Parkinson risk in idiopathic REM sleep behavior disorder: preparing for neuroprotective trials

Abstract

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.

Figure 1. Development of defined neurodegeneration in idiopathic RBD

Shown is the Kaplan-Meier plot of disease-free survival of patients with idiopathic REM sleep behavior disorder (RBD). Ticks indicate censoring events.

Figure 2. Predictive markers of neurodegeneration in idiopathic RBD

Shown is the Kaplan-Meier plot of disease-free survival of patients with idiopathic REM sleep behavior disorder (RBD), stratified according to presence of baseline markers: (A) olfaction, (B) color vision, (C) mild motor dysfunction, (D) autonomic dysfunction, (E) depression/anxiety, and (F) REM atonia loss. To mimic a clinical trial recruitment strategy, results are presented according to baseline assessment only (i.e., patients who develop a de novo marker abnormality over the course of the follow-up remain in the “marker-free” group). Solid line indicates patients with normal values, dashed line abnormal values. The 50% REM atonia (F) is for percentage tonic REM. Hazard ratios (HRs) are with Cox proportional hazards, adjusting for age and sex.

Figure 3. Combining predictive markers of neurodegeneration in idiopathic RBD

Shown is the Kaplan-Meier plot of disease-free survival of patients with idiopathic REM sleep behavior disorder (RBD), stratified according to combinations of baseline markers: (A) removing antidepressant-triggered RBD and age 55 years and older; (B) addition of olfaction and motor combined; (C) addition of olfaction and color vision combined; and (D) addition of motor and color vision combined. Solid line indicates patients with normal values, dashed lines mean that 1 of 2 measures is abnormal, dotted lines mean both measures are abnormal.