# Rapid eye movement sleep behaviour disorder: Past, present, and future

Birgit Högl, Isabelle Arnulf, Melanie Bergmann, Matteo Cesari, Ziv Gan-Or, Anna Heidbreder, Alex Iranzo, Lynne Krohn, Pierre-Hervé Luppi, Brit Mollenhauer, et al.

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► To cite this version:

Birgit Högl, Isabelle Arnulf, Melanie Bergmann, Matteo Cesari, Ziv Gan-Or, et al. Rapid eye movement sleep behaviour disorder: Past, present, and future. Journal of Sleep Research, 2022, 31 (4), pp.e13612. 10.1111/jsr.13612. hal-03763546

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# Rapid eye movement sleep behaviour disorder: Past, present, and future

Birgit Högl<fnref n="1" /> ID | Isabelle Arnulf<fnref n="2" />,<fnref n="3" /> ID | Melanie Bergmann<fnref n="1" /> | Matteo Cesari<fnref n="1" /> ID |

Ziv Gan-Or<fnref n="4" />,<fnref n="5" />,<fnref n="6" /> | Anna Heidbreder<fnref n="1" /> ID | Alex Iranzo<fnref n="7" /> | Lynne Krohn<fnref n="4" />,<fnref n="5" />,<fnref n="6" /> |

Pierre-Hervé Luppi<fnref n="8" />,<fnref n="9" /> | Brit Mollenhauer<fnref n="10" />,<fnref n="11" /> | Federica Provini<fnref n="12" />,<fnref n="13" /> ID |

Joan Santamaria<fnref n="7" /> | Claudia Trenkwalder<fnref n="11" />,<fnref n="14" /> | Aleksandar Videnovic<fnref n="15" /> |

Ambra Stefani<fnref n="1" /> ID

**Correspondence**

Birgit Högl, Department of Neurology, Medical
University of Innsbruck, Austria.
Email: birgit.ho@i-med.ac.at

**Funding information**

No funding was received for this manuscript.

**Summary**

This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.

**KEYWORDS**

alpha-synuclein, dream enactment, RBD, REM sleep without atonia, REM-parasomnia, RWA

This is an open access article under the terms of the [Creative Commons Attribution License](https://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2022 The Authors. *Journal of Sleep Research* published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.

<footnote n="1">¹Department of Neurology, Innsbruck Medical University, Innsbruck, Austria</footnote>

<footnote n="2">²Service des Pathologies du Sommeil, Hôpital Pitié-Salpêtrière, Paris, France</footnote>

<footnote n="3">³Faculty of Medicine, Sorbonne University, Paris, France</footnote>

<footnote n="4">⁴Montreal Neurological Institute and Hospital, McGill University, Montréal, Québec, Canada</footnote>

<footnote n="5">⁵Department of Neurology & Neurosurgery, McGill University, Montréal, Québec, Canada</footnote>

<footnote n="6">⁶Department of Human Genetics, McGill University, Montréal, Québec, Canada</footnote>

<footnote n="7">⁷Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII) Barcelona, University of Barcelona, Barcelona, Spain</footnote>

<footnote n="8">⁸Centre of Neuroscience of Lyon, UMR 5292 CNRS/U1028 INSERM, Lyon, France</footnote>

<footnote n="9">⁹Centre Hospitalier Le Vinatier, Bron, France</footnote>

<footnote n="10">¹⁰Paracelsus-Elena-Klinik, Kassel, Germany</footnote>

<footnote n="11">¹¹Department of Neurology, University Medical Center Göttingen, Göttingen, Germany</footnote>

<footnote n="12">¹²IRCCS Institute of Neurological Sciences, UOC NeuroMet, Bellaria Hospital, Bologna, Italy</footnote>

<footnote n="13">¹³Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, Italy</footnote>

<footnote n="14">¹⁴Department of Neurosurgery, University Medical Center, Göttingen, Germany</footnote>

<footnote n="15">¹⁵Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA</footnote>
# 1 | INTRODUCTION: HISTORY OF RAPID EYE MOVEMENT SLEEP BEHAVIOUR DISORDER (RBD)

