Social determinants of neurocognitive and academic performance in sickle cell disease.

BACKGROUND: Sickle cell disease (SCD) is associated with poor neurocognitive outcomes due to biomedical and psychosocial factors. The aims of this study were to investigate associations between household and neighborhood socioeconomic status (SES) with cognitive and academic outcomes in SCD and to determine if these relationships were modified by sickle genotype, fetal hemoglobin, or age. PROCEDURE: We prospectively recruited patients to complete a battery of neurocognitive and academic measures. Household SES was measured using the Barratt Simplified Measure of Social Status, a composite index of parent education and occupation. The Social Vulnerability Index was used to classify individuals based on social vulnerabilities at the neighborhood level. RESULTS: Overall, 299 patients between the ages of 4 and 18 (mean = 11.4, standard deviation = 4.3) years diagnosed with SCD (57% SS/SB0 -thalassemia) completed testing. Stepwise multivariate models demonstrated that patients with low social vulnerability (i.e., high SES) at the neighborhood level displayed intelligence and math scores that were 4.70 and 7.64 points higher than those living in areas with moderate social vulnerability, respectively (p < .05). Reading performance did not differ based on neighborhood SES; however, the effect of neighborhood SES was dependent on age, such that older participants living in neighborhoods with moderate or high levels of social vulnerability displayed poorer reading scores than those with low social vulnerability (p < .05). CONCLUSIONS: This study identified patients with SCD at higher risk of poor academic performance based on SES. Interventions addressing academic difficulties should be offered to all children with SCD, but should be emergently offered to this subpopulation.

Neurocognitive risk in sickle cell disease: Utilizing neuropsychology services to manage cognitive symptoms and functional limitations.

Sickle cell disease (SCD) is an inherited blood disorder that is associated with developmental delays and neurocognitive deficits. This review details key findings related to neurocognitive outcomes for children and adults with emphasis on the impact of neurological correlates and disease severity. Associations between neurocognition, demographic factors and social determinants of health are also reviewed. Emerging literature has reported on the neurocognitive impact of SCD in children and adolescents in Africa and Europe, including children from immigrant communities. Neurocognitive deficits are linked to poor functional outcomes, including transition from paediatric to adult care, medication adherence and unemployment. Integrating neuropsychology into multidisciplinary care for individuals with SCD can assist with identification and management of neurocognitive concerns, intervention development, individualized care plan development and continued multidisciplinary research.

Neurocognitive functioning in preschool children with sickle cell disease.

BACKGROUND: Children with sickle cell disease (SCD) experience neurodevelopmental delays; however, there is limited research with preschool-age children. This study examined neurocognitive risk and protective factors in preschoolers with SCD. PROCEDURE: Sixty-two patients with SCD (60% HbSS/HbSß0 -thalassemia; 40% HbSC/HbSß+ -thalassemia) between the ages of 3 and 6 years (mean = 4.77 years) received a neuropsychological evaluation as routine systematic surveillance. Patients were not selected for disease severity, prior central nervous system findings, or existing cognitive concerns. Thirty-four patients (82% HbSS/HbSß0 -thalassemia) were prescribed hydroxyurea (HU) at the time of their neuropsychological evaluation. On average, these patients had been prescribed HU at 2.15 (standard deviation = 1.45) years of age. The average dose was 28.8 mg/kg/day. Besides genotype, there were no group differences in medical or demographic factors based on HU treatment status. RESULTS: Patients with HbSS/HbSß0 -thalassemia scored below normative expectations on measures of intelligence, verbal comprehension, and school readiness (false discovery rate-adjusted p-value [pFDR ] < .05). Age, sickle genotype, and HU treatment exposure were not associated with measured neurocognitive outcomes (pFDR  > .05). Greater social vulnerability at the community level was associated with poorer performance on measures of intellectual functioning, verbal comprehension, visuomotor control, and school readiness, as well as parent report of executive dysfunction (pFDR  < .05). Greater household socioeconomic status was positively associated with academic readiness. CONCLUSIONS: Preschoolers with severe SCD (HbSS/HbSß0 -thalassemia) perform below age expectations on measures of intelligence and academic readiness. Sociodemographic factors were stronger drivers of neurocognitive performance than disease severity or disease-modifying treatment. Neurodevelopmental interventions targeting the home and broader community environment are needed.

