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

Study Overview
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Brief Summary
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This study will use positron emission tomography (PET) to compare how people with Gaucher disease or Gaucher disease carriers with parkinsonism, and their family members, use dopamine in their brains in comparison with healthy normal volunteers and people who have Parkinson disease. PET assesses organ function by measuring metabolism. In this study, magnetic resonance imaging (MRI) is used in conjunction with PET to help better interpret and understand the information gleaned from PET. People 21 years of age and older with the following conditions may be eligible for this study: Gaucher disease and parkinsonism Parkinsonism and a family history of Gaucher disease Gaucher disease and a family history of parkinsonism Gaucher disease carriers who have parkinsonism or a family history of parkinsonism Unaffected people with a family history of Gaucher disease and parkinsonism Healthy volunteers Participants undergo the following tests and procedures: Personal and family medical history Physical examination PET scan: The subject lies on a table that slides into the PET scanner until his or her head is positioned properly in the scanner. A catheter is inserted into a vein. An initial scan is done to obtain images before radionuclides are injected. Radioactive water is then injected through the catheter and the subject is asked questions in order to stimulate blood flow in certain areas of the brain to show what parts of the brain are activated. Fluorodopa is then infused through the catheter over 3 minutes. The PET scan can last up to 2 hours. MRI scan: This test uses a magnetic field and radio waves to obtain images of organs. The subject lies still on a bed in the middle of a circular scanner for about 30 minutes.

Detailed Description
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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 comprehensively and longitudinally. This in-vivo study employs multiple imaging modalities to better define the phenotype in GBA1-associated parkinsonism, follow disease progression, and identify at-risk individuals. The subjects include patients with Gaucher disease and Gaucher carriers with parkinsonian manifestations. In addition, clinically unaffected but at-risk individuals carrying GBA mutations, with and without a family history of parkinsonism will also be included. The control groups consist of individuals with Gaucher disease but no parkinsonian symptoms and relatives of probands without GBA mutations as well as PD patients without GBA mutations and healthy volunteers enrolled in NIMH clinical protocols. Positron emission tomography (PET) with 6-[F-18] Fluoro-L-Dopa (6FD) is used to evaluate presynaptic dopaminergic function, where 6FD uptake in putamen and striatum is employed as a measure of neuronal structural integrity in the substantia nigra. H2 15O PET is used to evaluate changes in resting regional cerebral blood flow (rCBF) associated with regional changes in cortical synaptic activity and metabolism. Each subject is screened with an MRI to rule-out anatomic brain abnormalities, and to further delineate areas of interest in the PET scans. Subjects also undergo transcranial ultrasonography (TCS) to assess the substantia nigra. 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, olfactory testing and will be surveyed for potential non- motor manifestations.

Official Title
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Functional Imaging in Subjects With Glucocerebrosidase Mutations

Conditions
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Parkinson Disease, Gaucher Disease

Intervention / Treatment
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* Drug: 15-0 H20


Participation Criteria
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Eligibility Criteria
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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 GBA1 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: With severe cognitive deficits impairing decision making Unable or medically unsafe to withdraw from their current medications, such as subjects on SSRIs and other psychoactive drugs. Pregnant or nursing. All women of child bearing potential will undergo a pregnancy test. 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. Cannot lie on his/her back for a prolonged period of time

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Asymptomatic<br>Unaffected at-risk individuals with or without a first degree family member with parkinsonism, GD with and without a family history of PD, Gaucher carriers with and without a family history of PD. | Drug: 15-0 H20<br> <br> |
| Control<br>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. | Drug: 15-0 H20<br> <br> |
| PD<br>Subjects with parkinsonism to better characterize the parkinsonian phenotype (e.g.,GD/PD, Sporadic PD, Gaucher carrier PD). | Drug: 15-0 H20<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Imaging techniques | Imaging techniques will evaluate whether there are early changes in cerebral L-Dopa stores associated with glucocerebrosidase mutations in subjects with and without parkinsonism. | Ongoing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lysosomal Storage Disorder, Carrier, L-Dopa Uptake, Glucocerebrosidase, Pathogenesis, Natural History, Gaucher Disease, Healthy Volunteer, HV