The first description of dream-enacting behaviours dates back to the early Roman empire where reports on animals were provided as proof that non-human animals also dream (Pline l'Ancien, 1961). In the 17th century, Miguel de Cervantes described an episode of dream-enacting behaviour (Iranzo et al., 2004), in which Don Quixote shouts and vigorously attacks some wineskins while dreaming that he is fighting a giant. In 1881, Lasègue observed that patients with delirium tremens presented with dream-like behaviours, vocalisations, and rampaging in bed (Lasègue, 1881), features possibly resembling rapid eye movement (REM) sleep behaviour disorder (RBD). A major advance was made in 1965 when Jouvet and Delorme (1965) created an RBD model in cats 20 years before it was identified as a disorder in humans. Sastre and Jouvet sought to determine the origin of REM sleep muscle atonia and injected ibotenic acid in various nuclei to suppress atonia. They observed that lesions of the perilocus coeruleus alpha (an equivalent to the human locus subcoeruleus) resulted in dream-like behaviours ("oneiric behaviours"), including predatory attack, rage, flight, and grooming in cats (Sastre & Jouvet, 1979).

Europeans were also among the first to observe REM sleep without atonia (RWA) in individuals with parkinsonism. In 1969, Traczynska-Kubin et al. (1969) observed patients with Parkinson's disease (PD) having persistent mental electromyography (EMG) activity despite REMs resembling REM sleep. In 1975, Mouret (1975) described a persistence of mental EMG activity during paradoxical sleep in patients with PD compared with healthy individuals. Similar findings were named "stage 1-REM" by Japanese researchers (for a review see Tachibana, 2009) and "stage 7" sleep by Guilleminault et al. (1976) in patients with narcolepsy treated with clomipramine. The Europeans were also the first to document video-polysomnographic (v-PSG) recording of an RBD episode in a patient with Shy-Drager syndrome (Coccagna et al., 1985). Shortly after, Salva and Guilleminault (1986) described the disappearance of REM sleep atonia and the appearance of complex dream-enacting behaviours in patients with olivopontocerebellar degeneration. Following on from this there were several reports by Japanese researchers of stage 1-REM, possibly resembling RWA in otherwise healthy-seeming elderly individuals experiencing their first manifestations of somnambulism-like behaviours (Tachibana et al., 1991), as well as in patients with brainstem degeneration (Shimizu et al., 1990), and under clomipramine treatment (Niiyama et al., 1993). A more detailed history of the detection of RWA and RBD has been provided in a review (Frauscher & Högl, 2012).

The landmark discovery of RBD as a disorder is attributed to Carlos Schenck and Mark Mahowald who described the first case series of people showing dream-enacting behaviours linked to a polysomnographic confirmation of RWA and gave RBD its name. Schenck and Mahowald identified the sleep-related violence and risk of injury, linked it with Jouvet's cat model, and discovered the benefit of clonazepam (Schenck et al., 1986). In the first brain neuropathological

examination of a case with isolated RBD (iRBD), abnormal α-synuclein deposits were found in the locus coeruleus/subcoeruleus (Uchiyama et al., 1995). Schenck and Mahowald followed up their first 30 idio-pathic RBD patients finding that one-third of their cohort later converted to parkinsonism (Schenck et al., 1996). This major finding occurred before Braak et al. suggested that abnormal α-synuclein propagates in a bottom-up pattern in prodromal and defined PD, starting in the gut and medulla oblongata (stage 1), then in the locus coeruleus/subcoeruleus (stage 2) and later in the substantia nigra (stages 3 and 4) and cortex (stages 5 and 6) (Del Tredici et al., 2002). In 2007, Boeve, Silber, et al. (2007b) postulated that dysfunction in the sublaterodorsal nucleus (corresponding to stage 2 in the Braak staging system) could lead to RWA and RBD. This phenoconversion from RBD to parkinsonism and dementia was later confirmed in several countries, and other synucleinopathies were associated with RBD (Fantini et al., 2005; Iranzo et al., 2006).

