Understanding the mechanisms linking small vessel cerebrovascular disease and Alzheimer's disease pathophysiology with neurodegeneration and cognition during midlife

了解小血管脑血管疾病和阿尔茨海默病病理生理学与中年神经退行性变和认知之间的联系机制

• 批准号: 10756193
• 负责人: PATRICK JORDAN LAO
• 金额: $ 24.9万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10756193
• 关键词: Acceleration; Address; Affect; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Area; Autopsy; Award; Biological; Biological Markers; Black Populations; Blood Vessels; Cerebrovascular Disorders; Cerebrovascular system; Clinical Trials; Cognition; Cognitive; Communities; Data; Data Collection; Dementia; Development; Disease; Disease Progression; Education; Ethnic Origin; Ethnic Population; Evaluation; Exclusion; Functional disorder; Funding; Goals; High Prevalence; Hispanic Populations; Impaired cognition; Impairment; Individual; Intervention; Lead; Link; Magnetic Resonance Imaging; Mediating; Memory; Memory Loss; Memory impairment; Mentors; Mission; National Institute on Aging; Nerve Degeneration; Neuropsychology; Neurosciences; Not Hispanic or Latino; Outcome; Pathologic; Pathology; Pathway interactions; Phase; Population Heterogeneity; Positioning Attribute; Race; Recommendation; Regional Disease; Research; Role; Socioeconomic Status; Statistical Models; Techniques; Thick; Thinness; Time; Training; burden of illness; cardiovascular risk factor; cerebrovascular amyloid; clinically relevant; cohort; comorbidity; ethnic difference; ethnic disparity; ethnic diversity; ethnic minority; ethnic minority population; executive function; flexibility; follow-up; longitudinal analysis; middle age; multi-ethnic; multimodal neuroimaging; multimodality; neglect; neuroimaging; neuron loss; offspring; programs; racial difference; racial disparity; racial diversity; racial minority; racial minority population; racial population; skills; statistics; tau Proteins; tau-1; therapeutic target

PROJECT SUMMARY The overall goal of this K99/R00 proposal is to elucidate the extent to which small vessel cerebrovascular disease (svCBVD) and Alzheimer’s disease (AD) pathophysiology are additive or synergistic in their effects on neurodegeneration and cognition in midlife, and to determine if that differs across racial/ethnic groups. Comorbid svCBVD and AD pathology is observed in most dementia cases at autopsy, and is more prevalent in racial/ethnic minorities. Evidence is building that svCBVD has detrimental effects on amyloid clearance and tau phosphorylation, which exacerbates neurodegeneration and cognitive impairment in AD. It is crucial to include svCBVD, amyloid, and tau when considering primary drivers of disease, and neurodegeneration and cognition when considering the consequences of those primary drivers. While initial cognitive impairments in svCBVD are in executive function and those in AD are in memory, the consequences of the two become less distinct when they co-occur. Equally as important, studies in midlife are necessary to elucidate how svCBVD and AD pathophysiology initially develop, and how a particular mixture of AD and svCBVD influences disease progression. Aim 1 (K99) determines the biological consequence that svCBVD and amyloid have on tau- related neurodegeneration, and explores racial/ethnic differences in these associations. Aim 2 (K99) determines the cognitive consequence that svCBVD and amyloid have on tau-related memory dysfunction, and explores racial/ethnic differences in these associations. The central hypothesis is that, in middle age, individuals with svCBVD demonstrate more AD-related neurodegeneration and subsequently more cognitive impairment, and that this effect will be stronger in racial/ethnic minorities due to the higher prevalence of svCBVD. To achieve these goals, the applicant will undergo quick, but essential mentored training in three areas: (1) tau and small vessel cerebrovascular disease, (2) applied neuroscience, and (3) advanced statistical modeling. With these skills, the applicant will be well equipped to independently pursue Aim 3 (R00), which determines the longitudinal consequences that baseline svCBVD and amyloid have on neurodegeneration and memory decline over time. Understanding the consequences of single or mixed svCBVD and AD pathology will inform therapeutic targets and help determine whether interventional strategies need to differ by race/ethnicity. The strengths of this proposal include formal training in the underlying pathology represented by biomarkers and its connection to cognition, as well as formal training in statistics to rigorously implement a flexible National Institute on Aging(NIA)-Alzheimer’s Association-recommended research framework to directly address the current missions of the NIA. For the applicant, this accelerated training period will facilitate the development of an independent research program focused on large-scale neuroimaging studies of AD and related dementias in diverse populations.

项目概要 该 K99/R00 提案的总体目标是阐明小血管脑血管的程度 疾病（svCBVD）和阿尔茨海默氏病（AD）的病理生理学在其对健康的影响方面是相加或协同的。 中年神经退行性变和认知，并确定不同种族/族裔群体之间是否存在差异。 在尸检时大多数痴呆病例中都观察到了 svCBVD 和 AD 共病病理，并且在 越来越多的证据表明 svCBVD 对淀粉样蛋白清除和 tau 蛋白具有不良影响。 磷酸化会加剧 AD 中的神经变性和认知障碍。 在考虑疾病的主要驱动因素以及神经变性和认知时，svCBVD、淀粉样蛋白和 tau 蛋白 当考虑这些主要驱动因素的后果时，svCBVD 的初始认知障碍。 属于执行功能，而 AD 属于记忆功能，两者的后果变得不太明显 同样重要的是，中年时期的研究有必要阐明 svCBVD 和 AD 是如何发生的。 病理生理学的最初发展，以及 AD 和 svCBVD 的特定混合物如何影响疾病 目标 1 (K99) 确定 svCBVD 和淀粉样蛋白对 tau 的生物学影响。 相关的神经变性，并探讨这些关联中的种族/民族差异。 确定 svCBVD 和淀粉样蛋白对 tau 相关记忆功能障碍的认知后果，以及 探讨这些关联中的种族/民族差异。中心假设是，在中年， 患有 svCBVD 的个体表现出更多与 AD 相关的神经退行性变，并随后表现出更多的认知能力 损害，并且由于种族/族裔的患病率较高，这种影响在少数种族/族裔中更为强烈 为了实现这些目标，申请人将接受三个快速但必要的指导培训。 领域：(1) tau 蛋白和小血管脑血管疾病，(2) 应用神经科学，(3) 高级统计 有了这些技能，申请人将有能力独立追求目标 3 (R00)，即目标 3 (R00)。 确定基线 svCBVD 和淀粉样蛋白对神经退行性变的纵向影响， 了解单一或混合 svCBVD 和 AD 病理学的后果将随着时间的推移而下降。 告知治疗目标并帮助确定介入策略是否需要因种族/民族而异。 该提案的优点包括对生物标志物所代表的基础病理学的正式培训 及其与认知的联系，以及统计方面的正式培训，以严格实施灵活的国家政策 老龄化研究所（NIA）-阿尔茨海默病协会推荐的研究框架，直接解决 对于申请人来说，这个加速培训期将促进 NIA 当前的任务。 一个专注于 AD 和相关痴呆症的大规模神经影像学研究的独立研究项目 在不同的人群中。