Medicine & Research

Emerging DMTs for Neurodegeneration

By By Ellen Whipple, Pharm.D.
Multiple sclerosis has traditionally been considered a disease affecting the white matter of the brain. More recent data has suggested 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.” 

Although both gray and white matter undergo atrophy, data suggests the loss of gray matter may be a more sensitive marker of the neurodegeneration and cognitive impairment. Dr. Thrower explained that 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 atrophy with ambulatory dysfunction,
  • Hippocampal atrophy with ambulatory deficits, and
  • Thalamic volume with cognitive impairment.

Importance of early diagnosis and treatment 

MS is characterized by both inflammation and progressive neuroaxonal damage. This damage occurs even in the early stages of MS; however, 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.
Brain atrophy occurs early in the disease process.

Because brain atrophy creates permanent damage and correlates with physical and cognitive disability, it is important that patients with MS be treated as early in the disease process as possible with DMTs. Additionally, patients having CIS and RIS who are at high-risk for developing clinically-definite MS should also receive treatment with DMTs as soon as possible.

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 and volume of brain lesions was also improved with early treatment. The figure below further describes the effects of currently available DMTs on brain atrophy.
Effect of currently approved DMTs on brain atrophy.

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 (more than two years) are needed to detect significant changes.
  • In the short-term, DMTs that have immuno-suppressive properties actually decrease brain volume because of the resolution of inflammation. This volume loss is not a sign of neurodegeneration, because there is no loss of brain volume. This phenomenon (known as “pseudo atrophy”) can last for up to a 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.

In addition to the available medication options for treating MS, new modalities that act on different biologic pathways are always being developed and improved upon. The figure below describes the proposed effects of these modalities on brain atrophy in patients with MS.
Effect of other modalities on brain atrophy.

More knowledge on neurodegeneration is still needed

In recent years, knowledge about the proposed mechanisms that may be responsible for axonal injury and loss has rapidly increased. A better understanding of the mechanisms responsible for neurodegeneration will contribute to the development of novel therapies that may further delay, eliminate, or even reverse neurodegeneration.