## 1.1 | RBDpathophysiology

Glutamatergic neurons located in a small pontine nucleus localised ventral to the laterodorsal tegmental nucleus (LDT) - named sublaterodorsal tegmental nucleus (SLD) in rats and locus coeruleus in humans - are responsible for inducing muscle atonia during REM sleep. These neurons express the vesicular transporter 2 of glutamate (vGLUT2), the specific marker of glutamatergic neurons, and cFos, a marker of activation in rats displaying a REM sleep hypersomnia (Clement et al., 2011). Unit recordings of these neurons confirmed that they are selectively active during REM sleep (Boucetta et al., 2014). It has also been shown that genetic inactivation of glutamatergic SLD neurons in rats and mice induces RBD and a 30% decrease in REM sleep quantities (Uchida et al., 2021; Valencia Garcia et al., 2017).

It has also been shown that combined microdialysis of bicuculline (a GABA-A antagonist), strychnine (glycine antagonist), and phaclophen (a GABA-B antagonist) in the trigeminal nucleus are necessary to restore jaw muscle tone during REM sleep (Brooks & Peever, 2012). Furthermore, SLD neurons directly excite GABA/glycinergic neurons located in the ventral medullary reticular nuclei (Boissard et al., 2002; Valencia Garcia et al., 2017; Valencia Garcia et al., 2018). Nearly all c-Fos-labelled neurons localised in these nuclei express GAD67 and glycine transporter 2mRNA after 3 h of paradoxical sleep recovery following 72 h of paradoxical sleep deprivation (Sapin et al., 2009; Valencia Garcia et al., 2018). These neurons directly project to spinal motoneurons (Valencia Garcia et al., 2018). Inactivation of the GABA and glycinergic neurons of these nuclei in rats and mice induces RBD (Uchida et al., 2021; Valencia Garcia et al., 2018). All these experiments indicate that GABA/glycine neurons located in the ventral medulla project to and hyperpolarise motoneurons during REM sleep leading to muscle atonia.

Interestingly, functional neuroimaging and postmortem brain studies report the presence of Lewy bodies and neuronal loss in SLD and ventral medulla (Arnulf, 2012; Boeve, Dickson, et al., 2007a;
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Iranzo et al., 2013). It is, therefore, probable that RBD is due to spe-
cific neurodegeneration of the glutamate SLD and/or GABA/glycine
medullary neurons.

It is well accepted that motoneurons are also phasically excited
by glutamate during REM sleep (Burgess et al., 2008). It is, therefore,
likely that RBD behaviours are due to phasic excitation of motoneu-
rons by glutamate in the absence of tonic GABA/glycine inhibition.
Glutamate pre-motoneurons are interneurons located in close vicinity
of motoneurons and neurons located in ponto-medullary reticular
nuclei and the red nucleus (Rekling et al., 2000). These neurons are
directly excited by glutamatergic pyramidal neurons of the motor cor-
tex to induce voluntary movements (Rekling et al., 2000). The reticular
formation and the red nucleus could play a major role in exciting
motoneurons during REM sleep without the need for cortical activa-
tion (Blumberg & Plumeau, 2016; Del Rio-Bermudez et al., 2015).
However, patients often show long and complex behaviours, such as
singing and giving long speeches, which strongly suggests that the
motor cortex drives such behaviours (De Cock et al., 2007). In line
with this, activation of the human motor cortex, similar to that
observed during a voluntary movement during wakefulness, has been
observed during REM sleep (De Carli et al., 2016).

Due to the characteristic emotional component of RBD dream-
enacting behaviours and vocalisations, involvement of the limbic sys-
tem has been postulated. This hypothesis is supported by animal stud-
ies on cats and by reports of RBD in humans affected by limbic
encephalitis (Iranzo, 2018).

Everything considered, RBD is likely induced by neu-
rodegeneration of the ponto-medullary GABA/glycinergic and/or glut-
amatergic neuronal system physiologically inducing muscle atonia
during REM sleep, although other circuits are also involved in the gen-
eration of RWA and dream-enacting behaviours.

