1. Myotonic Dystrophy Research: What’s Next?
Ian DeVolder, PhD
June 10, 2017
Department of Psychiatry, Nopoulos Lab
Psychiatry
Iowa
Neuroimaging
Consortium

2. Outline Iowa DM1 Brain Research Study: What and Why?
Lesson on brain anatomy
Iowa DM1 Brain Research Study: What and How?
How does DM1 affect the brain?
Does this change over time?

3. Outline Iowa DM1 Brain Research Study: What and Why?
Lesson on brain anatomy
Iowa DM1 Brain Research Study: What and How?
How does DM1 affect the brain?
Does this change over time?

4. The Search For Biomarkers in the Central Nervous System
Biomarkers are needed to test effectiveness of clinical drug trials in DM1.
Central Nervous System (CNS) biomarkers are especially lacking.

5. Caveat of Drug Trials in DM1
Many drugs can’t cross the Blood-Brain Barrier (BBB)

6. Directly From the MDF
“Exploration of the central nervous system (CNS) in DM has produced sparse natural history data and few insights into biomarkers that can provide early indications of target engagement and modulation and clinically meaningful endpoints.”
“A gap in longitudinal data, understanding how CNS symptoms progress with age, was identified as particularly acute. To drive interventional studies, it is necessary to establish strong correlations between CNS functioning and endpoints (such as imaging) that can be easily and reproducibly assessed in clinical trials of manageable duration.”

7. Iowa to the Rescue!

8. Neuroimaging as a Potential Biomarker in DM1
MRI (Magnetic Resonance Imaging) is a non-invasive way to examine the structure and function of the brain and the CNS (central nervous system)

9. Gastrointestinal – Symptoms similar to irritable bowel syndrome
DM1 Symptoms
CNS and Psychiatric – mild cognitive deficits, hypersomnolence, apathy, depression, anxiety
Vision - Cataracts
Neuromuscular - Myotonia and Muscle Atrophy; mainly on “distal” muscles
Gastrointestinal – Dysphagia (difficulty swallowing; at-risk for aspiration pneumonia)
Cardiac – conduction disturbances and tachyarrhythmias; pacemakers are common
Gastrointestinal – Symptoms similar to irritable bowel syndrome
Endocrine – Disturbances of the thyroid, pancreas, hypothalamus, and gonads; testicular atrophy, insulin resistance

10. Outline Iowa DM1 Brain Research Study: What and Why?
Lesson on brain anatomy
Iowa DM1 Brain Research Study: What and How?
How does DM1 affect the brain?
Does this change over time?

11. Neurons in the Brain
“Gray Matter”
“White Matter”

12. Cerebral spinal fluid (CSF)
Magnetic Resonance Imaging (MRI)
Gray Matter
Where the cell bodies are
Cerebral spinal fluid (CSF)
Surrounds the brain and fills internal cavities
White matter
Where the axons are (electrical cables)
Coating on the axons is called MYELIN

13. How do we “measure” white matter?
We can detect ‘lesions’ in the white matter
Places where myelin has been ‘stripped’

14. How do we “measure” white matter?
White Matter is made of organized tracks of fibers
Kind of like roads
We can measure how straight the fibers are
Straight roads are “better”
Called diffusion tensor imaging (DTI)

15. DTI Overview
Higher Fractional Anisotropy (FA) = diffusion occurs more readily in the primary axis.
White matter is “fiber-like” and forms bundles/tracts.
Higher FA = healthier white matter.
Equally as likely/able to swim in any direction: Low FA
Much more likely to move through the tunnel: High FA

16. Outline Iowa DM1 Brain Research Study: What and Why?
Lesson on brain anatomy
Iowa DM1 Brain Research Study: What and How?
How does DM1 affect the brain?
Does this change over time?

17. Study Design Study Participants (n = 120)
Individuals with Family History of DM1
(n = 60)
“Healthy Controls”
(n = 60)
“Pre-DM” = Diagnosed but no symptoms yet
“At-Risk” = Family history of DM1, unsure on gene status
“DM1” = Diagnosed with DM1and showing symptoms

18. CTG Repeat Length and Age of Onset
Number of CTG Repeats
DM1
5-37
Normal Range
38-49
Pre-mutation
50-150
Late Onset
Adult Onset
Childhood Onset
>1000
Congenital Onset
*Age of onset at least 21 for “adult-onset”

19. * 3-Year Longitudinal Study Design
Time
Year 1 Visit:
Brain and Leg MRI
Neuropsychological Testing
Neurophysiological Measures
Year 2 Visit:
Brain and Leg MRI
Neuropsychological Testing
Neurophysiological Measures
Year 3 Visit:
Brain and Leg MRI
Neuropsychological Testing
Neurophysiological Measures

