In people with Parkinson's disease, dementia with Lewy bodies, and even other neurodegenerative diseases, slower, deeper sleep is associated with better cognitive performance and slower motor progression over time.
Yet, these patients have very serious sleep problems. They often take a nap intermittently, which fails to address the phase of deeper, more restorative slow wave sleep in which waste disposal speeds up in the brain as demonstrated in several previous studies.
More recently, scientists have begun to understand that slow wave sleep abnormalities also affect people with Parkinson's disease (Schreiner et al., 2021). Could their slow wave sleep disruption be similarly related, to the major protein aggregates of PD and their clearance?
The main finding of a new study is indeed that the modulation of slow waves in sleep influences neuropathological outcomes in two different mouse models of synucleinopathy. http://www.ncbi.nlm.nih.gov/pubmed/34878820
The study showed less synuclein buildup after improving slow waves with sodium oxybate compared to placebo, while sleep deprivation had the opposite effect.
The scientists used mice deficient in the vesicular monoamine transporter of dopamine transport protein 2 (VMAT2). Without VMAT2, dopamine builds up and damages neurons, causing α-synuclein aggregation, loss of motor function. and sleep disturbances.
They implanted an electroencephalography / electromyography machine in the skulls of young mice to track their sleep over 24 hours. Animals deficient in VMAT2 actually spent more time awake, with less REM and non-REM sleep, than their wild-type siblings.
What about old mice? As the aged mice deficient in VMAT2 did not tolerate the EEG / EMG implantation procedure, the scientists were therefore unable to analyze their sleep. Instead, they did it on 14 month old wild type mice.
They either sedated them with sodium oxybate, a narcolepsy drug, or kept them awake by placing them on a small platform over water for 16 hours. During 24 hours of EEG / EMG recording in each condition, mice that took sodium oxybate had slower waves during non-REM sleep, while sleep-deprived animals had shallower waves and less depth. more fragmented non-REM sleep.
Well-rested mice had less phosphorylated synuclein and less aggregates than controls, while the reverse was true in sleepless mice.
In addition, the researchers gave sodium oxybate to 5.5-month-old A53T mice (another animal model of Parkinson), which carry mutant human α-synuclein and develop Lewy body-like synuclein aggregates.
The drug increased clearance of α-synuclein aggregates so well that the western spots of their mesencephalic tissue almost looked like wild-type ones. "I thought it was fascinating that sleep so drastically alters the pathology in mice genetically intended to accumulate synuclein," Schreiner said.
Morawska et al. have also added a sleep deprivation arm using the platform over water method. They found that, in general, sleep deprivation increased synuclein aggregation, while improvement in SWS reduced it. However, it is difficult to directly compare the methods of sleep deprivation and improvement, as one is pharmacological (oxybate) and the other behavioral, and potentially stressful.
These results are consistent with previous studies on the link between slow sleep and pathological protein accumulation in Alzheimer's disease and imply that similar mechanisms may be present in synucleinopathies such as Parkinson's disease.
The present study is exciting because it provides more rationale to further explore the role and therapeutic potential of sleep, particularly slow-wave sleep, in clinical populations with neurodegenerative disorders, including synucleinopathies.
This is of interest because there are highly specific pharmacological and emerging non-pharmacological methods to improve sleep on the in humans.
Even so, the change in sleep in mice may not translate directly to humans, as humans and rodents have different stages of sleep (Matsumoto & Tsunematsu, 2021). Scientists are also uncertain whether sodium oxybate affects the neuropathology of people with Parkinson's disease.
It is a paper that complements for synucleinopathies what previous articles by Kang and colleagues (Kang et al., 2009) and Holth and colleagues (Holth et al., 2019) have done for amyloid and protein tau, respectively.
It is likely that for an intervention to be effective in patients, it will need to be given over the long term, and possibly to neurologically asymptomatic patients, and it is not certain whether sodium oxybate will work given the its propensity to cause side effects in the elderly adults.
In addition, we lack excellent biomarker readings for the burden of synuclein pathology in humans, so hampering clinical trials.
In their next study the researchers will use auditory stimulation by playing certain tones during slow sleep to try to specifically improve or decrease these brain waves in mouse models of Alzheimer's and Parkinson's disease.