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

Background and objectives: Cognitive difficulties in people with sickle cell anemia (SCA) are related to lower processing speed index (PSI) and working memory index (WMI). However, risk factors are poorly understood so preventative strategies have not been explored. Brain volumes, specifically white matter volumes (WMV) which increases through early adulthood, have been associated with better cognition in healthy typically developing individuals. In patients with SCA, the reduced WMV and total subcortical volumes noted could explain cognitive deficits. We therefore examined developmental trajectories for regional brain volumes and cognitive endpoints in patients with SCA. Methods: Data from two cohorts, the Sleep and Asthma Cohort and Prevention of Morbidity in SCA, were available. MRI data included T1-weighted axial images, pre-processed before regional volumes were extracted using Free-surfer. PSI and WMI from the Weschler scales of intelligence were used to test neurocognitive performance. Hemoglobin, oxygen saturation, hydroxyurea treatment and socioeconomic status from education deciles were available. Results: One hundred and twenty nine patients (66 male) and 50 controls (21 male) aged 8-64 years were included. Brain volumes did not significantly differ between patients and controls. Compared with controls, PSI and WMI were significantly lower in patients with SCA, predicted by increasing age and male sex, with lower hemoglobin in the model for PSI but no effect of hydroxyurea treatment. In male patients with SCA only, WMV, age and socioeconomic status predicted PSI, while total subcortical volumes predicted WMI. Age positively and significantly predicted WMV in the whole group (patients + controls). There was a trend for age to negatively predict PSI in the whole group. For total subcortical volume and WMI, age predicted decrease only in the patient group. Developmental trajectory analysis revealed that PSI only was significantly delayed in patients at 8 years of age; the rate of development for the cognitive and brain volume data did not differ significantly from controls. Discussion: Increasing age and male sex negatively impact cognition in SCA, with processing speed, also predicted by hemoglobin, delayed by mid childhood. Associations with brain volumes were seen in males with SCA. Brain endpoints, calibrated against large control datasets, should be considered for randomized treatment trials.

Brain volume in Tanzanian children with sickle cell anaemia: A neuroimaging study.

Brain injury is a common complication of sickle cell anaemia (SCA). White matter (WM) and cortical and subcortical grey matter (GM), structures may have reduced volume in patients with SCA. This study focuses on whether silent cerebral infarction (SCI), vasculopathy or anaemia affects WM and regional GM volumes in children living in Africa. Children with SCA (n = 144; aged 5-20 years; 74 male) and sibling controls (n = 53; aged 5-17 years; 29 male) underwent magnetic resonance imaging. Effects of SCI (n = 37), vasculopathy (n = 15), and haemoglobin were assessed. Compared with controls, after adjusting for age, sex and intracranial volume, patients with SCA had smaller volumes for WM and cortical, subcortical and total GM, as well as bilateral cerebellar cortex, globus pallidus, amygdala and right thalamus. Left globus pallidus volume was further reduced in patients with vasculopathy. Putamen and hippocampus volumes were larger in patients with SCA without SCI or vasculopathy than in controls. Significant positive effects of haemoglobin on regional GM volumes were confined to the controls. Patients with SCA generally have reduced GM volumes compared with controls, although some subcortical regions may be spared. SCI and vasculopathy may affect the trajectory of change in subcortical GM and WM volume. Brain volume in non-SCA children may be vulnerable to contemporaneous anaemia.

Quantitative susceptibility mapping (QSM) and R2* of silent cerebral infarcts in sickle cell anemia.

