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Although the source of excess brain iron remains unclear, haemoglobin is one possible source. To test this hypothesis, we conducted a case\u2013control study to determine whether erythrocytes are more fragile in people with progressive MS (PwPMS) and examined associations between erythrocyte fragility and brain atrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u2010matched cohorts. However, the haemolysis curve slope in PwPMS was less steep than healthy controls (median PwPMS\u2009=\u2009\u221224.76, controls\u2009=\u2009\u221228.73,\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.017), consistent with a subpopulation of fragile erythrocytes, with a similar trend in the age\u2010matched subset (\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.056). Erythrocyte fragility was associated with normalized whole brain volume at the time of osmotic fragility testing and up to three years thereafter.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70595","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T13:53:37Z","timestamp":1776434017000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Erythrocyte Fragility in Progressive Multiple Sclerosis"],"prefix":"10.1111","volume":"33","author":[{"given":"Carmen","family":"Jacob","sequence":"first","affiliation":[{"name":"Clinical Neurosciences, Clinical &amp; Experimental Sciences, Faculty of Medicine University of Southampton  Southampton UK"},{"name":"Wessex Neurological Centre, Southampton General Hospital University Hospital Southampton NHS Foundation Trust  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas E.","family":"Williams","sequence":"additional","affiliation":[{"name":"Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, Faculty of Brain Sciences University College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte M.","family":"Stuart","sequence":"additional","affiliation":[{"name":"Clinical Neurosciences, Clinical &amp; Experimental Sciences, Faculty of Medicine University of Southampton  Southampton UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviva","family":"Witkover","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Faculty of Medicine Imperial College London  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Hametner","sequence":"additional","affiliation":[{"name":"Division of Neurochemistry and Neuropathology Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8617-5052","authenticated-orcid":false,"given":"Hans","family":"Lassmann","sequence":"additional","affiliation":[{"name":"Department of Neuroimmunology, Center for Brain Research Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles R. 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