Characterizing demyelinating lesion formation and neurodegeneration


REPORT FROM THE EUROPEAN CHARCOT FOUNDATION ANNUAL MEETING – BAVENO, ITALY, NOVEMBER 28-30, 2013 – A decade ago, four immunopathological patterns of demyelination were described for MS lesions (Lucchinetti et al. Ann Neurol 2000;47:707-717). Patterns I and II resembled a T-cell-mediated and T-cell plus antibody-mediated autoimmune encephalomyelitis, while patterns III and IV were suggestive of a virus- or toxin-mediated demyelination rather than autoimmune processes. This lesion heterogeneity is evident early in MS; patterns converge to one of T cell, macrophage and microglia involvement later in the disease course (Lassmann H. ECF 2013).

Recent work has focused on patterns III/IV in an attempt at further characterizing the underlying pathogenetic mechanisms. These patterns resemble the hypoxic damage found in stroke-associated lesions. However, this hypoxia is due not to vascular occlusion, ischemia or systemic hypoxia, but rather to the release of reactive oxygen species (ROS) during CNS inflammation, which contributes to mitochondrial dysfunction and histotoxic hypoxia (Aboul-Enein & Lassmann. Acta Neuropathol 2005;109:49-55).

It has been suggested that mitochondrial dysfunction may explain certain pathological features of MS lesions, such as demyelination, oligodendrocyte apoptosis, and astrocyte dysfunction (Veto et al. Brain 2010;133:822-834; Sharma et al. Acta Neuropathol 2010;120:223-236). A recent comparison of progressive MS lesions and non-MS inflammatory and non-inflammatory lesions found that genes associated with ROS-associated tissue damage, mitochondrial injury and apoptosis were involved in chronic MS lesions.

These findings have led to the suggestion that early in the MS disease course, neurodegeneration is driven by inflammatory processes that lead to microglial activation, oxidative bursts and mitochondrial dysfunction. Mitochondrial dysfunction can further amplify the process through increased ROS production and liberation of intracellular iron stores. These amplification factors appear to be more important in the early stages of MS (Lassmann H. J Neurol Sci 2013;333:1-4).

Thus, a more aggressive onset and early progression may be attributable in part to mitochondrial dysfunction, which results in diffuse neurodegenerative lesions. This is seen in Harding’s disease, which resembles MS but which is characterized by more aggressive forms of tissue injury, such as cystic holes (pattern IV lesions).

Reviewer: Dr. Daniel Selchen. Head of Neurology, St. Michael’s Hospital, Toronto, Canada.

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