Nocturnal Hypoxia and Sleep-Disordered Breathing as Potential Early Biomarkers of Respiratory Progression in Mild ALS

ABSTRACT Background: Early detection of respiratory decline is crucial in amyotrophic lateral sclerosis (ALS). We tested if nocturnal polysomnography (PSG) predicts dyspnea onset in mild ALS patients with preserved daytime function. Methods: In this study, 41 mild ALS patients (ALS Functional Rating Scale-Revised [ALSFRS-R] ≥ 37, sitting forced vital capacity [FVC] ≥80% predicted, no dyspnea) and 41 matched controls underwent baseline assessment, including ALSFRS-R scoring, pulmonary function tests, and overnight PSG. ALS patients were followed for 12 months. Baseline apnea–hypopnea index (AHI) and oxygen saturation (mean SpO 2 , minimum SpO 2 ) were analyzed as continuous predictors and using exploratory thresholds (AHI ≥ 5 events/h, min SpO 2 ≤ 88%, mean SpO 2 ≤ 95%) for dyspnea onset (Dyspnea-ALS-15 [DALS-15] > 0). Results: Compared to controls, ALS patients had significantly higher AHI (p = 0.004) and lower minimum SpO 2 (p = 0.018). The ALSFRS-R orthopnea subscore showed a significant positive correlation with mean and minimum SpO 2 (P < 0.05). Cox regression identified baseline AHI (HR 1.08 per event/h; 95% CI 1.01–1.15, p = 0.028) and minimum SpO 2 (HR 0.94 per %; 95% CI 0.88–0.99, p = 0.033) as independent predictors of dyspnea onset within 12 months. Thresholds AHI ≥ 5 (HR 2.28, p = 0.031) and min SpO 2 ≤ 88% (HR 2.42, p = 0.027) also predicted increased risk. Patients meeting ≥1 threshold (n = 25/37) showed trends toward greater FVC and ALSFRS-R decline. Conclusions: In patients with mild ALS and normal daytime function, specific nocturnal PSG parameters (AHI, minimum SpO 2 ) predicted the risk of dyspnea within 12 months. This longitudinal study provides novel evidence that PSG could identify early respiratory vulnerability in the incipient stage, earlier than conventional FVC-based monitoring, supporting its potential utility in refining early intervention strategies. Validation in larger cohorts is warranted.