Cognitive Dysfunction Worsens with Age in Patients with Sickle Cell Disease in the Modern Treatment Era

Introduction

Patients with sickle cell disease (SCD) suffer from cognitive dysfunction compared to those unaffected by the disease. Such cognitive dysfunction in patients with SCD is further exacerbated by the occurrence of overt stroke or silent cerebral infarcts (SCIs). Fortunately, treatments such as hydroxyurea and red blood cell (RBC) transfusion for patients with SCD have been shown to be neuroprotective. Studies that predate guidelines recommending all patients with HbSS or HbS beta thalassemia null genotypes receive primary disease modification with hydroxyurea report that cognitive dysfunction worsens with age in patients with SCD. However, there is limited investigation into cognitive trajectories across the lifespan during the modern treatment era for patients with SCD. While neuroprotective interventions are widely recommended, we hypothesize that patients with SCD will continue to experience cognitive decline.

Methods

Patients >5 years of age with any genotype of SCD, excluding those receiving chronic RBC transfusions, were included in these analyses. Cognitive data, as measured by the NIH Toolbox-Cognitive Battery (NIHTB-CB) and the Wechsler Abbreviated Scale Intelligence 2^nd edition (WASI-II), were combined from three prospective research studies at a single institution. A subgroup of participants had multiple timepoints of data collected. Multivariate general linear mixed-level models, accounting for multiple timepoints per participant, were used to predict each cognitive subdomain while controlling for the independent variables of age and sex. Age squared (age²) was included in models if necessary to account for a second-order polynomial fit. Significance was defined as α<0.05 and the Benjamini-Hochberg procedure was used to correct for multiple comparison.

Results

Data was collected from 123 participants with SCD between 2014-2022. The cohort was 45.4% male (56/123 participants). Thirty-four participants had 2 timepoints and 7 participants had 3 timepoints of cognitive data included in the analyses, for 164 total timepoints. First and last-timepoints were separated by 1-4 years for the NIHTB-CB and 1-8 years for the WASI-II tests. The average (SD, range) number of months between the first and last encounters was 31.2 (10.9, 14.2-47.7) for completion of NIHTB-CB testing and 43.9 (22.2, 14.2-89.3) for completion of WASI-II testing. Table 1 describes the cohort. The average (SD, range) hemoglobin at all timepoints was: 9.0 (1.6, 5.6-13.3). The number (percent) of participants taking hydroxyurea and the mean (SD, range) dosage for all timepoints was: 97/164 (59.1%), 380.9mg (649.4, 11.0-2000.0). Using multivariate general linear mixed-level models to predict each cognitive subdomain and composite score provided in the NIHTB-CB and WASI-II, the Flanker Inhibitory Control and Attention (age p=0.0164), Oral Reading (age p=0.0006, age² p=0.0018), Pattern Comparison Processing Speed (age p=0.0210, age² p=0.0206, sex p=0.0041), Crystallized Composite (age p=0.0038, age² p=0.0063) and Total Composite (age p=0.0215, age² p=0.0219) scores decreased with age while controlling for the effect of sex (Table 1, Figure 1). There was not a significant relationship between age and cognitive outcome measure for the Picture Vocabulary, List Sorting Working Memory, Dimensional Change Card Sorting, Picture Sequence Memory, Fluid Composite, Matrix Reasoning or Full-Scale IQ tests.

Conclusion

We conclude that cognitive abilities, encompassing executive function abilities (Flanker Inhibitory Control and Attention Test), non-executive function abilities (Oral Reading Test and Crystallized Composite) and processing speed (Pattern Comparison Processing Speed Test), decrease as patients with sickle cell disease age during the modern treatment era. Further analyses are required to determine the impact of age on cognitive outcomes while controlling for the presence of infarction, primary disease modification, hemoglobin and additional biologic covariates. These preliminary analyses support further investigation into the pathophysiology of SCD on both brain development and aging, and consideration of neurocognitive outcomes in the development of new therapeutics.

King:Global Blood Therapeutics: Consultancy, Research Funding. Fields:Global Blood Therapeutics: Consultancy; Proclara Ciosciences: Other: Equity Ownership.