Molecular and Functional Imaging of Age Related Cognitive Decline

描述（由申请人提供）：大脑老化可能导致额叶/执行系统类别下的认知功能下降。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的重要记忆形式。大量来自行为和正电子发射断层扫描（PET）和功能性磁共振成像（fMRI）的成像研究的证据表明，工作记忆的各个方面随着年龄的增长而下降或改变。工作记忆依赖于一个将多巴胺作为神经递质的神经化学系统，这个系统也会随着年龄的增长而衰退。虽然各种神经系统可以补偿这种损失，但补偿是不完全的，并且随着年龄的增长，工作记忆的行为和生理测量存在相当大的变化。该项目的核心假设是，这种与年龄相关的变化与老年人多巴胺神经支配的不同水平有关。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），他们将使用示踪剂[18F]荧光酪氨酸（FMT）进行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。在功能磁共振成像过程中，受试者将执行可变负荷的工作记忆任务（斯滕贝格任务），该任务旨在引起背外侧前额叶皮层的激活。我们将纹状体和皮质中FMT摄取的测量与大脑激活和行为的模式相关联，假设FMT摄取较低的老年人在fMRI期间会显示出大脑激活增加，工作记忆表现较差，而FMT摄取较高的老年受试者会显示出与年轻人相似的fMRI激活和工作记忆模式。该项目意义重大，因为大脑老化是一个多因素的过程，其特征是不同大脑系统的变性和补偿。了解这些与年龄相关的变化的基础可以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衰退的不同病因的方法。

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.