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Exploring the origins of grey matter damage in multiple sclerosis

Nature Reviews Neuroscience volume 16, pages 147–158 (2015)Cite this article

Subjects

Key Points

  • Although multiple sclerosis has been characterized previously as a white matter disease, it is becoming increasingly apparent that extensive cortical and deep grey matter pathology can be present.

  • Several imaging studies have documented convincing correlations between white matter lesions and grey matter atrophy, suggesting that neurodegeneration can be a consequence of white matter demyelination via retrograde degeneration.

  • Another equally important theory suggests that white matter and grey matter demyelination are two, at least partly, independent phenomena and that neuronal loss is not caused by white matter abnormalities per se.

  • Several inflammatory cells types, including CD4+ and CD8+ T cells, are implicated in grey matter damage.

  • A role for B cells and meningeal inflammatory infiltrates in multiple sclerosis has been recently proposed.

  • It is becoming more widely accepted that microglial activation is necessary and crucial for host defence and neuronal survival, whereas microglial over-activation may be deleterious to neurons and oligodendrocytes.

  • The neuronal energy deficit is crucial for inducing axonal swelling and subsequent neuronal death, especially when it occurs as a consequence of inflammation. Several lines of evidence have led to the hypothesis that mitochondrial injury, and therefore the energy deficit, is a primary phenomenon in multiple sclerosis.

  • A recent theory — the inside-out model — notes the inconsistencies in the inflammatory model described above and suggests a degenerative model as the primary cause of the disease.

Abstract

Multiple sclerosis is characterized at the gross pathological level by the presence of widespread focal demyelinating lesions of the myelin-rich white matter. However, it is becoming clear that grey matter is not spared, even during the earliest phases of the disease. Furthermore, grey matter damage may have an important role both in physical and cognitive disability. Grey matter pathology involves both inflammatory and neurodegenerative mechanisms, but the relationship between the two is unclear. Histological, immunological and neuroimaging studies have provided new insight in this rapidly expanding field, and form the basis of the most recent hypotheses on the pathogenesis of grey matter damage.

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Figure 1: Cortical lesion subtypes in multiple sclerosis.
Figure 2: Inflammatory and non-inflammatory grey matter neurodegeneration mechanisms.
Figure 3: Is grey matter atrophy a primary or secondary pathological process?
Figure 4: Immune-mediated mechanisms of subpial cortical demyelination in progressive multiple sclerosis.

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Acknowledgements

M.C. is supported by the Progressive MS Alliance (PA-0124). R.Magliozzi is supported by an Italian Multiple Sclerosis Foundation grant (FISM 2011/R/23) and by an Italian Ministry of Health grant (GR-2010-2313255). R.R. is supported by the UK Multiple Sclerosis Society and the UK Medical Research Council. R. Martin and the Neuroimmunology and Multiple Sclerosis Research Section are supported by the Clinical Research Priority Program MS (CRPPMS) of the University of Zurich, the Swiss National Science Foundation (SNF), a European Research Council (ERC) Advanced Grant, the EU-FP7 framework programme and the Swiss Multiple Sclerosis Society.

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Authors and Affiliations

  1. Department of Neurological and Movement Sciences, Advanced Neuroimaging Laboratory of Neurology B, University Hospital Verona, Piazzale Ludovico Antonio Scuro 10, Verona, 37134, Italy

    Massimiliano Calabrese

  2. Division of Brain Sciences, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, W12 0NN, UK

    Roberta Magliozzi & Richard Reynolds

  3. Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Viale Regina Elena 299, Rome, Italy

    Roberta Magliozzi

  4. National Institute for Health Research, University College London/University College London Hospitals NHS Foundation Trust (NIHR UCL/UCLH) Biomedical Research Centre, 149 Tottenham Court Road, London, W1T 7DN, UK

    Olga Ciccarelli

  5. Queen Square Multiple Sclerosis Centre, University College London, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Olga Ciccarelli

  6. Department of Anatomy and Neurosciences, Section of Clinical Neuroscience, VU University Medical Center, van der Boechorststraat 7, Amsterdam, 1081 BT, The Netherlands

    Jeroen J. G. Geurts

  7. Department of Neurology, Neuroimmunology and Multiple Sclerosis Research Section, University Hospital Zurich, University of Zurich, Frauenklinikstrasse 26, Zurich, 8091, Switzerland

    Roland Martin

Authors
  1. Massimiliano Calabrese
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  2. Roberta Magliozzi
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  3. Olga Ciccarelli
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  4. Jeroen J. G. Geurts
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  5. Richard Reynolds
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  6. Roland Martin
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Corresponding author

Correspondence to Massimiliano Calabrese.

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Competing interests

M.C. has received speaking and consultancy honoraria from Biogen Idec, Merck Serono, Genzyme (a Sanofi company), and Teva Pharmaceutical companies. J.J.G.G. has received research support from Novartis and Biogen Idec and was a consultant for Novartis, Biogen Idec, Genzyme, Merck Serono, and Teva Pharmaceutical companies.

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Glossary

Complement proteins

A set of plasma proteins that coats pathogens; the coated pathogens are then cleared by phagocytes.

MRI

(Magnetic resonance imaging). A non-invasive method used to obtain images of living tissue. It uses radio-frequency pulses and magnetic field gradients; the principle of nuclear magnetic resonance is used to reconstruct images of tissue characteristics (for example, proton density or water diffusion parameters).

Wallerian degeneration

The degeneration of an axon distal to a site of injury, which begins to occur approximately 1.5 days after the injury.

Clinically isolated syndrome

A syndrome present in a patient experiencing their first clinical episode that is suggestive of an inflammatory demyelinating disease of the CNS.

Relapsing–remitting multiple sclerosis

(RRMS). The early phase of multiple sclerosis characterized by several neurological episodes followed by complete or incomplete recovery.

Radiologically isolated syndrome

A syndrome present in a patient who has radiological evidence of an inflammatory demyelinating disease of the CNS but no clinical signs or symptoms of such disease.

Primary and secondary progressive disease

Phases of multiple sclerosis characterized by a slow progression of disability without a well-defined clinical relapse. These phases usually follow the relapsing–remitting phase (secondary progressive phase) but they can also be in the first phase of the disease (primary progressive multiple sclerosis).

T cell

A lymphocyte that mediates cell-dependent immune responses by providing help (in the form of cytokines, for example) to other immune cells or by cytotoxicity (killing of a virus-infected cell).

B cells

Lymphocytes that express immunoglobulins as surface receptors or, when they are fully mature following antigenic stimulation, release antibodies that are directed against a virus or bacteria.

Natural killer cells

A white blood cell population that does not express antigen-specific recognition receptors such as those expressed by T and B cells, but recognizes cells that express fewer or no HLA class I molecules (such as virus-infected cells). Natural killer cells are important in controlling viral infections and recognition of mutated (tumour) cells.

Experimental autoimmune encephalomyelitis

An animal model of multiple sclerosis that is initiated in animals by injecting myelin proteins or peptides to raise autoreactive T cells or by the transfer of autoreactive T cells into naive recipients.

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Calabrese, M., Magliozzi, R., Ciccarelli, O. et al. Exploring the origins of grey matter damage in multiple sclerosis. Nat Rev Neurosci 16, 147–158 (2015). https://doi.org/10.1038/nrn3900

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