The goals of this project are to determine, with in vivo emission tomography, the temporal and spatial sequence of declines in cerebral cholinergic enzyme activity and cholinergic terminal integrity in patients suspected of early Alzheimer s disease (AD) and in Parkinson s disease (PD), with and without dementia, and to correlate these neuronal biochemical alterations with associated cognitive declines. Hypotheses to be tested include: 1) in normal aging, AD, and PD, patterns differ, but cholinergic enzyme loss always precedes and exceeds cholinergic terminal loss both in severity and in extent; 2) in patients suspected of early AD, those with cholinergic enzyme deficits will progress to AD and those without enzyme deficits will not; and 3) patients with early AD who have the most severe temporal cholinergic deficits and occipital hypometabolism also have the premortem clinical criteria and neuro-psychological profile which have been attributed to Diffuse Lewy Body Disease (DLBD). These issues are difficult to establish with postmortem examinations due to the lack of tissue from early disease. Emission tomography studies using radioactive ligand markers of the presynaptic vesicular acetylcholine transporter (VAChT) and acetylcholinesterase (AChE) substrate utilization are proposed in well characterized controls and patients. In parallel with these imaging studies, the development of a new AChE-inhibitor ligand is proposed. This agent will be evaluated in small animal and primate studies in preparation for radiotracer pharmacokinetic evaluation in humans. Success in these efforts is expected to aid the early differential diagnosis of dementing disorders and to provide new insights into the basic pathophysiology of these diseases. Such information could facilitate new pharmacologic classifications of patients, better matches of patients to therapies, more rational pathways to new drugs, and guides to new therapies and strategies for neuroprotection.
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