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: 10196917
• 负责人: PATRICK JORDAN LAO
• 金额: $ 13.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196917
• 关键词: Address; Affect; Alzheimer associated neurodegeneration; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid; Area; Autopsy; Award; Biological; Biological Markers; Blood Vessels; Cerebrovascular Disorders; Cerebrovascular system; Clinical Trials; Cognition; Cognitive; Communities; Data; Data Collection; Dementia; Development; Disease; Disease Progression; Ethnic Origin; Ethnic group; Evaluation; Functional disorder; Funding; Goals; High Prevalence; Hispanics; 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; Phosphorylation; Population Heterogeneity; Positioning Attribute; Race; Research; Role; Socioeconomic Status; Statistical Models; Techniques; Thick; Thinness; Time; Training; base; cardiovascular risk factor; clinically relevant; cohort; comorbidity; ethnic difference; ethnic minority population; executive function; flexibility; follow-up; longitudinal analysis; middle age; multi-ethnic; multimodality; neglect; neuroimaging; neuron loss; offspring; programs; racial and ethnic; racial and ethnic disparities; skills; statistics; tau Proteins; tau phosphorylation; 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.

项目总结

项目成果

Brain Aging Among Racially and Ethnically Diverse Middle-Aged and Older Adults.

不同种族和民族的中年人和老年人的大脑老化。

• DOI: 10.1001/jamaneurol.2022.3919
• 发表时间: 2023
• 期刊: JAMA neurology
• 影响因子: 29
• 作者: Turney,IndiraC;Lao,PatrickJ;Rentería,MiguelArce;Igwe,KayC;Berroa,Joncarlos;Rivera,Andres;Benavides,Andrea;Morales,ClarissaD;Rizvi,Batool;Schupf,Nicole;Mayeux,Richard;Manly,JenniferJ;Brickman,AdamM
• 通讯作者: Brickman,AdamM

Brain areas with normatively greater cerebral perfusion in early life may be more susceptible to beta amyloid deposition in late life.

早年脑灌注通常较高的大脑区域在晚年可能更容易受到β淀粉样蛋白沉积的影响。

• DOI: 10.1016/j.cccb.2020.100001
• 发表时间: 2020
• 期刊: Cerebral circulation - cognition and behavior
• 作者: Meier,IreneB;Lao,PatrickJ;Gietl,Anton;Vorburger,RobertS;Gutierrez,José;Holland,ChristopherM;Guttmann,CharlesRG;Meier,DominikS;Buck,Alfred;Nitsch,RogerM;Hock,Christoph;Unschuld,PaulG;Brickman,AdamM
• 通讯作者: Brickman,AdamM