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

BackgroundSleep-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. MethodsIn 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. ResultsFifty plwALS were enrolled. Compared with controls, plwALS showed an earlier DLMO (20:24{+/-}1:18 vs 20:58{+/-}0:50; 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. ConclusionsCircadian 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. Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSSleep and circadian disturbances are increasingly recognised as early, biologically relevant non-motor features of amyotrophic lateral sclerosis (ALS), and recent translational and neuroimaging studies support early involvement of sleep-regulatory and hypothalamic networks. Dim-light melatonin onset (DLMO) is an established objective marker of central circadian phase, but endogenous melatonin timing in ALS and its prognostic relevance have not been previously defined. What this study addsIn a prospective cohort of patients with early-ALS, salivary DLMO was altered relative to matched controls, and within the ALS cohort a later baseline DLMO was associated with worse functional and motor status, faster subsequent progression, incident respiratory symptoms at 6 months, and poorer survival/tracheostomy-free outcome. These findings identify circadian phase timing as a clinically informative signal in early-ALS. How this study might affect research, practice or policyIf validated, DLMO could complement established prognostic tools in early-ALS and support enrichment of phase-aware clinical trials. They also provide a rationale for phase-aware longitudinal studies integrating circadian phenotyping, respiratory, imaging, and plasmatic biomarker and for testing whether interventions targeting circadian alignment can improve symptoms or clinical trajectories in selected patients with ALS.