Brain atrophy in multiple sclerosis: mechanisms, clinical relevance and treatment options

Abstract

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system characterized by focal or diffuse inflammation, demyelination, axonal loss and neurodegeneration. Brain atrophy can be seen in the earliest stages of MS, progresses faster compared to healthy adults, and is a reliable predictor of future physical and cognitive disability. In addition, it is widely accepted to be a valid, sensitive and reproducible measure of neurodegeneration in MS. Reducing the rate of brain atrophy has only recently been incorporated as a critical endpoint into the clinical trials of new or emerging disease modifying drugs (DMDs) in MS. With the advent of easily accessible neuroimaging softwares along with the accumulating evidence, clinicians may be able to use brain atrophy measures in their everyday clinical practice to monitor disease course and response to DMDs. In this review, we will describe the different mechanisms contributing to brain atrophy, their clinical relevance on disease presentation and course and the effect of current or emergent DMDs on brain atrophy and neuroprotection.

Keywords: Atrophy; Axon; Bran; Drugs; Inflammation; Multiple sclerosis; Neurodegeneration; Neuroprotection.

Fig. 1

Mechanisms of late axonal loss. Molecular and cellular mechanisms driving neurodegeneration and atrophy. Key elements are considered to be: (1) Mitochondria Dysfunction: Inflammation in acute demyelinating lesions lead to respiratory protein complexes inhibition, mitochondrial injury and dysfunction, release of apoptosis-inducing factors and mitochondrial DNA deletions. In chronic inactive plaques, ionic imbalance, high energy demands and clonal expansion of defective mitochondria further impair oxidative damage. These mitochondrial alterations of functional impairment and structural damage lead to histotoxic hypoxia and energy failure and consequently to neurodegeneration. [146] Upregulation of sodium channels, acid sensing ion channels and expression of maladaptive isoforms (Nav1.6 channels), paranodal (Caspr) and juxtparanodal (Kv1.2) protein lead to high energy demands, intra-axonal calcium accumulation, and subsequent axonal degeneration. (3) Glutamate Excitotoxicity: Increased glutamate production by activated microglial cells and lymphocytes, and impaired clearance by resident cells such as astrocytes lead to higher lever of glutamate. High levels of glutamate lead to over-activation of N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (which are permeable for calcium and sodium ions) and subsequent calcium overload and oligodendocyte and neuron cell death. (4) Iron release: In MS lesions free iron [Fe2+] is released in the extracellular space leading to production of highly reactive hydroxyl molecules (OH⁻) by the Fenton reaction. Further, iron is released by activated glial cells, which become dystrophic and disintegrate, leading to a second wave of Fe²⁺ release