REM sleep without atonia is associated with increased rigidity in patients with mild to moderate Parkinson’s disease
Introduction
Rigidity is one of the cardinal motor signs of Parkinson’s disease (PD) and is characterized by a marked increase in muscle activity in response to imposed muscle stretch. Increasing rigidity correlates with greater disease severity, yet, there is considerable heterogeneity in the expression of rigidity both within and across individuals with PD, even in individuals who are considered to have an akinetic-rigid predominant phenotype of PD (Vu et al., 2012). Heterogeneity in rigidity is particularly evident in the early stages of disease. The mechanisms contributing to the expression of rigidity are poorly understood, but alterations in the excitability of both cortical and subcortical pathways mediating long-latency stretch reflexes (Rothwell et al., 1983, Tatton and Lee, 1975) and stretch induced co-activation of agonist-antagonist muscles (Xia, 2011, Xia et al., 2009, Xia et al., 2006, Xia and Rymer, 2004) are considered to contribute to increased resistance during imposed movements.
Muscle activity is also abnormally elevated during rapid eye movement (REM) sleep in a substantial percentage (approximately 40%) of people with PD (Chahine et al., 2014). Increased phasic or tonic muscle activity during REM sleep is termed REM sleep without atonia (RSWA) and, in conjunction with the phenomenon of dream enactment, characterizes the parasomnia of idiopathic REM sleep behavior disorder (iRBD). Idiopathic RBD affects approximately 1% of the general population, and its prevalence is near 5% in the elderly (Boeve et al., 2013, Haba-Rubio et al., 2018). It is now well recognized that the presence of iRBD is highly predictive of progression to a neurodegenerative disease with alpha-synuclein pathology. It has been estimated that more than 75% of people with iRBD will develop PD, multiple system atrophy, or dementia with Lewy bodies over the course of 12 years (Postuma et al., 2019, Schenck et al., 2013). In a cohort of patients with de novo PD, 51% exhibited movement events during REM sleep (Mollenhauer et al., 2013). It is estimated that over 40% of individuals with PD have RSWA and more than 20% have a diagnosis of iRBD (Chahine et al., 2014, Zhang et al., 2017). Individuals with PD and iRBD are more likely to present with a non-tremor dominant subtype of PD (Folle et al., 2019, Kumru et al., 2007, Postuma et al., 2008, Romenets et al., 2012), and are more likely to develop postural instability, gait problems including freezing of gait, and orthostatic symptoms compared to individuals with PD alone (Postuma et al., 2008, Romenets et al., 2012). Higher levels of phasic muscle activity during REM sleep are associated with increased severity and more symmetric expression of disease (Bliwise et al., 2010). These findings suggest that among people with PD, RSWA is associated with increased pathology of both nigrostriatal and non-dopaminergic pathways.
The increased prevalence of the akinetic-rigid phenotype in people with PD and idiopathic RBD suggests that mechanisms mediating abnormally increased phasic and tonic muscle activity during REM sleep may also contribute to alterations in muscle activity regulation during wakefulness, and thus the expression of rigidity. Increased brainstem pathology in conjunction with a higher rate of disease progression may also lead to a more symmetric presentation of rigidity in people with elevated REM sleep muscle tone. Degeneration in brainstem regions with bilateral descending projections that impact muscle tone, such as the locus coeruleus, caudal raphe, and medullary magnocellular region of the reticular formation (Braak et al., 2006), would be expected to contribute to a more symmetrical presentation of rigidity. PD symptoms also tend to become more symmetric with disease progression, reflecting increasingly bilateral degeneration of nigrostriatal dopaminergic pathways, so more rapid disease progression may lead to earlier presentation of symmetric rigidity (Marinus and van Hilten, 2015). To date, no study has used quantitative measures to compare rigidity between people with PD with and without RSWA. The purpose of this study was to examine the level and symmetry of forearm rigidity during pronation-supination using quantitative metrics in a cohort of individuals with mild to moderate PD. We hypothesized that people with PD and RSWA would present with more severe and symmetric rigidity compared with individuals with PD without RSWA and age-matched controls.
Section snippets
Participants
Forty-one people with PD (26 males, 15 females, age = 64 ± 7.5) and 20 healthy controls (8 males, 12 females, age = 60.2 ± 7.4) were included in this study (demographic summary in Table 1). Clinical diagnosis of PD was determined by movement disorders neurologists according to the Movement Disorder Society Clinical Diagnostic Criteria for PD (Postuma et al., 2015). Individuals in this study were part of a long-term prospective study, and those who were subsequently diagnosed with another form
Clinical measures
There were no significant differences in age between the three groups or disease duration between PD groups. However, the levodopa daily equivalent (LDE) was significantly different between the PD groups, with the PD-RSWA+ group having higher LDE than the PD-RSWA− group (p = 0.009). The MDS-UPDRS Part III total score and rigidity subscore showed a significant effect of group (p < 0.001), with both scores significantly higher in both PD groups compared to controls (p < 0.001), but there was no
Discussion
There were two main findings from this experiment. First, measures of forearm rigidity were significantly increased in the PD-RSWA+ group compared to control subjects. In contrast, significant differences in forearm rigidity between the PD-RSWA− and control group were only observed in the more affected limb during the activation maneuver condition. Second, asymmetry in the expression of forearm rigidity (calculated as the difference in quantitative scores between the more and less affected
Conclusions
Our findings confirm that people with PD and RSWA have unique dysfunction in the regulation of muscle tone during both sleep and wakefulness. They also suggest that RSWA in the setting of PD predicts distinctive brain stem neuropathology. These discoveries are fundamentally important because they help investigators understand the physiology of motor activity and the pathophysiology of Parkinsonian disorders. To our knowledge, this is the first study to use quantitative measures to compare the
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.
Acknowledgements
We would like to thank our research volunteers for their participation in this study, Joshua De Kam for his role in coordinating this research, Devin O’Connell and Minwoo Kim for assistance in data collection and administration, Drs. Martha Nance, Julia Johnson, Daniel Kuyper, and Sotirios Parashos for referring volunteers to our study, and Dr. Lynn Eberly for statistical consultation. This work was supported by the National Institutes of Health grants R01 NS070264, R01 NS088670, P50 NS09857,
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