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

项目摘要/摘要 阿尔茨海默病(AD)风险和AD病理负担的性别差异 广泛研究；然而，关于AD病理负担与临床症状之间的关系却知之甚少。 女人对男人。阿尔茨海默病临床前阶段认知优势的证据，但陡度是前者的两倍 此后认知功能下降提示AD的临床表现存在性别差异的问题 病理学是一门重要的学科。这些性别差异具有临床意义，因为我们已经建立了 通常生成用于诊断和跟踪疾病的AD临床和生物标志物的阈值 不考虑性别差异。如果女性能够更好地保持我们目前的认知 阈值被认为是“正常”的认知，直到比男性更高级的病理状态，然后诊断为MCI 可能会推迟，从而限制了及早干预的机会。我们假设性别差异存在于 AD病理的临床翻译是大脑相关恢复力/风险因素的性别平衡的结果 这一点随着疾病阶段的变化而变化。我们的建议特别创新，因为我们将首先描述性行为的特征 不同疾病阶段AD病理与临床症状的关系差异，然后检查其 神经生物学基础和临床意义。 我们将利用阿尔茨海默病神经成像中的体内纵向生物标记物数据 多发性阿尔茨海默病患者脑组织的主动(ADNI)和前瞻性神经病理学数据 研究中心(ADRC)。考虑到他们与AD病理的密切联系以及我们之前 数据显示，我们将研究(1)PET测量的大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志，和(3)转位蛋白18kDA (TSPO)水平，小胶质细胞激活的标志。具体地说，Aim 1将利用ADNI数据来检查性别 认知功能轨迹的差异及其与AD病理纵向变异的关系 (aβ和Tau)和AD分期的脑代谢。在目标2中，我们将进行体外放射自显影 60例正常对照组、60例轻度认知障碍和60例阿尔茨海默病患者的海马区和皮质区脑组织 尸检病例以确定斑块、缠结、NMDAR和TSPO密度的性别差异及其相互关系 对三个诊断组中的每一个的生前认知功能的影响。在《目标3》中，我们将 对这些性别差异采取行动，为认知测试生成性别特定的削减分数，通常用于 敏感度/特异度达到最佳平衡的MCI/AD诊断标准 临床--AD生物标志物/病理学的显著水平。我们的项目对公众健康的好处是 通过了解和解释我们临床和生物标记方法中的性别差异，这一点意义重大 在AD诊断方面，我们将改进临床和生物标志物方法，以诊断和跟踪这两种疾病 性别，并可能确定针对性别的治疗目标。

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.