Positron emission tomography (PET) has increased understanding of Alzheimer's disease (AD) by demonstrating specific abnormalities of regional cerebral blood flow and metabolism. However, these studies have not generally been longitudinal and have been limited to small patient groups; thus questions remain regarding the progression of these changes over time, and their relationship to neuropathological abnormalities and clinical progression of the disease. This application propose to utilize the more practical and widely available technique of single photon emission computed tomography (SPECT) to follow a large cohort of patients with AD and Parkinson's disease (PD) in order to understand the evolution of regional blood flow changes, their relationship to neuropathology and clinical disease progression, and the relationship of the two diseases to each other. The project will enroll 30 new AD patients and 20 new PD patients per year for the first three years and follow them with yearly SPECT studies and neuropsychological evaluations for the 5 years of the study. A total of 90 patients with AD and 60 patients with PD will be evaluated. A group of 26 AD patients is already enrolled in a preliminary study and will continue to be followed and augmented, assuring a long period of observation. The blood flow tracer 123I-N-isopropyl-p-iodoamphetamine (IMP) will be utilized with the Cleon multidetector scanner for SPECT imaging. A subset of 20 patients from each group will be studied using PET with the quantitative blood flow tracer 122I-N,N,N'-trimethyl-N'- (2-hydroxy-3-methyl-5-iodobenzyl)-1,3-propanediamine (HIPDM) in order to validate the SPECT studies. A major hypothesis is that while patients with mild and moderate AD will show temporoparietal blood flow deficits (which will increase in severity as the disease progresses), severely demented patients will also show frontal lobe hypoperfusion. Patients with PD, on the other hand, are expected to demonstrate frontal deficits in early disease stages while a temporoparietal pattern of hypoperfusion will appear in some patients and predict the development of a severe dementia with Alzheimer neuropathological features. These physiological abnormalities are expected to correlate with both the cognitive abnormalities revealed on neuropsychological testing, and the regional histopathological abnormalities seen post-mortem. Of major potential clinical significance is the prospect that different perfusion patterns will identify different clinical subtypes, elucidating the pathophysiological mechanisms responsible for the clinical heterogeneity of these diseases.
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