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.

项目摘要 该K99/R00建议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）病理生理学对它们对它们的影响是累加或协同作用 中年的神经变性和认知，并确定这在种族/族裔群体之间是否有所不同。 在尸检时，在大多数痴呆症病例中观察到合并症SVCBVD和AD病理学，并且在 种族/族裔少数民族。有证据表明，SVCBVD对淀粉样蛋白清除和TAU有不利影响 磷酸化，加剧了AD中神经变性和认知障碍。包括 当考虑疾病的主要驱动因素以及神经退行性和认知时，SVCBVD，淀粉样蛋白和TAU 在考虑这些主要驱动因素的后果时。而SVCBVD的最初认知障碍 在执行功能中，广告中的功能在记忆中，两者的后果变得不那么明显 同样重要的是，需要对中年的研究来阐明SVCBVD和AD如何 病理生理学最初发展，以及AD和SVCBVD的特定混合物如何影响疾病 进展。 AIM 1（K99）确定了SVCBVD和淀粉样蛋白对tau-的生物学结果 相关的神经变性，并探索这些关联中的种族/种族差异。目标2（K99） 确定SVCBVD和淀粉样蛋白对TAU相关记忆功能障碍的认知后果，并且 探索这些关联中的种族/种族差异。中心假设是，在中年， 具有SVCBVD的个体表现出更多与广告相关的神经变性，随后更具认知能力 损害，由于较高的患病率 SVCBVD。为了实现这些目标，申请人将经过快速但本质上的培训三个 区域：（1）tau和小血管脑血管疾病，（2）应用神经科学和（3）高级统计 造型。借助这些技能，申请人将有能力独立追求AIM 3（R00）， 确定基线SVCBVD和淀粉样蛋白对神经变性和 记忆随着时间的推移而下降。了解单一或混合SVCBVD和AD病理的后果将 告知热目标并帮助确定介入策略是否需要因种族/种族而有所不同。 该提案的优势包括生物标志物代表的基本病理的正式培训 及其与认知的联系，以及统计的正式培训，以严格实施灵活的国家 老化研究所（NIA） - 阿尔茨海默氏症协会推荐的研究框架，直接解决 NIA的当前任务。对于适用的，这个加速的培训期将有助于发展 一个独立的研究计划，重点介绍了广告和相关痴呆症的大规模神经影像学研究 在潜水员人群中。