1.2 | Clinical features of isolatedRBD (iRBD)

The prevalence of iRBD in the general population over 60 years old is 0.5-1% (Haba-Rubio et al., 2018; Pujol et al., 2017), and the mean age at clinical consultation is usually in the seventh decade. iRBD is rare in those under 50 years (Fernandez-Arcos et al., 2016). For unknown reasons, people seeking medical consultation for iRBD at sleep centres are more frequently men than women, although this finding may be due to a selection bias as RBD in men is more violent than in women. Ageing, head injury, farming, pesticide exposure, antidepressant therapy, and GBA mutations are all risk factors for developing iRBD (Postuma et al., 2012). Hyposmia, depression, and constipation are more common in iRBD than in controls (Aguirre-Mardones et al., 2015).

The main clinical features of iRBD are dream-enacting behaviours
and nightmares, but this symptomatology also occurs in posttraumatic
sleep disorder, sleep terrors, as well as in some patients with severe
obstructive sleep apnoea and periodic limb movement disorder. Recal-
led dreams are short, vivid, intense, frightening, and negatively toned
(e.g., being attacked or chased by an unknown person for an unknown

reason). Clinical manifestations consist in vocalisations (e.g., yelling,
swearing, crying, or laughing) and vigorous behaviours (punching,
kicking, jumping out of bed) where patients appear to be enacting
their dreams. These behaviours occur in REM sleep, with eyes closed,
are usually confined to the bed, and may result in injuries to the
patient and the bed partner (Fernandez-Arcos et al., 2016). However,
the most common abnormal behaviours seen in REM sleep during
video-polysomnography (v-PSG) are prominent jerks. Interestingly, an
important proportion of iRBD patients report good sleep quality and
are unaware of their nocturnal episodes, indicating that bed partners
are essential for informing about and describing these behaviours. To
reduce the intensity and frequency of the nightmares and motor
behaviours (therefore, also reducing the risk of injury) clonazepam and
melatonin can be used. Both these treatments are suggested as Level
B treatment for RBD by the Standards of Practice Committee of the
American Academy of Sleep Medicine (Aurora et al., 2010). Clonaze-
pam is usually effective at a dose <2 mg, melatonin at a dose 3-
12 mg. Long-term treatment is usually required. Melatonin has a
favourable side effect profile (dose-related side effects include morn-
ing headache, morning sleepiness, and delusions/hallucinations),
whereas clonazepam should be used with caution in patients with
dementia, gait disorders, or concomitant obstructive sleep apnea. The
most common side effects of clonazepam are sedation, impotence,
early morning motor incoordination, confusion, and memory dysfunc-
tion (Aurora et al., 2010). Besides symptomatic treatment, improving
safety within the bedroom environment is also often necessary
(Fernandez-Arcos et al., 2016).

After 15 years of follow-up, about 95% of iRBD patients will be
clinically diagnosed with the synucleinopathies dementia with Lewy
bodies (DLB, 45%), PD (45%), or multiple system atrophy (MSA, 5%)
(Iranzo et al., 2016). Indeed, the presence of abnormal synuclein in the
cerebral spinal fluid (CSF), olfactory mucosa, and peripheral organs
(colon, skin, and salivary glands) is detected in most iRBD patients.
Markers of short-term conversion to a clinically overt synucleinopathy
are hyposmia, abnormal DAT-SPECT, mild cognitive impairment, and
minor parkinsonian signs. Patients with long-standing iRBD of more
than 15 years may show synuclein in the CSF and organs, hyposmia
and DAT deficit, indicating a slow but ongoing neurogenerative pro-
cess (Hogl et al., 2018; Iranzo et al., 2017; Teigen et al., 2021).

