Biomarkers of preclinical Alzheimer disease and cognition

 描述（由申请人提供）：随着年龄的增长，即使没有临床疾病，通常也会发现逐渐、持续的认知能力下降，这通常归因于大脑中的“正常衰老”过程。认知中与衰老相关的差异也被归因于衰老过程之外的生理机制，包括退行性疾病，如阿尔茨海默病（AD）。然而，直到最近，与临床前AD相关的病理生理学脑差异一直难以直接在体内研究，并且这些临床前生物标志物对认知的影响在正常认知老化中受到有限的研究。随着结合AD病理级联的生物标志物（例如，tau，淀粉样蛋白-β [Aβ]），现在存在允许直接检查的工具。 我们假设，在认知正常的老年人中，与AD相关的临床前生物标志物差异与葡萄糖代谢和认知障碍有关。特别是，年龄增加和弥漫性新皮质区纤维状Aβ蓄积增加将分别影响MTL亚区和MTL亚区以外的tau蓄积，tau将直接影响使用FDG PET测量的脑代谢，并间接影响认知功能。我们还将使用包括中介和路径分析在内的方法来研究tau如何介导Aβ对认知的影响，以及葡萄糖代谢如何介导tau积累对认知表现的影响。在许多研究晚年逐渐认知衰退的研究中，AD病理级联反应的临床前进展沿着可能会无意中与正常衰老过程相混淆。因此，我们的目标是研究tau蛋白和Aβ积累对大脑葡萄糖代谢的影响，已知大脑葡萄糖代谢本身在临床前AD中会发生变化，以及这些大脑差异对多个领域认知表现的相对影响。拟议的研究将有助于建立一个模型，说明在其他正常老年人中，临床前AD相关差异如何破坏脑功能和认知能力。这项研究有望通过最终临床应用于与年龄相关的认知衰退以及与Aβ和tau积累相关的疾病来影响公共卫生。我的研究计划将为我作为一名衰老和痴呆症的转化认知神经科学家的发展提供不可或缺的培训。我将在与William Jagust博士的培训期间获得PET和MRI成像以及认知老化研究方面的宝贵经验，并从其信件包含在此应用程序中的合作者那里获得宝贵的指导，利用UC Berkeley和Lawrence Berkeley National Laboratory以及与UC San弗朗西斯科合作提供的丰富学术资源。

 DESCRIPTION (provided by applicant): Gradual, consistent cognitive declines commonly found with advancing age, even in the absence of clinical disease, are often ascribed to "normal aging" processes in the brain. Age-related differences in cognition have also been attributed to physiological mechanisms beyond the aging process, including degenerative diseases such as Alzheimer's disease (AD). Yet until recently the pathophysiological brain differences associated with preclinical AD have been difficult to study in vivo directly, and the effects of such preclinial biomarkers on cognition have received limited investigation in normal cognitive aging. With the advent of positron emission tomography (PET) ligands that bind biomarkers of the AD pathological cascade (e.g., tau, amyloid-beta [Aβ]), tools now exist to permit direct examination. We hypothesize that, among cognitively normal elderly, preclinical biomarker differences associated with AD are linked with disrupted glucose metabolism and cognition. In particular, increased age and increased fibrillar Aβ accumulation in diffuse neocortical regions will influence tau accumulation in and beyond MTL subregions, respectively, and tau will directly affect brain metabolism measured using FDG PET, and indirectly affect cognitive function. We will also examine, using approaches including mediation and path analysis, how tau may mediate the effect of Aβ on cognition, and how glucose metabolism may mediate the effect of tau accumulation on cognitive performance. Preclinical progression along the AD pathological cascade may be inadvertently conflated with normal aging processes in many studies investigating gradual cognitive decline late in life. Therefore, our goal is to investigate effectsof tau and Aβ accumulation on cerebral glucose metabolism, which itself is known to change in preclinical AD, and the relative effects of these brain differences on cognitive performance across multiple domains. The proposed research will contribute to a model of how preclinical AD-related differences, in otherwise normal elderly, disrupt brain function and cognitive performance. This research holds promise for impacting public health, through eventual clinical applications to age-related cognitive decline and disorders associated with Aβ and tau accumulation. My proposed research will provide training integral to my development as a translational cognitive neuroscientist of aging and dementia. I will gain valuable experience in PET and MRI imaging and in cognitive aging research during my training with Dr. William Jagust, and gain valuable mentorship from the collaborators whose letters are included with this application, taking advantage of the rich academic resources available through UC Berkeley and Lawrence Berkeley National Laboratory and through collaboration with UC San Francisco.