Population neuroscience of sex differences in the Alzheimer's disease biomarker cascade: The role of cerebral small vessel disease

阿尔茨海默病生物标志物级联中性别差异的群体神经科学：脑小血管疾病的作用

• 批准号: 10370484
• 负责人: C. Elizabeth Shaaban
• 金额: $ 12.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10370484
• 关键词: Address; Age; Aging; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Area; Biological Markers; Blood Vessels; Brain; Cerebral small vessel disease; Cerebrum; Clinical; Data; Dementia; Deposition; Development; Disease Marker; Early Intervention; Education; Elderly; Epidemiologic Methods; Epidemiology; Event; Evolution; Female; Functional disorder; Future; Gender; Goals; Image; Impairment; Incidence; Intervention; Knowledge; Life Expectancy; Magnetic Resonance Imaging; Measures; Mentored Research Scientist Development Award; Mentors; Methods; Modeling; Neurosciences; Pathologic; Pathway interactions; Persons; Population; Positron-Emission Tomography; Public Health; Reporting; Research; Research Personnel; Research Priority; Risk; Role; Sampling; Sampling Studies; Scientist; Selection Bias; Sex Differences; Target Populations; Testing; Time; Tissues; Training; United States National Institutes of Health; Ursidae Family; Venous; Weight; White Matter Hyperintensity; Woman; Work; base; career; career development; cerebral microbleeds; cerebrovascular; cohort; comorbidity; data harmonization; experience; improved; innovation; insight; leadership development; men; mild cognitive impairment; neuroimaging; neuroimaging marker; older men; older women; personalized intervention; population based; programs; sex; tau Proteins; tau aggregation; vascular contributions

ABSTRACT The purpose of this proposed Mentored Research Scientist Career Development (K01) Award is to support the Candidate’s long-term career goal of leading a research program to elucidate sex-specific vascular contributions to AD and related dementias (ADRD) by applying the most cutting-edge assess- ments of cerebrovascular integrity and advanced epidemiologic methods. Whether there are sex differ- ences in the cerebral small vessel disease (cSVD)-to-Alzheimer’s disease (AD) pathophysiological cas- cade is currently unknown. The first aim of this proposal is to test for sex differences in tissue-based cSVD markers, Aβ, tau, and the cSVD-AD pathway. The second aim is to evaluate the role of vessel- based cSVD markers, measured by ultra-high field MRI, in the AD cascade and whether there are sex- related differences. To successfully achieve the Candidate’s career development goals and research objectives, the proposed K01 Award builds upon the Candidate's training in population neuroscience of aging and state of the art methods of ultra-high field small vessel imaging in older adults and adds four key areas of new training in addition to career and leadership development: 1) cohort harmoniza- tion methods; 2) causal inference methods to address external validity of highly selected study samples; 3) PET neuroimaging of AD pathology; and 4) sex and gender effects on cerebral pathophysiology of AD. This proposal incorporates several innovations that will allow the Candidate to better assess the importance of cSVD for sex differences in the AD biomarker cascade in the population at large: 1) application of state-of-the-art ultra-high field MRI to obtain direct vessel measures of early cSVD and 2) use of innovative neuroimaging harmonization and causal inference analytic approaches to over- come the “catch 22” obstacle that typical neuroimaging biomarker studies are not high in external va- lidity, but collecting neuroimaging in large, population representative cohorts is typically not feasible. The application is also innovative in relation to the current theoretical framework guiding AD research, testing boundaries of the extant dynamic AD biomarker model which does not include cerebrovascular biomarkers. Achieving these training and research objectives will support the Candidate's development as an independent investigator and a leader in sex-specific trajectories of AD. Ultimately, the Candi- date’s broader career goal is to develop an impactful research program which identifies sex-specific intervention targets and improves the lives of older men and women.

抽象的 这项拟议的指导研究科学家职业发展（K01）奖的目的是 支持候选人的长期职业目标，即领导一项研究计划以阐明特定性别 通过应用最尖端的评估 - 提及脑血管完整性和高级流行病学方法。性别是否不同 - 在脑小血管疾病（CSVD）中加密to-alzheimer病（AD）病理生理学 Cade目前未知。该提案的第一个目的是测试基于组织的性别差异 CSVD标记，Aβ，TAU和CSVD-AD途径。第二个目的是评估血管的作用 通过超高场MRI测量的基于CSVD标记，在AD级联中以及是否有性别 相关差异。成功实现候选人的职业发展目标和研究 目标是拟议的K01奖基于候选人在人群神经科学方面的培训而建立的 老年人的超高场小容器成像的老化和最先进的方法 除职业和领导力发展外，新培训的四个关键领域：1） 方法； 2）解决高度选择的研究样本外部有效性的因果推理方法； 3）AD病理学的PET神经影像学； 4）性别和性别对脑病理生理学的影响 广告。该提案结合了几项创新，使候选人可以更好地评估 CSVD在广大人群中的广告生物标志物级联对性别差异的重要性：1） 应用最先进的超高场MRI以获得早期CSVD的直接船只量度和 2）使用创新的神经影像学和协调和因果推理分析方法过度 来到“捕获22”障碍，典型的神经影像学生物标志物研究在外部VA-中不高 有效，但在代表人群的大量人群中收集神经影像通常是不可行的。 该应用程序也与当前的指导广告研究的当前理论框架有关 不包括脑血管的额外动态AD生物标志物模型的测试边界 生物标志物。实现这些培训和研究目标将支持候选人的发展 作为独立的研究者和广告性别轨迹的领导者。最终，候选人 日期的更广泛的职业目标是制定一个有影响力的研究计划，该计划识别特定于性别的研究计划 干预目标并改善了老年男女的生活。