The previous funding period of this project supported the use of positron emission tomography (PET) and single photon emission computed tomography (SPECT) to study the changes in regional cerebral blood flow and metabolism in Alzheimer's disease (AD). This application proposes to use PET to investigate the relationship between these perfusion abnormalities, cognitive deficits, and regional changes in dopamine metabolism in patients with AD and Parkinson's disease (PD), an illness associated with a dementia sharing clinical, pathological, and imaging characteristics with AD. While the striatal dopamine deficiency in PD is well established, evidence from PET and neuropsychological investigations also implicates the frontal lobes as an area affected by the disease. In AD, clinical and pathologic studies suggest a role for dopaminergic dysfunction in the pathophysiology of frontal lobe and extrapyramidal symptoms. The use of the dopamine metabolic tracer (18F)-6-fluorodopa with high resolution PET will allow the determination of the role of frontal lobe, putaminal, and caudate dopamine deficiency in the production of frontal lobe hypoperfusion and cognitive symptomatology in these diseases. The study design entails the evaluation of PD and AD patients and controls, with specific reference to the presence of frontal lobe perfusion abnormalities, extrapyramidal symptoms, and frontal cognitive deficits. All patients will be selected from a larger cohort enrolled in an ongoing longitudinal study of changes in blood flow using SPECT, and will receive continued clinical follow up with a view to ultimate autopsy correlation. The PET-600 tomograph, which has a resolution of 2.6 mm, will be used for all studies. Immediately following a study to evaluate regional blood flow using the tracer (122I)-HIPDM (210 sec half life), subjects will undergo a fluorodopa PET study. Quantitative analysis of the data will utilize an input function determined via an arterial catheter with an on-line technique, together with dynamic PET brain uptake data. The blood and brain time-activity curves will be used in conjunction with models for blood flow and dopamine metabolism to derive parameters describing regional cerebral blood flow and dopamine metabolism. The dopamine metabolkc model will employ the known time course of significant metabolic products of the tracer in order to quantitate rate constants for transport and metabolism. The major hypothesis is that putaminal abnormalities of dopamine metabolism will be related to the extrapyramidal symptoms seen in PD and AD subjects. In addition, the frontal lobe perfusion deficits ans cognitive deficits are expected to be associated with diminished frontal lobe dopamine metabolism. Such studies will expand our understanding of the specific pattern of dopamine deficiency in these states and will relate neurotransmitter deficits to cognitive and blood flow abnormalities which have important implications for understanding the pathophysiology and potential treatments for both diseases.