2 | VIDEO-POLYSOMNOGRAPHY (V-PSG) AS A DIAGNOSTIC REQUIREMENT AND PROGRESSION MARKER INRBD

The current criteria for the diagnosis of RBD (American Academy of
Sleep Medicine, 2014) require the demonstration of RWA on v-PSG.
Several manual/visual methods have been proposed to quantify RWA,
but the most validated method that is also recommended by recent
international guidelines (Cesari et al., 2021) is the one proposed by
the Sleep Innsbruck Barcelona (SINBAR) group (Frauscher
et al., 2012). This method measures "any" (i.e. phasic or tonic) muscu-
lar activity in the chin and phasic muscular activity in both flexor
digitorum superficialis muscles in the upper limbs, either in 30 s epochs or in 3 s epochs, and the respective cut-offs of 27% and 32% have shown to be sensitive and specific to distinguish RBD from controls (Frauscher et al., 2012). Quantification of RWA in the lower extremities has lower specificity than in the upper extremities (Cesari et al., 2021). Because manual/visual RWA quantification is extremely laborious, several (semi-)automatic methods have been proposed. Of these, the REM atonia index (Ferri et al., 2010) is the most validated one, but it quantifies RWA only in the chin. Only one semi-automatic method measures muscular activity both in the chin and the upper extremities (Frauscher et al., 2014).

RWA is not only the electrophysiological hallmark of RBD but is also a biomarker of neurodegeneration in iRBD (McCarter et al., 2019; Nepozitek et al., 2019) and could potentially be used as a biomarker for impending progression to an overt α-synucleinopathy in iRBD patients, although more studies are needed to confirm this.

v-PSG documentation of behaviours during REM sleep is not strictly required in the current American Academy of Sleep Medicine (AASM) criteria (American Academy of Sleep Medicine, 2014), but new diagnostic guidelines by the International RBD study group (Cesari et al., 2021) require the demonstration of at least one RBD episode. An RBD episode is defined as one or more motor events and/or vocalisation in REM sleep suggestive of dream enactment, thus including jerky, discontinuous simple and complex movements with or without vocalisations. Studies have shown that large, vigorous movements during REM sleep represent only the tip of the iceberg in RBD patients, who mostly have simple, minor jerks, requiring a careful video analysis (Frauscher et al., 2007). Research to develop automatic tools that can identify such movements and, therefore, help to diagnose RBD (Waser et al., 2020), is essential.

## 2.1 | Sex issues in RBD

Since the seminal first description of five patients with RBD, a male predominance has been reported (Schenck et al., 1986). This was supported by subsequent studies that reported up to 80% of RBD patients being male (Schenck et al., 2019).

A more recent epidemiological study, however, suggested that the prevalence of RWA does not differ between the sexes (Habarubio et al., 2018). As women with RBD often present less violent dreams and behaviours, it has been suggested that RBD might be underestimated in women due to milder symptoms or lack of perception by bed partners (Fernandez-Arcos et al., 2016).

Differences in dream content between men and women, investigated in people with PD-RBD, showed that women dream more about activities of daily living, family and friends, while men have more performance-related dreams, including about sports, employment and can also be more aggressive (Borek et al., 2007), although data on this in iRBD are lacking. Nonetheless, differences in dream content could explain why men more often show harmful behaviours during RBD episodes (Mahale et al., 2016) and have a higher risk of injuries compared with women (Comella et al., 1998).

In line with this, a polysomnographic study investigating motor features of sleep behaviours reported that men have higher EMG phasic activity, more myoclonic movements, and more movements involving the trunk, whereas segmental movements were more frequent in women (Bugalho & Salavisa, 2019). Another polysomnographic study investigating RWA in both legs and arms, reported a higher RWA index in the legs in men compared with women, and a higher RWA index in the arms in women. The authors postulated that this finding might reflect a different character of RWA among the sexes (Borek et al., 2007; Tatman & Sind, 1996).

Despite frequent reports of sex differences in RBD phenotypes, this aspect has yet to be studied extensively. Future studies are needed to better elucidate the reasons for sex differences in the prevalence of RBD, as well as to characterise potential differences in muscle activity and motor events during REM sleep between women and men (Bodkin & Schenck, 2009; Borek et al., 2007; Bugalho & Salavisa, 2019; Comella et al., 1998; Fernandez-Arcos et al., 2016; Habarubio et al., 2018; Mahale et al., 2016; Schenck et al., 1986; Tatman & Sind, 1996; Zhou et al., 2015).