20. DM1 Study MRI Protocol MRI sequences to be obtained are:
T1 (structural)
T2 (structural)
FLAIR (white matter lesion load)
Diffusion Tensor Imaging (DTI; white matter microstructure)
Diffusion Kurtosis Imaging (DKI; white matter microstructure)
Resting-State functional connectivity fMRI (functional connectivity)

21. Age at Onset of Symptoms
Visit #1 Sample
DM1
(n = 30)
Control
Age
47.0 (9.6)
45.5 (13.2)
Sex (F/M)
21/9
17/13
Years Since Diagnosis
7.1 (6.5)
Disease Duration (DD)
12.4 (7.4) -
CTG Repeat Length
289 14
Education (years)
15.5 (2.5)
16.0 (2.4)
* Disease Duration (DD) = Age – Time of Onset of Symptoms
Age (years) 10 20 30 40 50 60
Age at Onset of Symptoms
Current Age
DD (years)

22. Hypotheses
White matter health and structure in the brain will be disrupted in patients with DM1.
Disease Duration (DD) will predict white matter health: The longer you have had the disease, the more disrupted the white matter.

23. Outline Iowa DM1 Brain Research Study: What and Why?
Lesson on brain anatomy
Iowa DM1 Brain Research Study: What and How?
How does DM1 affect the brain?
Does this change over time?

24. In DM1, the White Matter is Affected Most
DM1 patients have more white matter lesions than controls that are matched by sex and age
Control scan in Yellow box
Patient scan in red box

25. *ANCOVA controlling for age, gender, and ICV, F= 8.02, p<0.01
In DM1, the White Matter is Affected Most
MRI measures show that subjects with DM1 had LOWER white matter volumes compared to control *
*ANCOVA controlling for age, gender, and ICV, F= 8.02, p<0.01

26. *ANCOVA controlling for age and gender, F= 62.58, p<0.0001
In DM1, the White Matter is Affected Most
DTI Measure
Higher FA means straighter white matter fibers
Higher is BETTER
DM1 subjects have lower FA than controls *
*ANCOVA controlling for age and gender, F= 62.58, p<0.0001

27. What is affected by changes in brain white matter?
Thinking skills
DTI Measure
How “straight” the “roads” are in your white matter
The lower the DTI measure, the lower the thinking skills score.
Thinking Skills Score
Lower Higher
DTI Measure of White Matter Health
Lower Higher
*Pearson for age, gender, and eduction, r = 0.788, p<0.0001

28. Outline Iowa DM1 Brain Research Study: What and Why?
Lesson on brain anatomy
Iowa DM1 Brain Research Study: What and How?
How does DM1 affect the brain?
Does this change over time?

29. Does the white matter get less healthy over time?
DTI Measure of White Matter Health
Lower Higher
Disease Duration (in years)
Shorter Longer
* The longer the disease duration, the more affected the white matter in DM1

30. Does the White Matter get less healthy over time?
We divided our research participants into groups, based upon how long they had symptoms of DM1.
Disease duration – determined by the age at which symptoms first started (not age of diagnosis)
Group
Duration of Disease (DD)
Mean (range) N
Age
Mean
Control
Not applicable 16
47.7
Group 1 (DD short)
1.87 (0 – 4.4) 8
37.0
Group 2 (DD medium)
10.01 (6.3 – 15.2)
53.3
Group 3 (DD long)
22.7 (19.0 – 25.4)
43.9

31. Does the White Matter get less healthy over time?
Worse Better
DTI Measure
* p<0.001
Control Short Medium Long
DD DD DD
* p=0.01
Even patients VERY early in the disease have decreased DTI measure
The longer the disease, the lower the measure

32. Take-Home Message
These measures of brain structure and function are consistent with what we observe and what patients/families tell us in clinic.
Knowing the specifics of how DM1 affects the brain over time can help researchers develop useful biomarkers of disease progression. This would allow for better-targeted treatments and can help clinicians track change and determine the effects of such treatments.
Even though DM1 may bring about various challenges, clinicians, patients and families can work together to compensate for many of the difficulties that arise.

33. Research participants – We couldn’t do this without you!
Thank You!
Research participants – We couldn’t do this without you!
Research Team
Neurology: Laurie Guttmann, Cheryl Smith
Genetic Counseling: Janel Phetteplace
Research Coordinators: Stephen Cross, Claire Johnson
Postdoctoral Fellow: Ian DeVolder
Imaging: Vince Magnotta, Hans Johnson, Eric Axelson, Joel Bruss
Psychiatry: Peg Nopoulos, David Moser
Statistics: Jeff Long