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

摘要 这个建议的指导研究科学家职业发展（K 01）奖的目的是 支持候选人的长期职业目标，领导一个研究项目，以阐明性别特异性 血管对AD和相关痴呆（ADRD）的贡献，通过应用最前沿的评估- 脑血管的完整性和先进的流行病学方法。是否存在性别差异- 脑小血管病（cSVD）至阿尔茨海默病（AD）病理生理学病例中的作用- cade目前未知。这项建议的第一个目的是测试基于组织的性别差异， cSVD标志物、Aβ、tau和cSVD-AD通路。第二个目的是评估船舶的作用- 基于cSVD的标记物，通过超高场MRI测量，在AD级联中以及是否存在性别- 相关差异。成功实现候选人的职业发展目标和研究 目标，拟议的K 01奖建立在候选人在人口神经科学的培训 老年人超高场小血管成像的最新方法， 除了职业和领导力发展之外，新培训的四个关键领域：1）队列协调， （2）因果推理方法，以解决高度选择的研究样本的外部效度; 3)AD病理学的PET神经成像;以及4）性别和性别对AD患者脑病理生理学的影响。 AD.这一建议包含了几项创新，将使候选人能够更好地评估 cSVD对AD生物标志物级联反应中性别差异的重要性：1） 应用最先进的超高场MRI获得早期cSVD的直接血管测量值， 2)使用创新的神经影像协调和因果推理分析方法， 出现了“第22条军规”的障碍，即典型的神经成像生物标志物研究在外部VA中不高， 然而，在大的人群代表性队列中收集神经成像通常是不可行的。 该应用程序在当前指导AD研究的理论框架方面也具有创新性， 测试不包括脑血管疾病的现有动态AD生物标志物模型的边界 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 作为一个独立的调查员和领导者在性别特异性轨迹的AD。最终，坎迪- Date更广泛的职业目标是开发一个有影响力的研究项目， 干预措施的目标是改善老年男女的生活。

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.