Abstract TP073: Glymphatic Dysfunction Is Impaired In Sickle Cell Disease And Associated With Microstructural Damage And Slower Processing Speed

Background: The role of waste clearance underlying brain injury and cognitive impairment in sickle cell disease (SCD) is understudied. Dilated perivascular spaces, a marker of glymphatic dysfunction, sleep disturbance, and chronic inflammation have been reported in individuals with SCD. We hypothesized that glymphatic clearance is impaired in patients with SCD and associated with infarct burden, microstructural damage, blood-brain barrier (BBB) permeability, and cognitive impairment. Methods: Adults with SCD and controls underwent diffusion tensor image MRI to quantify a nalysis a l ong the p erivascular s pace (ALPS) index (Table, Fig 1A), a proxy for glymphatic clearance. Imaging markers of brain injury were white matter microstructural disruption (increased mean diffusivity, MD) and infarct volume normalized by inverse normal transformation. BBB permeability (Ktrans) was measured using dynamic contrast enhancement MRI. Clinical metrics of inflammation were platelet and white blood cell counts. Cognitive function was measured by Pattern Comparison Processing Speed Test. ALPS index was compared between SCD vs. controls. Pearson correlations measured relationships between ALPS index and imaging, cognitive, and inflammatory variables. Linear regression adjusted for age and sex. Results: ALPS index was lower in SCD (N=41) vs. controls (N=40), before and after adjusting for age and sex (Fig 1B), suggesting impaired glymphatic clearance in SCD. ALPS index was associated with impaired microstructure (MD) before and after adjusting for age and sex in the SCD cohort, with a trend towards association with infarct burden. These associations were not found in controls. ALPS index negatively correlated with processing speed in the SCD cohort only, trending significance (r = 0.29, p=0.07, Fig 1E). Only a small subset had Ktrans (N=22), and no association with ALPS index was found (Fig 1F). ALPS index was negatively correlated with platelets in SCD and white blood cells in controls, suggesting a role of systemic inflammation in association with glymphatic clearance (Fig 2). Conclusion: Preliminary data suggest glymphatic clearance is impaired in SCD and associated with ischemic injury and cognitive dysfunction in SCD. We will test if sleep disturbance mediates the effects of glymphatic impairment on these outcomes, and if glymphatic dysfunction and BBB permeability mediate the effect of inflammation on these outcomes. This will be done by presentation (cohort, N~200).