Biomarkers of Disease Severity Predict Neurocognitive Functioning in Pediatric SCD

Abstract

Introduction: Research clearly documents the increased risk of silent and overt strokes in pediatric patients with sickle cell disease (SCD), as well as the associated neurocognitive deficits in domains such as working memory (WM) and attention regulation. However, less research has examined the effects of biomarkers of SCD severity, such as cerebral blood flow velocity (CBFV), hemoglobin, and blood pressure, on neurocognitive functioning. This investigation aimed to explore the utility of using biomarkers to predict caregiver-reported neurocognitive and behavioral functioning in pediatric SCD.Methods: Fifty-nine children with SCD ages 7-16 (M = 10.44, SD = 2.87, 42% male) enrolled in a larger study of the feasibility and efficacy of a computerized cognitive training program. As part of this study, a primary caregiver completed the Behavior Rating Inventory of Executive Function (BRIEF) and Conners-3, both caregiver-reported measures of behavioral, attentional, and emotional functioning in children and adolescents. Scores on the BRIEF and Conners-3 are both represented with T scores, where higher scores reflect greater problems. Complete blood count (CBC) and vital signs were extracted from patients' medical charts if results had been documented within 45 days of date caregivers completed the BRIEF and Conners-3. Transcranial Doppler (TCD) ultrasonography results were extracted if a TCD had been performed within 12 months of the testing date.Results: Mean hemoglobin was 9.05 (SD = 1.33), mean hematocrit was 25.84 (SD = 3.71), mean systolic blood pressure was 107.43 (SD = 8.89), and mean diastolic blood pressure was 63.69 (SD = 9.49). TCD results revealed a mean right middle cerebral artery (MCA) CBFV of 206.00 (SD = 21.30), left MCA CBFV of 127.84 (SD = 22.40), right distal cerebral artery (DiCA) CBFV of 86.44 (SD = 23.00), and left DiCA CBFV of100.45 (SD = 27.28). Bivariate Pearson correlations and linear regression analyses were conducted to examine the relationships between biomarkers (e.g., CBFV, blood pressure, CBC results) and caregiver-reported neurocognitive and behavioral functioning. Modest correlations were observed between CBC results (e.g., hemoglobin, hematocrit) and caregiver-rated cognitive and behavioral outcomes; though, these relationships were no longer significant after controlling for age and gender in subsequent regression analyses. However, higher left DiCA velocities significantly predicted more problems on the BRIEF Working Memory and Initiate subdomains (R2 = .569, b = 0.442, p < .001; R2 = .746, b = .466, p < .001, respectively). Additionally, higher left DiCA velocities significantly predicted more caregiver-rated problems on the BRIEF Organization of Materials and Plan/Organize scales (R2= .447, b = 0.191, p = .049; R2 = .377, b = 0.372, p = .00), respectively. TCD and blood pressure results also significantly predicted scores on the caregiver-reported Connors-3 Executive Functioning subscale, with higher left DiCA (R2 = .432, b = 0.446, p = .001) and systolic BP (R2 = .196, b = 0.859,p =.003) predicting more problems with executive functioning.Conclusion: Certain biomarkers of SCD severity appear to have a detectable and direct influence on neurocognitive and behavioral functioning in pediatric SCD. TCD results, specifically left DiCA CBFV, and systolic blood pressure significantly predicted scores on the BRIEF and Conners-3, two caregiver-reported measures of neurocognitive and behavioral functioning. More specifically, higher CBFV and systolic blood pressure were predictive of more caregiver-rated problems with working memory, executive functioning, and organizational skills. These cognitive and behavioral domains are of particular importance in children, who depend on such skills to learn and succeed academically. Progressive disease-related neurocognitive deficits may contribute to long-term difficulties in academic achievement, social functioning, and vocational attainment. Biomarkers of SCD severity, such as CBFV and blood pressure, may be useful indicators of worsening neurocognitive status and signal the need for preventative care to protect neurological integrity and preserve quality of life in pediatric patients with SCD. DisclosuresNo relevant conflicts of interest to declare.