title: Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis.
abstract: BackgroundA major cause of disability in secondary progressive multiple sclerosis (SPMS) is progressive brain atrophy, whose pathogenesis is not fully understood. The objective of this study was to identify protein biomarkers of brain atrophy in SPMS.MethodsWe used surface-enhanced laser desorption-ionization time-of-flight mass spectrometry to carry out an unbiased search for serum proteins whose concentration correlated with the rate of brain atrophy, measured by serial MRI scans over a 2-year period in a well-characterized cohort of 140 patients with SPMS. Protein species were identified by liquid chromatography-electrospray ionization tandem mass spectrometry.ResultsThere was a significant (p<0.004) correlation between the rate of brain atrophy and a rise in the concentration of proteins at 15.1 kDa and 15.9 kDa in the serum. Tandem mass spectrometry identified these proteins as alpha-haemoglobin and beta-haemoglobin, respectively.  The abnormal concentration of free serum haemoglobin was confirmed by ELISA (p<0.001). The serum lactate dehydrogenase activity was also highly significantly raised (p<10-12) in patients with secondary progressive multiple sclerosis.ConclusionsAn underlying low-grade chronic intravascular haemolysis is a potential source of the iron whose deposition along blood vessels in multiple sclerosis plaques contributes to the neurodegeneration and consequent brain atrophy seen in progressive disease. Chelators of free serum iron will be ineffective in preventing this neurodegeneration, because the iron (Fe2+) is chelated by haemoglobin.
authors.affiliation: Department of Epidemiology and Biostatistics, Imperial College London, London, UK.|Present address: Department of Mathematics, Brunel University, London, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Lewin
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK.
authors.forename: Shea
authors.identifier: 0000-0001-6308-0253
authors.initials: S
authors.lastname: Hamilton
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK.
authors.forename: Aviva
authors.initials: A
authors.lastname: Witkover
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK.
authors.forename: Paul
authors.identifier: 0000-0002-6368-4724
authors.initials: P
authors.lastname: Langford
authors.affiliation: Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.affiliation: National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust and Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, University College London, London, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Chataway
authors.affiliation: Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK.
authors.forename: Charles R M
authors.identifier: 0000-0003-2624-3599
authors.initials: CRM
authors.lastname: Bangham
keywords: Secondary progressive multiple sclerosis; brain atrophy; haemoglobin; iron; neurodegeneration; pathogenesis; proteomics