Abstract
Background: A 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. Methods: We 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. Results: There 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. Conclusions: An 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.
Highlights
In multiple sclerosis (MS), progressive disease develops in over half of those who present with an initial relapsing phase – secondary progressive MS (SPMS) – but can present as primary progressive MS (PPMS)
Unlike relapsing-remitting MS (RRMS), where an inflammatory response involving the adaptive immune system leads to episodic neurological deficits, in progressive MS neuroaxonal loss leads to an increasing neurological deficit and brain atrophy[5,6]
We used surface-enhanced laser desorption-ionization time-of-flight (SELDI-TOF) mass spectrometry to analyse serial serum samples from the population that participated in the MS-STAT study[1], to identify proteins whose abundance was associated with MRI-measured brain atrophy rate
Summary
In multiple sclerosis (MS), progressive disease develops in over half of those who present with an initial relapsing phase – secondary progressive MS (SPMS) – but can present as primary progressive MS (PPMS). The objective of the present study was to use an unbiased, high-throughput technique to identify protein biomarkers of brain atrophy in a longitudinal cohort of patients with SPMS. Serum proteomics in MS has previously been investigated in small cross-sectional studies to compare relapsing MS and progressive disease[10,11,12]. These previous studies were neither designed nor powered to identify correlates of neurodegeneration in SPMS. A 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
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