#049: CogeX Study Insights for Progressive MS on Cognitive Rehabilitation with Prof. Anthony Feinstein

Today, I’m talking to Prof. Dr. Anthony Feinstein about the results of the CogeX study, that focussed on improving cognitive function, especially processing speed of patients with progressive MS. 

Even in the preliminary phase of MS, when those affected are diagnosed with a clinically isolated syndrome, cognitive problems occur in around 30% of cases. As multiple sclerosis progresses, the proportion increases steadily and is between 70 and 90 percent in primary and secondary MS. However, little research has been conducted into how cognitive impairment can be counteracted and how cognitive performance can even be improved.

The international study was funded by MS Canada and included researchers and patients in the USA, the UK, Italy and Denmark in addition to Canada.

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Nele Handwerker: Hi Anthony, I’m delighted to have you on the show and send a lovely welcome to Toronto in Canada. I was just talking to patient advocate Adra Shephard the other week and she told me that it’s pretty cold in Canada. I remember the cold winters in Chicago where I lived for a year and a half.

Prof. Anthony Feinstein: Thank you very much. We need a warm welcome because it’s cold here. I am very happy to be with you. You know what I’m talking about.

Nele Handwerker: It was minus 35 degrees Celsius in Chicago. We always greeted each other with „Stay warm!“ It’s not like that in Germany, unfortunately we hardly have any real winters.

But before we get to the interview, it would be nice if you could introduce yourself to the viewers so that they know who’s on the show with me today.

Introduction – Who is Prof. Dr. Anthony Feinstein?

Prof. Anthony Feinstein: Yes, thank you. I am Anthony Feinstein. I’m a professor of neuropsychiatry at the University of Toronto. I lead a clinical service and research team that cares for people with multiple sclerosis. We look at cognition, mood risk and cognition and also use brain imaging to understand how these conditions occur.

Personal motivation for your career choice?

Prof. Anthony Feinstein: I am old enough to have witnessed the first MRI scanner coming into the clinic. At the time, I was studying in the USA and had just started my PhD. I was at the Institute of Neurology, which had been given an MRI scanner. That was one of those transformative moments in medicine.

Especially in the area of multiple sclerosis, where until then you only had a CT scan, which didn’t show the brain with much clarity. Suddenly there was a new imaging modality, the MRI, that has shaped the field. You can see this inflammation in much greater definition, much greater sensitivity. That has started a new area of research that has led to behavioral change linked to multiple sclerosis. Up until then, it was a very quiet field. There wasn’t a whole lot published, but MRI energized it. And I arrived at this kind of, lucky for me, pivotal moment in medical history where MRI was available to be used both clinically and as a research tool.

Nele Handwerker: Great, fantastic. Then let’s dive a little bit into understanding cognitive impairment and progressive MS.

Understanding Cognitive Impairment in Progressive MS

Can you explain what cognitive impairment means in progressive MS?

Prof. Anthony Feinstein: Well, cognitive impairment refers to obviously difficulties in cognition intellect that can occur as part of MS. And the rates of impairment are high. We know that even before individuals develop the full-blown MS clinical picture, for example, clinically isolated syndromes, the rates of impairment are as high as 30%. And as you get through relapsing remitting MS, the impairment rates go up to about 40%.

When it comes to primary and secondary MS, to the existing degenerative forms in the disease, you can see the increase to 70% to 80%, some groups even say 90%. So many people with progressive MS show cognitive difficulties.

What are the common symptoms and challenges associated with cognitive impairment in MS patients?

Prof. Anthony Feinstein: There will be many. I think when cognitive abilities decline, it affects many individual aspects of life. You find it much harder to keep going to work. You can struggle with the activities of daily living. Even simple things can become overwhelming. If your cognitive abilities are impaired, it can also have a negative impact on your relationships. You see, life is difficult because of cognitive impairment. They can jeopardize rehabilitation.

So it’s a crucial clinical factor in the lives of people with MS.

Nele Handwerker: Yes, and I have to say that 20 years after diagnosis, I’m still afraid of losing my cognitive abilities, even though there’s nothing to suggest it yet. But it is definitely the biggest fear that is still there and sometimes pops-up.

