Cerebral Blood Flow, Brain Volume, and Age Predicts Executive Function in Sickle Cell Anemia
Authors: Prussien Kemar V. , Compas Bruce E. , Siciliano Rachel , Jones R. Sky , Ciriegio Abagail E. , Lee Chelsea A. , Kassim Adetola A. , DeBaun Michael R. , Donahue Manus Joseph , Jordan Lori C. 
Published: November 2021

Abstract
Introduction: Individuals with sickle cell anemia (SCA) are at increased risk for deficits in multiple domains of neurocognitive functioning, including executive functions. In addition to assessing the effects of silent cerebral infarcts (SCI) and stroke on cognition, prior research has focused on hemoglobin and transcranial Doppler velocity as hemodynamic correlates. Recent studies have begun to use more precise measures of blood delivery to the brain (e.g., cerebral blood flow; CBF) to determine more sensitive indicators of cognitive risk prior to neurological injury. Nevertheless, empirical and meta-analytic findings suggest that these deficits increase with age, which can have broad impact on psychosocial functioning, including self-management and navigation through the transition from pediatric to adult medical care. This study aimed to assess brain volume as a mediator of the association between CBF and executive functioning in a sample of individuals with SCA. The secondary aim was to assess age as a moderator of hemodynamic and structural correlates of executive function.
Methods: Children, adolescents, and young adults with SCA were enrolled prospectively. Each participant received a 3-Tesla non-contrast magnetic resonance imaging and magnetic resonance angiography of the brain, and a neurological examination by the study neurologist. Gray matter CBF was calculated from pseudo-continuous arterial spin labeling using the solution to the flow-modified Bloch equation after correcting for individual hematocrit. Three measures of brain volume were also computed from 3D-T1 images using Freesurfer version 7.1.1: total brain volume, gray matter volume, and white matter volume was calculated as the difference between the two. At a separate study visit, participants completed an age-appropriate Wechsler Working Memory Index (WMI). Pearson correlations assessed bivariate associations among variables, SPSS PROCESS macro was used to test gray matter volume as a mediator in the relation between CBF and working memory, and multiple linear regression analyses tested age as a moderator of the impact of CBF and brain volume on working memory.
Results: Twenty-nine children and adolescents (ages 6 to 17 years) and 25 adults (ages 18 to 31 years) were enrolled. Five participants were excluded from analyses due to history of overt stroke that resulted in significant brain volume loss. Of 49 included participants, 20 had SCIs. Working memory was inversely correlated with age (r = -.30, p = .037) and CBF (r = -.36, p = .013), such that WMI decreased cross-sectionally with older age and higher CBF. Working memory was positively correlated with gray matter volume (r = .42, p = .002); however, it was not related to white matter volume (r = -.05, p = .715) or total brain volume (r = -.07, p = .642). Finally, patient age was positively correlated with CBF (r = .36, p = .014), but the association of age with gray matter volume did not reach statistical significance (r = -.27, p = .065). Analyses in Figure 1 show that although CBF and gray matter were directly related to working memory (path c and path b, respectively), gray matter volume did not mediate the association between CBF and working memory (path a*b). However, regression analyses (Table 1) showed that age moderated the association between gray matter volume and working memory, such that there was only a significant relation in children and adolescents. This association did not exist for young adults (Figure 2).
Conclusions: Neurocognitive assessments has been cited as an important standard of care for children and adolescents with SCA. Given the increase in deficits with age, and the increase in mortality after transferring from pediatric to adult care, monitoring executive function abilities and potential impact on self-management should continue into adulthood. Findings from the current study provide preliminary evidence that cerebral hemodynamic compensation with elevated CBF may be insufficient to prevent gray matter volume loss in children and adolescents and decline in working memory ability. Some limitations of the current study include small sample size and whole brain gray and white matter volumes as opposed to specific regions relevant to executive functions (e.g., prefrontal cortex); however, findings from global measures provide promising evidence for future research on hemodynamic and structural predictors of executive function in SCA.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.