The neurodegenerative synucleinopathies, including Parkinson’s disease and dementia with Lewy bodies, are characterized by a typically lengthy prodromal period of progressive subclinical motor and non-motor manifestations. Among these, idiopathic REM sleep behavior disorder (iRBD) is a powerful early predictor of eventual phenoconversion, and therefore represents a critical opportunity to intervene with neuroprotective therapy. To inform the design of randomized trials, it is essential to study the natural progression of clinical markers during the prodromal stages of disease in order to establish optimal clinical endpoints. In this study, we combined prospective follow-up data from 28 centers of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behavior disorder subjects were assessed for prodromal Parkinson’s disease using the Movement Disorder Society criteria and underwent periodic structured sleep, motor, cognitive, autonomic and olfactory testing. We used linear mixed-effect modelling to estimate annual rates of clinical marker progression stratified by disease subtype, including prodromal Parkinson’s disease and prodromal dementia with Lewy bodies. In addition, we calculated sample size requirements to demonstrate slowing of progression under different anticipated treatment effects. Overall, 1160 subjects were followed over an average of 3.3 ± 2.2 years. Among clinical variables assessed continuously, motor variables tended to progress faster and required the lowest sample sizes, ranging from 151-560 per group (at 50% drug efficacy and 2-year follow-up). By contrast, cognitive, olfactory, and autonomic variables showed modest progression with higher variability, resulting in high sample sizes. The most efficient design was a time-to-event analysis using combined milestones of motor and cognitive decline, estimating 117 per group at 50% drug efficacy and 2-year trial duration. Finally, while phenoconverters showed overall greater progression than non-converters in motor, olfactory, cognitive, and certain autonomic markers, the only robust difference in progression between Parkinson’s disease and dementia with Lewy bodies phenoconverters was in cognitive testing. This large multicenter study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical endpoints and sample size estimates to inform future neuroprotective trials.

In drug-free patients with primary restless legs syndrome, hepcidin level is higher than in controls and may be associated with restless legs syndrome clinical severity. This result emphasizes the complex peripheral iron metabolism deregulation in restless legs syndrome, opening potential perspectives for a personalized approach with a hepcidin antagonist. © 2018 International Parkinson and Movement Disorder Society.

ObjectiveThe association between restless legs syndrome (RLS), cardiovascular diseases (CVD) and hypertension is inconsistent. This case-control study examined i) the association between primary RLS, CVD and hypertension by taking into account many potential confounders and ii) the influence of RLS duration, severity and treatment, sleep and depressive symptoms on CVD and hypertension in primary RLS.MethodsA standardized questionnaire to assess the RLS phenotype, history of CVD and hypertension, sleep and depressive symptoms, drug intake and demographic/clinical features was sent to the France-Ekbom Patients Association members. A CVD event was defined as a self-reported history of coronary heart disease, heart failure, arrhythmia or stroke. Hypertension was also self-assessed. Current treatment for hypertension and arrhythmia also defined underlying hypertension and arrhythmia. Controls without RLS and without consanguinity were chosen by the patients.Results487 patients with primary RLS (median age 71 years; 67.4% women) and 354 controls (68 years, 47.7% women) were included. Most of the patients (91.7%) were treated for RLS, especially with dopaminergic agonists. The median age of RLS onset was 45 years. CVD and hypertension were associated with RLS in unadjusted association, but not after adjustment for age, sex and body mass index. Patients with RLS and with CVD and/or hypertension were significantly older, with hypercholesterolemia, sleep apnea and older age at RLS and at daily RLS onset compared with patients without CVD and/or hypertension. No significant difference was found for other RLS features, ferritin levels, daytime sleepiness, insomnia and depressive symptoms.ConclusionDespite some limitations in the design of this study, we found that most of the treated patients for primary RLS had no association with CVD and hypertension after controlling for key potential confounders. Comorbid CVD or hypertension was associated with cardiovascular risk factors, but not with RLS features except for older age at onset.

Restless legs syndrome (RLS) is frequently comorbid with hypertension and cardiovascular diseases; however this relationship and underlying mechanisms remain controversial. After clinical evaluation, 84 drug-free patients with primary RLS (53 women; mean age 55.1 ± 12.3 years) and 76 controls (47 women; mean age 52.2 ± 15.3 years) underwent 24-hour ambulatory blood pressure (BP) and polysomnographic monitoring, and peripheral arterial tonometry to assess endothelial function for 61 patients and 69 controls. Hypertension was diagnosed in 11.9% of patients with RLS based on office measurement, and in 46.4% on the 24 h recording, with nighttime hypertension, two times more frequent than daytime hypertension. Periodic limb movement during sleep (PLMS), markers of sleep fragmentation, and systolic and mean BP non-dipping profile were more frequent among patients. BP non-dipping status was associated with older age, later RLS onset and diagnosis, RLS severity and higher sleep fragmentation. The mean 24-hour, daytime and nighttime BP values, the frequency of hypertension and the endothelial function were comparable between groups. However, both systolic and diastolic BP trajectories over a 24-hour period differed between groups. In conclusion, patients with RLS exhibit a 24-hour BP deregulation with increased frequency of systolic non-dipping profiles that could worsen the risk for CVD morbidity and mortality.

Background Whether depression and suicide thoughts relate to restless legs syndrome (RLS) or comorbidities associated with RLS remain unclear. Objectives To determine frequency of depressive symptoms and suicidal thoughts in patients with RLS and their change after RLS treatment, associated clinical and polysomnographic factors, and current major depressive episode (MDE) frequency and suicide risk in RLS. Methods Overall, 549 untreated patients with RLS and 549 age‐, sex‐, and education level‐matched controls completed a standardized evaluation, including the Beck Depression Inventory‐II that has one item on suicide thoughts. Patients underwent a polysomnographic recording and completed the Urgency, Premeditation, Perseverance, Sensation Seeking Impulsive Behavior scale. In a subgroup of 153 patients, current MDE and suicide risk were assessed with the face‐to‐face Mini‐International Neuropsychiatric Interview (MINI). A subgroup of 152 patients were evaluated in untreated and treated conditions. Results The frequency of depressive symptoms (32.5%) and suicidal thoughts (28%) was 10‐fold and 3‐fold higher, respectively, in patients with RLS than controls. Current MDE (10.5%) and suicidal risk (19.9%) (MINI) were also high. Moderate‐to‐severe depressive symptoms were associated with young age, female sex, insomnia symptoms, and urgency dimension. The suicide risk was associated with depression, impulsiveness, and RLS severity. RLS treatment improved depressive symptoms but not suicidal thoughts. Conclusion The rate of depressive symptoms, depression, and suicidal thoughts/risk was higher in patients with RLS, with key associations with insomnia symptoms, urgency dimension, and RLS severity. These results emphasize the importance of detecting these symptoms in current practice and of evaluating their change after treatment, especially in young women, to improve RLS management. © 2022 International Parkinson and Movement Disorder Society