Because of the effects, you mentioned, it is of course very important to think about cognitive rehabilitation.

Benefits of Cognitive Rehabilitation

What is cognitive rehabilitation, and how does it work to improve cognitive function in MS patients?

Prof. Anthony Feinstein: Dealing with cognitive impairment generally takes place on two levels.

A slower goal was to investigate cognitive, compensatory strategies. In other words: We can’t improve cognition. But how can we introduce strategies that make people’s lives easier? For example, if you have problems with your memory, you are shown how you can use memory aids to help you remember certain things. You have your smartphone, you have alarms and bells that tell you that you need to do something, and you’re less likely to forget.

This can be very helpful in everyday life, but it doesn’t improve cognitive abilities. With cognitive rehabilitation, the hope is to prevent the loss, prevent the loss and maybe even prevent the loss of the cognitive deficit. This is a much newer area of cognitive rehabilitation, cognitive work.

I would say that the field has only been run over the past five or six years, with a few different programs that are around improving cognition in people with MS. A lot of the literature has been offered to people with relapsing MS. It’s a very important point that when you review the literature, you see that the overwhelming majority of studies focus on the less severe forms of MS. And so people with progressive MS have been monitored when it comes to good symptom management, and certainly looking at cognition. Our study, which we’ll discuss a little bit later, focuses on these particular groups, those with progressive MS who are cognitively impaired.

Nele Handwerker: Yes, the low-hanging fruit is sometimes more attractive. Yet progressive MS patients need significantly more support with their cognitive abilities in order to lead a fulfilling life.

Can you elaborate on the specific cognitive rehabilitation techniques used in the CogeX study?

Prof. Anthony Feinstein: So, there is a whole range of measures for cognitive rehabilitation. They are becoming more and more computerized, which is not so surprising, because the whole world is moving in this direction. We used a particular program, RehaCom®, which is from Germany, by the way. And it’s probably the best-known cognitive rehabilitation package for people with MS. There are many studies that have mentioned RehaCom®.

And there are many advantages to it. Number one, it’s available in multiple languages and the study that I was part of was a study involving Canada, United Kingdom, United States, Italy, Belgium, and Denmark. So we had to have different languages.

You can also choose from a menu with RehaCom®. For example, there are going to be modules for memory, retention, and processing speed for executive functions. So, you can tailor your intervention according to where the deficits are. You have that option as well, so that’s very helpful. And then finally, there is a literature out there suggesting that RehaCom® is effective. It’s a small literature that’s growing.

We went with a program that had a little bit of data suggesting that this might work, and it gave us the flexibility to apply it to multiple languages and to choose the cognitive domain that we wanted to focus on.

Nele Handwerker: I see, makes sense, yes.

What are the potential benefits of cognitive rehabilitation for individuals with progressive MS?

Nele Handwerker: I mean, you were mentioning it already a little bit, that it’s kind of going into all dimensions of your life, but maybe you can explain it a bit more in detail.

Prof. Anthony Feinstein: I think that’s the crucial question. What can you achieve through rehabilitation? If you can demonstrate improvement in a particular area, what can that mean for people with MS? It can be a difficult measure, but the hope is of course that the symptoms will improve, begin doing some of the things that you’ve struggled with. That it’s going to be easier for you to integrate back into perhaps work, which I think is very ambitious. But it might improve your ability to function around the home and your day-to-day activities. You can master household skills, e.g. shopping, budget management. This can also have an impact on your relationships and improve psychosocial relationships. And so, there are many potential benefits from cognitive improvement.

There are theoretically some significant benefits to improving your cognition. I should say that we in the MS field have not yet demonstrated the positive effects of cognitive rehabilitation unfortunately. That’s one of the big challenges we face down the road. We’re still trying to attach the cognitive enhancement without necessarily moving into the next necessary step, which is real-world values. That’s still coming.

The Role of Aerobic Exercise

How does aerobic exercise contribute to cognitive improvement in MS patients, as observed in the CogeX study?

