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

正常衰老通常与认知、运动和感觉功能的普遍下降有关；然而，存在巨大的个体差异：一些老年人经历轻微的损害，而另一些人经历严重的认知下降。在设计未来的干预措施以解决与年龄相关的认知障碍时，了解衰老过程中个体差异的神经基础是必不可少的。利用行为测试、功能磁共振成像、光谱学和药理学操作，我提议调查与年龄相关的两个神经因素下降的范围、原因和后果，这两个因素可能在这些个体差异中发挥作用：(1)神经区别性(神经激活模式对不同刺激类别的反应有多相似/容易混淆)和(2)大脑信号变异性(与任务无关的神经活动的时刻变化)。这两项指标都被发现随着年龄的增长而下降，而且都与个体行为差异有关。在博士前阶段(F99)，我的研究将集中在健康老龄化：1)调查与年龄相关的感觉区域神经区分性下降的范围和原因(特别是GABA水平的作用)，2)与年龄相关的大脑信号变异性下降的原因，以及3)这两个神经指标与年龄相关的下降的行为后果。在博士后阶段(K00)，我将扩展我之前的研究，再次研究神经区别性和大脑信号变异性，但现在是在记忆和海马体功能障碍的背景下，并在临床人群(轻度认知障碍患者，MCI)中进行。我将使用基于任务的功能磁共振成像来测量神经特异性，使用静息状态功能磁共振成像来测量大脑信号的变异性，并使用磁共振波谱来测量各种神经递质(包括谷氨酰胺、谷氨酸、NAA和GABA)的水平，所有这些都在海马体中，在健康的年轻人和老年人以及MCI患者中。我还将在记忆相似性任务(MST)期间收集相同参与者的行为数据，MST是海马区功能障碍的一种高度敏感的衡量标准。我建议研究a)与年龄相关的神经区别性和海马区静息状态变异性的变化，b)这些神经变化的神经化学基础，以及c)这些神经变化的行为和病理后果。对于MCI患者，我还将获得UCI阿尔茨海默病研究中心(ADRC)收集的丰富的其他生物标记物的数据集(例如，脑脊液和基于PET的淀粉样蛋白和tau的纵向测量)。因此，我将能够在淀粉样蛋白tau神经变性(生物标记物剖析)框架的背景下检查神经区别性和脑信号变异性。总之，这项研究可能导致阿尔茨海默病(AD)临床前标志物的开发，并为早期药物干预开辟新的途径，以治疗健康和病理性衰老中的认知衰退。

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 behavioral 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 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 Alzheimer’s disease (AD) and open new avenues for early pharmacological interventions to treat cognitive decline in healthy and pathological aging.