Elsevier

The Lancet Neurology

Volume 14, Issue 2, February 2015, Pages 183-193
The Lancet Neurology

Series
Pathological mechanisms in progressive multiple sclerosis

https://doi.org/10.1016/S1474-4422(14)70256-XGet rights and content

Summary

A better understanding of the pathological mechanisms that drive neurodegeneration in individuals with multiple sclerosis is needed to develop therapies that will effectively treat patients in the primary and secondary progressive stages of the disease. We propose that the inflammatory demyelinating disease process in early multiple sclerosis triggers a cascade of events that lead to neurodegeneration and are amplified by pathogenic mechanisms related to brain ageing and accumulated disease burden. Key elements driving neurodegeneration include microglia activation, chronic oxidative injury, accumulation of mitochondrial damage in axons, and age-related iron accumulation in the human brain. Altered mitochondrial function in axons might be of particular importance. This process leads to chronic cell stress and imbalance of ionic homoeostasis, resulting in axonal and neuronal death. The evidence suggests that treatment of progressive multiple sclerosis should be based on a combination of anti-inflammatory, regenerative, and neuroprotective strategies.

Introduction

Multiple sclerosis is a chronic inflammatory disease of the CNS that leads to focal plaques of primary demyelination and diffuse neurodegeneration in the grey and white matter of the brain and spinal cord.1 In most patients, the disease starts with a relapsing-remitting course (RRMS), which is followed after several years by a secondary progressive phase (SPMS)'. Patients with primary progressive disease (PPMS) miss the relapsing and remitting stage and start with uninterrupted progression from disease onset.2 When patients die within the first year of the disease, it is referred to as acute multiple sclerosis.3 Current anti-inflammatory or immunosuppressive therapies are beneficial in patients with RRMS, but are not effective in patients with progressive disease.4

Although data have shown that the risk of disease development is determined partly by genetic factors related to immune function and activation,5 and environmental factors such as Epstein-Barr virus infections,6 the ultimate cause of multiple sclerosis is unknown. A commonly proposed idea is that multiple sclerosis is an autoimmune disease in which autoreactive T lymphocytes enter the CNS from the peripheral immune system in the initial stages of lesion formation (the outside-in hypothesis).7 So far, no multiple sclerosis-specific autoimmune reaction has been identified. However, aggressive immunomodulatory treatments not only reduce relapses of the disease, but also reduce sustained disability progression, suggesting an important role for inflammation, at least in the early stages of the disease.8 Alternatively, multiple sclerosis might be caused by a primary infection or neuronal disturbance within the brain, and inflammation might therefore occur as a secondary response to this initial trigger, which amplifies disease and tissue damage (the inside-out hypothesis).9 Although infectious agents and specific alterations in CNS components that initiate a secondary immune reaction have not been identified in the brains of patients with multiple sclerosis, cortical atrophy can occur before substantial white matter demyelination and predicts future disease progression. While this finding could be taken as support for the inside-out hypothesis of multiple sclerosis, events that occur outside and inside the CNS are likely to determine the clinical outcome of the disease.

As outlined in this Series paper, many conflicting ideas have been proposed to explain disease progression and lesion formation in multiple sclerosis, all of which seem to be supported by firm and convincing data. We aim to provide a unifying picture by defining a cascade of immunological and neurodegenerative events that act in concert to induce multiple sclerosis-specific brain damage, but change in their relevance in the course of chronic disease evolution (figure 1; table).1, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33

Section snippets

Neuropathological features of progressive multiple sclerosis

The most characteristic tissue injury in the multiple sclerosis brain is primary demyelination with partial preservation of axons,3 but the prominent pathological feature of progressive multiple sclerosis is brain atrophy (figure 2).34 Actively demyelinating plaques associated with inflammation and blood–brain barrier injury are seen mainly in patients with RRMS, and become rare in patients with progressive multiple sclerosis. A subset of lesions in progressive multiple sclerosis, which varies