Prof. Anthony Feinstein: Correct. That’s exactly it here. Okay, so let me just step back one step. So we realized that we were dealing with individuals who have advanced multiple sclerosis.

Before we started CogeX, we didn’t know that cognition could improve in this group. We assumed that it would be a very big challenge to bring about some improvement, and so we wanted to try and give our participants every opportunity to benefit from the interventions. And our hypothesis was that if we bring in more than one intervention, we might get a synergistic effect.

So, on the one hand, we have the rehabilitation of RehaCom®. There’s a little bit of data, some tentative data when we started our study, because we’re going back five years now. There is some tentative data that RehaCom® can help. The second intervention was aerobic exercise. And here the data is a bit more critical. There are some studies that show that this can help with cognition. There are other negative studies, but still.

There was enough evidence to suggest that this measure might also be helpful. So we thought that we should combine part of the rehab with exercise to give our participants the best chance of getting better. And the theory behind exercise is that it might also have anti-inflammatory properties, which could improve brain function. That was in theory our hypothesis, that if you combine two interventions, you’re more likely to get a benefit than giving yourself an intervention. So we had a pre-room study where we had cardio-rehabilitation plus exercises, than cardio-rehabilitation alone with a shamming exercise, then exercises with a shamming cardio-rehabilitation project and then a double shamming.

So, you can see that there are different arms.

Nele Handwerker: Yes, I found the study protocol very interesting, and we presented it in our Multiple Sclerosis Management Master’s program. We did it in the statistics module and found it very interesting how this study protocol was carried out.

There is still a lot to be improved in conducting studies in the next few years. I think it is a very modern and interesting approach that you have chosen. And there are many innovative ways how a study can work.

Prof. Anthony Feinstein: Yes, exactly. We had a special opportunity as a group because we had a large budget, because it was a needs study. We had a special opportunity, we had to be innovative, we had to try something different, we had to be brave because the stones were high. We knew we could deal with the group where the problem was big, and we didn’t know if they could get better.

All of that informed our protocol. There were two. Number one is we’re dealing with people who historically might be deconditioned and so you don’t want to put them into a protocol that’s going to come with complications. We needed to make sure that from a cardiovascular perspective, from a respiratory perspective.

Nele Handwerker: Yes, the right selection of participants is always very important.

Can you explain how exercise impacts cognitive function at a physiological level?

Nele Handwerker: I did an interview about it with Prof. Dr. Philip Zimmer, but in German, so the international audience can’t listen to it unfortunately.

Prof. Anthony Feinstein: I think it will be through an anti-inflammation mechanism. A transition can help with that and has a high effect on better function, one of which is cognition.

The CogeX Study

Could you provide an overview of the CogeX study and its objectives?

Prof. Anthony Feinstein: Yes, it’s a very large study in terms of data. We wanted to demonstrate that people with progressive MS can actually show cognitive improvements. We then had to focus on what aspect of compromise we were going to look at. We didn’t want to look at everything, because that would be overwhelming for someone with MS. So we focused on process speed, because we knew that it was probably the most common cognitive improvement in people with MS.

We also know that it can be measured very well with a test called the Symbol Digital Modalities Test (SDMT). There is also some real-world data for this test, so we know that improving by a certain number of points might have some benefit for you, which is important. It’s probably the only cognitive test in the MS literature that has this threshold effect that could be clinically significant.

We also wanted to have an international component to the study. We didn’t want to have a small, medical study. So this works in Toronto, but not only in Italy, but also in other countries. We wanted to have an international component, which was necessary. And the most important thing is that you work with some wonderful colleagues, but also the data collection increases because everybody collects data in their country.

You can get a very large sample size. That’s one of the big advantages of the CogeX study, that we have a robust sample size.

That gives us a lot of statistics, so we don’t have to implement that our results don’t show what we want because we’ve never had enough people in the study. We have enough individuals in the study to trust us that there are statistics here. For many reasons we wanted to be international, we wanted a large collection, we wanted to work in many different languages,

So that when we find something, we can say this is like a universal find. So in multiple countries we don’t have any worries that it won’t go in Europe and only in the US or Canada, for example. That’s the idea behind this project.

