Salivary dim-light melatonin onset in early Amyotrophic Lateral Sclerosis predicts functional decline, respiratory symptom emergence, and survival

Background: Sleep wake and circadian disturbances are increasingly recognised in people living with amyotrophic lateral sclerosis (plwALS), but endogenous circadian phase timing and its prognostic significance in early disease remain unclear. We assessed whether salivary dim-light melatonin onset (DLMO), an objective marker of central circadian phase, is altered in early plwALS and whether it provides prognostic information. Methods: In this prospective longitudinal observational study, plwALS 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 (HSO). Melatonin profiles were modeled using cubic smoothing splines, and DLMO was defined as the first time the fitted curve reached 3 pg/mL. Clinical, respiratory, and sleep assessments were collected at baseline (T0) and after 6 months (T6); a subgroup repeated saliva sampling at T6. Age and sex matched controls underwent melatonin profiling. Associations with disease progression, incident respiratory symptoms, and survival/tracheostomy were examined using regressions and survival analyses. Results: Fifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24 vs 20:58; p=0.028) despite similar HSO and chronotype. Within ALS cohort, a later baseline DLMO correlated with worse functional/motor status, faster progression of disease, incident dyspnea/orthopnea by T6 (adjusted OR 3.02; p=0.017), and poorer survival/tracheostomy-free outcome. In re-sampled subgroup (n=28), DLMO and other melatonin-derived metrics did not change over 6 months. Conclusions: Circadian phase alterations are detectable in early ALS. Baseline DLMO may represent a non-invasive prognostic biomarker for progression, respiratory symptom emergence and survival, warranting validation in larger multicentre cohorts.