PET Imaging Study of Amish and Mennonite Patients With CNTNAP2 Mutations

Study Overview
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Brief Summary
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The primary goal of the present study is to evaluate the utility of mGluR5 binding as measured by PET as biomarker of the CNTNAP2 mutation and related mTOR kinase pathway dysregulation.

Detailed Description
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The investigators will focus on mGluR5 PET binding as a surrogate measure for level of activity of the mTOR kinase pathway. This study is being conducted by the New York State Psychiatric Institute (NYSPI) and will take place at Columbia University Medical Center (CUMC) in New York City and at a research office in Strasburg, PA. Subjects (n=20) with the CNTNAP2 mutation with schizophrenia or a related condition will be recruited from the Amish and Mennonite communities and brought to CUMC for detailed investigation. Affected individuals will be compared to Amish and Mennonite control subjects drawn from the same families but not harboring CNTNAP2 mutations (n=20). The primary measure will consist of mGluR PET binding in DLPFC. In addition, secondary analyses will assess binding in other brain regions such as hippocampus and visual cortex. Exploratory measures, as well as relationships between PET mGluR5 binding and clinical symptomatology, will be assessed.

Official Title
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PET Imaging Study of Amish and Mennonite Patients With CNTNAP2 Mutations

Conditions
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Schizophrenia

Intervention / Treatment
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* Radiation: PET/SPECT Scan
* Device: MRI Scan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients: Meets DSM-5 diagnostic criteria for psychotic disorder, including schizophrenia, schizoaffective disorder or psychotic disorder not elsewhere classified Genetic confirmation that patient carries CNTNAP2 mutation Of Amish and/or Mennonite descent Has a relative willing to be part of the study and this relative will travel with the participant to CUMC in NYC and back to Lancaster, PA Stable enough to travel and participate in the study Control subjects: Genetic confirmation that subject does not carry CNTNAP2 mutation First-degree or second-degree relative of subject of Amish/Mennonite descent with CNTNAP2 mutation Exclusion Criteria (for patients and controls): Positive urine toxicology for drugs of abuse Positive history of severe neurological illness or history of brain trauma Positive history of severe medical illness that would increase risk due to PET scan procedure, or interfere with interpretation of research findings Low hemoglobin (Hb < 11 g/dL in males, Hb < 10 g/dL in females) Lifetime exposure to radiation in the workplace, or lifetime history of participation in nuclear medicine procedures, including research protocols. Blood donation within 8 weeks of study Presence of clinically significant brain abnormalities Female subjects of child-bearing age who are not surgically sterilized and between menarche and 1 year postmenopausal must test negative for pregnancy at the time of enrollment and prior to the PET scan based on a serum pregnancy test. Women who are breast-feeding are also excluded. Metal implants, pacemakers, other metal (e.g., shrapnel or surgical prostheses) or paramagnetic objects contained within the body which may present a risk to the subject or interfere with the MR scan Medicinal patch, unless removed prior to the MR scan Patients: current treatment with clozapine and/or medications other than antipsychotics PRN anxiolytics Use of the medications that would interfere with mGluR5 binding, including lamotrigine, gabapentin, topiramate, phenobarbital, pregabalin, zonisamide, N-acetylcysteine, D-cycloserine Control subjects: lifetime history of antipsychotic or antidepressant use

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: PET/SPECT and MRI scans<br>PET/SPECT scan will be used to evaluate the utility of mGluR5 binding as a biomarker of the CNTNAP2 mutation and related mTOR kinase pathway dysregulation. 30 minutes structural MRI will be obtained to permit co-registration of PET images. | Radiation: PET/SPECT Scan<br>* PET scan will be performed on a mCT scanner<br>* Other names: PET;Device: MRI Scan<br>* Structural MRI will be obtained to permit co-registration of PET images<br>* Other names: MRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of mGluR5 PET Binding in Dorsolateral Prefrontal Cortex (DLPFC) in CNTNAP2 Mutation Carriers vs. Comparison Subjects | Outcome measure is total distribution volume (VT) where distribution volume of the non displaceable compartment (VND) plus binding potential (BPP) with respect to the arterial plasma concentration of tracer. VT=VND + BPP | 90 minutes and the comparison will be binding in the specific regions listed (e.g., DLPFC) controlled by binding in the cerebellum/input function | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of mGluR5 PET Binding in Hippocampus | Evaluate PET mGluR5 binding in other regions of potential relevance, including hippocampus in order to determine ideal regions of interest for future intervention studies by using VT=VND + BPP. VND is assumed to be equal across brain regions and therefore VT will vary across brain regions with mGluR5 concentration. | 90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function | 
| Level of mGluR5 PET Binding in Primary Visual Cortex (Occipital Pole) | Evaluate PET mGluR5 binding in other regions of potential relevance, including primary visual cortex in order to determine ideal regions of interest for future intervention studies as measured by total distribution volume (VT). | 90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function |