Unraveling the intersection of synaptic biology, lifestyle, and cognitive resilience

揭示突触生物学、生活方式和认知弹性的交叉点

• 批准号: 10443614
• 负责人: Kaitlin B Casaletto
• 金额: $ 86.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10443614
• 关键词: Address; Adult; Adverse effects; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid; Animal Experiments; Animals; Attenuated; Autopsy; Behavior; Behavioral; Biological; Biological Markers; Biology; Brain; Brain Pathology; Calcium; Calcium Signaling; Cell Adhesion; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Cessation of life; Clinical; Cognition; Cognitive; Cognitive aging; Collaborations; Communication; Coupled; Cytoskeleton; Data; Decision Making; Dementia; Development; Dissection; Dominant Genetic Conditions; Elderly; Etiology; Evaluation; Exercise; Foundations; Frequencies; Goals; Health; Heterogeneity; Human; Human Biology; Impaired cognition; Individual; Infarction; Life; Life Style; Link; Liquid substance; Machine Learning; Maintenance; Mass Spectrum Analysis; Measurement; Measures; Memory; Modeling; Molecular; Monitor; Movement; Nature; Neurotransmitters; Participant; Pathology; Persons; Physical activity; Process; Proteins; Publishing; Research; Residual state; Resources; Role; S-nitro-N-acetylpenicillamine; Sampling; Signal Transduction; Symptoms; Synapses; Techniques; Technology; Time; Tissue Sample; Vesicle; Work; actigraphy; aged; aging brain; base; brain magnetic resonance imaging; brain tissue; clinically relevant; cognitive performance; cohort; design; emerging adult; end of life; human old age (65+); indexing; innovation; machine learning model; neurobehavioral; neurogranin; neuronal pentraxin; neuropathology; preservation; presynaptic; prevent; programs; prospective; protective factors; protein biomarkers; receptor; relating to nervous system; resilience; synaptic function; tau Proteins; theories; therapeutic candidate; therapeutic target

PROJECT SUMMARY / ABSTRACT Brain pathology begins accumulating in early adulthood and is detectable in almost all brains by older age. Yet, there is remarkable heterogeneity in cognitive aging, and most aged adults do not evidence cognitive impairment or dementia. Uncovering the naturally occurring processes that support this cognitive resilience to neuropathology burden may yield potent targets to prevent or slow Alzheimer's disease and related dementias (ADRD). We hypothesize that maintained synaptic integrity and physical activity may represent two such protective factors. Synaptic communication is the foundational underpinning of cognition. Increasing data suggest that preserved synaptic integrity may support clinical functioning regardless of pathology presence or etiology. Further, physical activity is a highly implicated resilience behavior that has also been linked to synaptic maintenance in animals. Our goal is to determine the synaptic biology that may underlie cognitive resilience and physical activity in humans. We will collaborate across two ADRC programs to leverage their unique strengths. In the Rush Memory and Aging Project (R-MAP), brain tissue samples from autopsied adults followed in life will be used to quantify >150 synaptic protein markers (n=869). In the UCSF Memory and Aging Center (UC-MAC), cerebrospinal fluid samples from longitudinally followed living older adults will be used to quantify seven synaptic protein markers (n=200). Both cohorts complete longitudinal actigraphy monitoring as an index of physical activity levels, and comprehensive neurobehavioral assessments. Cognitive resilience will be operationalized as the discrepancy between neuropathology markers and cognitive performances. Aim one will identify the in-depth synaptic networks (R-MAP) and the longitudinal, dynamic nature (UC-MAC) between synaptic markers and cognitive resilience. Aim two will apply innovative machine learning techniques to identify precise actigraphy features that most robustly relate to in-depth synaptic networks (R-MAP), longitudinal synaptic marker changes (UC-MAC), and cognitive resilience (both). Accomplishing these aims will significantly impact the ADRD field. We are designed to carefully identify synaptic and exercise features that support sustained cognitive resilience using cutting edge measurement technologies, analytics, and exceptional collaborative expertise. This proposal represents a bridging between two national ADRCs to more powerfully address high impact questions than could be answered by either individually.

项目概要/摘要 大脑病理学在成年早期就开始积累，到老年时几乎所有大脑都可以检测到。然而， 认知老化存在显着的异质性，大多数老年人没有证据表明认知老化 损伤或痴呆。揭示支持这种认知弹性的自然发生过程 神经病理学负担可能会产生预防或减缓阿尔茨海默病和相关痴呆症的有效目标 （ADRD）。我们假设维持突触完整性和身体活动可能代表两个这样的因素 保护因素。突触通讯是认知的基础。增加数据 表明保留的突触完整性可能支持临床功能，无论病理存在或 病因学。此外，体力活动是一种高度相关的复原力行为，也与 动物突触的维持。我们的目标是确定可能构成认知基础的突触生物学 人类的恢复力和体力活动。我们将在两个 ADRC 项目中进行合作，以利用他们的优势 独特的优势。在 Rush Memory and Aging Project (R-MAP) 中，来自尸检成人的脑组织样本 随后的生活将用于量化 > 150 个突触蛋白标记 (n = 869)。在加州大学旧金山分校记忆与衰老 中心（UC-MAC），纵向跟踪的在世老年人的脑脊液样本将用于 量化七个突触蛋白标记 (n=200)。两个队列均完成纵向体动记录监测 体力活动水平指数和综合神经行为评估。认知弹性将 可操作化为神经病理学标记与认知表现之间的差异。瞄准一个 将识别深度突触网络 (R-MAP) 和纵向、动态性质 (UC-MAC) 突触标记和认知弹性。目标二将应用创新的机器学习技术来识别 与深度突触网络（R-MAP）、纵向最有力相关的精确体动记录特征 突触标记物变化（UC-MAC）和认知弹性（两者）。实现这些目标将 显着影响 ADRD 领域。我们旨在仔细识别突触和运动特征 使用尖端的测量技术、分析和技术支持持续的认知弹性 卓越的协作专业知识。该提案代表了两个国家 ADRC 与更多国家之间的桥梁 有力地解决了比任何一个单独回答都可以回答的高影响力的问题。