1. The DM1-Neuro Study: Myotonic dystrophy research update
Mark Hamilton, Clinical Research Fellow

3. Key research questions
Which methods represent meaningful outcome measures for CNS-symptoms of myotonic dystrophy
How do structural brain changes relate to the severity of symptoms, in particular those of excessive daytime sleepiness?

4. The DM1-Neuro study Cohort
40 individuals with aDM1, plus 6 with MRI contraindications
20 age-matched controls
Recruitment
Comorbidities
Genotyping by SP-PCR
Clinical assessment
Neuropsychological assessment
Self-reported outcome measures
MRI brain
T1, T2 weighted imaging
Diffusion tensor imaging
Resting state functional MRI
Sleep Studies
Domiciliary polysomnography
Modified maintenance of wakefulness tests

5. The DM1-Neuro study Cohort
40 individuals with aDM1, plus 6 with MRI contraindications
20 age-matched controls
Recruitment
Comorbidities
Genotyping by SP-PCR
Clinical assessment
Neuropsychological assessment
Self-reported outcome measures
MRI brain
T1, T2 weighted imaging
Diffusion tensor imaging
Resting state functional MRI
Sleep Studies
Domiciliary polysomnography
Modified maintenance of wakefulness tests

6. Selection of neuropsychological assessment methods
Consensus recommendations of OMMYD1
Colour-word Stroop test
FAS word association
Trailmaking Tests A & B  Trailmaking tests from D-KEFS
Block design subtest from WAIS-R  WASI II
Cognitive screen without motor tasks
The Edinburgh Cognitive and Behavioral ALS Screen
Explained that we used all of the tests recommended by the ‘Outcome measures in Myotonic Dystrophy’ consensus meeting, plus the ECAS, which we selected based on non-interference by motor impairment
Self- and informant-reported outcome measures
Myotonic Dystrophy Health Index
DM1-ActivC©
Fatigue and Daytime Sleepiness Score
Self and carer Dex questionnaire
Beck Depression Inventory II
McGill pain scale
SF-36 pain items

7. Summary scores for main neuropsychology assessments
Mean score of DM1-affected participants
(SD)
Mean score of control participants
Cohen’s D effect size
Stroop colour-word task
41.74 (10.40)
53.80 (7.98)
1.301
Trailmaking test
(Number sequencing)
7.80 (3.74)
12 (1.59)
1.462
Trailmaking Test
(number-letter sequencing)
8.41 (4.20)
11.70 (2.00)
1.000
FAS word association
36.59 (11.15)
47.10 (11.11)
0.944
Block design subtest
37.57 (9.79)
52.15 (8.49)
1.591
ECAS Total score
(11.69)
(9.50)
0.763
ECAS Visospatial
11.02 (1.45)
11.85 (0.37)
0.783
ECAS verbal fluency
17.35 (3.73)
18.70 (3.91)
0.354
ECAS Executive
35.87 (6.12)
39.35 (5.80)
0.583
ECAS Memory
17.04 (3.77)
18.90 (2.83)
0.559
ECAS language
26.59 (1.94)
25.90 (5.99)
0.155
0.6
On the face of it, a large difference is seen between the performance of DM1 patients and controls in all of the recommended tests. Scores on ECAS are still significant, but generally somewhat more modest.
0.3

8. Correction for motor impairment in D-KEFS trailmaking tests
Component test
Cohen’s D effect size
(affected vs. control)
Trail 2
(number sequencing)
1.462
Trail 4
(number-letter switching)
1.000
Trail 5
(motor)
1.427
Motor contrast score
(Trail 4 scaled score – Trail 5)
0.087
Dm1-affected participants performed particularly poorly in Trailmaking /46 (24%) more than 2 SDs below predicted on the number-letter switching task. However, also poor at trail 2 (predominantly a test of attention), and trail 5 (motor component isolated). When corrected for motor slowness, the difference vs controls is lost.
Number-letter switching
Motor 2 B A
Start
Start 1 3 C

9. Corrected scores for Stroop test
Component test
Cohen’s D effect size
(affected vs. control)
Word test
0.992
Colour test
1.377
Colour-word test
1.301
Stroop Interference
0.553
ECAS executive score
0.583
Similarly, correction of the Stroop colour-word score for performance in the first two tasks shows a more modest impairment, comparable to the ECAS executive score.
Word test
Colour test
Colour-word test
GREEN BLUE RED
RED GREEN RED
BLUE GREEN BLUE
GREEN RED GREEN
RED BLUE RED
XXXX XXXX XXXX
GREEN BLUE RED
RED GREEN RED
BLUE GREEN BLUE
GREEN RED GREEN
RED BLUE RED

10. Self-reported muscle impairment correlates with performance in neuropsychology assessments with a manual task
Trail 5 (motor) scaled score
Block design test (T-score)
We cannot definitively say why DM1 patients are slow even at Trail 5 and the word test of Stroop. Attention and motivation may be factors. But we would suspect muscle impairment may play a role - further evidenced by the fact that performance in all of the trails correlate with self-reported muscle strength in DM1Active, as does score for block design test.
We must therefore be cautious in recommending these tests as measures of CNS response to a drug therapy.
p < 0.001; Adj R2 = 0.314
p = 0.001; Adj R2 = 0.191
ECAS subscores did not correlate with any scales of self-reported measures of muscle function

