ABSTRACT Background Aberrant iron homeostasis is increasingly recognized as a key pathological feature in progressive multiple sclerosis (MS). Although the source of excess brain iron remains unclear, haemoglobin is one possible source. To test this hypothesis, we conducted a case–control study to determine whether erythrocytes are more fragile in people with progressive MS (PwPMS) and examined associations between erythrocyte fragility and brain atrophy. Methods PwPMS and control individuals were recruited from two centres. Two measures of erythrocyte fragility were assessed at baseline: the Median Corpuscular Fragility (MCF) and haemolysis curve slope. A subset of PwPMS in one centre underwent MR imaging at the same time as osmotic fragility testing and annually for three years thereafter. Results A total of 174 participants were included (75 PwPMS, 99 controls), with MRI data available for 44 PwPMS. No significant differences in the MCF were observed between PwPMS and controls in either the full or age‐matched cohorts. However, the haemolysis curve slope in PwPMS was less steep than healthy controls (median PwPMS = −24.76, controls = −28.73, p = 0.017), consistent with a subpopulation of fragile erythrocytes, with a similar trend in the age‐matched subset ( p = 0.056). Erythrocyte fragility was associated with normalized whole brain volume at the time of osmotic fragility testing and up to three years thereafter. Conclusions Extracellular haemoglobin from lysis of an erythrocyte subpopulation may contribute to neurodegeneration in progressive MS. Further research is warranted to elucidate the interplay between erythrocyte health, inflammation and neurodegeneration, which may open avenues for novel therapeutic strategies.
Jacob et al. (Wed,) studied this question.