Medicine & Research

RX Update - Gray Matter Involvement and Neurodegeneration

By Ellen Whipple, Pharm.D

Traditionally, multiple sclerosis has been considered a disease affecting the white matter of the brain, but more recent data suggests that lesions and demyelination also occur in the gray matter structures of the brain. According to Dr. Ben Thrower medical director of the MS Institute at the Shepherd Center in Atlanta, “A growing body of evidence suggests that gray matter involvement is at least partially independent from white matter involvement.”
           
Dr. Thrower explained that magnetic resonance imaging (MRI) is the most important diagnostic and monitoring tool available to evaluate the progression of MS. White matter lesions are easily seen on MRI; whereas, gray matter lesions are hard to see on MRI. It has been estimated that up to 80 percent of gray matter lesions are missed using traditional MRI scans. According to Dr. Thrower, nonconventional MRI techniques are needed to detect gray matter lesions. These non-conventional MRI techniques evaluate pathology within gray matter lesions and normal-appearing brain tissue (e.g., edema, inflammation, demyelination, axon loss, and neuro-degeneration). Data suggests that some newer imaging techniques (e.g., ultra-high-field MRI and magnetic resonance spectroscopy) have high gray matter lesion detection rates. However, to date, no “gold standard” imaging model has been developed for detecting gray matter lesions.

Gray matter atrophy can lead to neurodegeneration
Several studies have demonstrated that brain atrophy occurs faster in people with MS. Compared with people who do not have MS, brain volume loss can be 10 times higher per year in persons with MS. Although gray and white matter both undergo atrophy, data suggest that loss of gray matter may be a more sensitive marker of the neurodegeneration and cognitive impairment.
           
Atrophy associated with gray matter structures correlates with certain clinical symptoms, such as:
• Cerebellar gray matter atrophy with cerebellar symptoms and hand function
• Upper cervical cord area with ambulatory dysfunction
• Hippocampal atrophy with ambulatory deficits
• Thalamic volume with cognitive impairment

While brain atrophy is considered a marker of advanced stages of MS, it also occurs in patients with clinically-isolated syndrome and radiologically-isolated syndrome.

Brain atrophy is now an endpoint in many clinical trials
Brain atrophy is now a recognized endpoint in all Phase III clinical trials for MS. It can be evaluated using traditional MRI scans; however, limitations do exist.

• Atrophy accumulates very slowly; therefore, longer follow-up studies (lasting longer than two years) are needed to detect significant changes. 
• In the short-term, DMTs that have immuno-suppressive properties appear to decrease brain volume due to the resolution of inflammation. This volume loss is not a sign of neurodegeneration, because there is no actual loss of brain volume. This phenomenon, which is known as “pseudo atrophy,” can last for up to one year after treatment with immunosuppressant DMTs.
• Physiological factors and non-MS factors (e.g., dehydration, alcohol consumption, smoking, genetic variation, comorbidities, and age) can also decrease brain volume.

Importance of early diagnosis and treatment
MS is characterized by both inflammation and progressive neuroaxonal damage. When this damage occurs in the early stages of MS, it may be masked by compensatory mechanisms. The progressive damage may go unrecognized until it is too late for intervention to be beneficial. As MS progresses, the balance between degenerative and reparative processes shifts, resulting in progressive neuroaxonal degeneration and increasing disability
           
Because brain atrophy creates permanent damage and correlates with physical and cognitive disability, it is important that people with MS be treated with DMTs sooner rather than later. In addition, those diagnosed with CIS and/or RIS, who are at high-risk for developing clinically-defined MS, should also be treated with DMTs sooner rather than later.
           
Several clinical trials have provided proof of concept for an early window of first treatment intervention in patients with CIS. Significant reductions (39-50 percent) in the risk of developing clinically definite MS were observed with the interferon-beta products and glatiramer acetate when early treatment was initiated. Physical disability and number of brain lesions was also improved with early treatment. Similar results have also been observed with some of the newer DMTs (e.g., teriflunomide, alemtuzumab, and fingolimod).
 
Gray matter lesions differ from white matter lesions
Gray matter lesions differ from white matter lesions pathologically and functionally. When compared with white matter lesions, gray matter lesions are:

• Less inflammatory
• Small and primarily occur in the cerebral cortex, basal ganglia, and gray matter of the spinal cord and brainstem
• Hard to distinguish from normal surrounding tissues of the brain.

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