## 2.2 | The genetics of RBD

Great strides forward have been made in iRBD genetic research over the past several years. iRBD likely has a distinct genetic risk profile compared with overt α-synucleinopathies, with evidence of both overlapping and contrasting risk loci across the conditions. RBD heritability, explained by common variants, is estimated at 12.3%, which is similar to the current estimation for DLB, and five RBD genetic loci have been identified by a genome-wide association study (GWAS) (Krohn et al., 2021). These genes are concentrated in the autophagy-lysosomal pathway (ALP) and are more specific to this pathway than any similarly powered GWAS of PD or DLB. Each of these RBD genes, SNCA, GBA, TMEM175, INPP5F, and SCARB2, are nominated PD risk loci (Nalls et al., 2019). However, the driving risk variants in SNCA and SCARB2 are independent, meaning different genetic mechanisms are driving the risk for RBD and PD at these loci. The top SNCA variant associated with an increased risk for PD may have an opposite effect in RBD, decreasing the risk (Krohn et al., 2020). There is evidence that these RBD and PD variants may be affecting gene expression differently, and in different brain regions, with RBD variants localised in cortical regions (Krohn et al., 2021). Additionally, prominent PD genes such as *LRRK2* (Fernandez-Santiago et al., 2016), *MAPT*, and autosomal recessive genes (Mufti, Rudakou, et al., 2021a) are not associated with isolated RBD. A similar pattern is found between RBD and DLB, where ALP genes SNCA, GBA, and *TMEM175* are shared risk factors in both conditions, however, DLB genes *APOE* and *BIN1* (Chia et al., 2021) are not associated with RBD (Gan-Or et al., 2017; Krohn et al., 2021). Mutations in *PSAP*, encoding for saposin C, a lysosomal activator of GBA, have also been implicated in iRBD (Sosero et al., 2022), as well as rare variants in *LAMP3* (encoding the lysosomal associated membrane protein 3) and other genes (Mufti, Yu, et al., 2021b). Overall, the shared loci across RBD and overt
<figure><img src="image_5.png" /></figure>

α-synucleinopathies are localised in the ALP, and genes associated with other neurodegenerative mechanisms (e.g., tau aggregation, mitochondrial dysfunction) do not appear to play a major role in RBD susceptibility. Genetics may also contribute to the phenoconversion rate from RBD to overt neurodegeneration; studies in SNCA (Krohn et al., 2020) and GBA (Honeycutt et al., 2019) show evidence that risk variants are associated with rapid phenoconversion, however, with limited confidence at these sample sizes.

## 2.3 | Biomarkers – classical and recent

Clinical trials with putative neuropreventive strategies in PD have been largely unsuccessful in the past, in part because the target populations were early/de novo PD patients with characteristic motor symptoms already present. At this stage, the degeneration of dopaminergic neurons is advanced with over 50% of nigrostriatal dopaminergic neurons already being affected by neurodegeneration. Therefore, strategies to prevent future disease conversion need to focus on risk cohorts. To achieve this important step, studies should be conducted in iRBD patients to assess progression biomarkers in the early disease stage in parallel to larger cohorts of at-risk individuals. With an average of only 6.3% of iRBD patients converting to disease per year (Postuma et al., 2019), conversion alone cannot serve as an outcome measure for future clinical trials and further objective trait markers are needed. Also, individuals with iRBD convert into different α-synuclein aggregation diseases (i.e., PD, MSA, DLB). It may, therefore, be important to stratify these groups in the prodromal state. For prodromal individuals and population-based screens, which are becoming more popular for identifying individuals at risk, we need biomarkers that are less invasive than CSF, as well as widely applicable screening instruments. Several strategies are currently being investigated, including imaging studies (e.g., dopamine transporter imaging, ¹⁸F FDG-PET), objective quantitative assessment of emerging mild motor disease, cognitive testing and tissue analyses with aggregation chemistry for α-synuclein (Miglis et al., 2021).

