PET Imaging of Phosphodiesterase-4 (PDE4) in Brain and Peripheral Organs of McCune-Albright Syndrome

Nervous System Disease

GsI+/-, Camp, GNAS

Background: McCune-Albright Syndrome (MAS) is a disorder that affects the bones, skin, and some hormone-producing tissues. It is associated with a mutation in a gene. This gene affects enzymes in the brain and body. Researchers want to learn more about one of these enzymes, Phosphodiesterase 4 (PDE4), in people with MAS. Objective: To see if people with MAS have higher levels of PDE4 than people without MAS. Eligibility: People ages 18 and older who have MAS and participated in protocol 98-D-0145, Screening and Natural History of Patients with Polyostotic Fibrous Dysplasia and the McCune-Albright Syndrome. Healthy adult volunteers are also needed. Design: This study requires 1 to 4 outpatient visits to the NIH Clinical Center. Some visits may take place on the same day. Participants with MAS will be screened with medical history and physical exam. They will have blood and urine tests. Participants will have a magnetic resonance imaging scan. Participants will have a full body positron emission tomography (PET) scan. A small amount of a radioactive chemical, \[11C\](R)-rolipram, will be given through an intravenous tube. Participants will have a brain PET scan with \[11C\](R)-rolipram. For this, a thin plastic tube will also be put into an artery at their wrist or elbow crease area. For the scans, participants will lie on a bed that slides in and out of a scanner. They may wear a plastic mask to hold their head in place. They will have blood drawn. Participants with MAS will be interviewed about their thinking and mood. They may complete questionnaires about how they feel or think.

Objective: McCune-Albright syndrome (MAS) is a mosaic disease arising from early embryonic somatic activating mutations of GNAS, which encodes the 3 \<=, 5 \<=-cyclic adenosine monophosphate (cAMP) pathway-associated G-protein, Gs . Constitutive activation of Gs leads to increased cAMP signaling in brain, as well as in peripheral organs, particularly bones. Although subjects with MAS show psychiatric and neurological symptoms, few studies have attempted to assess brain changes in these individuals. This protocol seeks to study changes in the cAMP cascade both in brain and peripheral organs of individuals with MAS using \[11C\](R)-rolipram PET, which binds to phosphodiesterase 4 (PDE4) and reflects cAMP cascade activity. Study population: Participants will include 20 subjects with MAS and 15 healthy subjects group-matched to MAS subjects for age and gender. Both MAS subjects and healthy controls will have one or two PET scans: one whole body and one brain scan. We expect about 10 brain and 10 whole body scan to be performed in each group. Design: Subjects with MAS will be recruited from participants in 98-D-0145 Screening and Natural History of Patients with Polyostotic Fibrous Dysplasia and the McCune-Albright Syndrome (PI: Alison M. Boyce, MD). Only participants in protocol (98-D-0145) who provided self-consent without a legally authorized representative will be recruited. Brain PET scans will be performed by measuring metabolite-corrected arterial input function. No venous blood sampling will be performed for whole body scans. Outcome measures: The primary outcome measure will be obtained in brain scans as the amount of radioligand binding quantified as distribution volume (Vt). Calculated from both brain and plasma data, Vt reflects rolipram binding to PDE4, corrected for any individual differences in metabolism of the radioligand or regional blood flow in brain. The secondary outcome measure will be obtained in whole body scans as area under the curve (AUC) of radioactivity expressed as standard uptake value (SUV). SUV is calculated by normalizing radioactivity in PET images to injection activity and body weight. Vt in brain will be compared between subjects with MAS and healthy controls. AUC will be compared within-subjects with MAS between areas of craniofacial fibrous dysplasia and adjacent unaffected bone. AUC of whole body scans will also be compared between subjects with MAS and healthy controls. We hypothesize that subjects with MAS will show greater rolipram binding than healthy controls in brain regions, as well as greater rolipram uptake in bones affected by fibrous dysplasia than in unaffected bones.

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