Mechanisms and Therapeutic Exploration of Early Sleep Abnormalities in Patients with Amyotrophic Lateral Sclerosis

Academic Background

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by the degeneration of motor neurons, leading to progressive muscle weakness and respiratory failure. Although the primary symptoms of ALS are motor dysfunctions, recent studies have shown that ALS patients also exhibit various non-motor symptoms, including sleep disturbances. However, research on sleep abnormalities in ALS patients remains limited, particularly regarding whether these abnormalities precede motor symptoms and their underlying mechanisms. Therefore, investigating the characteristics and neural mechanisms of early sleep abnormalities in ALS patients is crucial for understanding the disease’s pathogenesis and developing new therapeutic strategies.

The background of this study further highlights the potential dysfunction of the hypothalamus in ALS patients. The hypothalamus is a key brain region regulating sleep, appetite, and energy balance. Previous studies have shown that ALS patients exhibit hypothalamic atrophy and pathological changes. Specifically, two types of neurons in the hypothalamus—melanin-concentrating hormone (MCH) neurons and orexin (Orx) neurons—play essential roles in sleep regulation. Investigating the role of these neurons in ALS may provide new insights into the sleep abnormalities observed in the disease.

Source of the Paper

This paper was co-authored by Simon J. Guillot, Christina Lang, and others, with the research team hailing from multiple institutions, including the University of Strasbourg in France and the Department of Neurology at the University of Ulm in Germany. The paper was published on January 29, 2025, in Science Translational Medicine, titled “Early-onset sleep alterations found in patients with amyotrophic lateral sclerosis are ameliorated by orexin antagonist in mouse models.”

Research Process and Results

Research Process

1. Analysis of Sleep Architecture in ALS Patients and Asymptomatic Gene Carriers
   The study first analyzed the sleep architecture of 56 early-stage ALS patients and 41 healthy controls using polysomnography. Similar studies were conducted on 62 ALS gene mutation carriers (including C9orf72 and SOD1 mutations). To eliminate the impact of respiratory insufficiency on sleep architecture, researchers excluded patients with nocturnal hypercapnia using transcutaneous capnometry. Sleep data were analyzed using the YASA deep learning algorithm and manually scored according to the American Academy of Sleep Medicine (AASM) standards.

2. Study of Sleep Abnormalities in ALS Mouse Models
   To validate the findings from human studies, researchers conducted similar sleep studies in three ALS mouse models (SOD1G86R, FUSΔNLS/+, and TDP43Q331K). Mice were implanted with electroencephalography (EEG) electrodes in adulthood, and sleep monitoring was performed 5–6 days post-surgery. Sleep states were automatically analyzed using Neuroscore software.

3. Intervention Experiments on MCH and Orexin Signaling Pathways
   Researchers observed the effects of interventions on sleep patterns in mice by administering a single oral dose of an orexin receptor antagonist (Suvorexant) or continuous intracerebroventricular infusion of MCH via a pump for 15 days. Additionally, the impact of MCH treatment on motor neuron survival in SOD1G86R mice was assessed.

Key Findings

1. Sleep Abnormalities in ALS Patients and Gene Carriers
   The study found that both early-stage ALS patients and asymptomatic C9orf72 and SOD1 mutation carriers exhibited increased wakefulness and reduced non-REM sleep. The sleep abnormalities in C9orf72 mutation carriers were more similar to those in ALS patients, while SOD1 mutation carriers showed milder sleep disturbances.

2. Sleep Abnormalities in ALS Mouse Models
   In SOD1G86R mice, researchers observed increased wakefulness and decreased non-REM and REM sleep before the onset of motor symptoms (at 75 days). Similar phenomena were also observed in FUSΔNLS/+ and TDP43Q331K mice.

3. Effects of MCH and Orexin Interventions
   MCH treatment partially improved sleep abnormalities in ALS mice, particularly by increasing REM sleep and reducing wakefulness. However, MCH treatment did not extend the survival of SOD1G86R mice but reduced the loss of lumbar motor neurons. In contrast, the orexin receptor antagonist Suvorexant fully restored sleep abnormalities in all three ALS mouse models.

Conclusions and Significance

The study concludes that sleep abnormalities in ALS patients can occur early in the disease and are closely related to dysregulation of the hypothalamic MCH and orexin signaling pathways. By validating these findings in mouse models, the researchers further elucidated the potential therapeutic value of targeting these pathways in ALS-related sleep abnormalities. Notably, the orexin receptor antagonist Suvorexant effectively improved sleep abnormalities in ALS mice, providing a new approach for developing treatments for sleep disorders in ALS patients.

Research Highlights

1. Discovery of Early Sleep Abnormalities
   This study is the first to systematically reveal sleep abnormalities in ALS patients and asymptomatic gene carriers at early stages of the disease, providing critical insights into the non-motor symptoms of ALS.

2. Exploration of MCH and Orexin Signaling Pathways
   Through experimental validation, the study identified the key roles of MCH and orexin signaling pathways in ALS-related sleep abnormalities, offering potential therapeutic targets.

3. Therapeutic Potential of Orexin Receptor Antagonists
   The significant effects of Suvorexant in ALS mouse models suggest that orexin receptor antagonists could be an effective treatment for sleep disturbances in ALS patients.

Value and Significance

This study not only deepens the understanding of early sleep abnormalities in ALS patients but also provides a theoretical foundation for developing new therapeutic approaches. Additionally, it emphasizes the potential importance of early sleep interventions in ALS, which may delay disease progression and improve patients’ quality of life. Future clinical studies are expected to validate these findings in human patients, offering new hope for ALS patients.