What were the main findings of the CogeX study regarding cognitive rehabilitation and aerobic exercise?

Prof. Anthony Feinstein: Okay, so it was a mixed blessing from our point of view. Our hypothesis was if you get the dual intervention, cardio rehabilitation plus the exercises, the process unit would improve more than if you have just one intervention, just the cardio rehabilitation or just the exercises, which primarily leads to a big improvement than if you have just the SHAM intervention. That was our hypothesis. And we didn’t support that.

To our surprise, we showed that there was cognitive improvement, but across all treatment arms. In fact, the group that got the combined intervention did not do better than, for example, the group that got the double sham. That was a disappointing finding. The pleasant surprise was that when you use the threshold scores for improvement, that almost two-thirds of our members from all treatment arms showed clinically significant improvement after twelve weeks. And we did a six-month follow-up. I should have said that the interventions lasted twelve weeks. So we did twelve weeks of exercise, twelve weeks of circuit training, and then we did the same data again six months later to see if the benefits were still there. So at the end that was a pleasant surprise.

And when you break it down to individual data, not group questions, but individual data, we know that a 7-point improvement in the SDMT, the single digit modality test, is significant. And we also saw significant interventions. So, the pleasant surprise was that the people with progressive MS showed an improvement in cognitive ability. The challenge from an interpretive perspective was why the Sham group also showed improvement.

We concluded that our sham was not a sham. We thought that our sham exercise would be neutral from an aerobic perspective. And it was, we have metrics to show that, that the aerobic marks were not increased with our sham intervention. However, the individuals who had sham exercise who were offered balance exercises showed better walkability.

By the end of the 12 weeks, they could walk better. And we now know that there is evidence in the literature that processional steps can improve when you walk better. So physically supporting people also had a positive effect on the cognition rate. We didn’t know that before this study. We couldn’t wait to find out. So, in hindsight, our sham group was not a pure sham group. And we think that’s why we couldn’t find any differences between the groups.

Nele Handwerker: Yeah, and when I looked into the study protocol, I really liked the mock version because I thought, hey, nobody’s going to waste their time here. I thought, hey, this is nice. I mean, you’re giving these people something to help them in their daily lives. And so in a way it’s not that surprising to me.

Prof. Anthony Feinstein: Yes, yes.

Nele Handwerker: I don’t remember who it was, whether it was Alon Kalron or Ulrik Dalgas, but one of my interview guests mentioned that if you do one thing on your own to improve fatigue, it’s balance. Balance training helps a lot with fatigue, and fatigue is of course linked to cognitive things, so in a way not totally surprising and very nice.

Prof. Anthony Feinstein: I think you are right. The symptoms are interlinked. They don’t exist in isolation. They enhance one aspect of function. They can’t come from other causes. We have figured that out. We have learned that. We didn’t expect that our sham exercise would result in an improvement in walking ability. But it did. They were better on the walk. The 6-minute walk test improved with the sham intervention. We think that’s why the cognitive processes also improved.

I should say that there is one more variation that I think is important to the study. It wasn’t a part of our a priori hypothesis, but I think it’s very important, and that is this. We worked with those who have a very quiet life for the most part. They have progressive MS. I’m not going to say they were forgotten by the medical profession, but they were not a major priority.

Most of them do not undergo rehabilitation. They spend a lot of time at home. They are not socialized as much. They don’t engage as much in those temptations. And suddenly these energetic scientists come in. And they give them twelve weeks, not only of rehabilitation and exercising, but they also give them more. You will be transported with a cab that will take you to the center of rehabilitation. You’ll interact with the researchers. There will be social interaction. There will be a coffee break. You’ll be doing things that are very different from your own home. And you’ll do that twice a week. And suddenly these people started waking up. That was interesting. They love it. They had to plan when a cab was coming to get them.

It has given them meaning, it has given them purpose. They love the interventions. They have really done it. They have written notes to our research teams thanking us for this study. They felt that for many of them, for the first time that the medical professional paid them a lot of attention. And in terms of that, for that twelve-week period, they had a very different lifestyle.

