The scope, cause and consequences of age-related decline in neural distinctiveness and brain signal variability in healthy and pathological aging

项目摘要 然而，正常的衰老通常与认知、运动和感觉功能的普遍下降有关， 有很大的个体差异：一些老年人经历轻度损伤，而其他人 会出现严重的认知能力下降了解衰老过程中个体差异的神经基础， 在设计未来的干预措施，以解决与年龄有关的认知障碍。使用行为 测试，功能性MRI，光谱学和药理学操作在人类成年人，我建议， 调查范围，原因和后果与年龄有关的下降，在两个神经因素，可能发挥作用， 在这些个体差异中的作用：（1）神经独特性（如何相似/混淆神经激活模式） 响应于不同的刺激类别）和（2）大脑信号的可变性（大脑信号的瞬时变化）。 独立于任务的神经活动）。这两项指标都随着年龄的增长而下降， 与行为的个体差异有关。在博士前（F99）阶段的培训，我的 研究将集中在健康老龄化：1）调查的范围和原因（特别是GABA水平的作用）， 与年龄相关的感觉区域神经特异性下降，2）大脑中与年龄相关的下降的原因 信号变异性，以及3）这两种神经测量中与年龄相关的下降的行为后果。 在博士后（K 00）阶段，我将扩展我以前的研究，再次研究神经的独特性 和大脑信号的变异性，但现在在记忆和海马功能障碍的背景下，并在临床 人群（轻度认知障碍，MCI患者）。我会用基于任务的功能磁共振成像来测量 独特性，静息状态功能磁共振成像测量大脑信号的变化，和磁共振波谱测量水平 各种神经递质（包括谷氨酰胺，谷氨酸，NAA和GABA），都在海马体中， 健康的年轻人和老年人以及MCI患者。我还将收集相同的行为数据 参与者在记忆相似性任务（MST），海马功能障碍的高度敏感的措施。 我建议研究a）年龄相关的神经特异性和静息状态变异性的变化， 海马，B）这些神经变化的神经化学基础，和c）行为和病理 这些神经变化的后果。对于所有MCI患者，我还可以访问丰富的数据集， 其它生物标志物（例如，基于CSF和PET的淀粉样蛋白和tau的纵向测量）， 阿尔茨海默病研究中心（ADRC）。因此，我将能够检查神经的独特性， 在淀粉样蛋白Tau神经变性（生物标志物分析）框架的背景下的脑信号变异性。 总之，这项研究可能导致AD临床前标志物的开发，并为AD的治疗开辟新的途径。 早期药物干预，以治疗健康和病理性衰老中的认知能力下降。

Project Summary Normal aging is typically associated with pervasive declines in cognitive, motor and sensory function, however, there are substantial individual differences: some older adults experience mild impairments while others experience severe cognitive declines. Understanding the neural bases of individual differences during aging is imperative in designing future interventions to address age-related cognitive impairments. Using behavioural testing, functional MRI, spectroscopy and pharmacological manipulations in human adults, I propose to investigate the scope, cause and consequences of age-related decline in two neural factors that may play a role in these individual differences: (1) neural distinctiveness (how similar/confusable neural activation patterns are in response to different stimulus categories) and (2) brain signal variability (moment-to-moment change in neural activity independent of task). Both these measures have been found to decline with age and both have been associated with individual differences in behavior. During the predoctoral (F99) phase of the training, my research will focus on healthy aging: 1) investigating the scope and cause (specifically role of GABA levels) of age-related decline in neural distinctiveness in sensory regions, 2) the cause of age-related declines in brain signal variability, and 3) the behavioral consequences of age-related declines in these two neural measures. During the postdoctoral (K00) phase, I will extend my previous research to again study neural distinctiveness and brain signal variability, but now in the context of memory and hippocampal dysfunction, and in a clinical population (patients with Mild Cognitive Impairment, MCI). I will use task-based fMRI to measure neural distinctiveness, resting-state fMRI to measure brain signal variability, and MR spectroscopy to measure levels of various neurotransmitters (including glutamine, glutamate, NAA, and GABA), all in the hippocampus, in healthy younger and older adults as well as MCI patients. I will also collect behavioral data from the same participants during the Mnemonic similarity task (MST), a highly sensitive measure of hippocampal dysfunction. I propose to investigate a) age-related changes in neural distinctiveness and resting state variability in the hippocampus, b) the neurochemical basis of these neural changes, and c) the behavioral and pathological consequences of these neural changes. For all the MCI patients, I will also have access to a rich dataset of other biomarkers (e.g., longitudinal measures of CSF and PET-based amyloid and tau) collected at UCI’s Alzheimer’s Disease Research Center (ADRC). I will therefore be able to examine neural distinctiveness and brain signal variability in the context of the Amyloid Tau Neurodegeneration (biomarker profiling) Framework. Together, this research could lead to the development of preclinical markers for AD and open new avenues for early pharmacological interventions to treat cognitive declines in healthy and pathological aging.