Neurodegeneration in multiple sclerosis

Abstract

Axonal loss in multiple sclerosis (MS) is a key component of disease progression and permanent neurologic disability. MS is a heterogeneous demyelinating and neurodegenerative disease of the central nervous system (CNS) with varying presentation, disease courses, and prognosis. Immunomodulatory therapies reduce the frequency and severity of inflammatory demyelinating events that are a hallmark of MS, but there is minimal therapy to treat progressive disease and there is no cure. Data from patients with MS, post-mortem histological analysis, and animal models of demyelinating disease have elucidated patterns of MS pathogenesis and underlying mechanisms of neurodegeneration. MRI and molecular biomarkers have been proposed to identify predictors of neurodegeneration and risk factors for disease progression. Early signs of axonal dysfunction have come to light including impaired mitochondrial trafficking, structural axonal changes, and synaptic alterations. With sustained inflammation as well as impaired remyelination, axons succumb to degeneration contributing to CNS atrophy and worsening of disease. These studies highlight the role of chronic demyelination in the CNS in perpetuating axonal loss, and the difficulty in promoting remyelination and repair amidst persistent inflammatory insult. Regenerative and neuroprotective strategies are essential to overcome this barrier, with early intervention being critical to rescue axonal integrity and function. The clinical and basic research studies discussed in this review have set the stage for identifying key propagators of neurodegeneration in MS, leading the way for neuroprotective therapeutic development. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology Neurological Diseases > Molecular and Cellular Physiology.

Keywords: axonal injury; demyelinating diseases; multiple sclerosis; neurodegeneration; neuroinflammation.

FIGURE 1

Major multiple sclerosis disease courses. MS is diagnosed following a preclinical phase of an unknown period of time in which inflammatory activity may occur (black arrows), but does not reach clinical threshold. Inflammatory lesions as detected by MRI that cause clinical symptoms which resolve over time (green line) contribute to the relapsing–remitting disease course. However, despite remission of clinical symptoms, subclinical inflammatory activity may still occur as seen upon MRI and contributes to accumulating disease burden and loss of brain volume (brown line and red dashed line, respectively). Eventually, the disease can reach a secondary progressive course which is characterized by increasing disability and brain atrophy despite fewer inflammatory events. This phase of disease is an important area of research, as physiological mechanisms of remyelination and axon repair cannot overcome the damage that ultimately drives disease progression in MS. Reprinted with permission from Fox and Cohen (2001). Copyright © 2001. Cleveland Clinic Foundation. All rights reserved.

FIGURE 2

Lesion pathology in multiple sclerosis. MRI‐pathology correlations of a periventricular lesion with a paramagnetic rim and vessel. FLAIR images obtained in a post‐mortem in situ 3 T MRI (axial and coronal planes shown) demonstrate a periventricular T2‐hyperintense lesion outlined in yellow with the lateral ventricle noted with an asterisk. A 7 T MRI with a T2‐weighted image shown was done following fixation of the 1‐cm coronal tissue slice with the lesion outlined. The lesion border has a paramagnetic rim and a vessel in its center on SWI‐phase imaging. Immunohistochemistry of 30‐μ free floating sections of the area was stained for myelin (PLP) and activated microglia/macrophages (MHCII) and demonstrates a demyelinated periventricular chronic active lesion. A modified Turnbull iron histological stain shows areas of increased iron at the lesion border coinciding with MHCII and the SWI‐phase RIM (arrowhead). FLAIR, fluid‐attenuated inversion recovery; MHCII, major histocompatibility complex II (activated microglia/macrophages); PLP, proteolipid protein (myelin); SWI, susceptibility weighted imaging; T, Tesla; T2‐Turbo‐RARE, T2‐weighted Turbo Rapid Imaging with Refocused Echoes.