REM Sleep Behaviour Disorder in Prodromal Parkinson’s Disease

By Michelle Lam

Rapid eye movement (REM) sleep occurs 90 minutes after sleep onset and is characterised by muscle twitches, cortical activity resembling the wakeful brain and muscle atonia (temporal muscle paralysis). The most well-understood region of the brain generating muscle atonia during REM sleep is the sublateraldorsal (SLD) nucleus in the pontine tegmentum. The ventral area of the SLD contains a population of glutamatergic neurons that activate inhibitory neurons in the spinal cord and ventral medulla to trigger muscle atonia (Peever et al., 2017). REM sleep without atonia is a hallmark of REM sleep behaviour disorder (RBD). RBD leads to dream enactment and generation of large motor activity during REM sleep, often resulting in injuries to the affected individual or those around them (St. Louis et al., 2017). The parasomnia can be broadly divided into two categories: idiopathic RBD, where RBD is present on its own; and symptomatic RBD, in which RBD occurs in tandem with other neurological disorders (Liguori et al., 2019). Studies have shown that 80% of patients with RBD will develop a synucleinopathy within 6-15 years of diagnosis (Peever et al., 2017), and that 81% of idiopathic RBD patients developed parkinsonism after a 16-year follow-up from initial diagnosis (Schenck et al., 2012). Therefore, idiopathic RBD has been named a non-motor symptom of synucleinopathies.

Parkinson’s disease (PD) is a synucleinopathy, a genre of neurodegenerative disorders involving the accumulation of Lewy bodies, predominately comprising the α-synuclein protein, in the nervous system. The pathophysiology of PD also involves the progressive deterioration of dopaminergic neurons located in the substantia nigra of the midbrain (Capriotti et al., 2016). As a consequence, chemical disparity of dopamine and acetylcholine is established in the extrapyramidal tract of the midbrain, causing the bradykinesia (slow movements), uncontrollable tremors, freezing of gait, and dysphagia (swallowing difficulties) seen in PD patients (Reich et al., 2019). 

The pathogenesis of PD can be divided into two stages: the prodromal phase and the disease phase. In the prodromal phase, dopaminergic degeneration has started, but the individual does not display any motor dysfunctions. This is thought to last at least 20 years, with RBD occurring around 10 years before clinical diagnosis. In the disease stage, the individual will start to develop motor symptoms and can be diagnosed with PD. Bradykinesia and tremors are usually the motor dysfunctions observed first in the disease stage, followed by dysphagia and freezing of gait in the more advanced stages of PD (Kalia et al., 2015).

The current best model of Lewy body accumulation in PD is the spread of α-synuclein aggregates from the peripheral-to-central nervous system, proposed by Heiko Braak. These aggregates originate from a mutated α-synuclein protein, which acts as a template for other α-synuclein proteins to misfold in the same manner. They are then transferred from one cell to the next through connected neuronal pathways (Uchihara et al., 2015). The α-synuclein aggregates initially form in the olfactory bulb and the lining of the gastrointestinal tract. Following this, the misfolded proteins will advance into the dorsal motor nucleus of the vagus nerve and intermediolateral cell columns of the sympathetic system through the autonomic nervous system (Braak et al., 2003). In fact, phosphorylated α-synuclein aggregates have been detected in the colon and sympathetic chain of idiopathic RBD patients, thus providing evidence that idiopathic RBD is a sign of early parkinsonism. As mentioned prior, the SLD nucleus of the pons and the magnocellular nucleus of the medulla are two regions known to regulate muscle atonia during REM sleep. Since both structures are near to the locus coeruleus (one of the affected regions in stage 2 of Braak’s model), it has been hypothesised that patients suffering from idiopathic RBD would possess Lewy body inclusions in the locus coeruleus and peripheral autonomic nerves, which supports Braak’s staging hypothesis of PD (Knudsen et al., 2018).

If RBD can be considered a feature of PD during the prodromal stage, this poses the question: how important is an early diagnosis in PD treatment? Currently, diagnostic criteria are used to diagnose PD. Most of this is reliant on motor dysfunctions; however, by the time these are detectable, at least half of the dopaminergic neurons in the midbrain have degraded and cannot be restored (Chen et al., 2019). The diagnostic error rate of early PD with practitioners that have little experience can be as high as 25%, so a suitable hallmark, such as RBD, would be beneficial in increasing this accuracy. Earlier diagnosis and treatment could also delay the deterioration of dopaminergic neurons and these treatments could be observed to determine whether they exert a neuroprotective effect, before motor dysfunctions are seen (Miller et al., 2015). Such treatments are called disease-modifying therapies. Despite there being multiple clinical trials performed in the last few decades, there are currently no disease-modifying therapies for PD. One of the main challenges of designing a disease-modifying therapeutic for PD is the difficulty in prodromal diagnosis. PD pathogenesis is usually too advanced, even in patients who are in the very earliest stages of the disease phase, so disease-modifying therapeutics would provide little benefit by this point (Paoletti et al., 2020). 

It should be noted that patients have also developed RBD after PD diagnosis. The heterogenic nature of PD is another challenge in designing an effective disease-modifying therapeutic. Phenotypic screening showed that patients with idiopathic RBD had increased rigidity, gait disorders and increased cognitive impairment compared with the symptomatic RBD patients (Högl et al., 2017). Further phenotypic screening could be performed to provide more evidence of the clinical phenotypes of idiopathic RBD patients that exhibit parkinsonism in later life.

Currently, therapeutics for PD address symptoms rather than delay the pathophysiological processes underlying PD. Consequently, recent developments in research have shifted from targeting the dopaminergic system to regions of the nervous system involved in Braak’s model of α-synuclein aggregate propagation (Ortel, 2017). Despite this, inaccurate prodromal PD diagnosis, the heterogeneity of PD, and lack of biomarkers for monitoring therapeutic effects present challenges in designing disease-modifying therapies for PD (Paoletti et al., 2020). The prevalence of idiopathic RBD amongst PD patients is useful in diagnosing prodromal PD by providing a diagnostic criterion. Hence, further studies could be conducted to investigate idiopathic RBD as a pre-motor symptom of PD to potentially aid in the advancement of designing a successful disease-modifying therapy.


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