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

Abstract

Background and objectivesCognitive 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.MethodsData 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.ResultsOne 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.DiscussionIncreasing 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 Volumes and Cognition in Patients with Sickle Cell Anaemia: A Systematic Review and Meta-Analysis

“…Other studies looking at this association were from unpublished datasets. The analysis did not reveal any associations between GMV and IQ measured on Weschler Scales for Intelligence in paediatric or adult SCA patients [ 15 ], nor were any associations seen with Raven’s Progressive Matrices in Tanzanian children with SCA [ 27 ]. Although IQ remained lower in patients across all studies, GMV was significantly lower only in Tanzanian SCA children [ 27 ].…”

“…Two other studies revealed no association between WMV and IQ in SCA patients or controls. WMV, however, was associated with PSI only in male patients in one of the studies [ 15 ]. Haemoglobin appeared to be a predictor of WMV and IQ in both male and female patients [ 26 ], suggesting that early exposure to anaemia with compensatory cerebral haemodynamic mechanisms influences WMV.…”

“…When haemoglobin is lower, cerebral blood flow (CBF) increases to compensate for lower oxygen, also increasing the risk of stroke. While GMV in young adults is relatively preserved, the white matter may remain hypoxic, resulting in lower volumes and an increased risk for microstructural damage [ 15 , 26 ].…”

“…Adult studies have had mixed results in subcortical volumetric reductions. Two studies did not show any reductions in subcortical volume [ 15 ] and total hippocampal volume [ 16 ], nor were they associated with IQ, performance IQ [ 16 ] or working memory [ 15 ]. All four studies noted anaemia severity as a strong predictor of neurocognitive scores as well as volumetric reduction in SCA.…”

“…However, the relationship between brain volume and cognition is not clearly established. There was an association between working memory index (WMI) and subcortical volume in adult SCA patients [ 14 ], while in our original paper [ 15 ], processing speed index (PSI) was associated with white matter volume (WMV) in adult and paediatric males with SCA. Other studies [ 16 , 17 ] on the relationship between brain volumes and cognition do not report similar findings.…”