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: 10624877
• 负责人: Erin elizabeth Sundermann
• 金额: $ 53.24万
• 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/10624877
• 关键词: Acceleration; 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; Dementia; Detection; Diagnosis; Diagnostic; Diagnostic Procedure; Disease; Disease Progression; Early Intervention; Equilibrium; Female; Frequencies; Gender; Generations; Glutamates; Health Benefit; Hippocampus; Impaired cognition; In Vitro; Learning; Life; Measures; Mediator; 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; Variant; Woman; Work; abeta accumulation; advanced disease; biomarker validation; brain metabolism; brain size; brain tissue; clinical diagnostics; clinical translation; clinically significant; cognitive function; cognitive performance; cognitive testing; density; detection method; diagnostic accuracy; diagnostic criteria; diagnostic strategy; disease diagnosis; gender difference; glial activation; 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; resilience factor; response; sex; sex disparity; social culture; tau Proteins; therapeutic target; verbal

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.

项目概要/摘要 阿尔茨海默病 (AD) 风险和 AD 病理负担的性别差异 已得到广泛研究；然而，人们对 AD 病理负担与临床症状之间的关系知之甚少。 有证据表明，女性在 AD 临床前阶段具有认知优势，但其认知优势是男性的两倍。 此后认知能力下降表明 AD 临床表现存在性别差异 这些性别差异具有临床意义，因为我们已经确定了这一点。 通常会生成用于诊断和跟踪疾病的 AD 临床和生物标记的阈值 如果不考虑性别差异，女性是否能够更好地维持我们目前的认知。 阈值考虑“正常”认知，直到比男性更高级的病理状态，然后诊断 MCI 可能会被推迟，从而限制了早期干预的机会，我们利用了性别差异。 AD 病理学的临床转化源于大脑相关弹性/风险因素的性别特异性平衡 我们的建议特别具有创新性，因为我们将首先描述性别的特征。 AD 病理学与疾病阶段的临床症状之间的关系存在差异，然后检查其 神经生物学基础和临床意义。 我们将利用来自阿尔茨海默病神经影像学的体内纵向生物标志物数据 多种阿尔茨海默病脑组织的倡议 (ADNI) 和前瞻性神经病理学数据 鉴于研究中心 (ADRC) 与 AD 病理学的紧密联系以及我们之前发现的性别差异。 数据显示，我们将检查 (1) PET 测量的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物，以及 (3) 易位蛋白 18kDA 具体来说，目标 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 阶段的脑代谢 在目标 2 中，我们将进行体外放射自显影。 60名正常对照、60名轻度认知障碍和60名AD痴呆的海马和皮质脑组织 尸检病例以确定斑块、缠结、NMDAR 和 TSPO 密度的性别差异以及它们之间的关系 在目标 3 中，我们将研究三个诊断组中每个组之间的相互影响以及生前认知功能的影响。 通过为常用的认知测试生成特定性别的分数来对这些性别差异采取行动 MCI/AD 诊断标准在检测是否存在时具有灵敏度/特异性的最佳平衡 AD 生物标志物/病理学的临床显着水平 我们项目的公共健康效益将是 通过理解和解释我们的临床和生物标志物方法中的性别差异，这一点具有重要意义 对于 AD 诊断，我们将改进疾病诊断和跟踪的临床和生物标志物方法 性别并可能确定性别特异性治疗靶点。

项目成果

Improving Detection of Amnestic Mild Cognitive Impairment with Sex-Specific Cognitive Norms.

通过特定性别的认知规范改善遗忘型轻度认知障碍的检测。

• DOI: 10.3233/jad-215260
• 发表时间: 2021
• 期刊: Journal of Alzheimer's disease : JAD
• 作者: Sundermann,ErinE;Barnes,LisaL;Bondi,MarkW;Bennett,DavidA;Salmon,DavidP;Maki,PaulineM
• 通讯作者: Maki,PaulineM

Associations Between Parity and Cognition: Race/Ethnic Differences.

• DOI: 10.3233/jad-221210
• 发表时间: 2023
• 期刊: JOURNAL OF ALZHEIMERS DISEASE
• 影响因子: 4
• 作者: Araujo-Menendez, Carlos E. E.;Saelzler, Ursula G.;Stickel, Ariana M.;Sundermann, Erin E.;Banks, Sarah J.;Paipilla, Andrea;Barnes, McKinna L.;Panizzon, Matthew S.
• 通讯作者: Panizzon, Matthew S.

The mediating role of socioeconomic status on the relationship between pregnancy history and later-life cognition.

• DOI: 10.1080/13697137.2022.2129004
• 发表时间: 2022-12
• 期刊: CLIMACTERIC
• 影响因子: 2.8
• 作者: Giudicessi, A. J.;Saelzler, U. G.;Shadyab, A. H.;Posis, A. I. B.;Sundermann, E. E.;Banks, S. J.;Panizzon, M. S.
• 通讯作者: Panizzon, M. S.