Neuroimaging GABA Physiology in Fragile X Syndrome

Study Overview
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Brief Summary
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The investigators wish to compare the brain distribution of GABA(A) receptors and GABA levels in young adult males with Fragile X Syndrome compared to idiopathic intellectual developmental disorder. The radiopharmaceutical [18F]flumazenil has been used to study GABA(A) receptor distribution in other genetic syndromes with autistic features; however, despite overwhelming evidence supporting the importance of the GABAergic system in FXS, no clinical investigation of this system in human FXS has been reported in the literature. Therefore, this study will provide the first in vivo comprehensive examination of the GABAergic system in FXS using hybrid positron emission tomography/ magnetic resonance imaging (PET/MRI).

Detailed Description
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Fragile X syndrome (FXS) is the most common genetic cause of autism spectrum disorder (ASD). Converging evidence suggests that GABAergic dysfunction occurs in FXS. The investigators wish to examine brain distribution of GABA (A) receptors in young adult males with FXS using hybrid PET/MRI with [18F]flumazenil. This project will study the distribution of GABA(A) receptors in 15 young male adults with FXS (18-30 years old) compared to 15 age-matched male subjects with idiopathic intellectual developmental disorder (IDD) as controls. Simultaneous PET/MRI acquisition is an optimal technique to study in vivo GABAergic dysfunction and GABAa receptor distribution.

Official Title
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Cross-Species Multi-Modal Neuroimaging to Investigate GABA Physiology in Fragile X Syndrome

Conditions
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Fragile X Syndrome (FXS), Idiopathic Intellectual Developmental Disorder (IDD)

Intervention / Treatment
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* Drug: [18F]flumazenil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for participants with FXS: Have an established diagnosis of FXS (full mutation with aberrant FMR1 methylation) by genetic testing Diagnosis of intellectual disability Males who are physically healthy Age 18 to 30 years inclusive IQ between 40 and 80 points Ability to remain seated for more than 10 minutes Ability to travel to Stanford Exclusion criteria for participants with FXS: Diagnosis of a known genetic disorder (other than FXS). Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders. Significant sensory impairments such as blindness or deafness. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia. Pre-term birth (<34 weeks' gestation) or low birth weight (<2000g). Current use of benzodiazepines. Contraindication for PET or MRI. Inclusion criteria for participants with IDD: Age 18 to 30 years inclusive Adults who are physically healthy No significant recent changes in psychosocial stressors per history Diagnosis of intellectual disability IQ between 40 and 80 points Ability to remain seated for more than 10 minutes Ability to travel to Stanford Exclusion Criteria for participants with IDD: Genetic diagnosis of FXS. Active medical problems such as unstable seizures, congenital heart disease, endocrine disorders. Significant sensory impairments such as blindness or deafness. DSM-5 diagnosis of other severe psychiatric disorder such as bipolar disorder or schizophrenia. Pre-term birth (<34 weeks' gestation) or low birth weight (<2000g). Current use of benzodiazepines. Contraindication for PET or MRI.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 15 male subjects with FXS will be compared to 15 subjects with idiopathic intellectual developmental disorder, who will be the control group. Young male adults with idiopathic intellectual developmental disorder will be (group) matched to FXS participants for mean age (and age range), handedness, socioeconomic status and ethnicity.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fragile X Syndrome<br>Adult males aged 18-30 years diagnosed with FXS will undergo a non-invasive F18 FMZ PET/MRI scan to determine GABA(A) receptor density; developmental dynamics of GABA(A) receptor distribution, and structural neuroanatomy and connectional anatomy. | Drug: [18F]flumazenil<br>* [18F]flumazenil is a PET radiopharmaceutical that can be used to determine gamma-aminobutyric acid (GABA(A)) receptor density.<br>* Other names: F18 FMZ;|
| Experimental: Idiopathic Intellectual Developmental Disorder<br>Adult males aged 18-30 years diagnosed with idiopathic intellectual developmental disorder will undergo a non-invasive F18 FMZ PET/MRI scan to determine GABA(A) receptor density; developmental dynamics of GABA(A) receptor distribution, and structural neuroanatomy and connectional anatomy. | Drug: [18F]flumazenil<br>* [18F]flumazenil is a PET radiopharmaceutical that can be used to determine gamma-aminobutyric acid (GABA(A)) receptor density.<br>* Other names: F18 FMZ;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non-displaceable binding potential of [18F]flumazenil (F18 FMZ) | Binding potential provides an estimate of the GABA (A) receptor distribution and affinity of [18F]flumazenil-PET to the GABA receptors. Binding potential will be measured in patients with fragile X syndrome and control group comprising individuals with idiopathic intellectual developmental disorder. Using imaging data obtained from PET that was corrected for attenuation and partial volume effects by MRI, nuclear medicine physicians will draw regions of interest (ROI's) around the areas of the brain listed below to estimate the F18 FMZ non-displaceable binding potential (BPnd) of F18 FMZ to GABA (A) receptors in FXS. | Up to 2 hours per scan on a single study day | 
| GABA (A) receptor density in fragile X syndrome (FXS) patients relative to control group comprising individuals with idiopathic Intellectual Developmental Disorder (IDD) | Binding potential measurements will be compared between participants with fragile X syndrome and control group with idiopathic intellectual developmental disorder(IDD) using the PET radiotracer [18F]flumazenil-PET. Binding Potential (BPnd) is estimated as the distribution volume ratio (DVR) -1. DVR's of tracers are used in PET receptor studies where the radiopharmaceutical can be specifically bound to receptors; nonspecifically bound to other macromolecular components, or free in tissue (FT). DVR is calculated using a Logan Plot, which uses the dynamic PET images obtained during imaging and compartment modeling to graphically analyze by linear regression pharmacokinetic data for radiopharmaceuticals that undergo 'reversible' uptake. PET scans of FXS patients will be compared to the PET scans of control group. | Up to 2 hours per scan on a single study day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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FXS, Intellectual Disability