Christina Vogt:  Hello everyone, and welcome back to another podcast. I'm Christina Vogt, managing editor of Neurology Learning Network. Today, I'm joined by Dr Burcu Zeydan, from the Departments of Radiology and Neurology at Mayo Clinic, in Rochester, Minnesota.

Today, we'll be discussing aging and multiple sclerosis–a topic she recently discussed at MSVirtual2020. So first, what are some important considerations for the aging patient with multiple sclerosis?

Burcu Zeydan, MD: To start with, in patients with multiple sclerosis, genetic and epigenetic aging possibly impacts the immune system, as well as astrocyte neuron complex, microglia, and oligodendroglia. These lead to aging-related changes in MS plaques that we see on imaging.

Actually, all of these aging-related changes in genetic, immunological, and radiological aspects of the disease impact the evolution of clinical phenotypes in multiple sclerosis.

In the general population, but also in patients with MS, the central nervous system reserve decreases with aging. In 2 imaging studies on DTI, it has been shown that the white matter maturation terminates by the 30s, but then it starts to decline.

We think that this might be relevant to 2 aging-related observations–the decline in post-relapse recovery potential in aging MS patients, and the increase in the transition to a progressive phase in the fifth decade.

There are several important considerations in MS that are closely related to the interaction between aging, relapses, and progressive MS course. First, let's talk about relapses and how they seem to be impacted by aging.

The recovery potential after relapses clearly changes with aging in patients with MS. We recently showed that in a population-based cohort of patients with relapsing-remitting MS, as we compared the first and last of the relapses within the same individual, the post-relapse recovery potential significantly decreased with aging. Consequently, the accumulation of deficits after relapses increased with aging as well.

Although the post-relapse recovery potential declines with aging, we also see that the relapses and the subclinical lesions on imaging become less common with aging in patients with MS.

However, because even a single relapse that's unmoderated may significantly contribute to disability worsening, it is still important to prevent relapses in older individuals with MS. This is, of course, not surprising because certain things are likely to contribute to lower post-relapse recovery potential and a higher propensity for progressive disease course.

The increase in the evolution to progressive MS with aging is another important observation. It is interesting that the transition from a relapsed-and-remitting phenotype to a progressive phenotype usually happens around the same time, during the fifth decade. The transition to the progressive phase seems to be age-dependent in patients with MS.

In parallel, interestingly, when we look at the pathology studies in MS, we see that the pathological hallmarks of progressive MS, a predominance of inactive lesions and smoldering plaques, seem to peak during the same fifth decade.

Finally, I would like to talk about aging and disease-modifying therapies. In a 2017 meta-analysis, it has been shown disease-modifying therapies clearly lose efficacy with aging in patients with MS. This finding may summarize the relationship between aging and different, but intricate, mechanisms of relapses, recovery, progression, and central nervous system reserve.

Overall, we see that for aging patients with MS, the CNS reserve declines, the relapses become less common, but the post-relapse recovery potential declines, and the progressive MS disease course becomes more prominent.

Christina Vogt: How does MS phenotype impact the relationship between aging and the MS disease course?

Dr Zeydan:  As I emphasized earlier, aging mechanisms seem to affect many aspects of multiple sclerosis. The MS clinical phenotype evolution is primarily affected by the relationship between aging, CNS reserve, relapses, recovery, and progression.

When we talk about the clinical phenotypes in MS, first, we need to remember that there are 2 main phases of MS–the relapsing-remitting phase and the progressive phase. These phases are sequential, but also overlapping, with a transition phase in between.

In the relapsing-remitting phase, we have radiological-isolated syndrome, RIS, which is the asymptomatic phenotype of the disease. In the relapsing-remitting phase, there is also clinically-isolated syndrome, CIS, and relapsing-remitting phase, RRMS. Each of these phenotypes may potentially evolve into their corresponding phenotypes in the progressive phase.

Independent of whether the individual had RIS, CIS, or RRMS, this transition to the progressive phase usually happens during the fifth decade, with a mean age of 45 plus or minus 10 years.

As an example, when we focus on asymptomatic individuals with RIS, we see that in addition to being male and having spinal cord lesions, aging is an important predictor of the potential evolution from RIS to primary progressive MS.

It seems clear that the evolution to the progressive phase, therefore, all progressive phenotypes, such as primary progressive MS and secondary progressive MS, are age-dependent changes.

In a sense, there are the more immunologically-active phenotypes of the disease that slowly dampen by aging, while the more degenerative phenotypes slowly pick up with aging. One could say all phenotypes are impacted by the age of the individual.

Indeed, there are also many differences between the active nature of the disease in pediatric patients when compared to older individuals. Of course, this is beyond the discussion here, but certainly, age-related changes do not operate only in the older extreme, but earlier on as well.

Christina Vogt: What areas of future research are still needed in this field?

Dr Zeydan: The ultimate question, which is often raised on aging and MS, seems to be about patient management. After taking into consideration many relevant aging-related observations in MS and how aging impacts clinical MS phenotype evolution, it seems to be challenging when and how to make disease-modifying treatment discontinuation decisions in older patients with MS.

Therefore, we think we need further research to answer this question. We have recently studied the relationship between aging, recovery, and early DMT initiation, by reanalyzing the CHAMPS and CHAMPIONS data. We studied recovery after CIS in immediate vs late treatment with interferon beta-1a.

While the best outcome was observed in patients who were good recoverers with immediate treatment, patients who had poor recovery with late treatment showed worse outcomes. We see that aging, recovery from relapses, and the DMT initiation tracked with each other as early as CIS. Although we have more data on when to start DMTs, we need more research on when to stop.

Another important area of future research would be on repair and recovery strategies. We know that the current treatment strategies mostly target relapse prevention. As I mentioned earlier, the efficacy of DMTs significantly decreases with aging.

While the ultimate impact potential for DMTs seems to be early in life and early in the disease course, repair and recovery strategies become even more important later in life and later in the disease course.

Christina Vogt:  And lastly, what key takeaways about MS and aging do you hope to leave with neurologists and neurology providers?

Dr Zeydan:  Of course, the most important takeaway seems to be the age-dependent transition to the progressive phase of the disease. We know that aging plays a major role in the development of a progressive disease course, as neurodegeneration becomes more prominent with aging.

We also know that about 80-percent of patients ultimately evolve to the progressive phase of the disease. Therefore, it is important to emphasize the age-dependent nature of progressive MS onset, as severe disability is closely associated with progressive MS disease course.

From a treatment perspective, this also means that our current treatment strategies lose their benefit with aging. The relevant question may be raised about whether or not we need these treatments after a certain age, especially by the end of the sixth decade.

Similarly, younger individuals are more likely to benefit from immunomodulation because of a propensity for more active disease in the third and fourth decades. More work is needed in optimal treatment choices for age groups, but certainly, these general rules seem to pan out when studies are reviewed.

In practice, while making informed decisions tailored for each patient, a neurologist can keep these in mind when initiating or discontinuing DMTs in extreme age groups.

Christina Vogt: Thank you again for joining me today, Dr Zeydan. For more podcasts like this, visit NeurologyLearningNetwork.com.