In this small sample of children from Nigeria, we found worse cognitive functioning in children with SCA than in comparison children, and that sociodemographic and anthropomorphic factors were correlated with cognitive functioning.

Introduction: Sickle cell disease (SCD) is a genetic blood disorder characterized by a mutated hemoglobin that polymerizes when deoxygenated leading to sickle-shaped red blood cells. Tissue hypoxia and organ damage are downstream effects of red blood cell sickling. A manifestation of end organ damage that is of increasing concern, given its devastating functional effects, is cognitive impairment. Sub-Saharan Africa accounts for the highest annual SCD burden in the world, yet little is known about cognitive impairment in children from Africa with SCD. This knowledge gap inhibits the development of targeted interventions to prevent or mitigate cognitive deficits in children with SCD. In particular, it is unknown if hydroxyurea, the oldest FDA-approved drug for SCD, preserves cognitive functioning. The primary objective of this study was to assess the potential cognitive benefits of hydroxyurea administered over at least one year in children with SCD from Ghana. Methods: We conducted a cross-sectional study funded by an ASH Minority Resident Hematology Award at both the general pediatric sickle cell clinic and the hydroxyurea clinic at Korle Bu Teaching Hospital in Ghana. Children with a diagnosis of SCD (HbSS, HbSC and HbS/β-thalassemia) between the ages of 5 and 13 were approached and enrolled in two arms of the study - non-hydroxyurea and hydroxyurea groups - under an IRB-approved protocol. Children without any exposure to hydroxyurea were included in the non-hydroxyurea group while children who had been taking hydroxyurea for at least one year were included in the hydroxyurea group. Children's demographic data were obtained via an ad-hoc questionnaire. Anthropomorphic and laboratory data were obtained from the patients' charts. Cognitive function was assessed using Cogstate, a computer-based neurocognitive testing tool. A brief battery of tests was administered consisting of Detection, Identification, One Back and Groton Maze Learning tests, which assess psychomotor function, attention, working memory and executive functioning, respectively. We used multiple linear regression analysis and inverse proportional to weight propensity score analysis to test the association between hydroxyurea treatment and cognitive test scores. Results: We enrolled 58 children with SCD in the study, including 28 in the non-hydroxyurea group (mean age 9.2 ± 2.40, 54% girls), and 30 in the hydroxyurea group (mean age 9.2 ± 2.17, 57% girls). Children taking hydroxyurea had higher hemoglobin (9.34 vs 8.32 g/dL, P=0.02) and mean corpuscular volume values (94 ± 9.2 vs 77 ± 9.1 fL, P=<0.01) when compared to the non-hydroxyurea group. Children in the hydroxyurea group performed significantly better in the area of working memory (adjusted difference 0.19, p=0.02, Table 1), while there was no significant difference in the other domains. Other confounders including age, nutritional status, gender and subject education level did not impact the findings.Within the hydroxyurea group, increased transcranial doppler velocity in the left internal carotid and left anterior cerebral arteries (a stroke risk factor) was associated with worse psychomotor function (correlation coefficient 0.41, p=0.047). Conclusion:To our knowledge, this is the first study conducted in Africa to explore the impact of hydroxyurea on cognitive functioning. While causality cannot be inferred in this observational study, our results support the findings of a study conducted in the United States showing that children withSCD on hydroxyurea had improved cognitive functioning as compared to those not on the drug (Puffer et al.Child Neuropsychology. 2007). It is possible that hydroxyurea may result in improved cerebral oxygenation, potentially by ameliorating anemia. In a prior study we found that higher cognitive functioning in children with SCD is associated with higher maternal education (Oluwole et al.Pediatr Blood Cancer. 2016), however, the difference in working memory remained significant after adjusting for this variable. Future longitudinal and interventional studies are needed to further assess the potential benefits of hydroxyurea on cognitive functioning, particularly in sub-Saharan Africa, where other interventions aimed at reducing neurological complications of SCD, such as blood transfusions, remain limited. Disclosures No relevant conflicts of interest to declare.

