Molecular and environmental contributors to neurological complications in sickle cell disease

Abstract

Sickle cell disease (SCD) is an inherited hemoglobinopathy in which affected hemoglobin polymerizes under hypoxic conditions resulting in red cell distortion and chronic hemolytic anemia. SCD affects millions of people worldwide, primarily in Sub-Saharan Africa and the Indian subcontinent. Due to vaso-occlusion of sickled red cells within the microvasculature, SCD affects virtually every organ system and causes significant morbidity and early mortality. The neurological complications of SCD are particularly devastating and diverse, ranging from overt stroke to covert cerebral injury, including silent cerebral infarctions and blood vessel tortuosity. However, even individuals without evidence of neuroanatomical changes in brain imaging have evidence of cognitive deficits compared to matched healthy controls likely due to chronic cerebral hypoxemia and neuroinflammation. In this review, we first examined the biological contributors to SCD-related neurological complications and then discussed the equally important socioenvironmental contributors. We then discuss the evidence for neuroprotection from the two primary disease-modifying therapies, chronic monthly blood transfusions and hydroxyurea, and end with several experimental therapies designed to specifically target these complications.

Keywords: Sickle cell disease; cognitive decline; hemolytic anemia; hypoxemia; neuroinflammation; vasculopathy.

Figure 1.

The biological and environmental contributors to cognitive decline in sickle cell disease. Cognitive decline in individuals with sickle cell disease (SCD) is complex with diverse biological and environmental contributors. The biological components include chronic hemolytic anemia, cerebral hypoxemia, vasculopathy, including overt stroke and silent cerebral infarctions, and systemic and neuroinflammation. Societal and environmental components span from childhood household income, parental educational attainment, and chronic school absenteeism to a lack of funding for SCD research and societal implicit bias. As illustrated through the circular model, all of these contributors are interconnected and influence one another. Source: Created with BioRender.com.