Trial Outcomes & Findings for Investigation of Brain Nitrogen in Partial Ornithine Transcarbamylase Deficiency (OTCD) Using 1 H MRS, DTI, and fMRI (NCT NCT01569568)

Last Updated: 2024-03-08

Results Overview

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).

Recruitment status

COMPLETED

Target enrollment

49 participants

Primary outcome timeframe

Baseline

Results posted on

2024-03-08

Participant Flow

Participant milestones

Participant milestones
Measure	Subjects With OTCD males and females ages 7-60 years with OTCD MRI scanning: 1H Magnetic Resonance Spectroscopy (MRS), Diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI) Cognitive testing: Neuropsychological testing	Healthy Controls males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing
Overall Study STARTED	20	29
Overall Study COMPLETED	20	27
Overall Study NOT COMPLETED	0	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Subjects With OTCD males and females ages 7-60 years with OTCD MRI scanning: 1H Magnetic Resonance Spectroscopy (MRS), Diffusion Tensor Imaging (DTI), functional magnetic resonance imaging (fMRI) Cognitive testing: Neuropsychological testing	Healthy Controls males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing
Overall Study Physician Decision	0	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Subjects With OTCD n=20 Participants males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing	Healthy Controls n=27 Participants males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing	Total n=47 Participants Total of all reporting groups
Age, Continuous	30.3 years STANDARD_DEVIATION 19.4 • n=5 Participants	25.8 years STANDARD_DEVIATION 14.6 • n=7 Participants	28.05 years STANDARD_DEVIATION 17.02 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	19 Participants n=7 Participants	36 Participants n=5 Participants
Sex: Female, Male Male	3 Participants n=5 Participants	8 Participants n=7 Participants	11 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline

Population: Two OTCD patients and one healthy control were excluded due to excessive head motion.

Outcome measures

Outcome measures
Measure	Subjects With OTCD n=18 Participants males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing	Healthy Controls n=26 Participants males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing
Concentration of Glutamine and Myoinositol Concentration of myoinositol in PCGM	3.80 mM Standard Deviation 0.80	4.37 mM Standard Deviation 0.46
Concentration of Glutamine and Myoinositol Concentration of glutamine in PWM	2.61 mM Standard Deviation 1.07	1.66 mM Standard Deviation 0.93
Concentration of Glutamine and Myoinositol Concentration of myoinositol in PWM	2.23 mM Standard Deviation 0.84	2.69 mM Standard Deviation 0.48
Concentration of Glutamine and Myoinositol Concentration of glutamine in PCGM	5.22 mM Standard Deviation 1.70	3.62 mM Standard Deviation 0.91

PRIMARY outcome

Timeframe: Baseline

Population: Resting state data was not acquired for several of our participants (7 controls and 4 patients). Furthermore, 3 OTCD patients were excluded from the analyses due to excessive head motion.

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).

