The current paper is about an untested hypothesis. Scientists have proposed thousands of assumptions about the etiology of ALS, and the same is true for many other diseases. Single-authored papers are often dismissed, as are papers that make wild hypotheses without trying to test them. I mention this paper because the single author is a remarkable scientist in the field, not one of the countless hacks who write a paper on ALS today with very little knowledge of the disease and will never write about it again.
Another reason might be because it may have some relation with a drug developed by Richard B. Silverman, and P. Hande Ozdinler at Northwestern University. AKAVA Therapeutics, started last year by Silverman, is carrying out studies of the drug AKV9 (ex NU-9).
This article discusses the possible relationship between sleep, the glymphatic system, and neurodegenerative diseases. It suggests that sleep issues might exacerbate ALS disease progression by impairing the brain's waste-clearance mechanisms and compromising neuronal health, but it does not describe any experiment. It also tells that neuron health is diminished when the organism is sleep-deprived, in particular neurons experience dendritic spine loss.
Sleep is crucial for brain health because the clearance of metabolic waste and the remodeling of synapses happens during sleep. Many ALS and Parkinson's patients experience sleep disturbances. Disrupted sleep patterns, especially those associated with conditions like sleep apnea, a condition where upper airways collapse during sleep, can lead to impaired glymphatic function. The author equals poor glymphatic function with accumulation of agglomerates of misfolded proteins in cellular cytosol. I am not sure there is any evidence of this relation.
The glymphatic system is responsible for clearing waste products from the brain, primarily during sleep. It is facilitated by cerebrospinal fluid (CSF) circulation. During sleep, the glymphatic system operates optimally, removing waste products from the brain. Impaired glymphatic clearance, especially when sleep is disrupted, might be a significant contributor to protein buildup and possibly subsequent neurodegeneration.
Evidence from studies shows a faster CSF clearance during sleep, suggesting that adequate sleep is crucial for maintaining brain health. Dysfunction of this system can contribute to the accumulation of toxic proteins, such as amyloid-beta and tau, associated with neurodegenerative diseases. Yet this clearance happens in the periphery of the brain, so it's hard to see how a good clearance would improve the health of those neurons that are deep inside the brain.
Early signs of neurodegeneration in ALS include the loss of dendritic spines. A dendritic spine is a small membrane protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Motor neurons in the spinal cord, for example, can have a dense arrangement of dendritic spines in certain regions, as these neurons need to process a large number of excitatory and inhibitory signals to regulate muscle activity effectively. Sleep plays a vital role in spine pruning and remodeling, ensuring healthy neuronal connectivity.
Synaptic connections, especially dendritic spines, are dynamic and undergo constant remodeling, particularly during sleep. This process is crucial for maintaining neuronal network stability and function. Sleep deprivation or sleep apnea disrupts spine pruning, leading to excessive or unhealthy connections, which stresses neurons and hampers brain connectivity. Experiments show that even brief sleep deprivation reduces spine elimination, resulting in abnormal spine density and neuronal hyperactivity in brain areas like the hippocampus. This disruption may have a profound impact on memory and cognitive function.
Therefore investigating the relationship between sleep, glymphatic function, and biomarkers in CSF could lead to earlier diagnosis and more effective disease monitoring.
Yet, sleep is not routinely assessed in clinical diagnostics for neurodegeneration. Integrating sleep studies into patient assessments could enhance diagnostic precision and enable targeted interventions. Moreover, understanding the molecular changes in CSF associated with sleep problems could provide valuable biomarkers for monitoring disease progression. There’s potential for developing therapies focused on improving sleep quality, as addressing hypoxia and improving glymphatic function might reduce protein buildup and protect against neuronal damage.