Investigating age-related neural dedifferentiation longitudinally and in Alzheimer’s pathology

纵向研究阿尔茨海默病病理学中与年龄相关的神经去分化

• 批准号: 10469464
• 负责人: Thad A Polk
• 金额: $ 70.06万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469464
• 关键词: Age; Aging; Alzheimer' s disease pathology; Amyloid beta-Protein; Animals; Autopsy; Behavior; Behavioral; Brain; Childhood; Cognition; Cognitive; Cohort Effect; Cross-Sectional Studies; Data; Elderly; Exhibits; Functional Magnetic Resonance Imaging; Funding; Grant; Growth; Individual; Individual Differences; Intervention; Lead; Longitudinal Studies; Magnetic Resonance Spectroscopy; Measures; Mediating; Michigan; Modeling; Motor; Neurofibrillary Tangles; Neurotransmitters; Participant; Patients; Persons; Play; Positron-Emission Tomography; Research; Research Personnel; Role; Sample Size; Senile Plaques; Sensory; Stimulus; Testing; Time; Work; abeta accumulation; age difference; age group; age related; base; behavior test; behavioral impairment; experience; gamma-Aminobutyric Acid; healthy aging; imaging study; insight; interest; mild cognitive impairment; neuropathology; new therapeutic target; normal aging; novel; nutrition; pathological aging; recruit; relating to nervous system; response; tau Proteins; young adult; β-amyloid burden

Project Summary/Abstract A growing body of research has found that neural representations are less distinctive in older relative to younger adults, a phenomenon known as age-related neural dedifferentiation. Neural dedifferentiation has been associated with many of the behavioral impairments typically observed in healthy aging, and evidence collected by our group during the original funding period has found a strong relationship between neural dedifferentiation and gamma-aminobutyric acid (GABA), the brain’s major inhibitory neurotransmitter. Specifically, we found that GABA levels are lower in older vs. younger adults and that older adults with less GABA exhibit greater dedifferentiation. We propose to take this line of research in two new directions. (1) We will conduct a longitudinal study and explore age-related trajectories of change in GABA, neural distinctiveness, and behavior, as well as directional relationships among these measures (e.g., Do GABA levels at age 65 predict subsequent declines in neural distinctiveness? Does neural distinctiveness at age 65 predict behavioral declines over the next decade). (2) We will also examine how dedifferentiation is related to Alzheimer’s pathology by collecting the same measures in patients with Mild Cognitive Impairment in whom amyloid beta and tau burden has already been measured. The proposed studies will provide novel insights into how the brain changes with age and with neuropathology, whether those changes can explain the observed behavioral deficits, and whether changes in GABA levels are a contributing cause. Such insights could lead to novel interventions to alleviate the behavioral impairments associated with healthy and pathological aging.

项目概要/摘要 越来越多的研究发现，神经表征在以下方面不太独特： 相对于年轻人来说，年长的人，这种现象被称为年龄相关神经 去分化。神经去分化与许多行为相关 在健康老龄化过程中通常观察到的损害，以及我们小组收集的证据 在最初的资助期间发现神经网络之间存在很强的关系 去分化和γ-氨基丁酸（GABA），大脑的主要抑制物质 神经递质。具体来说，我们发现老年人的 GABA 水平低于年轻人 成年人和具有较少 GABA 的老年人表现出更大的去分化。我们建议 将这一研究方向推向两个新的方向。 （一）我们将进行纵向研究 并探索 GABA、神经独特性和年龄相关的变化轨迹 行为，以及这些措施之间的方向关系（例如，Do GABA 65 岁时的水平预示着随后神经独特性的下降？有神经吗 65 岁时的独特性预示着未来十年的行为衰退）。 (2) 我们将 还通过收集 对患有 β 淀粉样蛋白和 tau 蛋白的轻度认知障碍患者采取相同的措施 负担已经被衡量。拟议的研究将提供新的见解 大脑如何随着年龄和神经病理学变化，这些变化是否可以 解释观察到的行为缺陷，以及 GABA 水平的变化是否是一个 贡献原因。这些见解可能会导致新的干预措施来缓解 与健康和病理性衰老相关的行为障碍。