And that, I think, is a very key variable because it can help your cognition as well. Those are the kind of interventions that can boost what we call cognitive reserve, your intellectual capacity.

We know that if you’ve got high cognitive reserve, it can protect against cognitive decline. We know that. The literature is strong. There’s even a study out there showing that in progressive MS, that if you’ve got good cognitive reserve, it almost overrides the effects of brain atrophy or the brain metrics preserving relatively your cognition.

What we don’t know is that you can improve cognition with increased cognitive competition. It’s one thing to speed up and defend cognition, but can you actually improve it? We think we have a few tents of data here, and that wasn’t our primary goal, that’s not a hypothesis, but we think we hypothesize that with increased cognitive competition we’ve increased people’s intellectuality, with increased socializing competition, with more physically active competition, we’ve increased people’s cognition.

And this might, in this 12 week period, have led to some cognitive improvement as well. And if that’s the case, and I think we can explore this in a further study, that’s a very key finding, because it’s saying, and it makes perfect sense, sitting at home by yourself doing very little is bad for your brain function.

We know that from the aging literature, we know that from normal aging, you want to keep your brain active, you want to be doing things as you get older. And it’s exactly the same for people with an acquired brain problem. You want to use your brain, even if your brain is struggling to do the kind of things that you want to do, you have to stimulate it in many ways, not just with Internet, not just with exercise, but also with social activities, with leisure pursuits. And this was one of the unexpected but good consequences for the colleagues. We have an uplifting environment for twelve weeks for people who really love it. And we think it has some cognitive benefits as well. And that was on the side. It didn’t matter if it was your sham intervention or your foot exercise. You were still engaged in that twelve-week endbottom. For a lot of people it was a lot of fun and really interesting.

Nele Handwerker: It’s great, it’s really wonderful.

Based on the CogeX study's findings, what recommendations or advice can you offer to progressive MS patients regarding cognitive rehabilitation and exercise?

Nele Handwerker: I mean, I always say on my blog and on my podcast that when it comes to style and design, I’m a fan of less is more, but when it comes to MS, I’m absolutely a fan of a lot helps a lot.

Prof. Anthony Feinstein:

I think that’s right. I think the most important thing is that you use your brain. And you can do that in several ways. And the more ways, the better. So, try to train a little bit. It will be good for you. It will also be good for you physically. Use your brain intellectually.

Read, list to podcasts, audiobooks, get onto your computer, learn how to use your brain, and then be socially active, which can be a challenge when you’ve got a disabling disease. But you want to see your friends, you want to be able to go out, you don’t want to be housebound, you want to engage in the world around you. And so, the message I give my patients clinically all the time is that you’ve got to try and do these three things, intellectual, physical and social activity, because we think.

In truth, we know it will be good for our spirit function. Will it reverse the cognitive loss? You have to pay attention to the hope. There are many data that it will be possible. But it certainly won’t do any harm. And the potential benefits will be there. Exactly.

Nele Handwerker: Yes, and it certainly makes life richer. It certainly has its advantages. I’m 43 now and I’m doing this Master’s program on Multiple Sclerosis Management. It’s certainly very exciting and interesting. And I love reading lots of things. And I love traveling by myself when I’m on the train. Unfortunately, the train was not going, so I had to drive by car for many hours. But when I’m on the train, I love to meet new people, because it’s always interesting. And you get to meet people you would have never seen. So it’s always enriching your imagination of what life could be and all that.

Prof. Anthony Feinstein: Fantastic. Here we are. Exactly.

We know that. We know that the economic cycle of cognitive reserve is formed by lesion tests. There is solid data to back that up. If you’re active in terms of reading, hobbies, interests, etc., that’s going to help your economy. If you had an adult life, if you did music when you were young, if you had literature, if you did a lot of things that weren’t just related to school.

It was a significant environment that raised awareness. There is robust data to show that. I think it’s very important that we in the MS field learn about normal anxiety as well. There’s a lot of research that has been done on awareness. It’s a huge health service issue. What helps to maintain awareness?

