MELATONIN timing is altered in early amyotrophic lateral sclerosis (ALS), according to a new prospective study, with a later salivary dim-light melatonin onset (DLMO) linked to faster disease progression, respiratory symptoms, and poorer survival.
Disturbances of sleep and circadian rhythm have increasingly been recognised in patients with ALS, yet endogenous circadian phase timing and its prognostic significance in early disease remained unclear. Salivary DLMO is an objective melatonin-based marker of central circadian phase, and this study has assessed whether it is altered in early ALS and whether it provides prognostic information.
In this prospective longitudinal observational study, 50 patients with ALS within 18 months of symptom onset underwent home-based salivary melatonin sampling under dim-light conditions at six predefined time points around habitual sleep onset. Melatonin profiles were modelled using cubic smoothing splines, and DLMO was defined when the fitted curve first reached 3 pg/ml. Clinical, respiratory and sleep assessments were collected at baseline and after 6 months, when a subgroup repeated saliva sampling. Age- and sex-matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms and survival or tracheostomy were examined using regression and survival analyses.
Compared with controls, patients with ALS had an earlier DLMO (20:24±1:18 versus 20:58±0:50; p=0.028), despite similar habitual sleep onset and chronotype. Within the ALS cohort, a later baseline DLMO correlated with worse functional and motor status, faster disease progression, incident dyspnoea or orthopnoea by 6 months (adjusted odds ratio: 3.11; p=0.019) and poorer survival and tracheostomy-free outcomes. In the resampled subgroup (n=28), DLMO and melatonin-derived metrics did not change over approximately 6 months.
Exploratory Prognostic Biomarker Potential
These findings have indicated that circadian phase alterations are detectable in early ALS, and baseline DLMO has shown exploratory associations with functional, respiratory and survival outcomes. Larger independent cohorts are required before DLMO can be considered a validated prognostic biomarker, and the observational design means that causality cannot be inferred. Until then, DLMO remains an exploratory measure rather than a tool for clinical decisions.
Reference
Bombaci A et al. Salivary dim-light melatonin onset is associated with functional decline, respiratory symptom emergence, and survival in early amyotrophic lateral sclerosis. Ann Neurol. 2026;DOI:10.5281/zenodo.21745838.
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