Anemia predicts lower white matter volume and cognitive performance in sickle and non-sickle cell anemia syndrome

Abstract

Severe chronic anemia is an independent predictor of overt stroke, white matter damage, and cognitive dysfunction in the elderly. Severe anemia also predisposes to white matter strokes in young children, independent of the anemia subtype. We previously demonstrated symmetrically decreased white matter (WM) volumes in patients with sickle cell disease (SCD). In the current study, we investigated whether patients with non-sickle anemia also have lower WM volumes and cognitive dysfunction. Magnetic Resonance Imaging was performed on 52 clinically asymptomatic SCD patients (age = 21.4 ± 7.7; F = 27, M = 25; hemoglobin = 9.6 ± 1.6 g/dL), 26 non-sickle anemic patients (age = 23.9 ± 7.9; F = 14, M = 12; hemoglobin = 10.8 ± 2.5 g/dL) and 40 control subjects (age = 27.7 ± 11.3; F = 28, M = 12; hemoglobin = 13.4 ± 1.3 g/dL). Voxel-wise changes in WM brain volumes were compared to hemoglobin levels to identify brain regions that are vulnerable to anemia. White matter volume was diffusely lower in deep, watershed areas proportionally to anemia severity. After controlling for age, sex, and hemoglobin level, brain volumes were independent of disease. WM volume loss was associated with lower Full Scale Intelligence Quotient (FSIQ; P = .0048; r² = .18) and an abnormal burden of silent cerebral infarctions (P = .029) in males, but not in females. Hemoglobin count and cognitive measures were similar between subjects with and without white-matter hyperintensities. The spatial distribution of volume loss suggests chronic hypoxic cerebrovascular injury, despite compensatory hyperemia. Neurocognitive consequences of WM volume changes and silent cerebral infarction were strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

FIGURE 1

Top Row: Anemia is correlated with brain volume in specific WM regions. (Left) R-values for the correlation between Deformation Index and hemoglobin are shown superimposed on the brain atlas template. Red indicates a positive correlation (lower WM with anemia) and blue indicate a negative correlation (higher WM with anemia) as indicated by the colorbar. Only voxels having a P-value ≤.05 (after false discovery rate correction) are shown. (Middle and right) 3D-rendering of left and right hemispheres demonstrating significant voxels colored by region (purple: frontal lobe; green: parietal lobe; blue: temporal lobe; yellow: occipital lobe; white: deep WM and subcortex; red: corpus callosum; light brown: brainstem; dark brown: cerebellum). Bottom Row: Group comparisons of Deformation Index. Histograms of Deformation Indices from regions in top row. (Left) Anemic-controls and SCD patients have lower Deformation Indices than controls. (Right) After controlling for hemoglobin differences, there is complete overlap across the three subject groups

FIGURE 2

Associations between Deformation Index, hemoglobin level and FSIQ. Linear regression between mean Deformation Index, from the regions in Figure 1, and hemoglobin (left column) and Full- Scale Intelligence Quotient (FSIQ, right column). Females are shown in the top row and males in the bottom row. Solid lines represent the best linear fit, dark and light shaded area delimits the 95% confidence intervals for the regression line and for individual values respectively. Data points are labeled by disease state