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

项目概要/摘要 越来越多的研究发现，神经表征在 老年人相对于年轻人，这种现象被称为与年龄相关的神经 去分化神经去分化与许多行为学上的 健康老龄化中通常观察到的损伤以及我们小组收集的证据 在最初的资助期间，发现了神经元之间的强烈关系， 去分化和γ-氨基丁酸（GABA），大脑的主要抑制 神经传递素具体来说，我们发现老年人的GABA水平低于年轻人， 成年人和老年人较少的GABA表现出更大的去分化。我们提出 把这条研究线引向两个新方向。(1)我们将进行纵向研究 并探索与年龄相关的GABA变化轨迹，神经特异性， 行为以及这些度量之间的方向关系（例如，做GABA 65岁时的水平预示着随后的神经特异性下降？神经 65岁时的独特性预测未来十年的行为衰退）。(2)我们将 还研究如何去分化与阿尔茨海默病的病理学有关，通过收集 在患有轻度认知障碍的患者中进行相同的测量， 负担已经得到了衡量。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的变化，这些变化是否可以 解释所观察到的行为缺陷，以及GABA水平的变化是否是一个 贡献事业这些见解可能会导致新的干预措施，以减轻 与健康和病理性衰老相关的行为障碍。

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.