Molecular and Functional Imaging of Age Related Cognitive Decline

描述(申请人提供)：大脑老化可能导致被归入额叶/执行系统类别的认知功能下降。这些能力包括工作记忆，这是一种在相对较短的时间内存储和处理信息非常重要的记忆形式。来自正电子发射断层扫描(PET)和功能磁共振成像(FMRI)的行为和成像研究的大量证据表明，随着年龄的增长，工作记忆的各个方面都会下降或改变。工作记忆依赖于一种利用多巴胺作为神经递质的神经化学系统，该系统也会随着年龄的增长而衰退。尽管多种神经系统可以弥补这一损失，但补偿是不完整的，工作记忆的行为和生理指标随着年龄的增长有相当大的变异性。该项目的核心假设是，这种与年龄相关的变异性与老年人不同水平的多巴胺神经支配有关。我们将通过将多巴胺功能的PET测量与工作记忆表现的行为测量以及工作记忆任务期间大脑激活的fMRI测量相关联来探索这一假设。该项目将招募60名健康的老年人(年龄55-85岁)和30名健康的年轻人(年龄25-35岁)，他们将接受带有示踪剂[18F]荧光酪氨酸(FMT)的PET，以测量突触前多巴胺能功能。认知测试将评估广义认知和工作记忆。在功能磁共振成像中，受试者将执行一项可变负荷的工作记忆任务(斯特恩伯格任务)，该任务旨在刺激前额叶背外侧皮质的激活。我们将把纹状体和皮质中FMT摄取的测量与大脑激活和行为模式联系起来，假设FMT摄取较低的老年人在fMRI中大脑激活增加，工作记忆表现较差，而FMT摄取较高的老年人将显示出与年轻人类似的fMRI激活和工作记忆模式。这个项目意义重大，因为大脑老化是一个多因素的过程，其特点是不同大脑系统的可变退化和补偿。了解这些与年龄相关的变化的基础，可以为补救提供设计神经化学特异性治疗的能力，以及区分与年龄相关的认知下降的不同原因的方法。

DESCRIPTION (provided by applicant): Brain aging may result in the decline of cognitive functions subsumed under the category of frontal/executive systems. These abilities include working memory, a form of memory that is important in storing and manipulating information over relatively short times. Considerable evidence from both behavioral and imaging studies with positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) shows that various aspects of working memory decline or change with aging. Working memory depends upon a neurochemical system that utilzes dopamine as a neurotransmitter, a system that also declines with advancing age. Although a variety of neural systems may compensate for this loss, compensation is incomplete, and there is considerable variability in behavioral and physiological measures of working memory with aging. The core hypothesis of this project is that this age-associated variability is related to different levels of dopamine innervation in older people. We will explore this hypothesis by relating PET measures of dopamine function to behavioral measures of working memory performance and fMRI measures of brain activation during a working memory task. The project will recruit 60 healthy older (age 55-85) and 30 healthy younger (age 25-35) individuals who will undergo PET with the tracer [18F]fluorometatyrosine (FMT) to measure presynaptic dopaminergic function. Cognitive tests will assess generalized cognition and working memory. During fMRI subjects will perform a working memory task with variable loads (the Sternberg task) that is designed to elicit activation in dorsolateral prefrontal cortex. We will relate measures of FMT uptake in striatum and cortex to patterns of brain activation and behavior, hypothesizing that older people with lower FMT uptake will show increased brain activation during fMRI and poorer working memory performance, while older subjects with higher FMT uptake will show patterns of fMRI activation and working memory that are similar to younger individuals. The project is significant because brain aging is a multifactorial process characterized by variable degeneration and compensation in different brain systems. Understanding the basis of these age-related changes could provide the ability to design neurochemically specific treatments for remediation, as well as ways of differentiating different etiologies of age-related cognitive decline from one another.