Memory impairment is a common problem in Parkinson' disease (PD). This proposal investigates working memory (i.e. short-term memory) deficits in PD patients as compared to normal elderly. My first aim is to determine the nature of the working memory deficits in PD. 1 hypothesize an impairment in a specific component of working memory called the "central executive system" (CBS), that is critical for allocating limited attentional resources. This hypothesis will be tested by performing dual- task paradigms designed to directly examine CBS functioning. An alternative hypothesis, that PD patients have weakened working memory representations rather than a defective CBS, will also be tested. The second aim is to define the neuroanatomical basis of working memory. Primate studies have shown that the caudal principal sulcus is critical for working memory. Physiological studies have not examined the CBS of working memory in either primates or humans. Cognitive activation studies during dual-task paradigms using PET and functional MRI will be performed in normal human subjects to define the neural network subserving the CBS of working memory. I hypothesize that the dorsolateral prefrontal cortex (Brodmann areas 9 and 46) will activate during dual-task paradigms. I will also examine PD patients with CBS deficits. I hypothesize that CBS impairments found "off-line" in PD patients will correlate with resting hypoperfusion in the dorsolateral prefrontal cortex. Also, these patients will fail to activate the dorsolateral prefrontal cortex when performing these CBS tasks, suggesting that this region is functionally defective in this disease. The third aim is to determine the neurochemical basis of working memory. The role of dopamine in human working memory will be tested by studying PD patients "on" and "off' medications and investigating the effect of administering a dopaminergic agonist to normal elderly subjects. I hypothesize that the CBS of working memory will improve during the "on" state in PD patients and after dopamine stimulation in normal elderly subjects. In this fashion, a multi-factorial model characterizing the cognitive, neuroanatomical and neurochemical basis for working memory will be defined. These studies will improve our knowledge of working memory and provide a rational basis for diagnostic and therapeutic intervention in patients with working memory impairments.