And the data there is overwhelming. You want an active lifestyle. Physical activity, social activity, intellectual activity. So, we borrow from that. The MS literature is far behind the aging literature. But we can learn from that. And what our progress study does was, I think, replicating part of what the aging literature teaches us.

What have you learned from the study and how can or should research on cognitive rehabilitation in progressive MS patients continue?

We have learned a lot from this. We learned from our relative successors. We’ve learned from some of the things that we could do better. But I think the big challenge now is to try and expose why some people improve and others don’t. And it’s very clear that the one size fits all model of rehabilitation is education. We can’t say that the program is going to work for everybody because it’s not.
So we need to be more nimble, we need to be more flexible in our view, we need to contribute the intervention as we do that. And how do we do that? So we need to learn what is it about this individual and their brain that they need from this, where elsewhere the other person doesn’t. And that will hopefully be the next avenue of inquiry to try to develop us in our response and a more flexible intervention. In an intervention study, we can actually change direction. We can see that this person is not responding as we hoped. What can we do differently as part of the study to improve that response? There are study designs that allow you to do that.

In the future, we think that’s the way to go, to have a capped intervention, based on personal brain function and response. We haven’t talked about it yet, but there is an imaging component CogeX that gives us a mechanistic understanding of why some people got better and some didn’t. I think we can use brain imaging as a very useful guide to help us understand the mechanisms of improvement.

And so the next study will be, once again, with friends from other disciplines, from different countries, and it will be a more subtle study, a more fine-tuned study that lends itself to individuals and people as a large group.

Nele Handwerker: The modern study designs are not easy to plan, but they are very interesting if, for example, you change one person or a whole arm, and the person switches to another study arm that has shown better potential for improvement. And of course, all of our medicine is about individualization of activity.

Prof. Anthony Feinstein: Yes, exactly. It’s like this. All we need now is a lot of money.

Nele Handwerker: It totally makes sense because we are all very different, this disease is very different in each person, so very interesting and exciting things are on the horizon.

Yes, unfortunately I can’t help with the money. But I hope all your smart boys and girls find ways to get it. But as the population gets older, including the MS population, it becomes more interesting. And most of the countries, where the disease burden is high are rich countries. Hopefully they will fund such important research.

People are interested in new studies. That is good.

Prof. Anthony Feinstein: Yes, we need to get more money, but we’ve kept the CogeX group in tact. We have a bit of seed funding over the next year to be together as a group and decide how we plan our next money.

It’s all exciting. We’re still analyzing some of the data. It’s a huge dataset. There will still be a lot of new plays coming from the data we already have. We’ll output our main finding, but we still have to try some of the imaging data. We may even look at the individual differences again. We’re not done analyzing our data yet. Thank you very much.

Nele Handwerker: Okay, there will probably be a few more papers about CogeX. Fantastic


How and where can interested people follow your research activities?

Prof. Anthony Feinstein: I think the best way is through the MS Canada website, they list the study there. It was a very big investment for MS Canada. They made a little video of people talking about it. The website says that there are new studies that are being funded. It lets people know what the research environment is like in Canada. That’s a good starting point.

Nele Handwerker: Okay, fantastic, and I will of course include the link in the show notes and blog article. Anthony, thank you so much. Such an interesting study. And of course, good luck with everything that’s coming. Thank you for diving into this with me and the listeners.

And for you out there, please be and stay active and take advantage of every opportunity you have. I think one very important thing is that you take care of your symptoms so that you can be active. It’s always bad when someone doesn’t dare to talk about problems like incontinence in order to treat them and instead stays at home because he or she doesn’t feel well or feels embarrassed.

Prof. Anthony Feinstein: Exactly.

Nele Handwerker: You should never do that, you should use the medical tools, you should use the symptomatic treatment options that are available, and you should stay as active as possible and try to live as full a life as you can, because life can be good even with progressive MS. Thank you, goodbye.

Prof. Anthony Feinstein: I think that’s the suggestion. Excellent. Thank you for your interest in this topic.

You can find out more about the research activities of Anthony Feinstein on PubMed.

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