Advanced neuroimaging technology, using diffusion tensor imaging, volumetric averaging, fMRI, and magnetic resonance spectroscopy, allows non-invasive investigations of the brain in complex conditions such as hyperammonemia in UCDs. Andrea Gropman, M.D., and her team, including John VanMeter, Ph.D. (Georgetown University), and Matthew Whitehead, M.D., and Stanley Fricke, Ph.D., have been using these methods to identify biomarkers that reflect the downstream impact of UCDs on cognition. Previous imaging research performed as part of the UCDC identified specific biomarkers of neurologic injury in ornithine transcarbamylase deficiency (OTCD). Specifically, the study showed that elevations in brain glutamine, a storage depot for ammonia, may persist and be associated with alterations in mental status and cognition even in the presence of normal plasma ammonia and normal or only slightly elevated plasma glutamine.
In addition, another small biomarker, myoinositol, may be associated with cognitive reserve in patients who have had hyperammonemia. Female carriers of OTCD, an X-linked UCD, who are expected to have milder symptoms, demonstrate challenges in executive function and working memory, although they may function well with simple tasks. This was shown by performance on a number of cognitive tests that target frontal lobe function and by activation and resting state studies on fMRI. While characterization of mutations can be achieved in most cases, this information does not necessarily predict the severity of the underlying neurological compromise in patients. The clinical phenotype varies from one patient to another and results in significant outcome heterogeneity. The group’s neuroimaging studies revealed affected cognitive domains, which include nonverbal learning, fine motor processing, reaction time, visual memory, attention, and executive function. Deficits in these capacities may be seen in symptomatic patients, as well as in asymptomatic carriers with normal IQ, and correlate with variances in brain structure and function in these patients.
These studies allow the team to begin to understand the brain pathophysiology in hyperammonemia and correlate the results with different variables, including treatment modalities. Current studies are aimed at understanding the chronology of recovery from hyperammonemia using neuroimaging biomarkers and studying the brain effects of other UCDs besides OTCD. Dr. Gropman’s group is also exploring the use of optical imaging as a totally non-invasive technique to target the very young and more cognitively challenged patients with OTCD