The total α-synuclein in CSF is 15% lower in PD and MSA, while in iRBD levels are slightly higher for, as yet, unknown reasons (Mollenhauer et al., 2019). More promising is the detection of α-synuclein aggregation by seeding aggregation assays (SAA; RT-QuiC or PMCA) with sensitivities and specificities above 90–95% for PD in CSF (Shahnawaz et al., 2017). One study in iRBD showed a sensitivity of 90.4% and a specificity of 90.0%. In one individual, positivity of SAA was detected 10 years before the conversion to disease (Iranzo et al., 2021). Major hurdles faced by SAA are the lack of quantification and the fact that the best performance is shown in CSF compared with colon, salivary glands, olfactory mucosa, and skin (Antelmi et al., 2017; Doppler et al., 2017; Fernandez-Arcos et al., 2016; Iranzo et al., 2018; Sprenger et al., 2015; Stefani & Hogl, 2021; Vilas et al., 2016). The current mechanism of the molecular processes leading to α-synuclein aggregation and disease are still unknown and cannot yet be explained in relation to the assay parameters. While for CSF the results are promising, the first studies also report SAA

positivity in skin samples in PD as well as in olfactory mucosa (De Luca et al., 2019; Wang et al., 2020). Some groups also show different seeding dynamics in patients with MSA and PD, which could indicate different α-synuclein strains (Shahnawaz et al., 2020).

A more peripherally acting biomarker is the neurofilament light chain (NfL), which can now reliably be quantified in peripheral blood. Although nonspecific and elevated in several other neurological diseases, slightly higher values of plasma NfL are shown for PD and RBD and markedly higher for MSA patients (Mollenhauer et al., 2020).

In the future, we will know if other biomarkers such as inflammatory panels, faecal microbiome, and miRNA hold their promise of being adequate screening tools for those at risk of converting to disease. Unfortunately, none of the previous biomarkers, including SAA, can be currently used for individual quantification to differentiate between individuals at risk for conversion and those remaining free of a neurodegenerative disease. Larger cohorts are needed.

## 2.4 | Implications of the RBD diagnosis

The implications of establishing the diagnosis of RBD are multifaceted. These encompass (i) clinical implications centred on the management strategies and risk mitigation of potential injurious RBD behaviours, (ii) implications related to very strong associations between RBD and evolving synuclein-specific neurodegeneration, (iii) the need to increase awareness about this disorder among physicians, allied health professionals, and the general public, and (iv) the opportunity to engage numerous stakeholders around RBD as a unique disorder that is positioned on the intersection of neurology, sleep medicine, and neuroscience.

The clinical implications of RBD as a parasomnia are centred on symptomatic management and safety precautions in sleeping environments aimed at preventing injuries from RBD-related motor behaviours (St Louis & Boeve, 2017). The relative paucity of well-designed randomised symptomatic clinical trials should be a call for action for a more robust clinical trial RBD pipeline (Gilat et al., 2020; Shin et al., 2019). The success of such trials will largely depend on the adequate selection of outcome measures and trial duration, which will allow for proper ascertainment of the intervention's effectiveness.

Implications of RBD as a prodromal stage of an evolving α-synucleinopathy are complex. RBD patients are increasingly becoming aware of their risk of developing one of these disorders in the future. This necessitates proper counselling on the risk of phenoconversion so that appropriate planning for the future can be considered. Currently, there is a substantial gap in prognostic counselling offered to the patient as reports indicate that only 50% of patients with RBD receive counselling (Feinstein et al., 2019). There is, therefore, a need to develop best practices for prognostic counselling in iRBD.

