By Daniel A. Barone, MD, FAASM

Assistant Professor of Neurology, Weill Cornell Medical College, Center for Sleep Medicine

Dr. Barone reports he is on the speakers bureau for Jazz Pharmaceuticals and is a consultant for Molecule Mattress.

SYNOPSIS: In this well-designed prospective cohort study of patients with REM behavior disorder, the investigators reported that 73.5% of patients developed a neurodegenerative disorder after a 12-year follow-up.

SOURCE: Postuma RB, et al. Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: A multicentre study. Brain 2019;142:744-759.

Idiopathic REM sleep behavior disorder (iRBD) is a well-known early sign of the alpha-synucleinopathies, which include Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). It is characterized by active (sometimes violent) movements during REM sleep and is interpreted as “acting out dreams.” As such, the presence of iRBD allows researchers to observe prodromal neurodegenerative states and potentially intervene when neuroprotection becomes available. Postuma et al sought to assess the neurodegenerative disease risk and the predictors of neurodegeneration in a multicenter cohort of patients with iRBD. They included prospective follow-up data from 24 centers of the International RBD Study Group.

In total, 1,280 patients were recruited following a diagnosis of polysomnographically confirmed iRBD without parkinsonism or dementia. The average age was 66.3 ± 8.4 years, and 82.5% of participants were male. Patients underwent motor, cognitive, autonomic, and sensory testing, and were followed prospectively for an average of 4.6 years (range one to 19 years), during which time their risk of dementia and parkinsonism was assessed using a Kaplan-Meier analysis. The authors used Cox proportional hazards analysis to predict phenoconversion and a time-to-event analysis to calculate sample size estimates for disease-modifying trials.

The authors reported a conversion rate from iRBD to a neurodegenerative disorder to be 6.3% per year, with 73.5% converting after 12-year follow-up. Abnormal quantitative motor testing significantly increased the phenoconversion rate (hazard ratio [HR], 3.16), as did objective motor examination (HR, 3.03), olfactory deficit (HR, 2.62), mild cognitive impairment (HR, 1.91-2.37), erectile dysfunction (HR, 2.13), motor symptoms (HR, 2.11), an abnormal DaTscan (HR, 1.98), color vision abnormalities (HR, 1.69), constipation (HR, 1.67), REM atonia loss (HR, 1.54), and age (HR, 1.54). By contrast, the authors did not see significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Finally, there was a difference in cognitive variables at baseline between those converting to primary dementia vs. those converting to parkinsonism.

Postuma et al also attempted to determine a sample size estimate for neuroprotective trials. Using phenoconversion as a categorical endpoint, the authors found that sample sizes for a two-year trial with HR = 0.5 ranged from 142 to 366 patients per arm. They pointed out that stratification could decrease sample sizes further. Olfaction and the Movement Disorder Society prodromal criteria appeared to be the two most efficient approaches. It is fortunate that the total sample size for a future neuroprotective trial was discovered to be less than the number of participants who were recruited to this study. Postuma et al confirmed the high phenoconversion rate from iRBD to an alpha-synucleinopathy, and have provided estimates of the potential predictive value of prodromal markers. This information can be used to stratify patients for neuroprotective trials.

COMMENTARY

As demonstrated in this large and well-done study, patients with a new diagnosis of iRBD should be examined for existing subtle signs of neurodegenerative disorders. Aside from those studied by Postuma et al, new biomarkers are in development that could further aid risk stratification and perhaps even therapeutic options. For example, Gámez-Valero et al recently reported that glucocerebrosidase gene variants are found in iRBD patients more frequently compared to controls, and this finding is associated with PD and DLB.1 Similarly, patients with iRBD recently were found to exhibit increased microglial activation in the substantia nigra along with reduced dopaminergic function in the putamen as detected through PET.2

Perhaps the most important opportunity for research in the intersection of sleep medicine and neurology is the potential discovery and testing of a neuroprotective strategy to prevent ongoing neurodegeneration in identified at-risk individuals. The Postuma et al study, along with others, will provide a much better platform for the understanding and treatment for iRBD and for the characterization of its conversion to a more debilitating neurodegenerative disease. To this point, individuals with iRBD are enrolling in the Parkinson’s Progression Markers Initiative study,3 as well as other similar prospective cohorts around the world.

REFERENCES

  1. Gámez-Valero, et al. Glucocerebrosidase gene variants are accumulated in idiopathic REM sleep behavior disorder. Parkinsonism Related Dis 2018;50:94-98.
  2. Stokholm MG, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: A case-control study. Lancet Neurol 2017;16:789-796.
  3. Parkinson’s Progression Markers Initiative. Available at: http://bit.ly/2UT9CCa. Accessed April 24, 2019.