Structural connectivity mediates the relationship between blood oxygenation and cognitive function in sickle cell anemia

Abstract

In sickle cell disease (SCD), the relative importance of reduced hemoglobin and peripheral oxygen saturation (SpO2) on brain structure remains uncertain. We applied graph-theoretical analysis to diffusion MRI data to investigate the effect of structural brain connectivity on cognitive function, alongside presence/absence, number and volume of silent cerebral infarction (SCI). In patients, we investigated the relationships between network properties, blood oxygenation and cognition (working memory, WMI, and processing speed, PSI, indices). Based on streamline counts and fractional anisotropy (FA), we identified a subnetwork with weakened connectivity in 92 SCA patients (49 males; 8.0-38.8 years), compared to 54 non-SCA controls (22 males; 6.7-30.6 years). Multiple regression analyses showed a significant effect of hemoglobin on full-network edge density (p<0.05), and of peripheral SpO2 on streamline-weighted subnetwork efficiency (p<0.01). There were effects of FA-weighted full-network and subnetwork efficiency on WMI (both p<0.05), and of streamline-weighted subnetwork efficiency on PSI (p=0.05) but no effects on SCI. Streamline-weighted efficiency was progressively lower with lower SpO2, with a downstream effect on PSI. In path analysis, indirect relationships between blood oxygenation and cognition, mediated by network properties, were better supported than direct alternatives, with an indirect relationship between low SpO2 and PSI in patients, mediated by structural connectivity efficiency in a subnetwork of the brain differing from controls. Our findings are consistent with the notion that cognitive impairment is primarily mediated by hypoxic-ischemic effects on normal-appearing white matter, and highlight the utility of network-based methods in providing biomarkers of cognitive dysfunction in SCA patients.

Mind the gap: trajectory of cognitive development in young individuals with sickle cell disease: a cross-sectional study

“…Several studies of blood oxygenation measures and cognition have found that reduced haemoglobin is associated with reduced IQ in adolescents and young adults ( 51 ) and also neurodevelopmental delay in 9- to 12-month old infants living with SCD ( 77 ). Similarly, reduced processing speed was linked to lower CaO 2 , poor white matter microstructural integrity in ( 35 ) and reduced white matter structural connectivity ( 78 , 79 ) in CYA-SCD. Taken together, these data suggest that cerebral haemodynamic stress, central to sickle cell anaemia pathology, may result in poor long-term cognitive outcomes.…”

Effects of regional brain volumes on cognition in sickle cell anemia: A developmental perspective

“…Participants were enrolled in two studies ( 23 ): the Sleep Asthma cohort study (SAC) and the Prevention of Morbidity in SCA 2b (POMS) trial, and were aged >8 years at recruitment and assessment (2015–2019). Participants were ineligible if they were participating in blood transfusion or oxygen therapy trials, receiving nocturnal oxygen support, had chronic lung diseases (except asthma) or respiratory failure.…”

Executive Function and Processing Speed in Children Living with Sickle Cell Anemia

“…Executive function includes skills that represent the capacity to plan and meet goals, maintain focus despite distractions, engage in goal-directed behavior, display self-control, and follow multiple-step directions [33,34]. SCA infarction often occurs in the frontal lobe regions [35], which are greatly affected by hypoxia (reduced tissue oxygenation) and hypoxemia (decrease in the partial pressure of oxygen in the blood) [13], and these regions are vital in facilitating executive function [35][36][37][38].…”