Genetic ALS-Progressive Sleep Defects Precede the Onset of Clinical Disease.

Authors

Christina Lang, Simon J Guillot, Antje Knehr, Patrick Weydt, Johannes Dorst, Hayrettin Tumani, Albert C Ludolph, Luc Dupuis, Matei Bolborea

Published in

European journal of neurology. Volume 33. Issue 9. Pages e70755.

Abstract

The onset of amyotrophic lateral sclerosis (ALS) is preceded by non-motor signs detectable many years before motor symptom onset. We recently showed that early ALS patients and presymptomatic carriers of ALS-associated gene mutations display altered sleep macroarchitecture, characterised by increased wakefulness and decreased non-REM sleep, together with altered microarchitecture, particularly reduced slow oscillations and sleep spindles. Here we aimed at determining whether sleep alterations are progressive in premanifest carriers of ALS-associated gene mutations.
This longitudinal observational cohort study included presymptomatic first-degree relatives of ALS patients carrying pathogenic gene mutations (n = 18) and noncarrier family members (n = 3). Sleep macroarchitecture and sleep microarchitecture were assessed using standardised polysomnography and electroencephalographic analyses at baseline and in a follow-up examination after 2.3 ± 1.5 years.
In all carriers, sleep alterations were more severe at follow-up compared to the initial examination, for both macro- and microarchitecture. The progression of sleep alterations was seemingly independent of proximity to motor onset, whether evaluated by increased neurofilament levels or phenoconversion during the study period.
Sleep macro- and microarchitectural abnormalities progressively worsen during the premanifest phase of ALS. These findings suggest that polysomnography-derived sleep measures and their neurochemical correlates may serve as sensitive, noninvasive surrogate biomarkers of disease progression in clinically silent ALS. This could support disease prevention, for example, by the antisense oligonucleotide tofersen in patients carrying SOD1 mutations.

PMID:
42765595
Bibliographic data and abstract were imported from PubMed on 21 Sep 2026.

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