Sublingual Microvascular Findings in Sickle Cell Disease and Correlation with Neurocognition
Authors: Tukakira John , Carpenter Michael , Snitz Beth E. , Rosano Caterina , Novelli Enrico M , Oluwole Olubusola 
Published: December 2024

Aim: Sublingual imaging has been used in several research and clinical settings. Its use in sickle cell disease (SCD) is limited. We evaluated its role in detecting sublingual microvascular pathology. In line with existing literature, we also investigated the association of endothelial glycocalyx with cognition. This is the first study to examine endothelial glycocalyx changes and cognition in SCD. We hypothesized that endothelial glycocalyx reductions in SCD may correlate with worse cognition, with multiple domains explored.

Methods: This ongoing cross-sectional pilot study aimed at enrolling 20 participants (10 with SCD and 10 without SCD) between the ages of 18 and 65 who previously participated in a longitudinal trial assessing the association between neurocognition and neuroimaging abnormalities. All participants underwent sublingual imaging. We examined vessel density, endothelial glycocalyx, and red blood cell (RBC) filling percentage, comparing these findings between patients with SCD and controls. Vessel density is the number of blood vessels with more than 50% RBC content. Endothelial glycocalyx is the polysaccharide layer lining the luminal end of endothelial cells. It is inversely related to the perfused boundary region (PBR) measured on sublingual imaging. The red blood cell filling percentage is the average red blood cell content of individual blood vessels, expressed as a percentage. We performed cognition testing using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Delis-Kaplan Executive Function System (D-KEFS). Scores were analyzed across total and domain-specific scales. Statistical analyses were performed using R version 4.4.0. Given small samples, we focused on effect sizes between groups using Cohen's d statistic (d), and correlations using Kendall's tau test (tau).

Results: We enrolled 10 participants (5 with SCD and 5 non-SCD) with an average age of 53.7 years (SD 9.3). None of the following analyses were statistically significant. SCD patients had a lower average vessel density (438.6 vs 494.0, d=-0.3) and a lower RBC filling percentage (70.54% vs 71.4%, d=-0.1). PBR was higher in patients (2.176 µm vs 1.98 µm, d=0.8). Patients also had lower executive function scores on average (7.15 vs 9.15, d=-0.7) and lower total cognitive scores on RBANS (85.2 vs 91.2, d=-0.5). Individuals with SCD showed better scores in the immediate memory domain (93.8 vs 87.2, d=0.4) but worse in visuospatial/constructional (89.4 vs 98.2, d=-0.7), language (87.6 vs 96.6, d=-0.8), attention (82.2 vs 88.4, d=-0.3), and delayed memory (93.0 vs 98.4, d=-0.5) domains. The correlation between endothelial glycocalyx and executive function was weaker in SCD patients compared to controls (tau 0.4 vs 0.6). There was no correlation between endothelial glycocalyx and the total cognitive scale for SCD patients and controls. In the different domains among SCD patients, there was a very weak correlation in the immediate memory domain (-0.2), a weak correlation in the visuospatial/constructional domain (0.3), a moderate correlation in the language domain (-0.6), a strong correlation in the attention domain (0.8), and a weak correlation in the delayed memory domain (0.2). In the different domains among control participants, there was a moderate correlation in the immediate memory domain (0.6), a weak correlation in the visuospatial/constructional domain (0.4), a very weak correlation in the language domain (0.1), a very weak correlation in the attention domain (0.2), and a very weak correlation in the delayed memory domain (0.2).

Conclusion: Preliminary data suggests patients with SCD show reduced endothelial glycocalyx, vessel density, and RBC filling percentage on sublingual imaging. We observed an apparent large effect size in endothelial glycocalyx between patients and controls. Cognition appeared generally lower among patients. The correlation between sublingual imaging findings and cognition was weak. Our statistics were not significant, likely due to the small sample size, which limited the power and generalizability of the findings. Larger studies are needed to detect reliable differences and correlations. Despite these limitations, the study provides preliminary insights into the neurocognitive impact of SCD and the potential role of the endothelial glycocalyx. Future work will expand enrollment and test confirmation of initial findings.