Active tissue injury is associated with inflammation

Results from genome-wide association studies support a major role for genes related to T-cell mediated inflammation11 in the determination of disease susceptibility.71 Although brain and spinal cord inflammation are present in RRMS, PPMS, and SPMS, the extent of inflammation declines with disease duration.12 Many infiltrating leucocytes can be seen in RRMS, especially in actively demyelinating white matter plaques. In progressive multiple sclerosis, divergent ideas have been proposed for the

Oxidative burst activation in microglia

Experimental studies show that many different mechanisms might lead to inflammatory demyelination and neurodegeneration. These mechanisms include direct cytotoxicity of CD8-positive T cells that recognise an antigen expressed in oligodendrocytes,79, 80 production of specific demyelinating antibodies,81 and activation of microglia by innate immunity.82 This variation might be reflected by the heterogeneity of mechanisms of demyelination and tissue injury seen in biopsies of active lesions taken

Mitochondria, oxidative stress, and axonal energy failure

The geometry of the neuron–axon unit presents a substantial challenge for efficient distribution of mitochondria and ATP production within axons, which can reach a metre in length in humans. Unlike the continuous mitochondrial reticulum seen in most cells, myelinated axons have two populations of mitochondria. Most axonal mitochondria are located at stationary mitochondrial sites distributed along the entire axonal length. Individual stationary sites can contain several long (1–4 μm)

Histotoxic (virtual) hypoxia versus genuine hypoxia in multiple sclerosis lesions

In pathology, the consequences of mitochondrial injury are defined by the term histotoxic hypoxia, which means a state of reduced oxygen consumption and energy failure in conditions of normal blood and oxygen supply. A similar mechanism has been proposed for multiple sclerosis lesions under the term virtual hypoxia.106 When the brain tissue is affected by histotoxic hypoxia, additional reduction of oxygen tension within the tissue is likely to amplify neurodegeneration. Experimental models show

Age-dependent iron accumulation in the human brain

Oxidative injury is amplified in the presence of divalent cations, such as iron (Fe2+) or copper (Cu2+). In the presence of these ions, H2O2 is converted into highly reactive hydroxyl molecules by the Fenton reaction. Iron accumulates within the normal human brain in an age-dependent manner,23 and is stored in myelin, oligodendrocytes, and microglia in the non-toxic ferric (trivalent, Fe3+) form bound to ferritin.107 In multiple sclerosis lesions, iron is liberated from damaged myelin and

Final pathways of demyelination and neurodegeneration

Acute and chronic oxidative injury lead to cell stress and, when they pass a threshold level, to cell degeneration. Therefore, unsurprisingly, many proteins associated with cell stress, including heat shock proteins,26 proteins induced by oxidative stress and hypoxia,27, 32, 111, 112, 113 and markers for endoplasmic reticulum stress, are expressed in active multiple sclerosis lesions and in the normal-appearing white matter.28, 114 Mitochondrial injury in multiple sclerosis lesions is shown by

Conclusions and therapeutic implications

As outlined in this Series paper, inflammation seems to drive a pathogenic cascade in multiple sclerosis, leading to oxidative damage and mitochondrial injury, which, particularly in the progressive stages of the disease, is further amplified by age-related changes in the human brain and microglia activation caused by accumulated brain damage. Similar mechanisms have been proposed in other human neurodegenerative diseases, but they seem to be especially prominent in multiple sclerosis because

Search strategy and selection criteria

This Series paper is based on the cumulative literature archives of the authors. Additionally, we searched PubMed for articles published in English up to July 1, 2014, with the search terms “multiple sclerosis”, “inflammation”, “neurodegeneration”, “demyelination”, “remyelination”, “microglia”, “mitochondria”, “iron”, “oxidative”, and “pathology”. Further search terms were included for the selective molecular mechanisms described in this Series paper. The final reference list was generated on

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