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

项目摘要/摘要 越来越多的研究发现，神经表征在 相对于年轻人来说，年龄较大的人，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 在健康老龄化中观察到的典型损害，以及我们小组收集的证据 在最初的资助期内发现了神经与 去分化与大脑的主要抑制因子--γ-氨基丁酸(GABA) 神经递质。具体地说，我们发现老年人的GABA水平比年轻人低 成年人和GABA含量较低的老年人表现出更大的去分化。我们建议 将这一研究带向两个新的方向。(一)我们将进行纵向研究 并探索与年龄相关的GABA、神经区别性和 行为以及这些指标之间的方向关系(例如，做GABA 65岁时的水平预示着神经清晰度的随后下降？神经性的 65岁时的独特性预示着未来十年行为能力的下降)。(2)我们会 还可以通过收集 轻度认知障碍患者中淀粉样β蛋白和tau蛋白的同样测量 负担已经被衡量了。拟议中的研究将提供新的见解 大脑如何随年龄和神经病理变化，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 有贡献的事业。这种洞察力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。

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.