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A Graphic Look at Multiple Sclerosis—Part 1

#Atrophy #Imaging #Lesions

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS) driven by 2 distinct but interrelated pathologies: White Matter (WM) pathology and Grey Matter (GM) pathology.1-4

WM pathology targets White Matter tissue throughout the CNS. In the brain, MS attacks White Matter in the inner core, which comprises bundles of nerve fibers that help send messages to different parts of the CNS.

The main target of WM pathology is the myelin sheath, a protective coating that helps insulate nerve fibers.5 As this protective coating is destroyed, the ability of the CNS to send messages to the body is impaired, causing a wide range of symptoms.6 Over time, this damage results in permanent damage, which manifests as scars or lesions in the CNS.1

GM pathology targets both the outer layer of the brain (cerebral cortex) and the GM structures found at the core of the brain (Deep Grey Matter).7

Grey Matter is mostly made up of neurons, which help process information in the brain.5,6 With time, GM pathology destroys the neurons in the CNS, causing GM lesions and GM atrophy.7-9

PICTURING THE PATHOLOGIES

The graphic below provides a quick overview of some of the differences and similarities between WM pathology and GM pathology in multiple sclerosis.

When does the pathology begin?

white matter vs. grey matter - beginning of pathology icon
Pathology begins early in both WM and GM1,10-12

Numerous studies have shown that both White Matter and Grey Matter pathologies begin early in the course of multiple sclerosis.1,10-12 In both types of tissue, researchers have found evidence of lesions and atrophy from the very beginning of the disease.11,13-17 Using magnetic resonance imaging (MRI) and optical coherence tomography, studies have confirmed that axonal damage is present right from the onset, even before symptoms appear.12 While WM lesions are often one of the first visible signs of disease, researchers have confirmed that cortical GM lesions also occur early in MS, even in patients with no evidence of White Matter damage.14 Researchers have also found evidence of Deep Grey Matter lesions in patients with early disease.17 In addition, both White Matter and Grey Matter atrophy have been documented early in the disease process, with GM atrophy seen across a range of clinical subtypes.15,18

What is the primary target?

white matter primarly target icon
Myelin sheath5,6,19
grey matter primarly target icon
Neuronal cell bodies5,6

In White Matter pathology, the primary target is the fatty, white myelin sheath that covers and protects nerve fibers throughout the CNS (as noted above).5,6,19 As the myelin breaks down, the nerve fibers are exposed, making it difficult to send signals to other parts of the nervous system.5 In WM tissue, the process of demyelination can include a range of mechanisms, including T cell infiltration, activated microglia and macrophages, immunoglobulin deposition, and oligodendrocyte cell death.6,19 This process of demyelination occurs in well-defined, focal lesions (scars that develop in the White Matter tissue).5

In Grey Matter pathology, the primary targets are neurons, which are specialized cells that send, receive, and process signals from other parts of the body.5,6 Neurons typically consist of a nerve cell body (the metabolic center), an axon (a long structure that conducts electrical signals), and dendrites (branch-like structures that receive information).5 Although demyelination also occurs in GM pathology, neurons are the central target.20 Common features of GM pathology are neuron atrophy, neuron death, a decrease in neuron densities, and reduced synaptic densities.8 Like White Matter pathology, the process includes activated microglia.6

What does the pathology do?

white matter vs. grey matter - consequence of pathology icon
Both injure and destroy axons19,21-23

In WM pathology, T cell infiltration, activated macrophages, and activated microglia trigger the production of proinflammatory cytokines and chemokines, which results in acute axonal injury and axonal loss.19

In GM pathology, activated microglia, dysregulation of astrocytes, and injury of oligodendrocytes all lead to axonal injury and death of neuronal cell bodies.21-23

What is the end result?

white matter vs. grey matter - end result icon
Both cause lesions and atrophy6,15,18,19,24

WM pathology manifests as both focal inflammatory lesions and accelerated atrophy of White Matter in the brain.15,19,24 WM lesions can appear anywhere throughout the CNS, but are most likely to be found in the brain stem, the optic nerve, the periventricular areas of the brain, and the spinal cord.25

Like WM pathology, GM pathology also manifests as both lesions and atrophy.6,15,18,24 Using high-resolution imaging, researchers have confirmed the presence of lesions in various GM regions throughout the brain, including the cerebral cortex, the cerebellum, the spinal cord, and even Deep Grey Matter structures such as the thalamus and the hippocampus.6 Researchers also found that GM atrophy occurs in all MS phenotypes, even in patients with early forms of the disease, such as clinically isolated syndrome.18 A 2018 study that included more than 1400 participants reported that atrophy was present across a wide range of GM regions, including cortical, temporal, parietal, frontal, occipital, cerebellar, and Deep GM areas.18 Studies have shown that GM atrophy is a major driver of both physical and cognitive disability in patients with MS.14,20,26,27

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