Subclinical neurovascular injury and cognitive outcomes in adults with sickle cell disease: Prevalence and imaging correlates

Abstract Background Silent cerebral infarcts (SCI) are well-known risk factors for stroke and cognitive impairment in children with sickle cell disease (SCD), with IQ declining as abnormalities on magnetic resonance imaging (MRI) increase. These lesions accumulate with age, but their long-term impact in adults is less well characterized. Importantly, SCI represent only one category of cerebral vascular injury. Other radiological features—such as white matter hyperintensities, microangiopathy, and aneurysms—may also reflect chronic cerebrovascular damage but remain poorly studied in adults with SCD. Few studies have evaluated how the full spectrum of structural and vascular lesions correlates with cognitive function, education, and employment. The primary objective of this study was to determine the prevalence of the different structural and vascular brain lesions in adults with SCD. Secondly, we aimed to assess their association with cognitive performance and thirdly, examine relationships with educational attainment, occupational status and functional outcomes. Methods We conducted a retrospective cross-sectional study (2016–2024) at a tertiary SCD center. Adults (≥18 years) with any SCD genotype, at least one hematology clinic visit, and cerebral MRI and magnetic resonance angiography (MRI/MRA) with a formal neuroradiology report were included. Patients with prior symptomatic stroke were excluded. Radiological findings included SCI, white matter hyperintensities (WMH) consistent with small vessel disease, microangiopathy, aneurysms, intracranial artery stenosis, and Moya-Moya. SCI were defined as infarct-like lesions ≥3 mm on T2-weighted MRI without neurological symptoms. WMH were categorized based on descriptive terminology consistent with STRIVE-2 guidance. Outcomes included results on MoCA, mRS, educational attainment, years of schooling, and occupational status. Cognitive and functional assessments (MoCA, mRS) were obtained at last follow-up by vascular neurologists in a dedicated neurovascular-SCD clinic. Group differences were assessed using t-tests, Mann-Whitney U, or chi-square tests, as appropriate. A univariate ANCOVA model was used to adjust for age, sex and hypertension. Ethics approval was obtained. Results Among 391 adults (median age 32 [range 18–79]; 56.3% female), 54.2% had HbSS/HbSβ⁰ and 45.8% had HbSC/HbSβ⁺. Treatments included hydroxyurea (66.0%), transfusions (14.8%), and both (5.4%). Antiplatelets were used in 37.9%, anticoagulants in 5.6%, and antihypertensives in 8.7%. At least one silent structural or vascular brain lesion was identified in 259 (66.2%). SCI were found in 30 (7.7%). WMH were observed in 172 (44.0%), microangiopathy in 46 (11.7%), aneurysms in 57 (14.8%), intracranial stenosis in 12 (3.0%), and Moya-Moya in 2 (0.5%). MRI/A was normal in 132 (33.8%). Patients with any abnormality had lower mean MoCA scores (26 vs. 27; p=0.06), although there were no significant differences in mRS (0 [0–1] vs. 1 [0–1]; p=0.54), years of schooling (13 vs. 14; p=0.27), education (χ² (5)=3.40; p=0.64), or occupation (χ² (5)=2.98; p=0.70). SCI were not significantly associated with cognitive or functional outcomes. However, microangiopathy was associated with lower MoCA scores (24 vs. 26; p=0.03), suggesting potential clinical relevance. No significant differences were seen for WMH, aneurysms, or stenosis. Age was significantly associated with MoCA scores (B=-0.095, 95% CI: -0.132 to –0.057, p<0.001), with older age predicting lower scores, while sex (p=0.09) and hypertension (p=0.30) were not. After adjusting for age, sex and hypertension, presence of microangiopathy was significantly associated with lower MoCA scores ((ANCOVA) F (1, 237) = 8.486, p=0.004). Neither SCI (F(1,237) = 0.104, p=0.75), WMH (F(1, 237) = 0.054, p=0.82), aneurysms (F(1, 237) = 0.223, p=0.64), nor stenosis (F(1, 237) = 0.011, p=0.92) were significantly associated with MoCA after adjustment. These findings suggest that microangiopathy may reflect a clinically relevant marker of cognitive vulnerability in adults with SCD, independent of age-related decline. Discussion Subclinical neurovascular injury is common in adults with SCD, with microangiopathy emerging as the only lesion independently associated with lower cognitive performance. These findings underscore the need to look beyond SCI and integrate broader markers of small vessel disease in surveillance strategies aimed at preserving cognitive health in adults with SCD.

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