Adaptive Functioning in Children and Adolescents With Sickle Cell Disease.

OBJECTIVE: Risk for neurocognitive deficits in sickle cell disease (SCD) is well established, yet minimal research has evaluated the risk for deficits in adaptive functioning. We assessed adaptive functioning in pediatric patients with SCD to test the hypothesis that disease, treatment, and demographic factors were associated with adaptive outcomes. METHODS: Two hundred fifty-six patients (57% HbSS/HbSß0-thalassemia and 43% HbSC/HbSß+-thalassemia), ages 8-18, received routine neuropsychological assessments as part of a larger prospective lifetime cohort study. Adaptive functioning was measured using the Behavior Assessment System for Children, Second or Third Edition. Adaptive scores were compared with normative values using t-test or Wilcoxon signed rank test and linear regression models were used to measure associations between adaptive functioning and age, hydroxyurea (HU) use, sickle genotype, and socioeconomic status. Furthermore, we examined the influence of intellectual and executive functioning on adaptive behavior using hierarchical linear regression analyses. RESULTS: Parent ratings of adaptive functioning skills did not differ from normative expectations (all false discovery rate [FDR] adjusted p-value [pFDR] > 0.05). Social vulnerability was negatively associated with adaptive scores on most adaptive scales in both genotypes (pFDR < 0.05). HU treatment was not significantly associated with any adaptive scale. Overall IQ was positively associated with Functional Communication and Leadership only for those with HbSS/HbSß0-thalassemia. Higher parent ratings of executive difficulties were correlated with lower adaptive scores (estimate = -0.64, standard error = 0.051, p < .001). CONCLUSIONS: Poorer parent-rated adaptive skills were associated with increased social vulnerability, lower Full-Scale IQ, and parent-rated executive difficulties. Most adaptive scores were in the normal range; however, parent ratings may not fully capture the impact of disease complications and neurocognitive deficits on daily functioning.

Catechol-O-methyltransferase gene (COMT) is associated with neurocognitive functioning in patients with sickle cell disease.

PURPOSE: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. PATIENTS AND METHODS: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). RESULTS: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. CONCLUSION: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.

Corrigendum: Academic performance of children with sickle cell disease in the United States: a meta-analysis.

[This corrects the article DOI: 10.3389/fneur.2021.786065.].

Academic Performance of Children With Sickle Cell Disease in the United States: A Meta-Analysis.

Background: Students with sickle cell disease are at risk for poor academic performance due to the combined and/or interactive effects of environmental, psychosocial, and disease-specific factors. Poor academic performance has significant social and health consequences. Objective: To study academic achievement and attainment in children with sickle cell disease in the United States. Design: Medline, Embase, SCOPUS, CINAHL, ERIC, and PsycINFO were searched for peer-reviewed articles. Studies of children (ages 5-18) diagnosed with sickle cell disease of any genotype reporting academic achievement (standardized tests of reading, math, and spelling) or attainment (grade retention or special education) outcomes were included. Outcomes were analyzed using a random effects model. Achievement scores were compared to within study controls or normative expectations. Prevalence of grade retention and special education services were compared to national (United States) estimates for Black students. Age at assessment and overall IQ were evaluated separately for association with reading and mathematics scores. Subgroup analyses of reading and math scores were analyzed by cerebral infarct status (no cerebrovascular accident, silent infarct, stroke). Results: There were 44 eligible studies. Students with sickle cell disease scored 0.70, 0.87, and 0.80 (p < 0.001) SD below normative expectations on measures of reading, mathematics, and spelling, respectively. Compared to unaffected sibling and/or healthy controls (k = 8, n = 508), reading and math scores were 0.40 (p = 0.017) and 0.36 (p = 0.033) SD below expectations. Grade retention was approximately 10 times higher in students with sickle cell disease than Black students nationally. Intellectual functioning explained 97.3 and 85.8% of the variance in reading and mathematics performance, respectively (p < 0.001). Subgroup analyses revealed significant differences in reading (p = 0.034) and mathematics (p < 0.001) based on infarct status, with lower performance associated with presence of a silent infarct or stroke. Conclusion: Students with sickle cell disease demonstrate notable academic difficulties and are at high risk for grade retainment. Development of academic interventions and increased access to school support services are needed for this vulnerable population. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020179062.