Abstract A113: Reduced cerebral glutamine, as a metric of ischemic risk and brain health, associates with white matter microstructural impairment in adults with sickle cell anemia: an MR spectroscopy study

Background: Over 50% of sickle cell anemia (SCA) patients will have silent or overt cerebral strokes, which have been linked to cognitive impairment. L-glutamine supplementation has been FDA approved to reduce vaso-occlusive crises frequency. However, glutamine’s effect on stroke and cognitive impairment in SCA is unknown. Measurement of neurometabolites using conventional MR spectroscopy has been limited to a single voxel due to technical challenges. A novel, high-resolution MR spectroscopic imaging (MRSI) technique, termed SPICEx, permits measurement of critical neural substrates and metabolites. In this pilot study, we assessed the neurometabolomic profile of patients with SCA compared to healthy controls using MRSI. Hypothesis: As a marker of stroke risk and brain health, we hypothesized that SCA patients have lower cerebral glutamine compared to controls. Methods: Adults with SCA and healthy controls without history of stroke underwent 3T brain MRI. SPICEx RG1 produced 3D whole brain (WB) neurometabolite maps (2x3x3 mm 3 , acquisition time 12 minutes) including voxel-wise glutamine. MRI metrics of white matter (WM) microstructural disruption (increased mean diffusivity, MD) were also obtained. Gray matter (GM), WM and WB glutamine measures were compared between SCA vs. controls using Mann-Whitney U test. Spearman’s correlation assessed the relationship between cerebral glutamine, MD, and volume. Results: Of 8 SCA patients and 9 controls, we found lower WB, WM, and WM to WB glutamine ratio in SCA vs. controls (P=0.08, P=0.02, and P=0.01, respectively). Across the cohort, low GM glutamine was associated with reduced GM volume (ρ=0.5, p=0.04), and low WM glutamine was associated with elevated MD, (ρ=–0.5, p=0.04). Two SCA patients were prescribed 8-12 weeks of L-glutamine supplementation, and their WB glutamine increased compared to their first scan. Conclusion: Patients with SCA have reduced cerebral glutamine, likely due to increased energy expenditure from inflammation and erythropoiesis, leading to insufficient amino acid substrates for neural processing. Glutamine is a precursor for glutamate, GABA, and glutathione, the major antioxidant counteracting oxidative stress. The relative reduction of glutamine in the white matter may align with the propensity for silent infarcts occurring in the deep white matter. We are enrolling a larger cohort to investigate the role of L-glutamine supplementation to prevent stroke and cognitive impairment in SCA.