Introduction: Sickle cell disease (SCD) causes devastating complications that can affect any organ in the body. Particularly, SCD can present with neurological complications of overt strokes, silent infarcts and cognitive impairment. As patients are living longer with SCD, cognitive functioning is an important aspect of their disease as deficits can impact education, employment, or adherence to medications. Most of the studies assessing cognitive impairment in this population have been in children with limited data on adults. This study explored the results of cognitive testing in adult patients with SCD when compared to normative data. This study also sought to determine any association between psychological factors (baseline anxiety and depression) as well as biological factors (i.e. hemoglobin levels). Methods: This was a cross-sectional study conducted at the Sickle Cell Center of Southern Louisiana in New Orleans.The study included adults with a diagnosis of sickle cell disease regardless of subtype who were over the age of 18. Patients were excluded if they were not able to physically complete the tasks. Executive function, memory, psychomotor speed, and memory were assessed using the following tasks from standardized pencil-and-paper cognitive tasks from the Cambridge Neuropsychological Automated Battery (CANTAB) test: Stocking of Cambridge (SOC),Delayed Matching to Sample (DMS), Paired Associates Learning (PAL), Motor Screening Task (MOT), Intra-Extra Dimensional Set Shift (IED), Spatial Working Memory (SWM). The Hospital Anxiety and Depression Subscale (HADS) clinical assessment tool was used to screen for anxiety and depression at the time of testing. A HADS score >8 denotes significant anxiety or depression. Results: A total of 22 patients (59% females, mean age 29.6±2.1 years) were included in this study. Attention and psychomotor speed were relatively preserved cognitive domains with 59.1% of patients scoring greater than 75 thpercentile relative to normative mean. Conversely, executive functioning often appeared impaired with 72.7% and 77.3% of patients scoring below 25 thpercentile in outcome measures of IED and SWM, respectively. Similarly, a significant percentage of patients scored below 25 thpercentile in outcome measures of visual memory, PAL and DMS, 63.6% and 45.4%, respectively. Fifteen participants (68%) screened positive for anxiety while two screened positive for depression. Patients with anxiety tended to perform worse on most cognitive tasks, although the differences in scores did not reach statistical significance. Additional analyses of association of biologic factors and neurocognitive functioning are currently underway. Discussion and Conclusion: Our results support that adults with sickle cell disease often suffer from cognitive deficits, which was expected based on pediatric studies demonstrating cognitive impairment in children with SCD. Interestingly, we observed a predominance of poor executive function over changes in attention and psychomotor speed in this study. This is in contrast with what providers familiar with "mini mental assessment" for dementia may expect. Typical dementia patients develop attention and memory changes before executive function is affected. Therefore, it is possible that cognitive impairment in SCD may go by unnoticed without proper testing. Additionally, in this cohort, anxiety was frequent and tended to associate with worse performance. Since this is a cross-sectional study, it is unclear whether cognition is progressively impaired over the years. Prospective studies are required to help determine whether and how fast progression occurs and what risk factors are implicated in the development and progression of cognitive impairment. Such deficits have been demonstrated to be associated with difficulties around employment and adherence to medication, which ultimately jeopardizes long term outcomes. Overall, we recommend neurocognitive and psychological evaluations as part of the routine care for adult SCD patients since abnormal findings seem common and may not be obvious without adequate testing for different domains. Treatment of anxiety disorder and cognitive rehabilitation may prove helpful to improve cognition in SCD patients. Disclosures Fertrin: Sanofi Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kruse-Jarres: Genentech/Roche: Speakers Bureau; Pfizer: Consultancy; CSL Behring: Consultancy; CRISPR: Consultancy; Biomarin: Consultancy; Genentech: Consultancy, Research Funding.

Neurovascular complications are a common and major cause of morbidity and mortality in patients with sickle cell disease (SCD). Prior studies have demonstrated cortical thinness (Kim et al. 2016) as well as reduced cerebral volume in children with SCD (Kawadler et al. 2013) when compared to age-matched controls. There is very limited data regarding cerebral volume in adults with SCD. Recently, our group showed that adults with SCD have reduced cerebral volumes when compared to race and age-matched controls (Santini et al. 2021a). A prior prospective study by Nitkunan et al. 2011. demonstrated brain atrophy rate of −0.914%±0.8% in older adults (mean 68 years old) with Small Vessels Disease, which is about twice the rate of healthy controls. Transfusion therapy has been effective in the primary and secondary prevention of strokes and silent infarcts in SCD. Automated erythrocytapheresis (exchange transfusion), in particular, is the most aggressive disease modifying-treatment in SCD, by rapidly diluting sickle hemoglobin and replacing it with normal hemoglobin. We hereby present a case of a 42 -year-old woman with sickle cell anemia (HbSS) who developed accelerated loss of cerebral volume within a three-year period despite chronic exchange transfusion therapy. The patient underwent brain MRI in 2016 and 2019 as part of an NIH-funded, prospective, longitudinal study of the neuroradiological correlates of cognitive dysfunction in SCD. Past medical history is notable for prior right hemispheric stroke for which she was placed on chronic exchange transfusion monthly with the goal of reducing HbS to <30%. T1-weighted images were acquired at 7T MRI using a customized RF coil (Santini et al. 2021b) and with the following parameters: 3D MPRAGE, TE/TI/TR = 2.17/1200/3000 ms, resolution 0.75 mm isotropic, total acquisition time = 5 min. The extent of atrophy was estimated using the longitudinal analysis as part of the Freesurfer package (version 7.1.1) and ITK-snap (version 3.8.0). The pre-exchange HbS was reliably maintained <30% throughout the observation period, during which the patient did not develop new strokes or neurological complications. Unfortunately, in spite of the patient's excellent adherence with the treatment and the achievement of the target HbS values, we observed progression of cerebral atrophy of 2.47% in volume in the hemisphere contralateral to the stroke between the two time points. The differences are also visible in the raw data (Figure 1). Chronic exchange transfusion is the most aggressive preventive treatment for the neurological sequelae of sickle cell disease. This case demonstrates an accelerated brain atrophy, suggesting that this treatment may not be fully protective against progressive cerebral atrophy. Unfortunately, the mechanism of brain atrophy in SCD is not fully understood. More longitudinal studies are needed to assess cortical changes and cerebral volume changes as this can lead to further understanding of their pathophysiology and to the development of therapeutic options to arrest the progression of cerebrovascular disease in this population. Figure 1 Figure 1. Disclosures Novelli: Novartis Pharmaceuticals: Consultancy.

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