Biomarkers of preclinical Alzheimer disease and cognition

临床前阿尔茨海默病和认知的生物标志物

基本信息

批准号：
9050534
负责人：
Samuel Neal Lockhart
金额：
$ 5.24万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-01 至 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9050534
关键词：
Affect Age Age-associated memory impairment Aging Aging-Related Process Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid beta-Protein Biological Markers Brain Brain imaging Brain region Cerebrum Clinical Clinical Trials Cognition Cognition Disorders Cognitive Cognitive aging Cognitive deficits Collaborations Consensus Degenerative Disorder Dementia Deposition Development Diagnosis Diffuse Disease Elderly Episodic memory Etiology Failure Functional disorder Future Goals Hippocampus (Brain)Human Image Imagery Impaired cognition Investigation Knowledge Laboratories Letters Life Ligand Binding Link Magnetic Resonance Imaging Measures Medial Mediating Mediation Mentorship Metabolic Methods Nerve Degeneration Neurodegenerative Disorders Neuropsychological Tests Neurosciences Research Participant Pathology Patients Pattern Physiological Positron-Emission Tomography Pre-Clinical Model Public Health Relative (related person)Research Research Personnel Resources San Francisco Staging Structure Symptoms Techniques Temporal Lobe Testing Time Training abeta accumulation age related basal forebrain brain metabolism clinical application clinical diagnosis cognitive function cognitive performance executive function experience fluorodeoxyglucose positron emission tomography glucose metabolism improved in vivo interest mild cognitive impairment neocortical normal aging pre-clinical processing speed public health relevance radioligand relating to nervous system tau Proteins tau aggregation theories tool

项目摘要

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.

描述（适用提供）：逐渐，一致的认知能力下降，即使在没有临床疾病的情况下，年龄也会逐渐降低，通常也归因于大脑中的“正常衰老”过程。与年龄有关的认知差异也归因于衰老过程以外的物理机制，包括退化性疾病，例如阿尔茨海默氏病（AD）。然而，直到最近，与临床前AD相关的病理生理大脑差异一直很难直接研究，并且这种临床前生物标志物对认知的影响对正常认知衰老的投资有限。随着极性发射断层扫描（PET）配体结合AD病理级联反应的生物标志物（例如Tau，淀粉样蛋白β[Aβ]）的生物标志物，现在存在工具以允许直接检查。我们假设，在认知正常的临床前生物标志物差异中，与AD相关的差异与葡萄糖代谢和认知的破坏有关。特别是，弥漫性新皮层区域中的年龄增加和纤维化Aβ的积累分别将影响MTL子区域内和超越TAU的积累，而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进行检查，tau如何中位数Aβ对认知的影响以及葡萄糖代谢如何中值tau积累对认知性能的影响。在许多研究中，生命后期认知能力下降的许多研究中，沿AD病理级联的临床前进展可能与正常的衰老过程混合在一起。因此，我们的目标是研究tau和Aβ积累对脑葡萄糖代谢的影响，众所周知，临床前AD会发生变化，以及这些大脑差异对多个领域认知性能的相对影响。拟议的研究将有助于临床前广告相关的差异，在正常的较旧的，破坏大脑功能和认知性能中。这项研究有望通过最终将与年龄相关的认知下降和与Aβ和TAU积累相关的疾病进行临床应用来影响公共卫生。我提出的研究将为我作为翻译的衰老和痴呆症的认知神经科学家的发展提供培训的组成部分。在与William Jagust博士的培训期间，我将在PET和MRI成像以及认知老化研究中获得价值经验，并从合作者那里获得价值心态，这些合作者利用了该应用程序包含在此应用程序中的信件，利用了通过UC Berkeley和Lawrence Berkeley国家实验室获得丰富的学术资源，并通过与UC San Francisco的合作获得了。