PROJECT SUMMARY/ ABSTRACT Single ventricle heart disease (SVHD) adolescents show cognitive deficits (~50% subjects), affecting academic achievement, self-care ability, quality of life, and mortality and morbidity. Brain changes appear in areas (hippocampus, cingulate, insula, caudate, prefrontal) that mediate cognitive functions. However, the underlying processes for brain tissue changes in SVHD are unclear, but may include hypoxemia from lower O2 saturation and reduced cerebral blood flow (CBF) from low cardiac output. Chronically low cardiac output and lower O2 saturation are common in SVHD contributing to hypoxemia that induces oxidative stress and mitochondrial dysfunction. Mitochondrial dysfunction alters metabolites, including the N-acetyl-aspartate (NAA; neuronal integrity), choline (Cho; membrane metabolism), creatine (Cr; energy metabolism), and myo-inositol (MI; astrocyte proliferation). Also, antioxidants, including glutathione (GSH) levels that play a significant role against oxidative stress, regulate neuronal/cellular protection from excessive reactive oxygen species. However, regional brain metabolites and antioxidant status in SVHD is unknown that can be examined with the 3D Echo Planar Spectroscopic Imaging (3D EPSI) and the MEshcher–GArwood Point RESolved Spectroscopy (MEGA- PRESS). In addition, CBF is highly dependent on cardiac output, and lower cardiac output can result to reduced CBF, which has not been reported after completed staged surgical palliation. Impaired CBF and lower O2 saturation can further contribute to oxidative stress, leading to tissue changes in cognitive control areas, affecting associated functions. Regional brain CBF can be assessed by arterial spin labeling imaging, O2 saturation with pulse oximetry, and oxidative stress with serum inflammatory biomarkers. Thus, using 25 SVHD and 25 healthy controls, the specific aims are to: 1) assess whole-brain metabolites (NAA, Cho, Cr, and MI; using 3D EPSI) and antioxidant (GSH; using MEGA-PRESS) in SVHD and controls; 2) identify brain CBF differences, using ASL methods, baseline O2 saturation levels, using pulse oximetry, between SVHD and controls, and relationships between regional CBF, O2 saturation, and cognition (using the Wide Range Assessment of Memory and Learning 2) in SVHD patients; and 3) examine inflammatory serum biomarkers in SVHD and controls, and correlate those markers with brain metabolites, CBF, and O2 saturation values in SVHD subjects. In summary, mitochondrial and oxidative stress mechanisms contributing to changes in brain metabolites and antioxidant, reduced CBF in cognitive regulatory areas, and serum inflammatory biomarkers, as well as links among these measures in SVHD patients will be examined. The outcomes from this R21 exploratory study will have significant implications on identification of treatments for rescue/restore brain tissue that might include strategies to increase NAA, antioxidant, and Cr levels, as well as improve CBF, and could be implemented on a large clinical trial to improve cognition, school performance, and reduced morbidity and mortality, and increased life quality in SVHD patients.

PROJECT NARRATIVE Adolescents with single ventricle heart disease (SVHD) show brain injury in regions which impact cognition that can affect their academic achievement, self-care ability, quality of life, mortality, and morbidity. However, the potential processes that can contribute to brain changes in SVHD in cognitive regulatory areas are unclear, but may include hypoxemia from lower O2 saturation and reduced cerebral blood flow from lower cardiac output, resulting to impaired brain metabolites and antioxidant levels, and cerebral blood flow deficits in those areas, as well as altered serum biomarkers. The findings from this study will have potential implications for identifying effective interventions that could be implemented on large clinical trial to rescue/restore brain metabolites and cerebral blood flow, which could benefit cognitive health, as well as improve mortality and morbidity, academic performance, and increase quality of life in this high-risk patient population.