Assessment of Neurocognitive Functioning in Sickle Cell Disease and Thalassemia and the Association with Silent Cerebral Infarcts and Cerebral Hemodynamics and Oxygen Metabolism
Authors: Afzali-Hashemi Liza , Franse Melanie , Baas Koen P.A. , Schrantee Anouk , Wood John C. , Nederveen Aart J , Biemond Bart J. , O'Neil Sharon 
Published: December 2023

Introduction
Neurocognitive impairment is a significant problem in patients with sickle cell disease (SCD), affecting various life domains such as academic achievement, career progress, and general life quality. The cause of this impairment is not yet fully understood, however, it has been linked to silent cerebral infarcts (SCIs) and irregularities in blood perfusion and oxygenation, particularly in children with SCD. Previous research has identified cognitive deficits in adults with SCD, but the relationship with SCIs has not been thoroughly explored in this age group. This study aimed to examine the neurocognitive functioning among adult patients with three types of inherited chronic anemia (severe SCD, mild SCD, and thalassemia) and healthy controls. Additionally, we investigated potential associations of neurocognitive performance with cerebral perfusion and oxygenation, and SCIs.
Methods
This study included 70 severe SCD patients (60 HbSS, 10 HbSβ 0), 22 mild SCD patients (14 HbSC, 8 HbSβ +), 16 thalassemia patients (6 NTDT, 10 TDT), and 29 healthy controls. We assessed neurocognitive functioning through eight tasks divided into seven neurocognitive domains such as attention, processing speed, nonverbal IQ, working memory, verbal learning, visual memory, and fine motor dexterity. Each task score was standardized using published norm data, converted into Z-scores, and used to compute the mean Z-score per domain. SCIs were assessed and segmented using FLAIR MRI scans. Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) were derived using time-encoded pseudo-continuous arterial spin labeling (te-pCASL) and T 2-relaxation-under-spin-tagging (TRUST) techniques, respectively. Cerebral metabolic rate of oxygen (CMRO 2) was calculated from the CBF, OEF and oxygen content (calculated from hemoglobin and arterial saturation). One-sample t-tests or one-sample Wilcoxon-signed rank tests were used to compare the seven neurocognitive domains of each group with normative test data and ANOVA was used to compare these domains between participant groups. Independent-sample t-tests or Mann-Whitney U tests were used to compare the neurocognitive domains between patients with and without SCIs. Lastly, correlation analyses explored the relationships between the neurocognitive domains and SCI volume, CBF, OEF, and CMRO 2.
Results
In the severe SCD group, only processing speed and fine motor dexterity were significantly impaired after adjusting for multiple comparisons (Table 1 & Figure 1). Mild SCD patients exhibited lower scores in processing speed, working memory, and fine motor dexterity compared to the norms. In contrast, after adjustment for multiple comparisons, thalassemia patients and healthy controls only showed significantly lower scores in fine motor dexterity (Table 1). When comparing groups, SCD patients had significantly slower processing speed compared to thalassemia patients and healthy controls. Surprisingly, SCD patients without SCIs exhibited poorer fine motor dexterity than those with SCIs (p=0.03), while no such associations were identified in other groups. Finally, no associations were found between the neurocognitive domains and SCI volumes, CBF, OEF and CMRO 2.
Conclusion
Our results show slower processing speed in SCD patients compared to thalassemia patients and healthy controls, aligning with previous studies. However, unlike previous research, we did not find additional neurocognitive deficits in SCD patients. This could be due to variations in patient selection, environmental factors, socioeconomic status, or recent enhancements in SCD treatment approaches, such as the early administration of hydroxyurea and/or blood transfusion. Interestingly, all groups showed diminished fine motor dexterity, potentially due to the ongoing digital transition. A key observation from this study was the lack of association between neurocognitive performance and SCIs, hemodynamics, and oxygen metabolism, suggesting that SCIs and oxygenation might not be the only factors contributing to impaired processing speed.
Our results suggest that recent developments in medical treatments could have improved the neurocognitive function of SCD patients residing in Western countries. However, concerning the domain of processing speed, further studies are required to investigate other SCD-related factors that might influence this particular area.