Multiple sclerosis has classically been considered a disease of the white matter. What does this mean, exactly?
The brain and spinal cord (which together make up the central nervous system, or CNS) can be roughly categorized into two kinds of nervous tissue: white matter and grey matter. White matter is made up of bundles of nerve fibres that connect disparate parts of the brain together and allow these regions to communicate via electrical signals. These nerve fibers are coated in myelin, an insulating fatty layer that appears white when examined by the naked eye; hence the name.
Grey matter, in contrast, is predominantly made up of nerve cell bodies and glial cells, which provide energy and nutrients to nerve cells, help to create new myelin, and perform a host of other functions. These cell types give the grey matter a very light grey, almost pinkish-brown hue, although the grey matter does also contain a relatively small proportion of myelinated nerve cells. The grey matter predominantly makes up the outer surface, or cortex, of the brain, with white matter tracts buried deep below. In the spinal cord, this arrangement is flipped: the core is composed of grey matter that is surrounded by bundles of white matter.
Since MS is regarded as an autoimmune disease that targets and destroys myelin, research on multiple sclerosis disease mechanisms has historically focused overwhelmingly on the white matter. One reason for this is that the impact of white matter damage is easy to observe: common magnetic resonance imaging (MRI) techniques are adept at detecting MS lesions, or plaques, that form in the white matter. Similarly, visualizing brain tissue under the microscope shows clear and noticeable degradation of myelin in the white matter.
One puzzle facing MS researchers and clinicians is something called the “clinico-radiological paradox”. This paradox describes the all-too common situation in which the exact signs and symptoms shown by someone living with MS do not seem to be related to the location and/or number of MS lesions in their brain or spinal cord. One of the culprits may be a lack of sensitivity or specificity of the imaging tools at our disposal; in other words, there may be lesions present that are affecting specific regions of the CNS that can’t be picked up by conventional imaging. Another culprit is a phenomenon called grey matter lesions.
Grey matter lesions are quite unique in that they lack many of the hallmark characteristics of classic inflammation that are so evident in white matter lesions: there is little evidence of breakdown of the blood-brain barrier (BBB) or infiltration of immune cell called lymphocytes into the affected tissue. Those inflammatory cells that have been found in grey matter lesions primarily belong to the inherent CNS immune response rather than coming in from the periphery via the blood. Although scientists have observed demyelination of nerve fibers passing through the grey matter, there is also widespread degeneration of the nerve fibres themselves along with loss of nerve cell bodies and glial cells. In fact, grey matter atrophy (loss of tissue volume) and thinning of the layers of the brain cortex have a strong association with both physical disability and cognitive impairment in MS, and represent one of the strongest predictors of disease progression.
New developments in imaging technologies that permit better and more sensitive detection of grey matter lesions in people living with MS have allowed grey matter to take centre stage in MS research. Importantly, these refined imaging tools have shown that grey matter damage is often already present in early disease stages. While the brain’s innate ability to repair itself and compensate for nerve cell loss – a concept known as neuroplasticity – can mask the emergence of clinical disability in early stages of MS, accumulating grey matter damage can eventually overwhelm the brain’s reserve capacity and manifest as increasing disability. Fortunately, there has been a strong paradigm shift in the research community with a renewed focus on grey matter. I am confident that this shift will shed new light on disease mechanisms underlying MS, leading in turn to better imaging tools, biomarkers for disease screening, and therapeutic strategies for people living with MS.
- Guerts JJ & Barkhof F. (2008) Grey matter pathology in multiple sclerosis. Lancet Neurol. 7:841-51
- Steenwijk MD et al. (2014) What explains gray matter atrophy in long-standing multiple sclerosis? Radiology. 272(3):832-42