AAN Day 1: Modeling MS-like disease and exploring risk factors

This year’s AAN conference is filled to the brim with programming, with sessions starting bright and early at 6:30 am and continuing well into the evening to accommodate the staggering amount of new information pouring out of the labs and clinics of researchers around the world. Headlining the MS program for Day 1 was a series of presentations about new insights into MS gained from animal and cell studies. Although modeling disease necessarily reduces the complex mechanisms underlying MS into simplified models by design, these types of studies are crucial for uncovering important clues about the genes and molecules that can trigger and/or drive MS and for rapidly screening new therapeutics with the potential to treat MS by combating harmful inflammation, repairing damage in the brain and preventing injury from occurring in the first place. The evening poster presentations were a departure from the morning’s seminar series, shifting the focus from basic laboratory research towards observations about risk factors that both influence the likelihood of developing MS and predict how the disease changes over time in those already living with MS.

Modeling MS-like disease in the laboratory: insights into disease mechanisms and treatments

Mr. Alexander McGown, PhD student at University of Sheffield UK, presented a proof-of-concept demonstration that MS-like disease processes, such as demyelination and remyelination, could be reproduced in pre-natal zebrafish. Zebrafish are already used widely for understanding what happens during several neurodegenerative disorders at the level of the nerves owing to their rapid development, large numbers of offspring and transparency of their embryos that allows easy imaging of the central nervous system. These advantages can turn zebrafish into an important tool for screening large numbers of drug candidates for myelin repair therapies rapidly.

Prof. Frauke Zipp (Universitätsmedizin Mainz, Germany) presented data that could begin to unearth the missing link between the initial inflammatory immune attack of early relapsing-remitting MS and the extensive degeneration of nerve cells (neurodegeneration) in progressive forms of the disease. Her team used advanced imaging techniques in mice with MS-like disease to uncover that nerve cells in the cortex of the brain are intensely hyperactive during the remission phase when clinical symptoms are absent. This was mirrored by evidence of certain cognitive deficits in the mice during remission. Together, these pieces of evidence suggest that hyperactivity of nerve cells may be the starting point of neurodegeneration that characterizes progression.

Meningeal inflammation is an up-and-coming topic in the field of progressive MS research and was the subject of exhaustive discussion at the ACTRIMS forum earlier this year. Dr. Pavan Bhargava (Johns Hopkins University, USA) expanded on the findings he presented at ACTRIMS in which he used advanced imaging techniques to show evidence of persistent inflammation of the meninges – protective layers of tissue coating the brain and spinal cord – in mice with MS-like disease that mirrors progressive MS in humans. Importantly, being able to track meningeal inflammation in animal models is allowing Dr. Bhargava’s team to screen drug candidates, such as B-cell depleting therapies (examples are ritixumab and ocrelizumab) that have the potential to halt and reverse this damaging inflammation.


Risk factors for disease progression and treatment response

One recurring topic at the poster session was the association between obesity and MS risk/disease course in children and adolescents with MS. Dr. Jennifer Graves (University of California San Francisco, USA) and a large team of collaborators conducted a Mendelian Randomization study to determine the relationship between body mass index (BMI) and risk of developing pediatric-onset MS in a large cohort of youth with MS. Mendelian Randomization is a powerful genetic technique used to estimate causal relationships between risk factors and disease outcomes, and was most recently used to demonstrate a strong causal link between vitamin D deficiency and MS risk. Dr. Graves’ study showed that increased BMI interacts with another strong genetic MS risk factor (called HLA-DRB1*15:01) and is causally linked to higher pediatric-onset MS risk.

Right next door to Dr. Graves, Dr. Kristen Krysko presented her team’s research at the University of Toronto investigating whether BMI at diagnosis pf pediatric-onset MS can predict disease activity, including relapse rate and brain lesions. Although approximately half of their study group of youth with MS were overweight or obese at diagnosis, the researchers did not find that BMI at diagnosis influenced disease activity, although she acknowledged that a larger follow-up study with more participants should be conducted to verify this finding.

Other potential risk factors were also the subject of conversation at the poster session. In particular, vitamin D has been a hot topic in recent years due to the mounting data that vitamin D deficiency is linked to MS risk. Dr. Vittorio Martinelli (Hospital San Raffaele, Italy) and his team took a unique approach to this question by focusing on the entire vitamin D metabolic pathway rather than only on blood levels of the precursor 25-hydroxyvitamin D, which is traditionally used to assess vitamin D status. By analyzing levels of several vitamin D metabolites in people with clinically isolated syndrome, Dr. Martinelli’s team showed that a breakdown product of 25-hydroxyvitamin D provided an even clearer picture of this relationship that could help predict the protective effects of vitamin D on MS, although more work is needed to tease out the precise role of this metabolite further.

I hear a lot of questions from people affected by MS about diet: are certain foods or nutrients more likely to aggravate symptoms and, on the flip side, can certain diets reduce the number of relapses or alleviate disability? Consumption of red meat is one area that’s generated some discussion, since results from past research have been mixed as to whether eating red meat is potentially protective or detrimental. Dr. Neda Sattarnezhad (Brigham and Women’s Hospital, USA) got to the meat of the issue by conducting a questionnaire about dietary habits to MS participants enrolled in the CLIMB study. When comparing those who restricted their intake of red meat (looking at 2 years prior and following the time of restriction onset) and those who had never restricted red meat intake, Dr. Sattarnezhad found that there was no significant effect of red meat restriction on the number of relapses. She added that future studies should dig deeper by looking at the quality of red meat, particularly comparing lean and high fat meats as well as highly processed meats.

Finally, Dr. John Fisk (Dalhousie University) presented findings about the relationship between changes in clinical disability and health-related quality of life using health administrative data from people living with MS at the Dalhousie MS Research Unit in Nova Scotia. Dr. Fisk’s team found that more severe disability leads to substantially worsened health-related quality of life; while this relationship may seem intuitive, the empirical evidence correlating more severe disability with diminished quality of life is essential for helping health care decision-makers, clinicians, and policy makers make informed decisions about how health care services are prioritized and delivered to people living with MS.

Tune in for more updates from AAN, and leave any comments or questions below.

Categories Research

National vice-president, research, past MS researcher, and PhD in Cellular and Molecular Medicine from University of Ottawa. Leads the MS Society's research program to find the cure for MS and improve the quality of life for people affected by the disease.

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