11. Low mood, pain and fatigue
Significant correlations between depression scores and:
Sleepiness and fatigue (R2 0.42)
Pain (R2 0.25)
Low mood also strongly predicts:
Self-reported cognitive impairment (R2 0.61)
Impaired social performance (R2 0.41)
‘Frontal’ personality traits (R2 0.48)
Low mood 2%
33%
11% 0%
18%
In self-reported measures we saw fatigue as a frequent issue, often accompanied by pain and low mood. Low mood was generally predictive of higher self-reported central symptoms.
17% 4%
15%
Fatigue
Pain

12. Automated segmentation of white matter hyperintensities
MRI analysis:
Automated segmentation of white matter hyperintensities
It’s therefore useful to ask “do self-reported central symptoms correlate with any objective measures of disease?”. Neuropsychology ‘puzzles’ represent one objective measure, and imaging another. MRI analysis is in early stages (DTI, fMRI, regional volumes to come), but we do have white matter lesion volumes as illustrated

13. Self-reported cognitive impairment does not reflect severity of brain involvement
Self-reported cognitive impairment did not correlate with any objective measures of CNS disease
Trend towards higher depression scores and greater self-reported impairment in those with less white matter change
Self-reported central symptoms did not correlate significantly with performance in any of the tests, nor with severity of imaging changes. In fact, there was a trend towards an inverse correlation, with patients with less severe brain changes more likely to be low in mood and report higher cognitive impairment. Unclear why those with worse brain changes don’t - ? Acceptance over time, ?? Impaired insight
p = 0.129
p = 0.171

14. Informant-reported Dex score correlates significantly with severity of white matter disease
Only significant correlation with brain changes is the carer-reported outcome. ?? Role for development of more carer-reported outcomes for future clinical trials.
P = 0.001; R2 = 0.264
© Pearson Publishing 2006

15. Correlations with CTG repeat length
logPAL is associated with self-reported age at onset (p = 0.09; R2 0.05)
Modal allele length predicts scores in:
- DM1ActivC (R2 0.12)
- Trail 5 motor (R2 0.07)
- Block design (R2 0.18)
- Stroop interference (R2 0.16, in multivariate analysis with age)
Our patients have been very accurately genotyped by small pool PCR. This technique has recently shown very good correlations with muscle measures in other populations. Sureprising therefore that correlations with our brain measures to date have been comparatively poor. Reasons might include:
Self-reported measures are introduce subjectivity
Neuropsychological measures are subject to wide variation within normal range, with modest additional effect of DM1
Additional environmental/genetic factors may be important for development of WMHs
Based on previous literature, we would hope for better correlations with DTI measures.

16. Participants with variant trinucleotide repeats report fewer symptoms
There is evidence that patients with variant repeats (CCG sequence within their CTG expansion) may have less severe symptoms than those with similar gene expansions made of pure CTG repeats. We found two patients with variant repeats, both of whom reported few symptoms as illustrated.
AAT
CTG
CCG

17. Summary of first 15 domiciliary polysomnography studies
Measure
Mean (SD)
Apnoea-hypopnoea index
25 (27)
Central apnoea / hour
4 (8)
Obstructive apnoea/ hour
0.1 (0.3)
Central hypopnoea / hour
1.7 (4.0)
Obstructive hypopnoea / hour
20 (15)
Sleep efficiency (%)
76 (14.5)
Periodic Limb Movement Index
11 (26)
Mean sleep latency in mMWT
24 (10.0)
We are in early stages of sleep study analysis, but clearly detecting lots of pathology as illustrated
Sleep disordered breathing

18. Structure-phenotype correlations with MRI imaging
In particular, we have found several patients with central apnoeas. Will be very interesting to correlate this with structural changes in specific brain regions on MRI.

19. Conclusions
Recommended “executive” tests show significant interference from motor impairment
Low mood is associated with greater severity of self-reported symptoms, particularly in those with mild CNS disease
Correlations of brain phenotype with CTG repeat size are so far relatively poor compared with muscle
Future directions will explore structural correlations with neuropsychology performance and sleep disorder

20. And thank you to the study participants and their families
Acknowledgements
Supervisors
Darren G Monckton
Maria E Farrugia
University of Glasgow
Sarah Cumming
Gayle Overend
Josephine McGhie
Clarissa Hocking
Dept of Neuroradiology
John McLean
Ravi Jampana
The Scottish Myotonic Dystrophy Consortium
Dept of Health and Wellbeing
Jonathan J Evans
University of Newcastle
Antonio Atalaia
Hanns Lochmuller
Nikoletta Nikolenko
University of Iowa
Peg Nopoulos
Vincent Magnotta
Eric Axelson
Dept of Clinical Genetics
Bob Ballantyne
Cheryl Longman
Marina Di Marco
Dept of Respiratory Medicine
Eric Livingston
Scott Davidson
Alison Clarke
And thank you to the study participants and their families

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