Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI

Study Overview
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Brief Summary
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The purpose of this study is to use various types of MRI and cognitive testing to evaluate changes in the brain and cognitive function that occur in subjects with ornithine transcarbamylase deficiency (OTCD) relative to healthy individuals

Detailed Description
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The overall goal of this project is to characterize metabolic, structural and cognitive changes in OTCD using 1H MRS, DTI, volumetric averaging and fMRI with cognitive testing of executive function measures to validate biomarkers for the effect of HA and its treatment on the brain. The investigators will measure gln and mI in blood and brain (using 1H MRS) in affected participants, and mI in brain in controls, fractional anisotropy as a measure of white matter microstructural damage (by DTI) and brain activation pathways alterations with tasks probing working memory (fMRI). As a secondary outcome measure, the investigators will correlate the findings from neuroimaging with cognitive functioning. This protocol is based on the previous 5104 protocol, now includes children to evaluate the age and stage of disease on these indices in a cohort that is undergoing important developmental events against an age matched typically developing cohort.

Official Title
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Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI

Conditions
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Ornithine Transcarbamylase Deficiency

Intervention / Treatment
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* Other: MRI scanning
* Behavioral: Cognitive testing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject inclusion criteria: Patients with OTCD; Age range: 7-60 years Able to undergo neuroimaging safely (i.e. without presence of ferromagnetic devices) Subject has a documented full scale IQ > 70 Control participant inclusion criteria: Healthy males and females without metabolic disease aged 7-60 years Subject has a documented full scale IQ > 70 Exclusion Criteria: Subject exclusion criteria: Mental retardation (i.e., Full Scale IQ< 70) Age range <7 or >60 years Presence of ferromagnetic device(s) that preclude safe imaging Pregnant female Control exclusion criteria: Subjects with a documented history of an intellectual deficit (i.e., Full Scale IQ< 70) Age range <7 or >60 years Presence of ferromagnetic device(s) that preclude safe imaging Pregnant female

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 60 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Subjects with OTCD<br>males and females ages 7-60 years with OTCD who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing | Other: MRI scanning<br>* 1H MRS, DTI, FMRI<br>* Other names: MRI;Behavioral: Cognitive testing<br>* Behavioral testing<br>|
| Healthy controls<br>males and females ages 7-60 years who are healthy controls who are able to undergo MRI and cognitive testing MRI scanning 1H MRS, DTI, FMRI Cognitive testing Neuropsychological testing | Other: MRI scanning<br>* 1H MRS, DTI, FMRI<br>* Other names: MRI;Behavioral: Cognitive testing<br>* Behavioral testing<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of Glutamine and Myoinositol | Concentration based on area under curve on 1H Magnetic Resonance Spectroscopy(MRS) and quantitated by LCModel (a method that allows automatic quantitation of spectroscopy data). A metabolite's tissue concentration is related to the integrated amplitude, the area under the curve of the MRS signal, it produces. While MRS signals are usually acquired in the time domain as free induction decays or echoes, they are usually viewed and analyzed in the frequency domain. The frequency domain representation is derived from the acquired time domain data by the Fourier Transform. The protocol we use selects 257 averages. The machine summates the data at each time point to generate one value for the area under the curve. Therefore, we don't have the measurement at each time point. Furthermore, we measured voxels in two different brain areas containing different kinds of brain matter: one voxel was located in posterior cingulate gray matter (PCGM) and the other in parietal white matter (PWM). | Baseline | 
| Functional Connectivity of Assessed by Resting-state fMRI | Investigation of differences in functional connectivity of OTCD patients compared to healthy controls, particularly in the default-mode network (DMN) and the set-maintenance network (SMN). Participants underwent a resting-state scan using 3T fMRI. Combining independent component analysis (ICA) and region-of-interest (ROI) analyses, identified the nodes that comprised each network in each group, and assessed internodal connectivity. For each subject, this analysis generated a correlation value, which reflected the strength of functional connectivity between each ROI pair.The correlation r-values were normalized using Fisher's r-to-Z-transform, generating z-scores. The DMN was composed of 1) anterior cingulate/medial prefrontal cortex (ACC/mPFC), 2) posterior cingulate cortex (PCC), and 3) bilateral inferior parietal lobule (IPL). The SMN was composed of 1)ACC, 2) bilateral superior frontal gyrus (SFG), and 3) bilateral anterior insula/frontal operculum (aI/fO). | Baseline | 
| Fractional Anisotropy Assessed Using DTI | Fractional Anisotropy (FA) is a measure of the diffusion asymmetry within a voxel as defined by its eigenvalues. In our study, FA is being used as a measure of white matter integrity, because FA is very sensitive to small microstructural changes.Fractional anisotropy (FA) is a scalar value between zero and one (0-1) that describe anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions. | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychological Assessment | Testing consisted of the Wechsler Abbreviated Scale of Intelligence (WASI), Comprehensive Trail Making Test (CTMT) (range 17-87), and the Behavioral Rating Inventory of Executive Function (BRIEF) (range GEC: 70-210; BRI:39-82 ; MI:41-92). The WASI includes three measures of intelligence; including, performance IQ (sum of block design and matrices sub scales; range: 40-160), verbal IQ (sum of vocabulary and similarities sub scales; range 40-160), and total IQ (sum of all four subscales; range: 80-320). The CTMT measures simple attention and executive function, it consists of five dot to dots that increase with complexity and difficulty. Higher values indicate better outcomes for all scales. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neuroimaging, MRI, Urea cycle, hyperammonemia, cognitive function, ornithine transcarbamylase deficiency