The UK-based Wyck Foundation, in partnership with the Myotonic Dystrophy Foundation (MDF), has awarded a 2016-2017 postdoctoral fellowship to Dr. Ian DeVolder, Ph.D., a Graduate Research Assistant in the Department of Psychiatry at the University of Iowa Carver College of Medicine.
Dr. DeVolder’s research proposal is titled “Structural and Functional Connectivity in the Brains of Patients with Adult- and Late-Onset Myotonic Dystrophy Type 1 (DM1): A Potential Biomarker for Disease Progression.” In this study, Dr. DeVolder and his colleagues will evaluate brain structure and function in DM1 and correlate these with measures such as neurocognitive functioning and disease duration. The investigators will study 30 patients with classic adult-onset or with late-onset DM1, ages 21 to 65 years old, and compare them to 30 age-matched healthy controls.
Dr. DeVolder received his doctorate in neuroscience from the University of Iowa in 2015 and is a graduate research assistant in the laboratory of Peg Nopoulos, M.D., at the University of Iowa Carver College of Medicine. His work at Iowa has focused on the structure and function of the brain in children with clefts of the lip or palate and in children at risk for Huntington’s disease.
“If we can know how and when myotonic dystrophy type 1 affects the brain,” DeVolder says, “we can better time treatment so as to have a neuroprotective effect and try to prevent these brain changes from happening in the first place.” We recently talked with Dr. DeVolder to learn more:
MDF: Your previous work was focused mainly on the brain abnormalities that can accompany clefting disorders, such as cleft lip and cleft palate. [See DeVolder, I., et al., Abnormal cerebellar structure is dependent on the phenotype of isolated cleft of the lip and/or palate, The Cerebellum, April 2013.] How did you move from there into myotonic dystrophy?
ID: It’s definitely been a shift in terms of the clinical population that I’ve been working with. Clefting abnormalities and myotonic dystrophy are not directly related. However, in terms of the basic practice, the basic study we did, they’re actually not that far removed. It’s the same type of imaging techniques, the same type of neuropsychological evaluation.
And, even though my thesis work was with the clefting community, I actually have had a large role in a number of different studies in my lab. Importantly, one of those was our study on Huntington’s disease, which can be thought of as a sister disease to myotonic dystrophy. They’re both trinucleotide repeat disorders, and both previously were thought of as primarily neuromuscular diseases.
The Huntington’s study was focused on children who were at risk for developing HD. These children had either a parent or grandparent who was affected by the disease. We did a full neuropsychological evaluation, MRI and genetic testing. We were comparing children with the expanded repeat, who, in 30 years or so, will likely develop HD, with those who don’t have the expanded repeat. We were looking at Huntington’s from a developmental perspective to see whether, at an early age, there is something being set in motion in terms of neurodevelopmental changes. Results from this study should start being published within the coming year.
It’s been an interesting shift into myotonic dystrophy. We wanted to model our DM1 study after our Huntington’s study, looking at kids who were not yet showing symptoms but who were at risk for DM1. But we underestimated the role of anticipation in DM1. This is a phenomenon that is seen in Huntington’s but not nearly as frequently and not nearly as severely as in myotonic dystrophy.
We discovered that families with DM1 oftentimes don’t know that they have it or that their children are at risk until they have a child that’s born with an extremely expanded repeat and the congenital-onset or childhood-onset form of the disease. So it’s much harder to identify children with pre-DM1 than children with pre-HD. Therefore, we shifted our focus to adult-onset and late-onset myotonic dystrophy.
There have been some neuroimaging studies in myotonic dystrophy, but they’ve typically focused on the childhood-onset, adult-onset and congenital-onset forms all together in one group.
We really wanted to focus on one type of DM1, because the congenital-onset and childhood-onset forms seem to be so different in terms of the symptoms they show. We wanted to completely remove that confounding factor. We’re looking at a pretty big age range – 21 to 65 – but it’s still adult-onset DM1. We cut off the age for this study at 65 because we didn’t want to introduce aging effects as confounding factors.
We’re combining concepts from a lot of previous neuroimaging studies. We’re using several neuroimaging techniques and we’re combining those with a neuropsychological evaluation. We’re also making it a longitudinal study, where participants will come back once a year for three years. The study is unique in that sense. It’s the first neuroimaging study in DM1 to combine all of these elements.
MDF: What kinds of brain abnormalities are you looking for?
ID: The brain changes in myotonic dystrophy have been primarily found to be white matter-related. We expect to find some of the things that have already been seen, such as increased numbers of white matter hyperintensity lesions. White matter refers to the myelinated fibers that connect different regions of the brain, and there are variants that you can see on an MRI scan. They’re a little bit unclassified, but basically they’re considered to be abnormal white matter.
