Cognitive impairment is a characteristic feature of adult-onset myotonic dystrophy type 1 (DM1). While some progress has been made in understanding the molecular mechanisms underlying the CNS changes, it has been more difficult to assess DM1-associated cognitive deficits. Barriers to clarifying the patient cognitive profile include disease heterogeneity, difficulties in assembling a sufficiently powered cohort, uncertainty about optimal endpoint selection, and the little information available on the temporal window required to detect meaningful change. Key unresolved questions in DM1 include (a) is the cognitive impairment stable or progressive and (b) if progressive, is impairment restricted to specific functional domains or is there a more global pattern of decline?

The prominence of neuromuscular symptoms, and the accessibility of muscle for molecular, cellular, and functional evaluations, has focused DM1 therapy development on skeletal muscle endpoints. Yet pharmaceutical and biotechnology companies are now recognizing that cognitive changes represent substantial burden of disease, and thus are essential endpoints for patient-focused drug development. Just as was the case for skeletal muscle-focused efforts, a better understanding of the nature, variability, and progression of cognitive impairment in DM1 is needed to facilitate clinical assessment of CNS-targeted candidate therapies and improved patient care.

Cognitive Longitudinal Study

Dr. Benjamin Gallais, a Wyck Foundation/MDF Postdoctoral Research Fellowship recipient, and his colleagues at the University of Sherbrooke and University of Quebec at Chicoutimi have reported a 9-year longitudinal natural history study of cognitive function in a cohort of genetically confirmed, adult- (90 subjects) and late-onset (25 subjects) DM1 patients. The study assessed a battery of neuropsychological tests, including cognition (language, memory, visual attention, processing speed, visuoconstructive abilities, and executive functions) and intellect (WAIS-R 7) at two time points. Careful steps were taken to avoid or minimize unintended bias from subject selection, subjects lost to follow-up, and data collection and analysis.

The overall group of adult- and late-onset DM1 subjects showed major (significant in ≥ 2/3 of subjects) declines over the study period in verbal memory, visual attention, and processing speed, while improvement was noted in verbal fluencies and global intelligence. In addition, the percentage of all subjects with cognitive impairment increased between the initial and final evaluations. Both age and duration of disease at time of study entry negatively correlated with all cognitive domains studied. By contrast, the number of CTG repeats, degree of skeletal muscle impairment (MIRS), and education level all poorly correlated with cognitive and intellect scores. Finally, the rate of cognitive decline over the 9-year period was higher in late- than adult-onset subjects, although overall cognitive performance level at study end was worse for the adult-onset group.

Study Results

Gallais and colleagues concluded that cognitive impairment in adult- and late-onset DM1 is prevalent, moderate in severity, progressive, and global in the range of functions impacted. They suggest that the CNS phenotype seen in this DM1 cohort can be interpreted, at least in part, as an acceleration of normal aging, a hypothesis they support with reference to neuronal accumulation of a neurodegenerative protein (tau), white matter changes, and occurrence of aging-linked signs and symptoms in other organ systems (e.g., cataracts, baldness, erectile dysfunction, and endocrine dysfunction) in DM1.

These findings are important from the perspectives of size of and care in cohort selection, thoroughness of evaluations, and length of study. A caveat is that two time points, 9 years apart, do not provide sufficient resolution of the natural history of CNS impairment to guide clinical trial design. The authors do indicate that the study is continuing with shorter intervals between assessments. While recognizing the value that CNS imaging would have added, the authors note the challenges of including MRI measures in studies of cohorts that are adequately powered for neuropsychological assessments.

The lessons learned here must not be lost, but rather used to impact subsequent natural history studies of cognitive function in DM1. Taken together, the results from this study better characterize the disease and represent an important step forward for the design and selection of DM1 clinical trial endpoints to assess cognition, as well as for further guidance in recognizing and managing cognitive symptoms in patients with adult- and late-onset DM1.

Reference:

Cognitive Decline Over Time in Adults with Myotonic Dystrophy Type 1: A 9-year Longitudinal Study.
Gallais B, Gagnon C, Mathieu J, Richer L.
Neuromuscul Disord. 2016 Oct 14. pii: S0960-8966(16)30846-X. doi: 10.1016/j.nmd.2016.10.003. [Epub ahead of print]