One of the most important implications of RBD as a prodromal synucleinopathy is an opportunity to position the iRBD population as an ideal study cohort for testing disease-modifying treatments aimed at delaying or preventing phenoconversion to a synucleinopathy (Hogl
et al., 2018). Selecting the ideal patient candidates for disease-modifying trials, having effective and reliable screening and recruitment methods, employing robust clinical trial designs, and choosing appropriate outcome measures capable of demonstrating disease modification within the reasonable trial duration are the critical aspects of trial planning for iRBD. Some of these elements are more straightforward than others. The International RBD study group published two consensus statements on clinical trials in the RBD population that detail these aspects relevant to organisations and implementation of RBD clinical trials (Schenck et al., 2013; Videnovic et al., 2020).

Finally, raising awareness and promoting education about RBD is a very important implication of RBD, which is overall underdiagnosed, or the diagnosis is quite delayed. Bringing together various stakeholders such as clinicians, scientists, patients, disease-specific foundations, government agencies, industry, and the general public will enable us to advance various aspects of RBD clinic care, research, and therapeutic development.

3 | FUTURE DIRECTIONS

Since the first description of RBD, the disease has been better characterised through pathophysiologic, clinical and v-PSG studies, as well as through extensive research on biomarkers and genetics.

Despite these advances, the phase of phenoconversion from iRBD to overt α-synucleinopathy still needs to be further investigated. A combination of biomarkers will likely allow better identification of those with iRBD at high risk of short-term phenoconversion, whereas it is still unclear how iRBD individuals that go on to develop PD will be differentiated from those phenoconverting into DLB or MSA. Although a combination of biomarkers might be useful, it is also likely that a better phenotypic characterisation will be achieved through the identification of biomarkers or α-synuclein aggregates in biofluids or tissues, which are specific for one α-synucleinopathy (i.e., DLB, PD or MSA).

Another aspect that will become more relevant in the future and deserves further investigation is prodromal RBD. It has been defined as a stage in which symptoms and signs of evolving RBD are present, but do not yet meet established diagnostic criteria (Cesari et al., 2021; Hogl et al., 2018). International guidelines for the identification of prodromal RBD have been published recently by the International RBD study group, providing a framework that will ensure harmonised studies and, therefore, a better understanding of the clinical relevance of this condition and its evolution into iRBD.

All the previously mentioned aspects, as well as the identification of RBD in the general population, will likely take advantage of the implementation of artificial intelligence. Machine-learning approaches may provide new ways of identifying RBD patients (e.g., considering both muscle activity and movements), as well as new ways of phenotypic characterisation (e.g., based on a combination of biomarkers), dramatically improving detection and classification of RBD.

Some open issues in the RBD research field concern treatment. New insights into pathophysiology deriving from basic

science may lead to the development of novel treatments acting on specific pathways involved in the generation of RBD. Double-blind, randomised, controlled trials are still needed to assess the efficacy of symptomatic RBD treatment. Moreover, clinical trials testing neuroprotective drugs may represent a turning point in the development of disease-modulating treatments for alpha-synucleinopathies.

AUTHORS' CONTRIBUTIONS

BH and AS planned, coordinated, and edited the manuscript. All authors drafted a section of the work and revised the entire work critically for important intellectual content and gave final approval of the version to be published.

CONFLICT OF INTEREST

Author conflicts of interest in relation to the content of this manuscript.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

ORCID

Birgit Högl https://orcid.org/0000-0003-1894-7641

Isabelle Arnulf https://orcid.org/0000-0002-2240-2516

Matteo Cesari https://orcid.org/0000-0001-6554-1033

Anna Heidbreder https://orcid.org/0000-0002-9552-7619

Federica Provini https://orcid.org/0000-0001-9063-2658

Ambra Stefani https://orcid.org/0000-0003-4259-8824

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**How to cite this article:** Högl, B., Arnulf, I., Bergmann, M., Cesari, M., Gan-Or, Z., Heidbreder, A., Iranzo, A., Krohn, L., Luppi, P.-H., Mollenhauer, B., Provini, F., Santamaria, J., Trenkwalder, C., Videnovic, A., & Stefani, A. (2022). Rapid eye movement sleep behaviour disorder: Past, present, and future. *Journal of Sleep Research*, 31(4), e13612. https://doi.org/10.1111/jsr.13612