Outcome measures

Outcome measures
Measure	Subjects With OTCD n=13 Participants males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing	Healthy Controls n=22 Participants males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing
Functional Connectivity of Assessed by Resting-state fMRI DMN: PCC & right IPL connectivity	0.66 z-scores Standard Deviation 0.42	0.64 z-scores Standard Deviation 0.30
Functional Connectivity of Assessed by Resting-state fMRI DMN: ACC/mPFC & left IPL connectivity	-0.86 z-scores Standard Deviation 0.70	0.18 z-scores Standard Deviation 0.30
Functional Connectivity of Assessed by Resting-state fMRI DMN: ACC/mPFC & PCC connectivity	-0.10 z-scores Standard Deviation 0.70	0.12 z-scores Standard Deviation 0.40
Functional Connectivity of Assessed by Resting-state fMRI DMN: ACC/mPFC & right IPL connectivity	-0.26 z-scores Standard Deviation 0.53	0.07 z-scores Standard Deviation 0.34
Functional Connectivity of Assessed by Resting-state fMRI DMN: PCC & left IPL connectivity	0.69 z-scores Standard Deviation 0.63	0.69 z-scores Standard Deviation 0.31
Functional Connectivity of Assessed by Resting-state fMRI DMN: left IPL & right IPL connectivity	0.75 z-scores Standard Deviation 0.69	0.70 z-scores Standard Deviation 0.34
Functional Connectivity of Assessed by Resting-state fMRI SMN: ACC & left aI/fO connectivity	0.19 z-scores Standard Deviation 0.39	0.28 z-scores Standard Deviation 0.41
Functional Connectivity of Assessed by Resting-state fMRI SMN: ACC & left SFG connectivity	0.28 z-scores Standard Deviation 0.35	0.44 z-scores Standard Deviation 0.29
Functional Connectivity of Assessed by Resting-state fMRI SMN: ACC & right aI/fO connectivity	0.21 z-scores Standard Deviation 0.30	0.44 z-scores Standard Deviation 0.29
Functional Connectivity of Assessed by Resting-state fMRI SMN: ACC & right SFG connectivity	0.29 z-scores Standard Deviation 0.37	0.59 z-scores Standard Deviation 0.23
Functional Connectivity of Assessed by Resting-state fMRI SMN: left aI/fO & left SFG connectivity	0.10 z-scores Standard Deviation 0.35	0.22 z-scores Standard Deviation 0.38
Functional Connectivity of Assessed by Resting-state fMRI SMN: left aI/fO & right aI/fO connectivity	0.71 z-scores Standard Deviation 0.43	0.80 z-scores Standard Deviation 0.35
Functional Connectivity of Assessed by Resting-state fMRI SMN: left aI/fO & right SFG connectivity	0.05 z-scores Standard Deviation 0.33	0.11 z-scores Standard Deviation 0.33
Functional Connectivity of Assessed by Resting-state fMRI SMN: left SFG & right SFG connectivity	0.70 z-scores Standard Deviation 0.43	0.68 z-scores Standard Deviation 0.28
Functional Connectivity of Assessed by Resting-state fMRI SMN: right aI/fO & left SFG connectivity	0.02 z-scores Standard Deviation 0.22	0.25 z-scores Standard Deviation 0.21
Functional Connectivity of Assessed by Resting-state fMRI SMN: right aI/fO & right SFG connectivity	0.04 z-scores Standard Deviation 0.26	0.27 z-scores Standard Deviation 0.35

PRIMARY outcome

Timeframe: Baseline

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.

Outcome measures

Outcome measures
Measure	Subjects With OTCD n=20 Participants males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing	Healthy Controls n=27 Participants males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing
Fractional Anisotropy Assessed Using DTI	0.25 units on a scale Standard Deviation 0.003	0.3 units on a scale Standard Deviation 0.008

SECONDARY outcome

Timeframe: Baseline

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.

Outcome measures

Outcome measures
Measure	Subjects With OTCD n=20 Participants males and females ages 7-60 years with OTCD MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing	Healthy Controls n=29 Participants males and females ages 7-60 years who are healthy controls MRI scanning: 1H MRS, DTI, FMRI Cognitive testing: Neuropsychological testing
Neuropsychological Assessment WASI - Full IQ	103.28 units on a scale Standard Deviation 14.02	111.22 units on a scale Standard Deviation 16.89
Neuropsychological Assessment WASI - Verbal IQ	107.33 units on a scale Standard Deviation 14.52	107.77 units on a scale Standard Deviation 18.59
Neuropsychological Assessment WASI - Performance IQ	98.5 units on a scale Standard Deviation 13.14	112.59 units on a scale Standard Deviation 14.54
Neuropsychological Assessment Trails - Composite	48 units on a scale Standard Deviation 15	47 units on a scale Standard Deviation 12
Neuropsychological Assessment Brief - Behavioral Regulation Index (BRI)	55.59 units on a scale Standard Deviation 9.49	46.73 units on a scale Standard Deviation 8.90
Neuropsychological Assessment Brief - Metacognition Index (MI)	60.45 units on a scale Standard Deviation 11.75	47.38 units on a scale Standard Deviation 8.22
Neuropsychological Assessment Brief - Global Executive Composite Score (GEC)	59.05 units on a scale Standard Deviation 10.37	46.88 units on a scale Standard Deviation 7.67

Adverse Events

Subjects With OTCD

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Healthy Controls

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Dr. Andrea Gropman

Children's National Medical Center

Phone: 202-476-2120

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place