A non-invasive digital biomarker for the detection of rest disturbances in the SOD1G93A mouse model of ALS

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that affects both central and peripheral nervous system, leading to the degeneration of motor neurons, which eventually results in muscle atrophy, paralysis and death. Sleep disturbances are common in patients with ALS, leading to even further deteriorated quality of life. Investigating methods to potentially assess sleep and rest disturbances in animal models of ALS is thus of crucial interest. We used an automated home cage monitoring system (DVC(R)) to capture activity patterns that can potentially be associated with sleep and rest disturbances and thus to the progression of ALS in the SOD1G93A mouse model. DVC(R) enables non-intrusive 24/7 long term animal activity monitoring, which we assessed together with body weight decline and neuromuscular function deterioration measured by grid hanging and grip strength tests in male and female mice from 7 until 24 weeks of age. We show that as the ALS progresses over time in SOD1G93A mice, activity patterns during day time start becoming irregular, with frequent activity bouts that are neither observed in control mice nor in SOD1G93A at a younger age. The increasing irregularities of activity patterns during day time are quantitatively captured by designing a novel digital biomarker, referred to as Rest Disturbance Index (RDI). We show that RDI is a robust measure capable of detecting rest/sleep-related disturbances during the disease progression earlier than conventional methods, such as the grid hanging test. Moreover RDI highly correlates with grid hanging and body weight decline, especially in males. The non-intrusive long-term continuous monitoring of animal activity enabled by DVC(R) has been instrumental in discovering activity patterns potentially correlated with sleep and rest disturbances in the SOD1G93A mouse model of the ALS disease.