The role of **grey matter damage in multiple sclerosis (MS) progression** is central and increasingly recognized as a key factor driving the worsening of disability and cognitive decline in people with MS. Unlike the traditional focus on white matter lesions, grey matter injury contributes significantly to the disease’s clinical course, especially in progressive forms of MS.
Grey matter (GM) in the brain consists mainly of neuronal cell bodies, dendrites, and synapses, which are crucial for processing information, cognition, and motor control. In MS, damage to grey matter occurs through several mechanisms, including inflammation, demyelination (loss of the protective myelin sheath around nerve fibers), neurodegeneration, and iron dysregulation. This damage leads to brain atrophy, impaired neural signaling, and ultimately clinical disability.
One of the important aspects of grey matter damage in MS is its association with **progression independent of relapse activity (PIRA)**. PIRA refers to the gradual worsening of disability that occurs without obvious inflammatory relapses. Studies have shown that patients experiencing PIRA have accelerated loss of grey matter volume, particularly in the cerebral cortex and deep grey matter structures like the thalamus and basal ganglia. This grey matter atrophy correlates strongly with physical disability progression and cognitive impairment, highlighting its clinical relevance.
Iron dysregulation in grey matter also plays a significant role in MS progression. Abnormal iron accumulation in grey matter regions can promote oxidative stress, which damages neurons and oligodendrocytes (the cells responsible for myelin production). Excess iron catalyzes the formation of reactive oxygen species, leading to lipid peroxidation and a form of cell death called ferroptosis. This oxidative damage exacerbates demyelination and neurodegeneration. Conversely, iron deficiency in white matter may impair remyelination and immune regulation, further complicating disease progression.
Inflammation within grey matter is often compartmentalized and chronic, involving activated microglia and macrophages that accumulate iron and adopt a pro-inflammatory state. This persistent inflammation contributes to ongoing neuronal injury and synaptic loss. Unlike white matter lesions, which are often focal and linked to acute inflammation, grey matter lesions tend to be more diffuse and less visible on conventional MRI, making them harder to detect but no less damaging.
Astrocytic damage and reactive astrogliosis in grey matter also contribute to MS progression. Elevated levels of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, have been linked to disease severity and brain volume loss. Astrocytes play a role in maintaining the blood-brain barrier and supporting neurons, so their dysfunction can exacerbate neurodegeneration.
Structural changes in specific grey matter regions, such as the amygdala, thalamus, and cerebellar cortex, have been associated with MS progression. For example, atrophy of the thalamus correlates with worsening disability scores, while changes in the amygdala volume may reflect ongoing inflammation and neurodegeneration related to disease progression.
Overall, grey matter damage in MS represents a complex interplay of neuroinflammation, iron metabolism abnormalities, oxidative stress, and neurodegeneration. This damage underlies the transition from relapsing-remitting MS to secondary progressive MS and is a major determinant of long-term disability. Understanding these mechanisms is crucial for developing therapies that target not only white matter lesions but also grey matter pathology to slow or halt MS progression.
