MDF is pleased to announce that clinical psychologist Dr. Benjamin Gallais, Ph.D., a Postdoctoral Fellow in the Interdisciplinary Research Group on Neuromuscular Disorders at the Université de Sherbrooke has been awarded a 2016-2017 postdoctoral fellowship.

Dr. Gallais’ research project is titled “A 14‐year Longitudinal Study of Cognition and Central Nervous System Involvement in Adult- and Late‐Onset Phenotypes of Myotonic Dystrophy Type 1.” In this study Dr. Gallais and his colleagues will continue what is currently the largest and longest-running longitudinal study in patients with the adult-onset and late-onset types of type 1 myotonic dystrophy (DM1). That study, conducted on a very large group of patients over a nine-year period, produced strong results on the progression of intellectual and cognitive abilities.

The present project aims to extend the follow-up period and answer questions that include how symptoms progress over time, what the rate of progression is, whether progression is similar among patients, whether cognitive involvement progresses to dementia and what assessment tools will best permit assessment of change during clinical trials.

Dr. Gallais received his doctorate in clinical psychology from Paris 8 University in France in 2010. He is particularly interested in the cognitive and psychological effects of motor disorders. Dr. Gallais first became interested in studying DM1 when he was working with brain-injured patients in a sleep lab where a DM1 study was also taking place. We recently talked with Dr. Gallais to learn more:

MDF: How did you first become interested in studying the CNS aspects of DM1?

BG: About 15 years ago I was working in Paris on a study of sleep and fatigue in brain-injury patients in a sleep lab. In the same lab there was also a study in DM1 patients, and that was how I met these patients for the first time. I was about to start my Ph.D. studies in psychology, and I learned that the CNS aspects of DM1 had not been much studied. I decided to focus on the psychological and other CNS aspects of DM1 for my Ph.D. studies, and I got together with Dr. Bruno Eymard, a neuromuscular disease clinician and researcher in Paris.

The central nervous system (CNS) aspects of DM1 and the associated cognitive, personality and sleep-related features of the disease have not been studied as thoroughly as other effects of the disease. Dr. Gallais and colleagues want to study the long-term natural history of the CNS aspects of DM1 in people with the adult-onset and late-onset forms of the disease. They also want to see what changes (if any) occur in CNS-related functions over the course of a year, a typical time course for a clinical trial.

MDF: What is the typical cognitive and/or psychological profile in the adult forms of DM1?

BG: For the late-onset type of DM1 – which we define as having symptom-onset after age 40 – there is almost no description of cognitive and psychological features. That’s one reason why I think our study is very important.

For the classic adult-onset type of DM1, which we define as having symptom-onset between the ages of 20 and 40, there is a typical profile, although it varies among patients. There is often mild intellectual disability, executive dysfunction, visual-spatial and visual-constructional alterations, and attention deficit. Memory impairment has been described in some studies but not in others. There is also a high prevalence of fatigue, daytime sleepiness, and emotional and behavioral withdrawal.

Our research team has already conducted a nine-year study on a very large sample of patients with adult-onset and late-onset DM1 from the Saguenay-Lac-Saint-Jean region of Quebec province, where the prevalence of DM1 is much higher than in the rest of the world. The new project will extend the follow-up period and enroll some new participants.

Our study has two main objectives. The first is to learn a lot about the natural history of the cognitive and other CNS aspects of the disease. The second objective is to measure the progression of these aspects of the disease over a time period that mimics a future treatment trial. We are including a one-year re-test of the participants that will allow us to develop valid CNS outcome measures for trials.

MDF: What have you seen so far?

BG: At the June 2015 IDMC-10 meeting, we presented some results of our nine-year study, which started with 200 patients. [See Highlights from IDMC-10.] At the beginning of the study most participants showed some mild impairment in executive function, language and visual memory. Nine years later, the 115 people who completed the study also showed declines in verbal memory, visual attention and processing speed. Language and IQ remained stable.

These were both expected and unexpected findings. We found worsening in several cognitive functions, such as verbal memory, visual attention and processing speed, but interestingly, these were not the cognitive functions in which we expected to see progression.

The functions that are typically impaired in the classic type of DM1 did not decline, but other functions did. And the late-onset patients showed similar cognitive symptoms to the adult-onset patients, sometimes progressing faster than the adult-onset patients.

My interpretation is that there are two processes going on. One is more developmental, occurring early in life and leading to the typical DM1 profile. Those functions seem to reach a plateau and do not continue to decline.

Other functions that are not part of the typical DM1 profile start to decline in a second process, which appears to be more degenerative. It may be that in DM1 cognitive functions are fragile, and it may be that they become more fragile with advancing age.

As with all aspects of DM1, there is wide variability in the way the CNS aspects present themselves (or don’t). The number of CTG repeats is a factor in this variability, but it does not appear to be the only factor.

MDF: There are some DM1 patients who do not fit the typical DM1 cognitive and psychological profile. What might account for that?

BG: The variation in DM1 can be explained in part by the number of CTG repeats, but now there are hypotheses about the role of epigenetics in patient onset, severity and disease progression. It may be that there are epigenetic variations that make one patient totally express the CTG repeats while another one will have a factor of protection.

In addition there are differences in patients’ coping strategies and adaptive skills. Some people with mild impairment will become totally withdrawn and others will fight. Family and environment can also play a role in the differences between patients. The level of “handicap” can be thought of as the discrepancy between the impairment and the abilities. Very mild impairment with little to no support can yield a very large handicap, just as significant impairment that is coupled with compensation from a caregiver or spouse can yield a lower overall disease handicap.

In DM1 there is a high level of unemployment. People who don’t work and who stay at home don’t have the same stimulation as individuals who are employed. This may be a possible secondary contributor to the cognitive profile.

There is also often respiratory impairment, and there are links with respiratory events and some cognitive functions. Lack of oxygen in the brain can lead to deterioration of the brain and theoretically to cognitive dysfunction.

So we speculate that the progression of cognitive and psychological symptoms is not only explained by the direct effects of the disease but also by secondary factors – indirect effects. We do know however that cognitive deterioration is not statistically correlated with muscular impairment.

Understanding the CNS aspects of DM1 should lead to better outcome measures by which to measure the effects of new treatments, but it’s also crucial for providing optimal care to patients, whether or not they are in a study.

MDF: How will understanding CNS disease impacts help with DM research or therapy development?

BG: The project will permit the selection and validation of CNS-related outcome measures for use in trials. I hope that one day a CNS-targeting treatment will improve the psychological and brain-related symptoms of DM, but adequately assessing the symptoms is crucial. The CNS symptom measurement tools must be sensitive enough to demonstrate that the level of fatigue or apathy or memory has changed as a result of the treatment.

Understanding the cognitive and psychological effects is also important for clinical care. Understanding disease progression can help clinicians anticipate problems that may eventually occur and help patients prepare for them. Early preparation may help patients to more easily adapt to cognitive changes and assist them in informing family members and others. Eventually this information may help patients communicate their disease-related cognitive changes to their employers and successfully advocate for workplace adaptations, allowing them to remain in the world of work.

MDF: Do you think it may be possible to change CNS-related disease progression?

BG: Cognitive rehabilitation programs such as cognitive stimulation and adaptive strategies could be helpful, and we are interested in developing these in the future.