Silent cerebral infarction (SCI) is the most commonly reported radiological abnormality in patients with sickle cell anemia (SCA) and is associated with future clinical stroke risk. To date, there have been few histological and quantitative MRI studies of SCI and multiple radiological definitions exist. As a result, the tissue characteristics and composition of SCI remain elusive. The objective of this work was therefore to investigate the composition of segmented SCI lesions using quantitative MRI for R 2 * and quantitative magnetic susceptibility mapping (QSM). 211 SCI lesions were segmented from 32 participants with SCA and 6 controls. SCI were segmented according to two definitions (FLAIR+/-T1w-based threshold) using a semi-automated pipeline. Magnetic susceptibility (χ) and R 2 * maps were calculated from a multi-echo gradient echo sequence and mean SCI values were compared to an equivalent region of interest in normal appearing white matter (NAWM). SCI χ and R 2 * were investigated as a function of SCI definition, patient demographics, anatomical location, and cognition. Compared to NAWM, SCI were significantly less diamagnetic (χ = -0.0067 ppm vs. -0.0153 ppm, p < 0.001) and had significantly lower R 2 * (16.7 s-1 vs. 19.2 s-1, p < 0.001). SCI definition had a significant effect on the mean SCI χ and R 2 * , with lesions becoming significantly less diamagnetic and having significantly lower R 2 * after the application of a more stringent T1w-based threshold. SCI-NAWM R 2 * decrease was significantly greater in patients with SCA compared with controls (-2.84 s-1 vs. -0.64 s-1, p < 0.0001). No significant association was observed between mean SCI-NAWM χ or R2* differences and subject age, lesion anatomical location, or cognition. The increased χ and decreased R 2 * in SCI relative to NAWM observed in both patients and controls is indicative of lower myelin or increased water content within the segmented lesions. The significant SCI-NAWM R 2 * differences observed between SCI in patients with SCA and controls suggests there may be differences in tissue composition relative to NAWM in SCI in the two populations. Quantitative MRI techniques such as QSM and R 2 * mapping can be used to enhance our understanding of the pathophysiology and composition of SCI in patients with SCA as well as controls.

A Comparison of MRI Quantitative Susceptibility Mapping and TRUST-Based Measures of Brain Venous Oxygen Saturation in Sickle Cell Anaemia.

In recent years, interest has grown in the potential for magnetic resonance imaging (MRI) measures of venous oxygen saturation (Yv) to improve neurological risk prediction. T2-relaxation-under-spin-tagging (TRUST) is an MRI technique which has revealed changes in Yv in patients with sickle cell anemia (SCA). However, prior studies comparing Yv in patients with SCA relative to healthy controls have reported opposing results depending on whether the calibration model, developed to convert blood T2 to Yv, is based on healthy human hemoglobin (HbA), bovine hemoglobin (HbBV) or sickle hemoglobin (HbS). MRI Quantitative Susceptibility Mapping (QSM) is an alternative technique that may hold promise for estimating Yv in SCA as blood magnetic susceptibility is linearly dependent upon Yv, and no significant difference has been found between the magnetic susceptibility of HbA and HbS. Therefore, the aim of this study was to compare estimates of Yv using QSM and TRUST with five published calibration models in healthy controls and patients with SCA. 17 patients with SCA and 13 healthy controls underwent MRI. Susceptibility maps were calculated from a multi-parametric mapping acquisition and Yv was calculated from the mean susceptibility in a region of interest in the superior sagittal sinus. TRUST estimates of T2, within a similar but much smaller region, were converted to Yv using five different calibration models. Correlation and Bland-Altman analyses were performed to compare estimates of Yv between TRUST and QSM methods. For each method, t-tests were also used to explore group-wise differences between patients with SCA and healthy controls. In healthy controls, significant correlations were observed between QSM and TRUST measures of Yv, while in SCA, there were no such correlations. The magnitude and direction of group-wise differences in Yv varied with method. The TRUST-HbBV and QSM methods suggested decreased Yv in SCA relative to healthy controls, while the TRUST-HbS (p < 0.01) and TRUST-HbA models suggested increased Yv in SCA as in previous studies. Further validation of all MRI measures of Yv, relative to ground truth measures such as O15 PET and jugular vein catheterization, is required in SCA before QSM or TRUST methods can be considered for neurological risk prediction.