Sleep abnormalities are associated with greater cognitive deficits and disease activity in Huntington's disease: a...

Increasing evidence suggests that the sleep pathology associated with neurodegenerative diseases can in turn exacerbate both the cognitive deficits and underlying pathobiology of these conditions. Treating sleep may therefore bear significant, even disease-modifying, potential for these conditions, but how best and when to do so remains undetermined. Huntington's disease, by virtue of being an autosomal dominant neurodegenerative disease presenting in mid-life, presents a key 'model' condition through which to advance this field. To date, however, there has been no clinical longitudinal study of sleep abnormalities in Huntington's disease and no robust interrogation of their association with disease onset, cognitive deficits and markers of disease activity. Here, we present the first such study. Huntington's disease gene carriers (n = 28) and age- and sex-matched controls (n = 21) were studied at baseline and 10- and 12-year follow-up. All Huntington's disease gene carriers were premanifest at baseline and were stratified at follow-up into 'prodromal/manifest' versus 'premanifest' groups. Objective sleep abnormalities were assessed through two-night inpatient polysomnography and 2-week domiciliary actigraphy, and their association was explored against Montreal Cognitive Assessment, Trail A/B task, Symbol Digit Modalities Task (SDMT), Hopkins Verbal Learning Task (HVLT) and Montgomery-Asberg Depression Rating Scale (MADRS) scores, plus serum neurofilament light levels. Statistical analysis incorporated cross-sectional ANOVA, longitudinal repeated measures linear models and regressions adjusted for multiple confounders including disease stage. Fifteen Huntington's disease gene carriers phenoconverted to prodromal/early manifest Huntington's disease by study completion. At follow-up, these gene carriers showed more frequent sleep stage changes (P ≤ 0.001, η_p ² = 0.62) and higher levels of sleep maintenance insomnia (defined by wake after sleep onset, P = 0.002, η_p ² = 0.52). The latter finding was corroborated by nocturnal motor activity patterns on follow-up actigraphy (P = 0.004, η_p ² = 0.32). Greater sleep maintenance insomnia was associated with greater cognitive deficits (Trail A P ≤ 0.001, R ² = 0.78; SDMT P = 0.008, R ² = 0.63; Trail B P = 0.013, R ² = 0.60) and higher levels of neurofilament light (P = 0.015, R ² = 0.39). Longitudinal modelling suggested that sleep stage instability accrues from the early premanifest phase, whereas sleep maintenance insomnia emerges closer to phenoconversion. Baseline sleep stage instability was able to discriminate those who phenoconverted within the study period from those who remained premanifest (area under curve = 0.81, P = 0.024). These results demonstrate that the key sleep abnormalities of premanifest/early Huntington's disease are sleep stage instability and sleep maintenance insomnia and suggest that the former bears value in predicting disease onset, while the latter is associated with greater disease activity and cognitive deficits. Intervention studies to interrogate causation within this association could not only benefit patients with Huntington's disease but also help provide fundamental proof-of-concept findings for the wider sleep-neurodegeneration field.