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

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?

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?

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.

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

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.”

Iowa to the Rescue!

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)

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

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?

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

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

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

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)

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

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?

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

CTG Repeat Length and Age of Onset Number of CTG Repeats DM1 5-37 Normal Range 38-49 Pre-mutation 50-150 Late Onset 150-800 Adult Onset 800-1000 Childhood Onset >1000 Congenital Onset *Age of onset at least 21 for “adult-onset”

* 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

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)

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)

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.

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?

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

*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

*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

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

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?

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

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

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

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.

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