The long-term objective of this project is to advance the understanding of the pathophysiology and management of Parkinson's disease (PD), and allow the applicant to develop expertise in using functional MRI (fMRI) as a tool to study movement disorders. The primary mentor of this work will be Dr. Frank Longo, Chair of the Department of Neurology, and an established investigator in the area of neurodegenerative disease. Dr. Longo has particular experience in the long-term quantitative follow-up of movement disorder patients. The other mentors are Dr. Gregory McCarthy, a recognized expert in the use of fMRI for the study of cognition and behavior, and Dr. Martin McKeown, a clinical neurologist and an expert in fMRI in studying stroke patients, who will provide guidance in application of these techniques. Drs. Ray Watts, an established PD researcher, will provide critical external consultation. The clinical hallmarks of PD are tremor, muscle rigidity, bradykmesia, and postural instability; cognitive impairment related to frontal lobe dysfunction also clearly occurs. Clinical expression of the disease is not homogenous, however, as tremor-predominant PD (PDT) generally has better long-term motor outcome with fewer motor fluctuations, less levodopa-induced dyskinesias, a slower rate of progression, and fewer cognitive deficits when compared with akinetic-rigid-predominant PD (PDAR). Although most of the symptomatology of PD may be explained by the classic model of basal ganglia-thalamocortical circuitry as related to dopamine neuron degeneration, the resting tremor cannot. I propose a new model involving two segregated, but functionally related parallel loops of the basal ganglia-thalamocortical and cerebello-thalomocortical circuits. My working hypothesis is that the key differences between subtypes of PD are related to the differential involvement of the two major motor regulatory circuits due to different degrees and/or locations of neurodegeneration of melanin-containing neurons in PD. Study of the hypothesis will be accomplished via four specific aims: 1) Stratifiy the patients to PD subtypes 1) according to their clinical features; 2) Compare the differential fMRI activation of the frontal lobe areas (e.g. SMA, DLPFC) in different subtypes of PD patients using a alternative hands squeeze task, and a event-related Go-No-Go paradigm; 3) Compare the differential fMRI activation of cerebellum (i.e.. hemisphere, and anterior vermis/paravermis) in different subtypes of PD patients using a supination/pronation movement paradigm; 4) Assess the effects of levodopa on the clinical symptoms, activation patterns of frontal cortex, and cerebellum in different subtypes of PD patients.
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