Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis

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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 (Fe ²⁺) is chelated by haemoglobin.

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Most cited references 35

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The neuropathological basis of clinical progression in multiple sclerosis.

Richard Reynolds, Federico Roncaroli, Richard A Nicholas … (2011)

Multiple sclerosis is the major inflammatory condition affecting the central nervous system (CNS) and is characterised by disseminated focal immune-mediated demyelination. Demyelination is accompanied by variable axonal damage and loss and reactive gliosis. It is this pathology that is thought to be responsible for the clinical relapses that often respond well to immunomodulatory therapy. However, the later secondary progressive stage of MS remains largely refractory to treatment and it is widely suggested that accumulating axon loss is responsible for clinical progression. Although initially thought to be a white matter (WM) disease, it is increasingly apparent that extensive pathology is also seen in the grey matter (GM) throughout the CNS. GM pathology is characterised by demyelination in the relative absence of an immune cell infiltrate. Neuronal loss is also seen both in the GM lesions and in unaffected areas of the GM. The slow progressive nature of this later stage combined with the presence of extensive grey matter pathology has led to the suggestion that neurodegeneration might play an increasing role with increasing disease duration. However, there is a paucity of studies that have correlated the pathological features with clinical milestones during secondary progressive MS. Here, we review the contributions that the various types of pathology are likely to make to the increasing neurological deficit in MS.

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Perivascular iron deposition and other vascular damage in multiple sclerosis.

C W Adams (1988)

Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis.

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Sodium accumulation is associated with disability and a progressive course in multiple sclerosis.

David Paling, Bhavana S. Solanky, Frank Riemer … (2013)

Neuroaxonal loss is a major substrate of irreversible disability in multiple sclerosis, however, its cause is not understood. In multiple sclerosis there may be intracellular sodium accumulation due to neuroaxonal metabolic dysfunction, and increased extracellular sodium due to expansion of the extracellular space secondary to neuroaxonal loss. Sodium magnetic resonance imaging measures total sodium concentration in the brain, and could investigate this neuroaxonal dysfunction and loss in vivo. Sodium magnetic resonance imaging has been examined in small cohorts with relapsing-remitting multiple sclerosis, but has not been investigated in patients with a progressive course and high levels of disability. We performed sodium magnetic resonance imaging in 27 healthy control subjects, 27 patients with relapsing-remitting, 23 with secondary-progressive and 20 with primary-progressive multiple sclerosis. Cortical sodium concentrations were significantly higher in all subgroups of multiple sclerosis compared with controls, and deep grey and normal appearing white matter sodium concentrations were higher in primary and secondary-progressive multiple sclerosis. Sodium concentrations were higher in secondary-progressive compared with relapsing-remitting multiple sclerosis in cortical grey matter (41.3 ± 4.2 mM versus 38.5 ± 2.8 mM, P = 0.008), normal appearing white matter (36.1 ± 3.5 mM versus 33.6 ± 2.5 mM, P = 0.018) and deep grey matter (38.1 ± 3.1 mM versus 35.7 ± 2.4 mM, P = 0.02). Higher sodium concentrations were seen in T₁ isointense (44.6 ± 7.2 mM) and T1 hypointense lesions (46.8 ± 8.3 mM) compared with normal appearing white matter (34.9 ± 3.3 mM, P < 0.001 for both comparisons). Higher sodium concentration was observed in T₁ hypointense lesions in secondary-progressive (49.0 ± 7.0 mM) and primary-progressive (49.3 ± 8.0 mM) compared with relapsing-remitting multiple sclerosis (43.0 ± 8.5 mM, P = 0.029 for both comparisons). Independent association was seen of deep grey matter sodium concentration with expanded disability status score (coefficient = 0.24, P = 0.003) and timed 25 ft walk speed (coefficient = -0.24, P = 0.01), and of T1 lesion sodium concentration with the z-scores of the nine hole peg test (coefficient = -0.12, P < 0.001) and paced auditory serial addition test (coefficient = -0.081, P < 0.001). Sodium concentration is increased within lesions, normal appearing white matter and cortical and deep grey matter in multiple sclerosis, with higher concentrations seen in secondary-progressive multiple sclerosis and in patients with greater disability. Increased total sodium concentration is likely to reflect neuroaxonal pathophysiology leading to clinical progression and increased disability.

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Journal

Journal ID (nlm-journal-id): 101696457

Journal ID (pubmed-jr-id): 45902

Journal ID (nlm-ta): Wellcome Open Res

Journal ID (iso-abbrev): Wellcome Open Res

Title: Wellcome open research

ISSN (Electronic): 2398-502X

Publication date (Electronic): 15 November 2016

Publication date PMC-release: 16 December 2016

Volume: 1

Electronic Location Identifier: 10

Affiliations

[1 ]Department of Epidemiology and Biostatistics, Imperial College London, London, UK

[2 ]Division of Infectious Diseases, Department of Medicine, Imperial College London, London, UK

[3 ]Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK

[4 ]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

[5 ]Present address: Department of Mathematics, Brunel University, London, UK

[1 ]Department of Neurology, Medical University of Graz, Graz, Austria

[1 ]Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada

[1 ]Center for Brain Research, Medical University of Vienna, Vienna, Austria

Author notes

[a ] Alex.Lewin@ 123456brunel.ac.uk

[b ] s.hamilton@ 123456imperial.ac.uk

[c ] c.bangham@ 123456imperial.ac.uk

AL analysed data, wrote the manuscript; SH designed experiments, conducted experiments, analysed data, wrote the manuscript; AW designed experiments, conducted experiments, analysed data.; PL designed experiments, wrote the manuscript; RN designed experiments, wrote the manuscript; JC designed MS-STAT trial, designed experiments, wrote the manuscript; CB conceived the project, designed experiments, analysed data, wrote the manuscript.

Competing interests: No competing interests were disclosed.

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Charles R.M. Bangham http://orcid.org/0000-0003-2624-3599

Article

Manuscript ID: EMS70774

DOI: 10.12688/wellcomeopenres.9967.1

PMC ID: 5159626

PubMed ID: 27996064

SO-VID: 4cd2c92e-fd96-448b-af63-3e278e88f24d

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This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Free serum haemoglobin is associated with brain atrophy in secondary progressive multiple sclerosis

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Abstract

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Neuronal Signaling

Most cited references 35

The neuropathological basis of clinical progression in multiple sclerosis.

Perivascular iron deposition and other vascular damage in multiple sclerosis.

Sodium accumulation is associated with disability and a progressive course in multiple sclerosis.

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