PET Imaging Study of Amish and Mennonite Patients With CNTNAP2 Mutations

• Sponsor: Jeffrey A. Lieberman, MD (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02983058
• Collaborator: (none)
• Enrollment: 12
• Arm: 1
• Duration (Months): 8

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Radiation: PET/SPECT Scan; Device: MRI Scan	N/A

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: PET Imaging Study of Amish and Mennonite Patients With CNTNAP2 Mutations
• Study Start Date: Nov 1, 2016
• Actual Primary Completion Date: Jul 1, 2017
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Other: PET/SPECT and MRI scans 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; PET scan will be performed on a mCT scanner; Other Names: PET ; Device: MRI Scan; Structural MRI will be obtained to permit co-registration of PET images; Other Names: MRI

Outcome Measures

Primary Outcome Measures

1. Level of mGluR5 PET Binding in Dorsolateral Prefrontal Cortex (DLPFC) in CNTNAP2 Mutation Carriers vs. Comparison Subjects [90 minutes and the comparison will be binding in the specific regions listed (e.g., DLPFC) controlled by binding in the cerebellum/input function]

   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

Secondary Outcome Measures

1. Level of mGluR5 PET Binding in Hippocampus [90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function]

   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.

2. Level of mGluR5 PET Binding in Primary Visual Cortex (Occipital Pole) [90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 59 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Jeffrey A. Lieberman, MD

Investigators

• Principal Investigator: Sander Markx, MD, New York State Psychiatric Institute

Study Documents (Full-Text)

• Study Protocol - Nov 4, 2016
• Statistical Analysis Plan - May 22, 2019

More Information

Publications

None provided.

• Responsible Party: Jeffrey A. Lieberman, MD, Director, New York State Psychiatric Institute, New York State Psychiatric Institute
• ClinicalTrials.gov Identifier: NCT02983058
• Other Study ID Numbers: #7107
• First Posted: Dec 6, 2016
• Last Update Posted: Jun 2, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Additional relevant MeSH terms: Schizophrenia

Study Results

Participant Flow

Recruitment Details	Study subjects were exclusively recruited from the Amish and Mennonite community in Lancaster, Pennsylvania (PA). All subjects with psychotic spectrum disorder were receiving clinical care at the Clinic for Special Children in Strasburg, PA and identified an unaffected 1st or 2nd degree relative (unaffected subject).
Pre-assignment Detail	All subjects (affected and unaffected) who met inclusion/exclusion criteria were included in the study.

Arm/Group Title	Subjects With Psychotic Spectrum Disorders	Unaffected 1st or 2nd Degree Relatives
Arm/Group Description	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images
Period Title: Overall Study
STARTED	7	5
COMPLETED	2	2
NOT COMPLETED	5	3

Baseline Characteristics

Arm/Group Title	Subjects With Psychotic Spectrum Disorders	Unaffected Relatives	Total
Arm/Group Description	Subjects who met DSM-5 diagnostic criteria for psychotic disorder and had genetic confirmation of carrying CNTNAP2 mutation	Unaffected 1st or 2nd degree relatives of subjects who have psychotic spectrum disorder and carries the CNTNAP2 mutation. Unaffected relatives do not carry CNTNAP2 mutation	Total of all reporting groups
Overall Participants	7	5	12
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	5 100%	12 100%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	2 28.6%	3 60%	5 41.7%
Male	5 71.4%	2 40%	7 58.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	7 100%	5 100%	12 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	7 100%	5 100%	12 100%

Outcome Measures

1. Primary Outcome

Title	Level of mGluR5 PET Binding in Dorsolateral Prefrontal Cortex (DLPFC) in CNTNAP2 Mutation Carriers vs. Comparison Subjects
Description	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
Time Frame	90 minutes and the comparison will be binding in the specific regions listed (e.g., DLPFC) controlled by binding in the cerebellum/input function

Outcome Measure Data

Analysis Population Description

N was not reached and data was not analyzed

Arm/Group Title	Subjects With Psychotic Spectrum Disorders	Unaffected 1st or 2nd Degree Relatives
Arm/Group Description	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images
Measure Participants	2	2
Mean (Standard Deviation) [mL/cm^3]	13.58 (1.27)	11.12 (0.24)

2. Secondary Outcome

Title	Level of mGluR5 PET Binding in Hippocampus
Description	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.
Time Frame	90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Subjects With Psychotic Spectrum Disorders	Unaffected 1st or 2nd Degree Relatives
Arm/Group Description	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images
Measure Participants	2	2
Mean (Standard Deviation) [mL/cm^3]	10.61 (1.60)	11.29 (0.53)

3. Secondary Outcome

Title	Level of mGluR5 PET Binding in Primary Visual Cortex (Occipital Pole)
Description	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).
Time Frame	90 minutes and the comparison will be binding in the specific regions listed controlled by binding in the cerebellum/input function

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Subjects With Psychotic Spectrum Disorders	Unaffected 1st or 2nd Degree Relatives
Arm/Group Description	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images
Measure Participants	2	2
Mean (Standard Deviation) [mL/cm^3]	10.50 (0.87)	8.74 (1.21)

Adverse Events

Time Frame	From time of consent to 30 days after scans
Arm/Group Title	Subjects With Psychotic Spectrum Disorders		Unaffected 1st or 2nd Degree Relatives
Arm/Group Description	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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images		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. PET/SPECT Scan: PET scan will be performed on a mCT scanner MRI Scan: Structural MRI will be obtained to permit co-registration of PET images
All Cause Mortality
	Subjects With Psychotic Spectrum Disorders		Unaffected 1st or 2nd Degree Relatives
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/5 (0%)
Serious Adverse Events
	Subjects With Psychotic Spectrum Disorders		Unaffected 1st or 2nd Degree Relatives
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/5 (0%)
Other (Not Including Serious) Adverse Events
	Subjects With Psychotic Spectrum Disorders		Unaffected 1st or 2nd Degree Relatives
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/5 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.