Prodromal Parkinsonism and Neurodegenerative Risk Stratification in REM Sleep Behavior Disorder

Abstract

ObjectivesRapid eye movement (REM) sleep behavior disorder (RBD) is the most specific marker of prodromal alpha-synucleinopathies. We sought to delineate the baseline clinical characteristics of RBD and evaluate risk stratification models.MethodsClinical assessments were performed in 171 RBD, 296 control, and 119 untreated Parkinson’s (PD) participants. Putative risk measures were assessed as predictors of prodromal neurodegeneration, and Movement Disorders Society (MDS) criteria for prodromal PD were applied. Participants were screened for common leucine-rich repeat kinase 2 (LRRK2)/glucocerebrosidase gene (GBA) gene mutations.ResultsCompared to controls, participants with RBD had higher rates of solvent exposure, head injury, smoking, obesity, and antidepressant use. GBA mutations were more common in RBD, but no LRRK2 mutations were found. RBD participants performed significantly worse than controls on Unified Parkinson’s Disease Rating Scale (UPDRS)-III, timed “get-up-and-go”, Flamingo test, Sniffin Sticks, and cognitive tests and had worse measures of constipation, quality of life (QOL), and orthostatic hypotension. For all these measures except UPDRS-III, RBD and PD participants were equally impaired. Depression, anxiety, and apathy were worse in RBD compared to PD participants. Stratification of people with RBD according to antidepressant use, obesity, and age altered the odds ratio (OR) of hyposmia compared to controls from 3.4 to 45.5. 74% (95% confidence interval [CI] 66%, 80%) of RBD participants met the MDS criteria for probable prodromal Parkinson’s compared to 0.3% (95% CI 0.009%, 2%) of controls.ConclusionsRBD are impaired across a range of clinical measures consistent with prodromal PD and suggestive of a more severe nonmotor subtype. Clinical risk stratification has the potential to select higher risk patients for neuroprotective interventions.

REM Sleep Behavior Disorder: Diagnosis, Clinical Implications, and Future Directions

“…One very recent large cross sectional study of 171 RBD patients found that 74% (95% CI 66, 80%) met Movement Disorders Society criteria for a diagnosis of prodromal Parkinson’s disease. 41 Longitudinal cohort studies of patients with idiopathic RBD have shown consistent evidence for a strong association with eventual phenoconversion to a defined neurodegenerative disease, predominantly the synucleinopathy phenotypes of PD, nonamnestic MCI, DLB, and MSA (Figure 3). 10,11,28,31,93–97 Phenoconversion risk over 2 to 5 years is approximately 15% to 35%, and longitudinal follow-up between 12 and 25 years increases to 41% to 90.9%, although the risk of phenoconversion has substantial interindividual variability, sometimes occurring over 50 years after initial symptom onset.…”

“…Lastly, genetic studies of RBD remain limited, but RBD has been associated with glucocerebrosidase sequence variation and PD-related genetic loci including the microtubule associated protein tau ( MAPT ) gene in genome-wide association studies, 41,60,61 and the leucine rich repeat kinase ( LRRK2 ) mutation carriers with Parkinson disease. 41,62,63 It has been proposed that the variability in RBD expression in some genetic Parkinsonian disorders may reflect heterogeneous neuropathological substrate with less marked involvement of the brainstem REM atonia control structures in LRRK2 mutation carriers than in idiopathic PD.…”

“…41,62,63 It has been proposed that the variability in RBD expression in some genetic Parkinsonian disorders may reflect heterogeneous neuropathological substrate with less marked involvement of the brainstem REM atonia control structures in LRRK2 mutation carriers than in idiopathic PD.…”

“…23,30,31,41,42,45,89,99–101 In addition, neuropsychological deficits of dysexecutive, attentional, visuoperceptual, and short-term memory impairments appear to progress over time, 38,44,96,102–107 and neurophysiological markers such as electroencephalographic slowing, 108–111 and neuroimaging studies have also demonstrated findings indicating likely underlying synucleinopathy pathology.…”

“…10,12,15,18,21,23–32 In both idiopathic and symptomatic categories, RBD is strongly associated with neurodegenerative diseases, especially synucleinopathies including PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure. 1,10,12,24–28,31,33–41 Rapid eye movement sleep behavior disorder may manifest initially as an idiopathic prodromal state that occurs years to decades before the evolution of overt motor, cognitive, or autonomic impairments as the presenting manifestation of synucleinopathy. Dream enactment symptoms and idiopathic RBD diagnosis may be accompanied by other subtle prodromal features such as subjective cognitive symptoms without evidence of impairment on neuropsychological testing, asymptomatic cognitive or motor deficits, hyposmia, constipation, and orthostatic hypotension; many of these features are associated with a higher risk of pheno-conversion to a defined neurodegenerative disorder.…”