Multimodal neuroimaging and neurocognitive assessment in adolescents with and without sickle cell disease

Abstract Objective Neurocognitive complications in pediatric sickle cell disease (SCD)—even without overt stroke—are increasingly recognized, yet adolescents remain underrepresented in research. Adolescence is a critical window for brain maturation, particularly in regions supporting executive function, which are metabolically demanding and vulnerable to oxygen and nutrient deficits. This ongoing study aimed to characterize neurodevelopmental alterations in adolescents with SCD using comprehensive neurocognitive testing and multimodal MRI. Methods African American adolescents aged 12–17 years with severe SCD (HbSS or HbS/β⁰-thalassemia) and controls were enrolled. Stroke history was an exclusion criterion. Participants underwent a single visit including computerized neurocognitive assessment (NIH Toolbox), multimodal 3T MRI, and blood sampling. MRI protocols assessed cerebral perfusion (arterial spin labeling), brain structure (T1/T2-weighted imaging), metabolite levels (magnetic resonance spectroscopy), and white matter integrity (diffusion tensor imaging). Multivariable linear models included group and age as predictors. Results Sixteen participants (10 with SCD, 6 controls; mean age = 15.3 years; 53% female) were included. Adolescents with SCD showed significantly poorer executive function than controls (mean score: 89 vs. 109; p = 0.006). Cerebral perfusion was elevated in patients across all regions (p < 0.05). Significant group differences were observed in metabolite levels, including glutathione (difference (95% CI) = 0.07 [0.03, 0.11], p = 0.002), N-acetylaspartate (0.26 [0.04, 0.48], p = 0.025), and glycerophosphocholine (0.05 [0.01, 0.09], p = 0.015). Poorer executive function was associated with increased perfusion in the cerebrum (β = –1.60 [-2.61, -0.59], p = 0.005), cerebellum (β = -1.67 [-2.62, -0.73], p = 0.002), hippocampus (β = -0.93 [-1.75, -0.11], p = 0.029), and amygdala (β = -1.08 [-2.06, -0.10], p = 0.034). Reduced volumes of the hippocampus (β = -74.34 [-148.52, -0.17], p = 0.050), caudate (β = -68.12 [-131.54, -4.70], p = 0.037), and putamen (β = -105.99 [-193.15, -18.84], p = 0.021) were also significantly associated with executive dysfunction. Conclusion This study demonstrates that adolescents with SCD, even without stroke, show measurable disruptions in executive function that are potentially linked to altered perfusion, metabolite imbalance, and structural brain differences. These findings underscore the utility of multimodal neuroimaging in uncovering hidden neurodevelopmental vulnerabilities and support the need for targeted interventions during adolescence.