Mapping Total Cortical Volume of Children and Adolescents with Sickle Cell Disease Against Normative Growth Trajectories: First Baseline Results of the Brick Study

Background Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by sickle-shaped erythrocytes due to the production of hemoglobin S (HbS). SCD causes cumulative organ damage, leading to a shortened average life expectancy. The brain is particularly affected in SCD, with stroke being the most severe neurologic complication. Even in absence of stroke, patients with SCD exhibit significant cognitive deficits beginning in childhood. Recent quantitative analysis of brain magnetic resonance imaging scans (MRIs) in SCD have demonstrated subtle brain damage previously undetectable. Neurodevelopmental plasticity allows for high adaptability, however damage during sensitive periods can be more detrimental to the child's developmental trajectory. Since SCD is a chronic condition thought to continuously damage the brain through various vaso occlusive events (VOEs) as well as anemia and other hemodynamic factors, SCD children are at risk for brain insults that can alter brain maturation and cognitive development. We hypothesize that SCD patients have significantly different individual brain growth trajectories that deviate from typical trajectories beginning in childhood and worsening over time.

Methods Data was collected as part of a longitudinal observational cohort study: the Brain Structure and Neurocognitive Development in Sickle Cell Disease (BRICK Study; NCT05564845) and consist of 84 children with SCD aged 6-21 years from two Dutch centers. Anatomical T₁-weighted brain images were acquired using a 3T MRI scanner. Volumetric data were extracted using the standard recon-all pipeline in Freesurfer 6.0. SCD cortical volumes were plotted onto reference curves based on imaging data from the Generation R study, a prospective Dutch population-based cohort study which contains 7442 brain MRI studies of 4,646 children acquired in four age groups (age 6-10 years, age 9-12 years, age 12-17 years and age 17-20 years). The same scanner and sequences were used to generate the reference curves and the SCD patients. BRICK data were acquired and processed using identical methods to those employed in the Generation R study. Since the growth curves included children between 6 and 17 years of age, we also selected this subset of our cohort (n=45) from the Rotterdam site.

Results: The SCD group consisted of 24 males (12 HbSS , 2 HbSβ⁰, and 10 HbSC) and 21 females (15 HbSS, 5 HbSβ⁰, and 1 HBSC). The mean age was the following for the overall SCD group: 11.7 yo (SD 3.53), male: 11.6 yo (SD 3.8), and female: 11.8 yo (SD 3.3). The mean total cortical grey matter volume was 639.7 ml (SD 55.2), with males having a mean of 643.7 ml (SD 55.5) and females 635.2 ml (SD 56.0). Ninety-nine percent (23/24) and 88% (20/24) of males scored below the 50th percentile for total cortical volume at any age compared to the Western European and non-Western reference population growth curves, respectively. Similarly, 76% (16/21) and 62% (13/21) of females scored below the 50th percentile compared to the Western and non-Western growth curves, respectively

Discussion Preliminary data suggests that youth with SCD have lower cortical volumes than peers without SCD. More research is needed to understand the effect of SCD on longitudinal brain growth. Furthermore, it is crucial to consider population-based physiological differences to avoid pathologizing normal variability. Data on white matter and subcortical volumes are currently being collected and these will also be mapped onto population growth curves. These data provide valuable insights into typical brain growth and how SCD impacts brain development.