Sex-related differences in silent cerebral infarction burden among adults with sickle cell disease

Abstract Background: Patients with sickle cell disease (SCD) are at increased risk of both overt strokes and, more commonly, silent cerebral infarcts (SCI), largely due to cerebral vasculopathy and chronic severe anemia. Research on SCI in SCD has predominantly focused on pediatric and adolescent populations, in which a greater SCI burden has been reported in males. The burden of SCI and the existence of sex-related differences in adults with SCD remain poorly studied. Given the association between increased SCI burden and long-term cognitive decline, it is imperative to comprehensively characterize and identify associated risk factors, such as sex. In this study, we use cerebral MRI to quantify SCI burden and examine associated risk factors in adults with SCD compared to matched controls. Method: High-resolution cerebral images (voxel size: 0. 75 x 0. 75 x 1. 5 mm3) were obtained using Fluid-Attenuated Inversion Recovery (FLAIR) sequences acquired at 7 Tesla MRI with a customized first-generation head coil in age, sex, and race-matched adults with SCD (all genotypes) and healthy controls (IRB# PRO12040139, Ibrahim T. S et ISMRM 2013). White matter hyperintensities, representing areas of SCI, were segmented and quantified using an automated deep learning-based segmentation algorithm, wmhₛeg, and subsequently normalized to intracranial volume (Li J et arXiv 2024). Demographic and biochemical data were extracted from the electronic medical record. Associations between SCI burden and clinico-demographic variables were assessed using univariate and multivariable models. Result: A total of 81 participants (aged 20-62 years) were included in the study, comprising individuals with SCD (n=41; 25 (61%) females; mean age 35 +/- 12 years) and healthy controls (HC; n=42; 24 (57%) females; mean age 35 +/-13 years). Overall, SCI burden was increased in SCD compared to controls (p = 0. 0458). Among adults with SCD, females exhibited a significantly greater SCI burden compared to males (p = 0. 0142), a difference not observed in the HC group (p = 0. 648). Compared to the HC group, the SCD group had a lower mean hemoglobin (10. 3 g/dL vs. 13. 6 g/dL), which may have contributed to the higher SCI burden in the SCD group. However, there were no significant differences in hemoglobin level between female and male patients in the SCD group. After adjusting for age and hemoglobin in multivariable models, sex remained a significant predictor of SCI burden in the SCD group (beta=0. 78; p=0. 0160). Conclusion: This study demonstrates a high burden of SCI in adults with SCD. Our data suggest that sex-related differences in SCI burden exist in the adult population, but with females rather than males exhibiting greater SCI accumulation. The increased SCI burden is not explained by lower hemoglobin levels or older age, which are traditional contributors to cerebrovascular risk. These findings highlight the importance of incorporating sex as a key variable in the evaluation of cerebrovascular disease in SCD and highlights the need for further investigation into the mechanisms underlying sex-specific differences in SCI burden in this population.