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 a 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 (NYPSI) and the Research Foundation for Mental Hygiene Inc (RFMH) and will take place at Columbia University Medcial 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 Old-Order Amish control patients drawn from the same families but not harboring CNTNAP2 mutations (n=20). The primary measure will consist of mGluR5 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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Demonstration of mGluR5 Overexpression in Amish and Mennonite CNTNAP2 Mutation Carriers

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 Aged 18-59 years Genetic confirmation that patient carries CNTNAP2 mutation All patients will be 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 Columbia University Medical Center in New York City and back to Lancaster, PA In the judgment of the participant's treating physician as well as the evaluating consenter, the patient is stable enough to travel and participate in the study Control subjects: Aged 18-59 years 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, including cannabinoids, amphetamine, benzodiazepines, barbiturates, cocaine, methadone, opiates, and phencyclidine 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. However, in case of previous exposure to radioactivity due to research studies, subjects will be eligible if all conditions listed below are fulfilled: research studies in question have been performed in the context of a protocol from the Division of Translational Imaging (Anissa Abi-Dargham, M.D., Director) or as part of a research study within another division at Columbia University/NYSPI and the injected dose and dosimetry of the radiotracer are known Except for research studies, the patient has had no lifetime exposure to radiation in the workplace or in nuclear medicine procedures Adding the previous exposure to the exposure due to this study will result in a yearly cumulative exposure lower than the limit defined by the FDA for research subjects Blood donation within 8 weeks of study Presence of clinically significant brain abnormalities For female patients 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 PET scan based on a serum pregnancy test. Women who are breast-feeding are also excluded. Metal implants, pacemaker, 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, as determined in consultation with a neuroradiologist and according to the guidelines set forth in the following reference book commonly used by neuroradiologist: Guide to MR procedures and metallic objects, F.G. Shellock, Lippincott Williams and Wilkins NY 2001. 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 minute 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 CNTNAP mutation carriers vs comparison subjects | Evaluate the utility of mGluR5 binding as measured by PET as a biomarker of the CNTNAP2 mutation and related mTOR kinase pathway dysregulation. | 90 minutes and the comparison will be binding in the specific regions listed (e.g., dorsolateral prefrontal cortex) controlled by binding in the cerebellum/input function. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of mGluR5 PET binding in hippocampus and primary visual cortex (occipial pole) | Evaluate PET mGluR5 binding in other regions of potential relevance, including hippocampus and primary visual cortex in order to determine ideal regions of interest for future intervention studies | 90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function. |