Towards CNS Endpoints for Clinical Trials in DM1

CNS deficits represent an important component of the DM1 phenotype and play a key role in overall burden of disease. Yet, complex brain functional assessments may be complicated by the interaction of peripheral and central contributors, so it is important to understand any limitations imposed by such interactions.

The MDF Research News previously highlighted an important series of DM-focused reviews in Frontiers of Neurology. A new original research article in the same journal, by Mark Hamilton (Queen Elizabeth University Hospital, Glasgow) and colleagues (Hamilton et al., 2018), offers an important new perspective on developing clinical outcome measures for assessing CNS function in clinical studies of and interventional trials in DM1.

Deficits of Patient Motor and Cognitive Insight May Confound CNS Outcome Measures

The Glasgow-based research team assessed 45 adult or late-onset DM1 subjects and 20 controls using a battery of neuropsychological and symptomatic instruments, as well as assessments of CNS structure (by MRI) and CTG repeat length. Neuropsychological tests followed OMMYD recommendations, including Stroop test (controlled for reading speed), Trail Making tests (controlled for speed), Delis-Kaplan Executive Function System, and Block Design test. Study subjects also completed the Edinburgh Cognitive and Behavioral ALS Screen and the FAS controlled oral word association test. Self-reported instruments used assessed fatigue, daytime sleepiness, depression, pain, dysexecutive symptoms, as well as MDHI and DM1-ActivC. The overall test battery appeared to be well-tolerated by DM1 subjects.

Neuropsychological testing assessing multiple domains identified impairment in function of DM1 patients versus controls, although correction for reading or motor speed mitigated the magnitude of some of these differences. The researchers highlighted the impact that dysarthria and upper limb weakness could have upon some neuropsychological measures.

Self-reported assessments of cognitive function obtained data consistent with prior reports—that DM1 patients reported greater fatigue, lower mood, greater levels of pain, and executive dysfunction. However, findings of lower mood (including depression) strongly correlated with increased self-reporting of cognitive deficits. MRI gray and white matter measures correlated with various neuropsychological findings.

Selecting CNS Outcome Measures for DM1

The researchers concluded that muscle weakness interacts with and can potentially compromise the interpretation of data from cognitive assessment tools commonly used in studies of DM1. Moreover, they show that patient-reported assessments are subject to influence of mood and insight. The potential for peripheral physical limitations, mood, and/or insight (i.e., disease awareness) to influence CNS assessments should be considered in the choice of instruments for natural history studies or interventional clinical trials in DM1. Instruments not subject to limitations, or with known limitations that can be controlled for, of mood, basic speed of information processing or manual dexterity or dysarthria may be of greatest value in assessing CNS function in this multi-system disorder.

Reference:

Outcome Measures for Central Nervous System Evaluation in Myotonic Dystrophy Type 1 May Be Confounded by Deficits in Motor Function or Insight.
Hamilton MJ, McLean J, Cumming S, Ballantyne B, McGhie J, Jampana R, Longman C, Evans JJ, Monckton DG, Farrugia ME.
Front Neurol. 2018 Oct 2;9:780. doi: 10.3389/fneur.2018.00780. eCollection 2018.