Neuropsychological deficits, structural brain changes and excessive daytime somnolence in Myotonic dystrophy type 1

Myotonic dystrophy type 1 (DM1) is a dominantly inherited, multisystem condition, arising from pathological expansion of a CTG trinucleotide repeat. DM1 is characterised by myotonia, weakness and wasting of skeletal muscle, with additional features including ocular cataract, cardiac conduction abnormalities, hypogonadism, and cognitive deficits. The phenotype is highly variable, spanning a clinical continuum from symptom onset in late adulthood, to presence of severe symptoms from birth. The CTG repeat expansion responsible for DM1 is unstable in the germline, with a bias towards further expansion on transmission to subsequent generations. Larger repeats are broadly associated with earlier onset and more severe symptoms, accounting for the clinical anticipation of symptoms seen in affected families. The CTG repeat also shows expansion-biased instability in somatic cells, that is individual- and tissue- specific. Symptoms arising from central nervous system (CNS) involvement in DM1, such as cognitive deficits, fatigue, apathy, impaired social functioning and excessive daytime somnolence, are often those with the greatest impact on quality of life. With early clinical trials of potential disease-modifying therapies for DM1 already underway, there is a pressing need to identify valid outcome measures for CNS involvement in order to measure response to treatment. Moreover, improved understanding of the relationship between structural brain changes and clinical symptoms is required to identify new targets for therapeutic intervention, as well as highlight potential imaging biomarkers for disease progression. In this context, we aimed to evaluate the self-reported symptom questionnaires and cognitive tests currently recommended as outcome measures by expert consensus, with regard to their specificity for CNS involvement in DM1. We also aimed to describe the relationship between CTG repeat length and severity of CNS symptoms, in order to consider the validity of genetic measures as a basis for prognostication and patient stratification. By combining our own imaging data with that of a comparable cohort recruited in Iowa, USA, we sought to describe the landscape of volumetric brain changes in a large, case-control cohort with DM1, and to identify the regions in which structural change was most closely driven by CTG repeat length. Finally, we explored the prevalence and clinical correlates of sleep disorders in our well-characterised cohort. Forty-seven individuals with a diagnosis of adult-onset DM1 were recruited from the West of Scotland myotonic dystrophy service. Two were subsequently withdrawn from analysis: one due to an incidental finding of a possible glial neoplasm on MRI, and a second because she was found to carry a CTG repeat expansion within the premutation size range. Twenty age-matched control participants were recruited from patients’ families and the Scottish Health Research Register. For volumetric analysis of MRI brain, our sample was combined with a second cohort recruited in Iowa City, USA, to give a total sample of 79 adults with DM1 and 58 controls. Cognitive evaluation revealed the DM1-affected group performed, on average, less well in the Stroop test, Trail Making Tests, Block Design subtest, FAS oral word association, and in the Edinburgh Cognitive and Behavioural ALS Screen compared with controls. Adjustment of performance in the Stroop colour-word and number-letter switching Trail Making Test for basic reading and motor speed respectively, however, considerably attenuated this difference. This observation suggests primary muscle weakness in DM1 may influence performance in these complex cognitive tests, thus undermining their specificity as measures of CNS involvement. Symptom questionnaires confirmed that DM1-affected participants frequently experienced symptoms of fatigue, excessive daytime somnolence, cognitive difficulties and impaired social performance. Self-reported symptom scores did not correlate with objective measures of brain involvement, such as cognitive performance, questionnaires completed by a proxy or global MRI measures of structural brain change. Instead, self-reported CNS symptoms correlated most closely with symptoms of low mood. Increased self-reporting of low mood and cognitive deficits was more common in participants with milder white matter change on MRI. Together, these findings suggest responses in self-reported symptom questionnaires may be significantly influenced by mood, and confounded by impaired symptom awareness in those with more severe disease. Self-reported CNS symptoms and cognitive performance did not closely correlate with CTG repeat length, measured as estimated progenitor allele length (ePAL). Three individuals were identified in the Scottish cohort as carrying CCG interruptions within their CTG repeat array. Each reported mild muscle symptoms of DM1, but they were not clear outliers with respect to other clinical or imaging measures. Regional MRI analysis was undertaken on a combined Glasgow-Iowa cohort, consisting of 79 adults with DM1 and 58 controls. ICV was reduced in DM1-affected subjects. After correction for ICV, age and sex, significantly reduced volume was observed in whole cerebrum, frontal lobe, parietal grey matter, cerebellar white matter, corpus callosum, putamen, accumbens and thalamus. Hippocampus and amygdala volumes appeared larger relative to ICV in the DM1-affected group. CTG repeat length was inversely correlated with volume of occipital grey matter, putamen and thalamus, and positively associated with volume of cerebellar white matter and amygdala. Several affected structures have plausible associations with deficits observed within the DM1 clinical phenotype. For example, the thalamus plays a role in maintenance of wakefulness, and loss of function has been linked to slowing of cognitive processing. A relative increase in volume of structures implicated in the generation of negative emotions (amygdala), alongside reduced volume of structures involved in emotional modulation and motivation (frontal lobe and accumbens) could be hypothesised to underlie socially avoidant traits seen in DM1. Finally, sleep studies demonstrated altered sleep architecture in DM1, characterised by an increase in slow wave and REM sleep at the expense of stage 2 sleep. Clinically significant sleep-disordered breathing was present in over half of the DM1-affected participants who underwent sleep studies, and was associated with volume loss in frontal and parietal white matter. Risk factors for sleep-disordered breathing included increasing age, male sex, and increasing self-reported muscle weakness and fatigue, although no single clinical measure had strong predictive value. In summary, our findings confirm major involvement of the CNS in adult-onset DM1. Selection of outcome measures for CNS involvement presents a challenge for clinical trial design, since self-reporting of symptoms may be confounded by impaired disease awareness or concomitant depression, and performance in traditional tests of executive cognition may be influenced by primary muscle weakness. As such, identification of objective measures, such as brain imaging biomarkers, is an area of considerable unmet need. To this end, we undertook regional volumetric MRI analysis in the largest case-control cohort reported to date, identifying changes in several regions that were driven by CTG repeat length, and may account for key features of the DM1 phenotype. Further analysis of functional correlations, and longitudinal studies using a variety of imaging modalities is warranted to explore these insights further. With respect to current management of patients with DM1, our data also highlight proactive detection and treatment of sleep-disordered breathing, as well as provision of support to overcome low mood and promote social participation, as readily deliverable strategies to improve the wellbeing of people living with DM1