Inflammation vs. Neurodegeneration in Multiple Sclerosis: The great debate continues

I was sitting among the ACTRIMS Co-Chairs last week, listening to them recap the excellent research that was presented at the conference, and I realized that the debate as to whether it is neurodegeneration or inflammation that plays a primary role in the development of MS is still a burning one. Adding to the complexity of this discussion is whether inflammation plays any role in progressive MS, or if it’s mainly neurodegeneration that drives progression and disability.

These are the big questions that researchers are attempting to address through genetics, cell studies, and animal models. ACTRIMS served as a forum for sharing up-to-date evidence that will help the MS community gain a better understanding of the roles that inflammation and neurodegeneration play in MS, particular progressive MS.

Here are some highlights:

Dr. Pavan Bhargava from Johns Hopkins University was among the junior investigators who opened the conference last Thursday. His presentation focused on meningeal inflammation – inflammation which occurs within a group of layers that envelop and protect the brain and spinal cord. Meningeal inflammation has been observed in MS patients, and is especially common in progressive MS. Using preserved brain tissue and MRI, Dr. Bhargava and his colleagues identified areas of inflammation and axonal damage in mice with MS-like disease. They found that T and B white blood cells, inflammatory molecules called chemokines, and other structural cells had accumulated in parts of the meninges and areas surrounding these cells had evidence of demyelination and axon damage. The bottom line is that inflammation occurring from within the central nervous system appears to play a more predominant role in MS – especially progressive MS – than once believed, and now researchers like Dr. Bhargava are able to track and measure this type of inflammation using advanced imaging.

Dr. David Irani from the University of Michigan Medical School elegantly presented the inflammatory players that play a role in MS progression during his talk at ACTRIMS. More and more research is revealing that immune dysregulation and subsequent harmful inflammation occurs in progressive MS. To further understand this inflammation, Dr. Irani’s research team collected blood samples from people with relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), and healthy controls, and conducted a series of experiments that would allow them to monitor their immune cells over time to identify any changes and link those changes to clinical or imaging outcomes of disease progression and severity. They observed that highly inflammatory white blood cells that are reactive towards myelin were found in both RRMS and SPMS patients, and that a group of T cells called IL-17 cells were higher in the SPMS group. The level of IL-17 cells appeared to be associated with measures of disability (EDSS). They also found that inflammatory molecules CXCL1 and CCL11 were strongly correlated with disease duration and EDSS scores in SPMS group. Collectively, their data demonstrates immune dysregulation in patients with secondary progressive MS, and its association with CNS damage. Dr. Irani’s research sets the stage for the development of appropriate models of disease progression and may help identify patients who are progressing based on their immune signature.

In order to truly know what takes place in progressive MS, researchers rely on neuropathology. This is the study of tissues in the central nervous system and the story they are trying to tell about a neurological disease. MS Society funded researcher Dr. Wayne Moore is a seasoned neuropathologist that has spent many years of his career studying nerve tissue in great detail, and at ACTRIMS he provided the latest imaging evidence showing the mechanisms and effects of progressive MS. The detailed images showed marked depletion of axons in the white and grey matter (more on white matter and grey matter here), which seems to be a major contributor of progression in MS. The images also showed that ongoing demyelination and persistent inflammation is occurring in progressive MS lesions. What about differences between primary progressive MS (PPMS) and secondary progressive MS (SPMS)? In PPMS, Dr. Moore showed evidence of neurodegeneration that appeared to be unrelated to the presence of lesions, whereas in SPMS there is pathological evidence of lesions. He notes that it is possible that, in PPMS, neurodegeneration (defined as axon damage and loss) could result from smaller bouts of undetected inflammation, the effects of which slowly accumulate over time. The research he presented indicated that a variety of inflammatory and non-inflammatory processes are contributing to neurodegeneration in progressive MS, and that it is unclear if a primary neurodegenerative process is the trigger. The body of neuropathological evidence from Dr. Moore and other experts like him is regarded as a major breakthrough in our understanding of the mechanism underlying progressive MS, how tissue abnormalities can explain various symptoms, and the balance between inflammation and neurodegeneration across the spectrum of MS disease types.

While Dr. Wayne Moore is focusing on capturing the neurodegenerative hallmarks of progressive MS, Dr. Don Mahad from the University of Edinburgh is searching for answers to why there is neurodegeneration in progressive MS. One of 22 Challenge Award recipients from the International Progressive MS Alliance, Dr. Mahad has made significant headway in understanding the role that the mitochondria plays in progressive MS (more on the mitochondria here). The idea is that, in MS, mitochondria experience a reduced ability to produce energy needed by the nerve cell to function. This problem is compounded by the increased demand for energy by the cell following demyelination. Dr. Mahad suggests that mitochondrial dysfunction could explain neurodegeneration and symptoms like fatigue. His presentation at ACTRIMS summarized the next step in his research: developing an animal model of MS that involves mitochondrial dysfunction. He hopes that his model will provide a window into the mechanism of energy failure in the central nervous system of people with progressive MS and be among the first promising animal models to test future progressive MS treatments.

Do you have any questions or comments about the big debate on inflammation versus neurodegeneration in MS? Leave them below!

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