Parkinson risk in idiopathic REM sleep behavior disorder

Objective: To precisely delineate clinical risk factors for conversion from idiopathic REM sleep behavior disorder (RBD) to Parkinson disease, dementia with Lewy bodies, and multiple system atrophy, in order to enable practical planning and stratification of neuroprotective trials against neurodegenerative synucleinopathy. Methods: In a 10-year prospective cohort, we tested prodromal Parkinson disease markers in 89 patients with idiopathic RBD. With Kaplan-Meier analysis, we calculated risk of neurodegenerative synucleinopathy, and using Cox proportional hazards, tested the ability of prodromal markers to identify patients at higher disease risk. By combining predictive markers, we then designed stratification strategies to optimally select patients for definitive neuroprotective trials. Results: The risk of defined neurodegenerative synucleinopathy was high: 30% developed disease at 3 years, rising to 66% at 7.5 years. Advanced age (hazard ratio [HR] = 1.07), olfactory loss (HR = 2.8), abnormal color vision (HR = 3.1), subtle motor dysfunction (HR = 3.9), and nonuse of antidepressants (HR = 3.5) identified higher risk of disease conversion. However, mild cognitive impairment (HR = 1.8), depression (HR = 0.63), Parkinson personality, treatment with clonazepam (HR = 1.3) or melatonin (HR = 0.55), autonomic markers, and sex (HR = 1.37) did not clearly predict clinical neurodegeneration. Stratification with prodromal markers increased risk of neurodegenerative disease conversion by 200%, and combining markers allowed sample size reduction in neuroprotective trials by >40%. With a moderately effective agent (HR = 0.5), trials with fewer than 80 subjects per group can demonstrate definitive reductions in neurodegenerative disease. Conclusions: Using stratification with simply assessed markers, it is now not only possible, but practical to include patients with RBD in neuroprotective trials against Parkinson disease, multiple system atrophy, and dementia with Lewy bodies.

[1]  G. Deuschl,et al.  Time to Redefine PD? Introductory Statement of the MDS Task Force on the Definition of Parkinson's Disease , 2014, Movement disorders : official journal of the Movement Disorder Society.

[2]  R. Postuma,et al.  Antidepressants and REM sleep behavior disorder: isolated side effect or neurodegenerative signal? , 2013, Sleep.

[3]  C. Adler,et al.  Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder. , 2013, Sleep medicine.

[4]  C Trenkwalder,et al.  Rapid eye movement sleep behavior disorder: devising controlled active treatment studies for symptomatic and neuroprotective therapy--a consensus statement from the International Rapid Eye Movement Sleep Behavior Disorder Study Group. , 2013, Sleep medicine.

[5]  Carlos H Schenck,et al.  Delayed emergence of a parkinsonian disorder or dementia in 81% of older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder: a 16-year update on a previously reported series. , 2013, Sleep medicine.

[6]  R. Postuma,et al.  Prodromal autonomic symptoms and signs in Parkinson's disease and dementia with Lewy bodies , 2013, Movement disorders : official journal of the Movement Disorder Society.

[7]  J. Molinuevo,et al.  Neurodegenerative disease status and post-mortem pathology in idiopathic rapid-eye-movement sleep behaviour disorder: an observational cohort study , 2013, The Lancet Neurology.

[8]  T. Dang-Vu,et al.  Hippocampal perfusion predicts impending neurodegeneration in REM sleep behavior disorder , 2012, Neurology.

[9]  W. Oertel,et al.  Environmental risk factors for REM sleep behavior disorder , 2012, Neurology.

[10]  R. Postuma,et al.  REM sleep behavior disorder: From dreams to neurodegeneration , 2012, Neurobiology of Disease.

[11]  A. Lang,et al.  How does parkinsonism start? Prodromal parkinsonism motor changes in idiopathic REM sleep behaviour disorder. , 2012, Brain : a journal of neurology.

[12]  W. Oertel,et al.  Identifying prodromal Parkinson's disease: Pre‐Motor disorders in Parkinson's disease , 2012, Movement disorders : official journal of the Movement Disorder Society.

[13]  V. Mok,et al.  Prospective outcome of rapid eye movement sleep behaviour disorder: psychiatric disorders as a potential early marker of Parkinson's disease , 2012, Journal of Neurology, Neurosurgery & Psychiatry.

