Onset Time and Severity of RBD in PD

It is well recognized that RBD may precede the development of PD motor syndromes by 3–13 years^{Reference Gagnon, Bédard and Fantini22} with a mean duration of 10–12 years between RBD diagnosis and PD motor syndromes.^{Reference Iranzo, Molinuevo and Santamaría23,Reference Claassen, Josephs, Ahlskog, Silber, Tippmann-Peikert and Boeve30} It may precede motor symptoms or develop after PD onset; indeed, clinical manifestations of PD could vary depending on the timing of RBD onset.^{Reference Jin, Zhang, Shen and Liu9} We identified critical differences between PD patients reporting RBD symptoms before or after the onset of PD motor symptoms. Those patients who reported RBD symptoms after the onset of PD motor manifestations had an onset of the disease up to 4 years earlier with more psychotic symptoms than the group with prodromal RBD. This preliminary finding requires further exploration but suggests that the onset of RBD after motor symptoms is associated with a more aggressive clinical presentation in the PD-RBD phenotype.

In line with our results, other authors reported interesting clinical differences associated with the timing of RBD onset. For instance, Ferri et al.^{Reference Ferri, Cosentino, Pizza, Aricò and Plazzi25} found in their population that patients in whom RBD developed concomitantly or after the onset of PD motor symptoms had more severe symptoms, received higher doses of dopaminergic therapy, and had a longer disease duration than patients with prodromal RBD or those with PD without RBD who did not differ in those disease parameters.

Similarly, Gong et al.^{Reference Gong, Xiong and Mao31} found that worse cognition was associated with a shorter interval of RBD preceding PD onset, but not RBD duration. Nomura et al.^{Reference Nomura, Kishi and Nakashima32} found more significant cognitive impairment in patients with RBD starting after PD onset than in those with prodromal RBD despite similar motor and autonomic dysfunction with similar dopaminergic agents. Our findings support these authors' hypothesis that PD with prodromal RBD and PD with RBD symptoms after motor onset might constitute two possibly distinct clinical and pathophysiological groups, likely based on different progressive neuropathological sequences of events. This might also comply with the “brain first / body first” subdivision proposed by Horsager et al.^{Reference Horsager, Andersen and Knudsen33} in which de novo patients lacking RBD by the first year of clinical PD have more evidence of a top-down progression of features.

Relationship Between ICD and PD-RBD

ICD are behavioral addictions that may be debilitating for the patient or others. They negatively impact the quality of life of patients and their care partners,^{Reference Weintraub, Koester and Potenza34} remain underdiagnosed, lack clear recommendations regarding therapy, and may lead to severe social and legal consequences.^{Reference Sobrido, Dias-Silva and Quintáns35}

The estimated prevalence of ICD in PD is about 14%, while up to 31% experience at least one ICD during their illness.^{Reference Weintraub, Koester and Potenza34} In a recent longitudinal study of severity of ICD in PD-RBD, Baig et al.^{Reference Baig, Kelly and Lawton13} reported a prevalence of 19% in early PD. In our study, the prevalence of ICD in the PD-RBD group was 31% and significantly higher than in the group without RBD (21%), mainly related to hypersexuality and compulsive eating. The high variability in the reported prevalence of ICD in PD-RBD could be explained by the heterogeneity of the PD phenotype and due to the absence of semi-structured baseline interviews conforming to DSM-5 diagnostic criteria (or aligned with DSM-5).^{Reference Baig, Kelly and Lawton13}

PD-RBD has been reported to have a twofold higher risk of developing ICD,^{Reference Fantini, Figorilli and Arnulf10,Reference Lu, Shen and Zhao36} suggesting that a specific pattern of neurodegeneration may predispose to the emergence of ICD in the context of dopaminergic medications.^{Reference Marques, Roquet and Matar12} Notwithstanding, no longitudinal studies are currently available to estimate the actual risk of developing ICD over time in PD with and without RBD taking dopaminergic replacement therapy. However, taken together, cross-sectional data suggest that PD-RBD may have an increased vulnerability to developing ICD, compared to PD-non-RBD, probably due to more severe impairment in the meso-corticolimbic pathway.^{Reference Fantini, Durif and Marques29}

Although the mechanisms underlying ICD are not yet fully understood, the primary driver is thought to be dopaminergic medication, particularly DAs.^{Reference Baig, Kelly and Lawton13} Our study supports the coexistence of DA treatment and ICD in those PD patients who reported hypersexuality (see Table 1). Furthermore, recent findings^{Reference Marques, Roquet and Matar12} on the volumetric and functional connectivity characteristics of the reward system of patients with idiopathic RBD concluded that PD-RBD might ultimately predispose these individuals to the onset of ICD when receiving dopaminergic medications, following the onset of motor symptoms. These findings are supported by the fact that altered functional connectivity between limbic, striatal, and posterior cortical regions was associated with hypersexuality.^{Reference Marques, Roquet and Matar12} Further studies are needed to confirm the nature of this relationship and its pathophysiology.