The present exploratory study preliminary suggests that PD patients who experienced pRBD following the manifestation of motor symptoms had a faster motor progression compared to those without pRBD and those featured by pre-motor RBD, as demonstrated by the H&Y scale progression over a 5-year follow-up period.

Data on the potential role of RBD onset in PD are rare (Ferri et al. 2014), but they mostly indicate that RBD might influence the clinical presentation of PD; however, no previous study compared the effects of RBD occurrence in the different time points of PD progression.

PD is a heterogeneous syndrome characterized by the misfolding, aggregation, and subsequent cell-to-cell propagation of pathological α-synuclein inclusions, which share some similarities with prions (Conti et al. 2022). According to the recent “α-Synuclein Origin and Connectome Model (SOC Model)” of PD, the α-synuclein pathology starts in a single location, the body, or the brain, and then propagates symmetrically or asymmetrically, depending on the origin of the accumulation, defining two types of PD: a “brain first” subtype and a “body first” subtype (Grillo et al. 2022; Horsager et al. 2022; Bovenzi et al. 2023; Schirinzi et al. 2023).

RBD can arise in both PD subtypes; as pre-motor RBD in those “body first” subtypes, in which the involvement of pontine and medulla structures precedes the degeneration of mesencephalic dopaminergic nigral cells and the appearance of motor symptoms, and as post-motor RBD in those forms of “brain first” PD, when the descending synucleinopathy originating from the amygdala spreads caudally through the brainstem structures (Horsager et al. 2022).

In either case, RBD reflects the neuronal degeneration or dysfunction in the brainstem regions that regulate the suppression of skeletal muscle tone during REM sleep. Members of this complex circuit include the cholinergic pedunculopontine nucleus (PPN) and lateral dorsal tegmental nucleus (LDTN), the serotonergic raphe nucleus, and glutamatergic and noradrenergic projections from the parabrachial–precoeruleus regions and the locus coeruleus (LC) (Horsager et al. 2022).

Independently from the original site of synucleinopathy, it is now known that the overall burden of specific motor features, such as freezing of gait (FOG), postural instability, and falls, along with several NMS, including constipation, orthostatic hypotension, hyposmia, and cognitive decline, is markedly greater in PD patients with RBD (Assogna et al. 2021; Horsager et al. 2022). Moreover, PD patients with RBD display significantly elevated cerebrospinal fluid prion protein expression levels compared to patients without RBD, identifying a more severe form of neurodegeneration (Zhang et al. 2017a).

In our study, the development of pRBD in PD patients when the motor symptoms were already present was associated with a faster motor progression in a 5-year follow-up period compared to patients without pRBD and patients with pre-motor pRBD.

The finding of greater motor progression in patients with pRBD compared to those without pRBD is in line with the existing literature, indicating RBD as a marker of a more severe neurodegenerative process. However, we found a faster motor progression in patients with post-motor pRBD compared to those with pre-motor pRBD, in apparent contrast with the slower motor progression classically encountered in “brain first” PD. Nevertheless, the faster motor progression in our post-motor pRBD patients in a relatively narrow follow-up period (5 years) may display a particular moment in the track of the neurodegenerative process, in which there is an acceleration of the synucleinopathy in the brainstem areas, with multiple neurotransmitter systems dysfunction leading to the occurrence of sleep disturbances and possible worsening of some motor manifestations. Beyond the dopaminergic circuits, the noradrenergic, cholinergic, and serotonergic systems are deeply involved in PD pathophysiology (Zenuni et al. 2023). In particular, the noradrenergic and cholinergic systems are both involved in the pathophysiology of RBD, as well as postural stability, gait dysfunction, and FOG (Pasquini et al. 2021; Ray Chaudhuri et al. 2023).

The H&Y scale is the most widely used and accepted staging system for the severity of PD. Compared to the UPDRS motor scores, the H&Y scale is more heavily weighted toward some aspects of the disease, such as postural instability and mobility problems, and mixes both the motor impairment and the overall disability (Goetz et al. 2004). Thus, it is possible that the H&Y score, compared to the total UPDRS motor scores, might be more sensitive in detecting the worsening of some motor features mainly driven by noradrenergic and cholinergic network dysfunction, such as gait disturbances and postural instability. However, no significant differences emerged in the occurrence of FOG and falls between the three groups. On the other hand, no differences in terms of LEDD changes over time were observed in the three groups. The reasons underlying this discrepancy cannot be defined here; nevertheless, in advanced stages of PD, the same dosage of levodopa needed to relieve parkinsonian features may also induce motor complications, especially levodopa-induced-dyskinesias, often requiring a reduction in levodopa dosage (Bovenzi et al. 2023). Furthermore, many motor and non-motor symptoms, which arise from non-dopaminergic neurotransmitter dysfunction, including gait and balance dysfunction, are levodopa unresponsive or partially responsive, possibly influencing the amount of LEDD used as the most appropriate. Finally, no differences emerged in the occurrence of main non-motor symptoms, such as cognitive impairment, gastrointestinal disturbances, and cardiovascular symptoms, possibly due to a selection bias in our study population. Indeed, it is possible that a degree of homogeneity in the primary motor features at the first follow-up visit could have influenced the observed non-motor features outcomes.

The main limitations of the present study are the small sample size, although selected from a large group of patients to monitor at the 5-year follow-up, the retrospective design, and the lack of polysomnographic confirmations of RBD.

In conclusion, the present exploratory study suggests that the post-motor occurrence of pRBD may be associated with a fastening of the disease’s motor progression, possibly reflecting a later dysfunction in multiple neurotransmitter networks. Further studies, including larger cohorts or a validation cohort, should deepen the significance of this preliminary observation, also considering the importance of targeting sleep to improve patients’ well-being, as well as motor progression and NMS burden.