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®) to capture irregular 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® 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 start becoming irregular, especially during day time, with frequent activity bouts that are neither observed in control mice nor in SOD1G93A at a younger age. The increasing irregularities of activity pattern are quantitatively captured by designing a novel digital biomarker, referred to as Regularity Disruption Index (RDI). We show that RDI is a robust measure capable of detecting home cage activity patterns that could be related to rest/sleep-related disturbances during the disease progression. Moreover, the RDI rise during the early symptomatic stage parallels grid hanging and body weight decline. The non-intrusive long-term continuous monitoring of animal activity enabled by DVC® has been instrumental in discovering novel activity patterns potentially correlated, once validated, with sleep and rest disturbances in the SOD1G93A mouse model of the ALS disease.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that affects both central and peripheral nervous system, and it is characterized by the degeneration of upper and lower motor neurons that will result in muscle atrophy, paralysis and death within 2–5 years after diagnosis (Kiernan et al, 2011)
We introduce the use of a novel digital biomarker, referred to as Regularity Disruption Index (RDI), which has been developed to capture irregular animal activity patterns
While the activity of WT mice is very stable across the whole experiment, we observed a clear reduction of nocturnal activity in SOD1G93A cages around 19 weeks of age, corresponding to the fully symptomatic stage in this mutant strain
Summary
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disease that affects both central and peripheral nervous system, and it is characterized by the degeneration of upper and lower motor neurons that will result in muscle atrophy, paralysis and death within 2–5 years after diagnosis (Kiernan et al, 2011). ALS Rest Disturbances Detection with progressive voluntary skeletal muscle weakness and atrophy, symptoms include dysphagia, dysarthria, respiratory dysfunction and sleep disturbances. Sleep disruption is very common in ALS and it is often related to hypoventilation, hypoxia, hypercapnia, restless legs, immobilization, nocturnal cramps, and pain (Lo Coco et al, 2011; Boentert, 2019). Sleep disturbances are very common in other neurodegenerative diseases, as Alzheimer’s, Parkinson’s and have an enormous impact on the quality of life of patients (Iranzo, 2016; Falup-Pecurariu and Diaconu, 2017; Winer et al, 2019). Circadian and sleep dysfunctions are often premorbid and can serve as early diagnostic markers of neurodegeneration
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