Chronic Anemia Patients Demonstrate Diffuse Demyelination

Chronic anemia is observed in individuals with sickle cell disease (SCD) and thalassemia syndromes. It has been associated with a range of neurological complications, particularly progressive silent cerebral infarcts in brain regions with high oxygen extraction-specifically in vascular watershed areas-suggesting that regional tissue hypoxia may play a causal role. However, recent work in sickle cell mice reveals widespread white matter demyelination and chronic neuroinflammation superimposed upon regional ischemia. In light of these findings, we utilized high-fidelity diffusion imaging and modeling techniques to identify predictors of white matter damage in human subjects diagnosed with SCD (n = 76) and thalassemia (n = 20) compared to healthy individuals (n = 32). Our results demonstrate that white matter damage extended beyond vascular watershed areas in chronically anemic subjects and had MRI changes characteristic of demyelination. These findings were proportional to hemoglobin levels and largely disappeared after controlling for anemia severity. However, patients with SCD exhibited small but significant residual white matter derangements not seen in those with thalassemia. These residual abnormalities disappeared after LDH or reticulocyte count were included as markers of hemolytic rate. From a functional perspective, neuropsychological processing speed was correlated with white matter integrity in chronic anemia subjects, with stronger associations seen in patients with SCD. Taken together, these results demonstrate that chronic anemia is associated with widespread white matter demyelination that cannot be explained by regional blood flow variation and is proportional to anemia severity. Patients with SCD may have more severe disease and functional consequences than patients with thalassemia.