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; r 2 = .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 infarctionwere strongly sexually dimorphic. Understanding the possible neurological consequences of chronic anemia may help inform our current clinical practices.

Transient Hypoxia Model Revealed Cerebrovascular Impairment in Anemia Using BOLD MRI and Near‐Infrared Spectroscopy

“…These predictors have been demonstrated to be characteristic of the pathophysiology of SCD and chronic anemia disorders. 3,[14][15][16][17][18] All variables having univariate P < 0.10 were included as candidates for stepwise multivariate analysis. Variables were retained in the final model for P < 0.05.…”

“…Univariate and stepwise multivariate regressions were performed against predictors of anemia and SCD severity, including age, sex, hemoglobin, cerebral blood flow, presence of SCI, transfusion status, white blood cell count, platelet count, reticulocytes, fraction of S‐cells, fetal hemoglobin, and cell‐free hemoglobin level. These predictors have been demonstrated to be characteristic of the pathophysiology of SCD and chronic anemia disorders 3,14‐18 . All variables having univariate P < 0.10 were included as candidates for stepwise multivariate analysis.…”

Reduced global cerebral oxygen metabolic rate in sickle cell disease and chronic anemias

“…A 3-D T1-weighted, T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) 3D image and MR angiography image were acquired; details can be found in previous work. 13,24 Gray matter volume, white matter volume, cortical thickness and cortical surface area were calculated from T1 images based on previously-published methods. 9 Silent cerebral infarcts equal or greater than 3 mm in diameter in two orthogonal planes 25,26 were documented on T 2 -FLAIR images by the consensus of a neuroradiologist and neuroanatomist.…”

“…7,8 Despite having adequate resting oxygen delivery, chronically anemic subjects demonstrate diffuse brain volume loss and silent strokes, suggesting chronic or acute-on-chronic supplydemand imbalance. [9][10][11][12][13] Early prior works in SCD T 2 -relaxation-underspin-tagging (TRUST) 14 MRI with a calibration curve derived from bovine blood argued that brain oxygen extraction fraction (OEF) in SCD patients is increased proportional to the degree of anemia 15,16 to maintain normal cerebral metabolic rate of oxygen (CMRO 2 ). 17,18 Recent in vitro calibration work demonstrated unbiased and improved limits of agreement in OEF measurement using sicklespecific calibration compared to calibration derived from bovine blood.…”

Tract‐specific analysis and neurocognitive functioning in sickle cell patients without history of overt stroke

“…In addition to SCIs, which primarily damage the white matter (WM) in the brain, SCD patients also show reduced WM volume relative to controls (Choi et al, 2017(Choi et al, , 2019Steen et al, 2005). These abnormalities may lead to affective and cognitive consequences over time, including depression and isolation due to physical and mental limitations, as well as poor neurocognitive outcomes (Daniel Armstrong et al, 1996;Prussien et al, 2018;Schatz et al, 2001).…”