The Gap in Natural History Data
Cognitive impairment is a substantial unmet need in DM1. Increasingly, drug companies are aware that targeting therapies to the brain will be essential to addressing the overall burden of disease. Yet, therapy development efforts in other types of muscular dystrophy tell us that it is critical to understand disease natural history in order to facilitate efficient and effective clinical trials. Many of the studies to date that have characterized neuropsychological function in DM1 are both limited in scope and underpowered. As a consequence, it currently is unclear whether DM1 is characterized by a global pattern of cognitive deficits or whether specific functions are affected. The key question is—how do we best utilize available resources to construct a natural history of cognitive dysfunction in DM1 that is sufficient to support interventional trial outcome measure selection and to improve patient care?
A Path Forward Through Meta-Analysis
Kees Okkersen and colleagues at Radboud University Medical Center and the University of Amsterdam recently characterized the cognitive profile of DM1 patients through a meta-analysis of psychological data from 40 eligible studies identified in Embase, Medline, and PsychInfo (totaling 1122 patients and 952 controls). Eligible studies employed a large battery of neuropsychological tests. The analytic approach was to characterize the individual cognitive tests as informative of specific cognitive domains and then determine the level of effect from meta-data across each of 12 cognitive domains.
Although effect size varied, performance of DM1 subjects versus controls was impaired across all cognitive domains. Domains most heavily impacted by DM1 included global cognition, intelligence, visual memory, visuospatial perception, visuoconstruction, psychomotor speed, and social cognition. Analyses suggested that conclusions from the pooled data were not influenced by either publication bias or any inordinate impact of single studies.
Current Status of Understanding DM1 Cognitive Profiles
While the research team concluded, based on meta-analysis of a large cohort and the preponderance of evidence, that DM1 is characterized by significant deficits across all cognitive domains, they noted that heterogeneity is the hallmark of this patient group. Detection of a large effect size in any specific cognitive domain could either be due to consistent deficits across DM1 patients, substantial involvement of the specific domain among a subset of patients, or acute sensitivity of the neuropsychological tests that inform that domain. A recent meta-analysis of neuroimaging studies in DM1 validated a similar pattern of widespread and heterogeneous involvement in CNS.
While some of the neuropsychological tests assessed by the research team showed substantial levels of effect and consistency (e.g., Rey-Osterrieth Complex Figure, Wechsler Digit Symbol Coding, and Raven Progressive Matrices), these tests readout on multiple cognitive functions. The research team argued that future studies should include specific, rather than broad, cognitive assessments, and concluded that meta-analyses of the often small cohorts in individual DM1 studies can better elucidate CNS mechanisms as well as inform best practices for future patient assessment.
Okkersen K, Buskes M, Groenewoud J, Kessels RPC, Knoop H, van Engelen B, Raaphorst J.
Cortex. 2017 Aug 16;95:143-155. doi: 10.1016/j.cortex.2017.08.008. [Epub ahead of print] Review.