Increased muscle sympathetic nerve activity and impaired baroreflex control in isolated REM-sleep behavior disorder
Introduction
Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is accepted as a prodromal stage of α-synucleinopathies (Boeve et al., 2001). Patients with iRBD frequently (80%) develop idiopathic Parkinson’s disease (PD), Lewy body dementia or sometimes multiple system atrophy (Zanigni et al., 2011). The neuropathological hallmark is α-synuclein deposits, which are considered to spread from the brainstem via susceptible neurons in the mid-brain to cortical areas (stages 1 – 6) (Braak et al., 2003). PD manifests when the α-synuclein deposits markedly affect the substantia nigra. Stages 1 to 3 are prodromal stages. In iRBD (stage 2), α-synuclein can be detected in the locus coeruleus (LC) and neighboring structures, which are crucial for REM sleep–induced atonia (Garcia-Lorenzo et al., 2013).
Autonomic disturbances can precede motor symptoms in PD patients (Palma and Kaufmann, 2014). Ferini-Strambi et al. (Ferini-Strambi et al., 1996) demonstrated that iRBD patients have impaired sympathetic and parasympathetic functions, leading to cardiovascular symptoms. However, the main mechanism driving autonomic dysfunction is still unknown. Pathological meta-iodo-benzyl-guanidine (MIBG) myocardial scintigraphy indicates that the mechanism is reduced peripheral cardiac sympathetic transmitter reuptake or the loss of cardiac sympathetic innervation (Takatsu et al., 2000). However, impaired central sympathetic drive has been proposed as leading to impaired baroreflex function in PD patients (Kramer et al., 2019, Shindo et al., 2005). In humans, the baroreceptor buffers variations in blood pressure (BP). One major efferent branch is vasoconstrictor sympathetic activity to the skeletal muscle vascular bed. Another branch of baroreflex control is the adjustment of heart rate (HR) (mainly parasympathetic effects) (Vallbo et al., 2004). Taking into consideration that PD patients have impaired baroreflex control (Kramer et al., 2019), we sought to investigate the baroreflex function in iRBD patients.
Section snippets
Ethical approval
The study was approved by the Ethics Committee of the Medical Faculty of Justus Liebig University, Giessen, Germany (161/11). All of the participants gave their informed written consent according to the latest revision of the Declaration of Helsinki, and the study followed the recommendations of the STROBE statement.
Participants
Ten patients with polysomnography-confirmed iRBD were recruited from the outpatient clinic of the Department of Neurology at Philipps-University, Marburg, Germany. Patients were
Participant characteristics
The disease duration among iRBD patients was 53 months, according to the patients’ history (median; IQR: 36–77 months). DAT SPECTs were normal in seven patients and pathological (i.e. reduced) in two patients.
There were no significant differences between the iRBD and control groups regarding age, gender, HR, or BP at rest (for details see Table 1).
The data of the HRV is shown in Table 1. Our findings of reduced activity in the LF band, the VLF components, and the RR-standard-deviation reflect
Discussion
This study evaluates MSNA and its association with baroreflex control in patients with iRDB for the first time. We found that patients with iRBD showed increased MSNA at rest and during baroreflex stimulation compared to the controls. Simultaneously, the DBP among patients with iRBD was lower, although non-significant. These findings propose a possible disruption of baroreflex circuitry in patients with iRBD. These changes in MSNA at rest and during baroreflex stimulation can be considered as a
Study limitations
The sample size was rather small. However, our results showing increased MSNA could be detected in every iRBD patient, as compared to the controls. Moreover, MSNA is a reliable measure with low individual variance, as shown in previous studies (Vallbo et al., 2004, Wallin, 2007). The decrease in DBP was not significant. However, BP regulation is complicated and comprises not only the baroreflex but also other mechanisms, as mentioned above (Folkow, 1989, Groothuis et al., 2011, Henriksen and
Conclusion
Our study showed increased MSNA and disrupted baroreflex control in patients with iRBD. This was evident by the impaired sympathetic-mediated vasomotor responses to baroreflex activation in the iRBD patients, as compared to the healthy controls. We propose that the inhibitory input of LC on the RVLM is impaired, which disrupts the baroreflex circuit. Because MSNA is reduced in PD patients, repeated investigations of MSNA should be performed in iRBD patients. In this light, MSNA might even be a
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
We wish to thank Karl Kesper for his assistance with the analysis of the heart rate variability. This work contains essential parts of Isabella Strzedulla’s doctoral thesis.
Funding
ALCS was supported by Conselho Nacional de Pesquisa (CNPq #141856/2012-2) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). This study was made possible by Forschungsförderung §2 to HHK and a grant to WHO by the Parkinson Fonds Deutschland. WHO is a Hertie Senior Research Professor who is supported by the Charitable Hertie Foundation, Frankfurt/Main, Germany.
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