Interactions of Sex and Gender Factors in Risk for Alzheimers Disease: Links Between Stress, Neural Activity, Inflammation, and Memory

性别因素与阿尔茨海默病风险的相互作用：压力、神经活动、炎症和记忆之间的联系

• 批准号: 10456936
• 负责人: JESSICA KIRKLAND CALDWELL
• 金额: $ 45.07万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456936
• 关键词: Address; Affect; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Anterior; Binding Sites; Biological; Biological Process; Brain; Cessation of life; Chromosomes; Chronic stress; Clinic; Development; Diagnosis; Disease Outcome; Estradiol; Estrogens; Exposure to; Family; Female; Foundations; Functional Magnetic Resonance Imaging; Gender; Goals; Gonadal Steroid Hormones; Health; Health Care Costs; Health Sciences; Hippocampus (Brain); Impaired cognition; Individual; Inflammation; Inflammatory; Intervention; Knowledge; Link; Long-Term Effects; Measures; Mediating; Mediator of activation protein; Memory; Modeling; Movement; Neuropsychology; Organ; Outcome; Patient Recruitments; Pattern; Peripheral; Persons; Plasma; Prevention; Process; Public Health; Recording of previous events; Reporting; Reproduction; Research; Rest; Risk; Risk Factors; Risk Reduction; Scanning; Sex Factors; Shapes; Strategic Planning; Stress; Structure; Symptoms; Task Performances; Temporal Lobe; Translating; United States National Institutes of Health; Verbal Learning; Woman; Women' s Health; base; biological adaptation to stress; cost effective; cytokine; disease disparity; evidence base; experience; gender disparity; indexing; innovation; interdisciplinary approach; male; memory encoding; memory recognition; men; middle age; novel; relating to nervous system; reproductive organ; sex; sex disparity; stressor; therapy development

PROJECT SUMMARY/ABSTRACT Our proposed project focuses on understanding interactive effects of gender and sex on biological processes implicated in Alzheimer’s disease (AD) risk. Gender is defined as an individual’s presentation as female or male, and sex is defined by chromosomes and sex organs. Stress has both gender- and sex-linked components. However, whether exposure to gender-linked stressors relates to neural and peripheral processes that promote AD pathology, or whether sex hormones mediate these relationships, is unknown. In this proposal, we seek to understand interactive effects of gender-linked stressor exposure and estrogen levels on memory, memory- related neural activation, functional connectivity (FC) at rest, and peripheral inflammation. In doing so, the proposal enables further study of AD mechanisms and development of interventions to reduce AD risk. The objective of this proposal is to determine interactive effects of lifetime gender-linked stressor exposure and estrogen levels on memory-related brain activation, resting state FC, peripheral inflammation, and verbal memory in midlife women at risk for AD due to family history. The rationale for this project is that gender and sex, indexed by stress exposures and estrogen, interactively promote changes in neural activation, FC, and peripheral inflammation, which may facilitate AD pathology in women at risk for AD. Specific Aim 1 will investigate interactive effects of gender-linked stressor exposure and estrogen levels on fMRI activation during memory encoding, fMRI task performance, and default mode network (DMN) FC at rest. Specific Aim 2 will investigate effects of gender-linked stressor exposure and estrogen interactivity on peripheral inflammation and verbal memory. Specific Aim 3 will investigate the effects of peripheral inflammation on fMRI activation and FC at rest. To achieve these aims, we will recruit participants from our Women’s Alzheimer’s Movement Prevention Center at Cleveland Clinic, which serves women at risk for AD due to family history. Specific Aims 1-2 will include lifetime gender-linked stressor exposure as a predictor, and as outcomes, a pattern separation fMRI task, a resting state scan, plasma levels of pro-inflammatory cytokines, and neuropsychological measures of verbal memory. Specific Aim 3 will use plasma levels of pro-inflammatory cytokines as predictors of task-based activation and resting state FC. All analyses will include estradiol levels as a mediator. This study is expected to provide evidence relating greater lifetime gender-linked stressor exposures to poorer verbal memory in women at risk for AD, as well as to processes likely to contribute to sex and gender disparities in AD, such as hippocampal hyperactivation and reduced DMN deactivation during memory encoding, greater posterior to anterior DMN FC at rest, and higher peripheral inflammation. The proposed research is innovative in its focus on variables impacted by sex and gender that may catalyze AD pathology in women at risk for AD, and is significant in providing strong scientific justification for further study of inflammation and neural activity and FC as AD mechanisms. Results of our study will inform development of interventions targeting stress and inflammation to reduce AD risk.

项目摘要/摘要 我们提议的项目着重于理解性别和性别对生物过程的互动效果 在阿尔茨海默氏病（AD）风险中实施。性别被定义为个人的表现为女性或男性， 性别由染色体和性器官定义。压力既具有性别和性别相关的组成部分。 但是，暴露于性别关联压力源是否与促进的神经和外围过程有关 AD病理学，或性激素是否介导这些关系，尚不清楚。在此提案中，我们寻求 了解性别关联应激源暴露和雌激素水平对记忆的交互作用，记忆 - 相关的神经激活，静止的功能连通性（FC）和周围炎症。这样， 提案可以进一步研究AD机制和开发干预措施以降低AD风险。这 该提议的目的是确定终生性别链接压力源暴露和 与记忆有关的大脑激活，静止状态FC，外周感染和言语上的雌激素水平 由于家族史，中年妇女的记忆有危险的广告风险。该项目的理由是性别和 性别，由压力暴露和雌激素索引，互动地促进神经激活，FC和 周围炎症，这可能有助于有AD风险的女性AD病理。具体目标1将调查 性别关联应激源暴露和雌激素水平对记忆中fMRI激活的互动效果 静止时，编码，fMRI任务性能和默认模式网络（DMN）FC。具体目标2将调查 性别关联应激暴露和雌激素相互作用对周围感染和言语的影响 记忆。特定的目标3将研究外周感染对静电上fMI激活和FC的影响。 为了实现这些目标，我们将招募女性阿尔茨海默氏运动预防中心的参与者 在克利夫兰诊所，由于家族史，该诊所为处于广告风险的妇女提供服务。具体目标1-2将包括终生 性别链接压力源作为预测因子，作为结果，一种模式分离fMRI任务，静止状态 扫描，促炎细胞因子的血浆水平以及言语记忆的神经心理学测量。具体的 AIM 3将使用促炎细胞因子的血浆水平作为基于任务的激活和静止的预测指标 国家足球俱乐部所有分析都将包括雌二醇水平作为调解人。这项研究有望提供证据 将更大的终身性别联系压力源暴露与AD风险的女性较差的言语记忆有关 以及可能有助于AD中的性别和性别分布的过程，例如海马过度激活 并降低了记忆编码过程中DMN停用，在静止时较大的DMN FC的后部，并且 较高的周围炎症。拟议的研究具有创新性，重点是受性影响的变量 性别可能催化AD风险的女性AD病理，并且在提供强大方面具有重要意义 科学理由，以进一步研究感染和神经活动以及FC作为AD机制。结果 我们的研究将为靶向压力和感染以降低AD风险的干预措施的发展提供信息。