An association between Gaucher disease and parkinsonism has been demonstrated by the concurrence of parkinsonian manifestations in over 30 patients with Gaucher disease and an increased incidence of glucocerebrosidase mutations in subjects with parkinsonism. Furthermore, there appears to be a significant number of obligate and confirmed Gaucher carriers with parkinsonian manifestations. Thus, glucocerebrosidase mutations may be a risk factor for development of parkinsonism. However in affected and at-risk individuals, the identification and characterization of early parkinsonian manifestations and the rate of progression of symptoms have not been studied objectively. We propose an in-vivo study of regional cerebral dopamine neurochemistry and blood flow in subjects with glucocerebrosidase mutations. Presynaptic dopaminergic function and cerebral blood flow will be assessed using positron emission tomography (PET) with 6-[F-18] Fluoro-L-DOPA (6FD) and 15 O-H2O in a single PET session. The subjects will include patients with Gaucher disease and Gaucher carriers with parkinsonism, and/or with a family history of a first degree relative with parkinsonism. The control group will include family members lacking glucocerebrosidase mutations, age matched healthy controls, and subjects with parkinsonism without glucocerebrosidase mutations. The kinetic rate constant (Ki) for striatal dopaminergic uptake will be calculated. Using bivariate analysis we will compare the Ki in groups of subjects with glucocerebrosidase mutations, with and without parkinsonian manifestations, with aged-matched healthy volunteers, to identify potential abnormalities in striatal and putamenal presynaptic F-dopa uptake. Each subject will be screened with an MRI to rule-out structural abnormalities, and to further delineate areas of interest in the PET scans.

Subjects will also undergo transcranial ultrasonography (TCS) to assess echogenicity of the midbrain. This study will help us to identify abnormalities in L-Dopa uptake in subjects with glucocerebrosidase mutations, to better define the associated parkinsonian phenotype, follow the progression of parkinsonian manifestations and identify "at-risk" indiviuals. The baseline data regarding L-Dopa metabolism in subjects with glucocerebrosidase mutations will enable us to estimate the frequency and earliest onset of parkinsonian symptoms in at-risk subjects. The results of both the PET scans and TCS will be kept confidential, and will not be communicated to the individuals or families involved in the study.