- 10, and IL-6. We propose to follow these siblings further to investigate later midlife memory decline over 8 years, neurovascular dysfunction, and preclinical AD pathology assessed as amyloid deposition. We will use the same multimodal imaging as in MH090291 (structural, functional, and diffusion brain imaging-- sMRI/fMRI/dMRI) and same measures of verbal learning/memory, coupled with new measures of neurovascular function based on retinal imaging, novel transcriptomic analyses in the adult offspring’s peripheral blood mononuclear cells measuring innate immune gene expression, and amyloid deposition based on PiB PET imaging. We postulate that prenatal maternal biomarkers, indicating in utero immune disruptions at mid-gestation, coupled with innate immune gene expression, will be related to sex-dependent adult outcomes in later midlife. Further, we will test whether associations between prenatal inflammatory biomarkers and sex- dependent AD risk and neurovascular dysregulation are mediated by sex-dependent risk for MDD. Our lifespan perspective is an innovative approach that will identify potential therapeutic targets for AD associated with MDD and vascular function that are sex-dependent and can be applied to early periods for intervention prior to disease onset.

“抑郁对阿尔茨海默病的影响：产前免疫来源和性别的共同影响” 项目摘要 随着人口老龄化的大幅增加，早期预防阿尔茨海默病(AD)是其中之一 我们这个时代最重要的公共卫生和经济挑战。AD与重度抑郁有关 精神障碍(MDD)，两者在女性中的频率都是男性的两倍。然而，共同的病理生理学 MDD和AD背后的原因并不为人所知。我们将检验这一共同风险源于胎儿的假设 这涉及免疫应激和血管通路的异常，并导致性别依赖的后果。我们是 独一无二地准备在人类中首次检查这一点，使用我们60年的前瞻性产前队列 成人，从怀孕第二/第三个三个月开始跟踪，最近在MH090291上进行了年龄44-57岁的测试。在那 研究中，我们调查了胎儿编程的性别差异在记忆回路老化中的作用，跟踪212 不和谐的兄弟姐妹(一个暴露于先兆子痫(PE)或胎儿生长受限(FGR)，另一个未暴露) 其中，我们发现PE/FGR与母体产前免疫激活异常有关，其中肿瘤坏死因子-、白介素2- 10、IL-6。我们建议进一步跟踪这些兄弟姐妹，以调查超过8岁的中年后期记忆力下降。 多年来，神经血管功能障碍和临床前AD病理被评估为淀粉样沉积。我们将使用 与MH090291相同的多模式成像(结构、功能和扩散脑成像-- SMRI/fMRI/dMRI)和相同的语言学习/记忆测量，再加上新的测量 基于视网膜成像的神经血管功能，成年后代的新转录分析 外周血单核细胞检测先天免疫基因表达和淀粉样蛋白沉积 在PIB PET成像上。我们推测，产前孕妇的生物标志物，表明在子宫免疫紊乱 妊娠中期，加上先天免疫基因的表达，将与性别依赖的成人结局有关。 在中年后期。此外，我们将测试产前炎症生物标记物与性别- 依赖AD的风险和神经血管失调是由MDD的性别依赖风险介导的。我们的寿命 透视是一种创新的方法，将确定与以下相关的AD的潜在治疗靶点 MDD和血管功能是性别相关的，可以应用于早期干预 疾病发作。