Back to resultsNeuroimaging GABA Physiology in Fragile X Syndrome
Primary Purpose
Fragile X Syndrome (FXS), Idiopathic Intellectual Developmental Disorder (IDD)
Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
[18F]flumazenil
Sponsored by
About this trial
This is an interventional basic science trial for Fragile X Syndrome (FXS) focused on measuring FXS, Intellectual Disability
Eligibility Criteria
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.
Sites / Locations
- Stanford University
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Experimental
Arm Label
Fragile X Syndrome
Idiopathic Intellectual Developmental Disorder
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
Secondary Outcome Measures
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT04308954
Brief Title
Neuroimaging GABA Physiology in Fragile X Syndrome
Official Title
Cross-Species Multi-Modal Neuroimaging to Investigate GABA Physiology in Fragile X Syndrome
Study Type
Interventional
2. Study Status
Record Verification Date
January 2021
Overall Recruitment Status
Terminated
Why Stopped
Difficulty with patient recruitment due to COVID-19 pandemic
Study Start Date
November 1, 2016 (Actual)
Primary Completion Date
December 6, 2018 (Actual)
Study Completion Date
December 6, 2018 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Stanford University
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Fragile X Syndrome (FXS), Idiopathic Intellectual Developmental Disorder (IDD)
Keywords
FXS, Intellectual Disability
7. Study Design
Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
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)
Allocation
Non-Randomized
Enrollment
17 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Fragile X Syndrome
Arm Type
Experimental
Arm Description
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.
Arm Title
Idiopathic Intellectual Developmental Disorder
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
[18F]flumazenil
Other Intervention Name(s)
F18 FMZ
Intervention Description
[18F]flumazenil is a PET radiopharmaceutical that can be used to determine gamma-aminobutyric acid (GABA(A)) receptor density.
Primary Outcome Measure Information:
Title
Non-displaceable binding potential of [18F]flumazenil (F18 FMZ)
Description
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.
Time Frame
Up to 2 hours per scan on a single study day
Title
GABA (A) receptor density in fragile X syndrome (FXS) patients relative to control group comprising individuals with idiopathic Intellectual Developmental Disorder (IDD)
Description
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.
Time Frame
Up to 2 hours per scan on a single study day
10. Eligibility
Sex
Male
Gender Based
Yes
Gender Eligibility Description
Participants must be male adults with idiopathic intellectual developmental disorder (IDD) or fragile X-syndrome (FXS)
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
30 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Frederick T Chin, PhD
Organizational Affiliation
Stanford University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Stanford University
City
Stanford
State/Province
California
ZIP/Postal Code
94305
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
15109994
Citation
Lucignani G, Panzacchi A, Bosio L, Moresco RM, Ravasi L, Coppa I, Chiumello G, Frey K, Koeppe R, Fazio F. GABA A receptor abnormalities in Prader-Willi syndrome assessed with positron emission tomography and [11C]flumazenil. Neuroimage. 2004 May;22(1):22-8. doi: 10.1016/j.neuroimage.2003.10.050.
Results Reference
background
PubMed Identifier
11198279
Citation
Holopainen IE, Metsahonkala EL, Kokkonen H, Parkkola RK, Manner TE, Nagren K, Korpi ER. Decreased binding of [11C]flumazenil in Angelman syndrome patients with GABA(A) receptor beta3 subunit deletions. Ann Neurol. 2001 Jan;49(1):110-3. doi: 10.1002/1531-8249(200101)49:13.0.co;2-t.
Results Reference
background
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Neuroimaging GABA Physiology in Fragile X Syndrome
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