We’re also using diffusion imaging, which looks even more specifically at white matter structural integrity. Diffusion imaging measures the movement of water molecules in tissues. It’s a way to see if water is moving along the axon versus going out. From that we can get an idea of the actual shape and structure of the white matter. Typically, white matter in the brain forms tight fiber bundles and tracts, so healthier and better-myelinated white matter would lead to an increase in water movement along the axons, rather than out into the brain. This can be measured by diffusion imaging.
There’s been a fair amount of neuroimaging work in myotonic dystrophy, but there’s been hardly any functional neuroimaging. That’s something I’ve worked with in our studies and something I’ve really wanted to focus on for this population as well.
I was really excited and somewhat surprised when I saw the 2014 paper on functional brain connectivity in DM1. [See Serra, L., et al., Abnormal functional brain connectivity and personality traits in myotonic dystrophy type 1, JAMA Neurology, May 2014.]
They found that in patients with DM1 there was increased functional connectivity in certain parts of the brain compared to the control group. Specifically, they found increased network connectivity between the left and right posterior cingulate cortex and the left parietal node when the participant was in a resting state – in other words, not engaged in any specific task. They also found that the DM1 group was more likely to show certain personality traits, such as the presence of fixed ideas, rigidity of thought, and an acute sensitivity to anger or hostility in others, than the control group.
In our study, we’re looking at the resting state, and we’re looking at functional connectivity, but we’re also looking at the developmental component, whether these networks are changing over time and with disease duration.
In resting-state functional connectivity analyses, we’re examining low-level changes in blood flow throughout the brain. You can look at the time course of these blood-flow changes at each individual voxel [volume element] in the brain, and then can compare that time course to all other voxels of the brain. From this you can discover areas of the brain that are showing the same levels of blood-flow changes, with the idea being that those areas that are functionally connected to each other would show a more similar type of pattern to each other in terms of blood-flow. With this data we can examine functional networks in the brain, and how they may be changing in DM1.
In some of the questionnaires that we’re administering, we’re also looking for personality traits that may be typical. We’ll see whether or not we capture the same types of findings as the 2014 study.
MDF: If you do find brain abnormalities, are they necessarily the cause of the cognitive and personality differences sometimes seen in DM1? Could it be that focus on certain thoughts or activities could change the brain? Or could it be that respiratory or cardiac impairment associated with DM1 affect the brain?
ID: I think that if there’s a common pattern of brain abnormalities seen in a population, I would argue that it’s more neurobiologically based rather than the other way around. But it’s a hard thing to parse out.
In another part of your question, you asked about whether what we’re seeing might not be primary but secondary to some of the respiratory or cardiac issues. It’s an issue that we’ve run into, particularly in the clefting studies that I’ve been involved in.
A fair critique of that study is that some of the changes we measured may actually be secondary, a response to the things these kids experience at really young ages – like anesthesia during reparative surgeries when they’re not even one year old yet. They are facing these environmental insults at this critical developmental time point. It’s a potential caveat to some of our studies.
I think with myotonic dystrophy it won’t be quite as big an issue. In our screening process, we automatically exclude individuals who have a pacemaker installed, because they can’t go into the MRI scanner. As a result, I think those individuals who would be the most severely affected in terms of the cardiorespiratory symptoms are automatically being excluded from the study.
I think it’s going to be more reasonable in this study to really try and parse out the abnormalities that are directly caused by the gene expansion as opposed to other factors.
Also, we do get a pretty extensive medical history from all our study participants, so potentially we could create within the myotonic dystrophy group some separate subgroups, such as those that are most severely affected by arrhythmias, and see whether or not we are getting the same patterns of brain changes.
MDF: Would finding brain abnormalities in study participants with DM1 have therapeutic implications?
ID: We’re focusing on the longitudinal aspect in these studies. What we’re hoping to find is essentially biomarkers for the disease. These do have important therapeutic implications, but they’re not going to be immediately obvious.
As for the current drug trials that are going on with Ionis, they potentially could have a lot of therapeutic benefit. However, the drug they’re testing cannot cross the blood-brain barrier unless delivered intrathecally -- via spinal infusion. Right now, the potential drug treatments, which are delivered subcutaneously, won’t actually get into the central nervous system. [Ionis Pharmaceuticals is testing its antisense-based drug IONIS-DMPK-2.5Rx, which targets the abnormally expanded RNA from the DMPK gene in DM1.]
The thing is, we don’t have a good idea of the developmental component of the brain abnormalities in terms of the disease progression itself. Before drug discovery can start moving into that area, we have to know what’s actually happening in the brain. If we can get a better idea of when these changes are occurring and what the changes actually are, we can track disease progression much better, potentially having much better timing of when drug delivery should happen. With optimal timing of drug delivery, these drugs could have a neuroprotective effect and ideally prevent these brain changes before they happen.
MDF: Is your study still open to recruitment?
ID: The study is well under way, but yes, it’s still open. We will continue to recruit new participants over the next few years.
Note: For details about this and other DM studies, go to MDF’s Study and Trial Resource Center and select the Current Studies and Trials tab. The study discussed in this article is Brain Structure and Function in Adults with a Family History of DM1.