[14]  V. Pankratz,et al.  Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: A population‐based study , 2012, Annals of neurology.

[15]  R. Postuma,et al.  Cardiac autonomic denervation in Parkinson's disease is linked to REM sleep behavior disorder , 2011, Movement disorders : official journal of the Movement Disorder Society.

[16]  R. Petersen.  Clinical practice. Mild cognitive impairment. , 2011, The New England journal of medicine.

[17]  R. Postuma,et al.  Olfaction and color vision identify impending neurodegeneration in rapid eye movement sleep behavior disorder , 2011, Annals of neurology.

[18]  Michael Schocke,et al.  White and gray matter abnormalities in idiopathic rapid eye movement sleep behavior disorder: A diffusion‐tensor imaging and voxel‐based morphometry study , 2011, Annals of neurology.

[19]  J. Molinuevo,et al.  Decreased striatal dopamine transporter uptake and substantia nigra hyperechogenicity as risk markers of synucleinopathy in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a prospective study , 2010, The Lancet Neurology.

[20]  R. Postuma,et al.  Cardiac autonomic dysfunction in idiopathic REM sleep behavior disorder , 2010, Movement disorders : official journal of the Movement Disorder Society.

[21]  Yves Dauvilliers,et al.  Polysomnographic diagnosis of idiopathic REM sleep behavior disorder , 2010, Movement disorders : official journal of the Movement Disorder Society.

[22]  R. Postuma,et al.  Severity of REM atonia loss in idiopathic REM sleep behavior disorder predicts Parkinson disease , 2010, Neurology.

[23]  R. Postuma,et al.  Idiopathic REM sleep behavior disorder in the transition to degenerative disease , 2009, Movement disorders : official journal of the Movement Disorder Society.

[24]  R. Postuma,et al.  Mild cognitive impairment in rapid eye movement sleep behavior disorder and Parkinson's disease , 2009, Annals of neurology.

[25]  M. Vendette,et al.  Quantifying the risk of neurodegenerative disease in idiopathic REM sleep behavior disorder , 2009, Neurology.

[26]  R. Postuma,et al.  Manifestations of Parkinson disease differ in association with REM sleep behavior disorder , 2008, Movement disorders : official journal of the Movement Disorder Society.

[27]  E. Tolosa,et al.  Diagnostic procedures for Parkinson's disease dementia: Recommendations from the movement disorder society task force , 2007, Movement disorders : official journal of the Movement Disorder Society.

[28]  K. Hirata,et al.  Reduced cardiac 123I-MIBG scintigraphy in idiopathic REM sleep behavior disorder , 2006, Neurology.

[29]  C. Brayne,et al.  What is the evidence for a premorbid parkinsonian personality: A systematic review , 2006, Movement disorders : official journal of the Movement Disorder Society.

[30]  A. Lang,et al.  Potential early markers of Parkinson disease in idiopathic REM sleep behavior disorder , 2006, Neurology.

[31]  J. Cummings,et al.  The Montreal Cognitive Assessment, MoCA: A Brief Screening Tool For Mild Cognitive Impairment , 2005, Journal of the American Geriatrics Society.

[32]  Sid Gilman,et al.  Development and validation of the Unified Multiple System Atrophy Rating Scale (UMSARS) , 2004, Movement disorders : official journal of the Movement Disorder Society.

[33]  Mark W. Mahowald,et al.  Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behavior disorder , 1996, Neurology.

[34]  A. Lees,et al.  What features improve the accuracy of clinical diagnosis in Parkinson's disease , 1992, Neurology.

[35]  Cloninger Cr.  A systematic method for clinical description and classification of personality variants: A proposal. , 1987 .

[36]  A. Beck,et al.  An inventory for measuring depression. , 1961, Archives of general psychiatry.

[37]  Dean Farnsworth,et al.  The Farnsworth-Munsell 100-Hue and Dichotomous Tests for Color Vision* , 1943 .

[38]  M. Mahowald,et al.  Delayed emergence of a parkinsonian disorder or dementia in 81% of older males initially diagnosed with idiopathic REM sleep behavior disorder (RBD): 16 year update on a previously reported series , 2013 .

[39]  C. Robert Cloninger.  A systematic method for clinical description and classification of personality variants. A proposal. , 1987, Archives of general psychiatry.