Sex Differences in the Clinical Expression of Alzheimer's Disease Neuropathology and Their Underlying Biological Mechanisms

阿尔茨海默病神经病理学临床表现的性别差异及其潜在的生物学机制

• 批准号: 10301542
• 负责人: Erin elizabeth Sundermann
• 金额: $ 58.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10301542
• 关键词: Accounting; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease diagnostic; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Attenuated; Autopsy; Autoradiography; Biochemistry; Biological; Biological Markers; Brain; Buffers; Cessation of life; Clinical; Clinical Markers; Cognition; Cognitive; Data; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Early Intervention; Equilibrium; Female; Frequencies; Gender; Generations; Glutamates; Health Benefit; Hippocampus (Brain); Impaired cognition; In Vitro; Learning; Life; Measures; Mediator of activation protein; Memory; Modeling; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurofibrillary Tangles; Neuroimmune; Neurons; Pathology; Positron-Emission Tomography; Proteins; Proxy; Public Health; Research; Resistance; Risk; Risk Assessment; Risk Factors; Sensitivity and Specificity; Sex Differences; Symptoms; Testing; Time; Variant; Woman; Work; abeta accumulation; advanced disease; biological sex; brain metabolism; brain size; brain tissue; clinical biomarkers; clinical diagnostics; clinical translation; clinically significant; cognitive function; cognitive performance; cognitive testing; density; detection method; diagnostic accuracy; disease diagnosis; gender difference; glucose metabolism; improved; in vivo; innovation; men; mild cognitive impairment; neuroimaging; neuroinflammation; neuron loss; neuropathology; neurotransmission; pre-clinical; prodromal Alzheimer' s disease; prospective; receptor density; receptor function; resilience; response; sex; sex disparity; social culture; tau Proteins; therapeutic target

PROJECT SUMMARY/ABSTRACT Sex differences in the risk of Alzheimer’s disease (AD) and AD pathology burden have been extensively studied; however, little is known about how AD pathology burden relates to clinical symptoms in women versus men. Evidence of a cognitive advantage in the preclinical stage of AD, yet a two-times steeper cognitive decline thereafter indicate that the question of sex differences in the clinical manifestation of AD pathology is an important one. These sex differences have clinical implications in that our established thresholds for AD clinical and biological markers used to diagnose and track disease were typically generated without consideration for sex disparities. If women are better able to maintain what our current cognitive thresholds consider “normal” cognition until a more advanced pathology state than men, then diagnosis of MCI could be delayed, thus limiting the opportunity for early intervention. We hypothesize that sex differences in the clinical translation of AD pathology results from a sex-specific balance of brain-related resilience/risk factors that change with disease stage. Our proposal is particularly innovative in that we will first characterize sex differences in how AD pathology relates to clinical symptoms by disease stage and then examine its neurobiological underpinnings and clinical implications. We will leverage both in-vivo, longitudinal biomarker data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and prospective neuropathological data in brain tissue from multiple Alzheimer’s Disease Research Centers (ADRCs). Given their strong ties to AD pathology and the sex differences that our earlier data show, we will examine the brain resilience/risk mechanisms of (1) PET-measured brain glucose metabolism, (2) NMDAR density, a marker of glutamate neurotransmission, and (3) translocator protein 18kDA (TSPO) levels, a marker of microglial activation. Specifically, Aim 1 will utilize ADNI data to examine sex differences in trajectories of cognitive function and their relationship to longitudinal variation in AD pathology (Aβ and Tau) and brain metabolism by AD stage. In Aim 2, we will conduct in vitro autoradiography in hippocampal and cortical brain tissue of 60 normal control, 60 mild cognitive impairment and 60 AD dementia autopsy cases to determine sex differences in plaque, tangle, NMDAR and TSPO density and how they relate to each other and to antemortem cognitive function in each of the three diagnostic groups. In Aim 3, we will take action on these sex differences by generating sex-specific cut-scores for cognitive tests commonly used in MCI/AD diagnostic criteria with the optimal balance of sensitivity/specificity in detecting the presence of clinically-significant levels of AD biomarkers/pathology. The public health benefits of our project would be significant in that by understanding and accounting for sex disparities in our clinical and biomarker approaches to AD diagnosis, we will improve clinical and biomarker approaches to disease diagnosis and tracking in both sexes and possibly identify sex-specific therapeutic targets.

项目摘要/摘要 阿尔茨海默氏病（AD）和AD病理学风险的性别差异一直存在 广泛研究；但是，关于AD病理燃烧与临床症状如何相关的知之甚少 女人与男人。在AD的临床前阶段具有认知优势的证据，但两倍的Steeler 此后的认知下降表明AD临床表现的性别差异问题 病理是重要的。这些性别差异具有临床意义，因为我们已建立 通常产生用于诊断和轨道疾病的AD临床和生物标记的阈值 不考虑性别分布。如果女性能够更好地维护我们目前的认知 阈值考虑“正常”的认知直到比男性更先进的病理状态，然后诊断为MCI 我们假设性别差异 AD病理学的临床翻译是由于大脑相关的弹性/风险因素的性别平衡而导致的 随着疾病阶段的变化。我们的建议特别是创新的，因为我们将首先描述性 AD病理学与疾病阶段与临床症状相关的差异，然后检查其 神经生物学的基础和临床意义。 我们将利用来自阿尔茨海默氏病神经影像学的体内，纵向生物标志物数据 来自多个阿尔茨海默氏病的脑组织中的倡议（ADNI）和前瞻性神经病理学数据 研究中心（ADRC）。鉴于他们与AD病理学的紧密联系以及我们之前的性别差异 数据显示，我们将检查（1）宠物测量脑葡萄糖的大脑弹性/风险机制 代谢，（2）NMDAR密度，谷氨酸神经传递的标记和（3）易位蛋白18KDA （TSPO）水平，小胶质激活的标记。具体而言，AIM 1将利用ADNI数据检查性别 认知功能轨迹的差异及其与AD病理学纵向变化的关系 （Aβ和TAU）和大脑代谢按AD阶段进行。在AIM 2中，我们将在体外放射自显影 60个正常对照的海马和皮质脑组织，60个轻度认知障碍和60 AD痴呆症 尸检案例以确定斑块，纠缠，NMDAR和TSPO密度的性别差异及其如何联系 在三个诊断组中的每个组中，彼此之间以及触及认知功能。在AIM 3中，我们将 通过为常用的认知测试产生特定的性别剪切得分来对这些性别差异采取行动 MCI/AD诊断标准在检测存在时具有最佳的灵敏度/特异性平衡 AD生物标志物/病理学水平很重要。我们项目的公共卫生益处将是 重要的是，在我们的临床和生物标志物方法中理解和计算性别分布 为了进行广告诊断，我们将改善疾病诊断和跟踪的临床和生物标志物方法 性别并可能识别特定性别的治疗靶标。