Burden and Risk of Neurological and Cognitive Impairment in Pediatric Sickle Cell Anemia in Uganda (BRAIN SAFE II)

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Abstract Despite potentially effective stroke prevention strategy for children with sickle cell anemia (SCA) through risk screening and implementing targeted intervention, about 25% under age 12 develop clinically "silent cerebral infarcts" (SCI) - an MRI-based diagnosis not associated with neurologically apparent strokes. SCIs may impair cognitive function and school performance, and increase risk for overt stroke. Moreover, screening for stroke risk and reduced SCA cerebrovascular injury through disease-altering therapies are not widely available in Sub- Saharan Africa (SSA). In our current trial in Uganda of hydroxyurea (HU), “BRAIN SAFE II (BS2)” (1R01HD09655), we hypothesize that HU therapy over 2.5 years may prevent or stabilize SCA-associated brain injury, including cognitive dysfunction. Baseline MRI-MRA imaging performed in a random sub-sample (N= 90), demonstrated >1 cerebral infarcts in over 60%, of whom most had normal TCD. Alternative non-imaging screening modalities for pediatric SCA cerebrovascular injury – e.g. using blood-based biomarkers - are needed for targeted intervention, especially in SSA. In a pilot study using blood samples from our prior cross- sectional study, we assessed 4 blood-based brain biomarkers which are used in non-SCA adults for detecting brain injury, e.g. stroke. One of these biomarker levels, neuro-filament light chain (NfL), was significantly associated with MRI-detected infarcts, even among children with normal screening for stroke risk. With supplemental funding, in the 90 SCA participants with MRI-imaging at enrollment, we propose to: AIM 1. Replicate and better characterize our findings of higher NfL levels in participants at enrollment with: (a) MRI-detected cerebral infarcts overall and in sub-groups with or without normal stroke risk screening (replicate) and (b) Impaired neurocognition (characterize); AIM 2. Quantify longitudinal changes in NfL and the 3 other brain biomarkers while on HU therapy, and assess the relationship to cerebrovascular injury and cognitive impairment at trial midpoint and completion compared to baseline. Associations between NfL and other brain biomarkers and SCA cerebrovascular injury would support further investigation into blood-based alternatives to risk screening and MRI imaging, and potential use in assessing impact of interventions on cerebrovascular health in children with SCA.