HOW DOES RESERVE MODIFY LINKS BETWEEN COGNITION & IMAGING INDICES OF AD PATHOLOGY

描述（由申请人提供）：尽管病理学是阿尔茨海默病（AD）认知能力下降的根本原因，但储备机制的受试者间变异性解释了为什么一些受试者有更大的能力将疾病相关的神经病理改变的临床表现最小化。本建议的广泛目标是调查储备的措施如何修改病理和认知之间的关系。病理学将使用多模态PET和MRI成像生物标志物进行量化。指导阶段：对于该研究的Specific Aim 1，候选人将扩展其已发表的从结构MRI （sMRI）自动量化AD神经退行性变的结果，以开发从其他成像方式（PiB-PET：斑块负担指标；FDG-PET：神经元功能障碍指标；FLAIR：脑血管疾病指标以及sMRI：神经退行性变指标）量化体内病理成像测量的算法。这些算法将被应用于我们的非痴呆人群队列中，包括认知正常和轻度认知障碍受试者，计算特定模式的病理成像测量。在此期间，她将接受Clifford Jack博士在AD多模态成像方法领域和David Knopman博士在衰老和痴呆临床方面的直接指导。作为拟议研究的一部分，候选人将学习认知神经科学和临床方法课程，以加强这里概述的多学科研究所需的技能。独立阶段（R00）：在此阶段，将通过静息状态功能磁共振成像（fMRI）和其他来源(如智力生活方式（教育、职业、认知活动）和身体活动测量（身体活动和锻炼）得出的功能连通性指标来确定储备措施。这些将被应用（目标2）来建立病理成像测量和认知表现之间的关系，以及这些关系如何通过储备测量和与其他病理成像测量的相互作用来修改。在目标3中，建立病理成像测量和随着时间的推移认知表现变化之间的关系以及这些关系如何通过储备测量和与其他病理成像测量的相互作用而被修改。

DESCRIPTION (provided by applicant): Although pathology is the underlying cause of cognitive decline seen in Alzheimer's disease (AD), inter- subject variability in reserve mechanisms explains why some subjects have greater capacity to minimize the clinical expression of disease related neuropathological changes. The broad objective of this proposal is to investigate how measures of reserve modify the relationship between pathology and cognition. Pathology will be quantified using multi-modality PET and MRI imaging biomarkers. Mentored Phase: For Specific Aim 1 of the study, the candidate will extend her published results for automated quantification of neurodegeneration in AD from structural MRI (sMRI) to develop algorithms for quantifying in vivo imaging measures of pathology from other imaging modalities (PiB-PET: indicator of plaque burden; FDG-PET: indicator of neuronal dysfunction; FLAIR: indicator of cerebro-vascular disease along with sMRI: indicator of neurodegeneration). These algorithms will be applied to calculate modality-specific imaging measures of pathology in our non-demented population-based cohort consisting of cognitively normal and mild cognitive impairment subjects. During this time, she will receive direct mentorship from Dr. Clifford Jack in the area of multi-modality imaging methods in AD and Dr. David Knopman in clinical aspects of aging and dementia. As part of the proposed research, the candidate will take courses in cognitive neuroscience and clinical methods to strengthen the skill set necessary for the multi-disciplinary research outlined here. Independent Phase (R00): During this phase, measures of reserve will be identified from functional connectivity metrics derived from resting state fMRI and from other sources such as intellectual lifestyle (education, occupation, cognitive activities) and physical activity measure (physical activity and exercise). These will be applied (Aim 2) to establish the relationships between imaging measures of pathology and cognitive performance and how these relationships are modified by measures of reserve and by interactions with other imaging measures of pathology. And in Aim 3, establish the relationships between imaging measures of pathology and change in cognitive performance over time and how these relationships are modified by measures of reserve and by interactions with other imaging measures of pathology. PUBLIC HEALTH RELEVANCE: Understanding factors that modify the association between cognition and pathology in individual subjects will play a key role in the success of preventive strategies in non-demented elderly and are relevant for improving our understanding of the Alzheimer's disease.