Positron Emission Tomography (PET) Imaging in People With Gaucher Mutations

An association between Gaucher disease and parkinsonism has been demonstrated by the
concurrence of parkinsonian manifestations in patients with Gaucher disease and an increased
incidence of glucocerebrosidase (GBA) mutations in subjects with parkinsonism of various
ethnicities. Furthermore, there is a significant number of obligate and confirmed Gaucher
carriers with parkinsonian manifestations. Thus, alterations in GBA appear to be a more
common risk factor than previously thought for the development of sporadic Parkinson disease
and related disorders. 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 that will employ
multiple imaging modalities to better define the phenotype in GBA-associated parkinsonism,
follow disease progression, and identify at-risk individuals. The subjects include patients
with Gaucher disease and Gaucher carriers with parkinsonian manifestations, and clinically
unaffected but at-risk individuals carrying GBA mutations, and have/ a first degree relative
with parkinsonism. The control groups consist of individuals with Gaucher disease but no
parkinsonian symptoms, relatives of probands without GBA mutations, PD patients without GBA
mutations, and healthy volunteers. Positron emission tomography (PET) with 6-[F-18]
Fluoro-L-Dopa (6FD) will be used to evaluate presynaptic dopaminergic function, where 6FD
uptake in putamen and striatum will be employed as a measure of neuronal structural integrity
in substantia nigra. Each subject will be screened with an MRI to rule-out anatomic brain
abnormalities, and to further delineate areas of interest in the PET scans. Subjects will
also undergo transcranial ultrasonography (TCS) to assess the substantia nigra
non-invasively. 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. In addition to the
imaging studies, all patients will undergo a physical and neurological examination,
neurocognitive evaluation, and olfactory testing.

- INCLUSION CRITERIA:

The study will include adult subjects age 21 or older carrying GBA mutations. The two major
study groups will include subjects with parkinsonism and unaffected subjedcts yet at risk
with a first degree family member with parkinsonism.

Controls will include subjects without GBA mutations, with sporadic PD and healthy
volunteers who do not have a family history of parkinsonism or Gaucher disease.

Healthy Volunteers and Control subjects will be matched for age, gender and handedness for
statistical purposes.

EXCLUSION CRITERIA:

The subjects excluded from the study are those:

1. with severe cognitive deficits impairing decision making

2. unable or medically unsafe to withdraw from their current medications, such as
subjects on SSRIs and other psychoactive drugs.

3. pregnant or nursing. All women of child bearing potential will undergo a pregnancy
test.

4. With a history of neurologic conditions such as stroke or any focal brain lesion that
may result in parkinsonian manifestations. Individuals with such MRI findings will be
excluded from the study.