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. ? ? ?
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