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To sleep or not to sleep: links with neurodegenerative disease

Turning lamps off before sleeping

Disrupted sleep is a major consequence of Alzheimer’s Disease, but could it also help cause the condition by altering the dynamics of amyloid deposition? And do sleep disorders also play a part in the build-up to clinical Parkinsonism?

The acting out of dream content – the ability to make movements, often violent, that correspond to the imaginings of the sleeping brain – is a curious phenomenon, since in normal circumstances most of our muscles are paralysed during the rapid eye movement (REM) phase.1 For bed partners, dream enactment is a disturbing and sometimes threatening sleep disorder. But to those researching the prodrome to Parkinson’s Disease, it may offer intriguing insights into the early stages of the illness.

REM sleep behaviour disorder (RBD), with dream enactment as its most striking component, is common among patients with recently diagnosed Parkinson’s Disease. A 2017 meta-analysis of eight studies found a 24% prevalence of RBD among new Parkinson’s patients, compared with 3% among controls. 2

“Spousal-arousal” syndrome

But the sleep disorder seems to be part of a cluster of prodromal non-motor features, which include constipation, pain and olfactory dysfunction. Autopsy studies suggest that these manifestations of incipient disease relate to Lewy-type alpha-synucleinopathy which can be seen outside the nigro-striatal pathway well before classical Parkinsonian features are evident. 3

Recently, a multi-centre German group found an unusually high prevalence of alpha-synuclein deposits in dermal nerve fibres of patients with REM behaviour disorder. 4 Such deposits were found in ten of 18 people with RBD (56%), in twenty of 25 patients with early PD (80%), and in none of twenty healthy controls.

On the assumption that RBD represents prodromal Parkinson’s Disease in people with no motor symptoms, dermal alpha-synuclein seems to be a peripheral histopathological marker helpful in identifying people suited to the testing of potentially disease-modifying drugs at an early stage of the disease.

Prodromal features in PD

At the 2016 European Academy of Neurology (EAN) Congress in Copenhagen, delegates heard that people with idiopathic RBD, along with people showing olfactory dysfunction, represent a promising group for research into biomarkers of Parkinson’s Disease. People who have both disturbances of smell and disturbances of sleep at baseline have a high transition rate to Lewy body disease over 2-3 years.

It is likely that many mechanisms are involved in the abnormal regulation of sleep in patients with prodromal and established PD. Noradrenaline dysregulation can be linked to both sleep disturbance and autonomic dysfunction, and abnormally low levels of noradrenaline in several brain areas have been reported. 

Loss of orexin/hypocretin cells in the brain is associated with REM behaviour disorder and daytime somnolence has been linked to low levels of the wake-promoting neuropeptide orexin in ventricular CSF.

Identification of REM sleep disorder may offer opportunities for early intervention.

Amyloid and AD: sleep takes the stage

Extracellular levels of many metabolites accumulate in the brain while we are awake, and levels drop during sleep as they are cleared. Among these CNS proteins is beta amyloid.

So far, poor sleep has not featured among the lifestyle factors associated with risk of dementia. With increasing evidence that sleep disturbance affects the kinetics of amyloid beta production, turnover and clearance, this situation may change.

Researchers at the Washington University School of Medicine, St Louis, Missouri, assayed the cerebrospinal fluid of 77 adults with and without evidence of existing amyloid deposition.5 The concentration of amyloid fluctuated with the sleep-wake cycle, but the presence of amyloid deposition in older adults attenuated this circadian pattern. Less amyloid was cleared.

Along with other degenerative diseases, people with AD often suffer from disrupted diurnal rhythms. In established AD, severe sleep pathology and circadian rhythm disturbance is seen in up to 40% of patients. This contributes to agitation and confusion, diminishes the quality of life of both patients and caregivers, and is a major reason for transfer to an institution. 6

Growing evidence relates disturbed sleep to the dynamics of amyloid deposition

The clearest abnormality is a decrease in REM sleep: periods of REM are shorter and there is less total time spent in this sleep state. Overall, sleep is fragmented and interrupted by long periods of wakefulness. In some AD patients, there is virtual reversal of the sleep-wake cycle.

Sleep disruption in AD is also associated with reduced survival. Part of the reason may be AD-related atrophy of the suprachiasmatic nucleus.

Consequence or cause?

Data from the Washington University Knight Alzheimer’s Research Center, presented at the 2016 EAN Congress, suggested that -- in the preclinical stages of AD prior to any cognitive impairment -- poor sleep quality is associated with amyloid deposition. Such a correlation does not imply causality, of course. But -- speaking at the 2016 EAN Congress -- Sebastiaan Overeem, of the Sleep Medicine Centre of the Eindhoven University of Technology in The Netherlands, argued that we now have growing evidence that the links between AD and poor sleep are bidirectional.

In addition to the human data, work in mice shows that sleep deprivation increases deposition of amyloid plaque in several cortical areas.7

Writing in a 2017 review, Jonathan Cedernaes and colleagues (from Uppsala University, Sweden, and the New York University Langone Medical Center) support the idea of an interplay between the pathogenesis of AD and disruption of sleep/wake cycles that can promote disease development and progression.8

Sleep may be a modifiable risk factor for AD

In part, as discussed above, this interaction is due to the reduced clearance of amyloid from the brain during periods of disrupted sleep. But Cedernaes and colleagues also cite links between sleep disruption and increased neuronal oxidative stress and impaired function of the blood-brain barrier – factors that are also thought to play a part in the natural history of AD.

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

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