Progression of clinical markers in prodromal Parkinson's disease and dementia with Lewy bodies: a multicentre study.

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 behaviour disorder 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 end points. In this study, we combined prospective follow-up data from 28 centres of the International REM Sleep Behavior Disorder Study Group representing 12 countries. Polysomnogram-confirmed REM sleep behaviour 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 to 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 multicentre study demonstrates the evolution of motor and non-motor manifestations in prodromal synucleinopathy. These findings provide optimized clinical end points and sample size estimates to inform future neuroprotective trials.

Role of sleep in neurodegeneration: the consensus report of the 5th Think Tank World Sleep Forum.

Sleep abnormalities may represent an independent risk factor for neurodegeneration. An international expert group convened in 2021 to discuss the state-of-the-science in this domain. The present article summarizes the presentations and discussions concerning the importance of a strategy for studying sleep- and circadian-related interventions for early detection and prevention of neurodegenerative diseases. An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years; discussed the current challenges in the field of relationships among sleep, sleep disorders, and neurodegeneration; and identified future priorities. Sleep efficiency and slow wave activity during non-rapid eye movement (NREM) sleep are decreased in cognitively normal middle-aged and older adults with Alzheimer's disease (AD) pathology. Sleep deprivation increases amyloid-ß (Aß) concentrations in the interstitial fluid of experimental animal models and in cerebrospinal fluid in humans, while increased sleep decreases Aß. Obstructive sleep apnea (OSA) is a risk factor for dementia. Studies indicate that positive airway pressure (PAP) treatment should be started in patients with mild cognitive impairment or AD and comorbid OSA. Identification of other measures of nocturnal hypoxia and sleep fragmentation could better clarify the role of OSA as a risk factor for neurodegeneration. Concerning REM sleep behavior disorder (RBD), it will be crucial to identify the subset of RBD patients who will convert to a specific neurodegenerative disorder. Circadian sleep-wake rhythm disorders (CSWRD) are strong predictors of caregiver stress and institutionalization, but the absence of recommendations or consensus statements must be considered. Future priorities include to develop and validate existing and novel comprehensive assessments of CSWRD in patients with/at risk for dementia. Strategies for studying sleep-circadian-related interventions for early detection/prevention of neurodegenerative diseases are required. CSWRD evaluation may help to identify additional biomarkers for phenotyping and personalizing treatment of neurodegeneration.

Ethical Aspects of Prodromal Synucleinopathy Prognostic Counseling.

Alpha-synucleinopathies can be identified in their prodromal phase, raising several ethical issues. In this review, we first provide definitions of prodromal α-synucleinopathies and discuss the importance of distinguishing between prodromes and risk factors. Next, we discuss the implications of a diagnosis of prodromal α-synucleinopathy and considerations regarding prognostic counseling in both clinical and research settings. We review available data on patient preferences regarding disclosure as well as providers' perspectives. We examine the pros and cons of disclosing a diagnosis of prodromal α-synucleinopathy, taking into consideration the differences between clinical and research settings. Asking about willingness to know in clinical and research settings and the shared decision-making process applied to prognostic counseling is discussed. Concerning research settings, ethical aspects regarding clinical trials are addressed. Availability of direct-to-consumer technologies will likely lead to novel contexts requiring prognostic counseling, and future neuroprotective or neuromodulating treatments may require further considerations on the timing, role, and importance of prognostic counseling. Recommendations on how to address ethical gaps should be a priority for patients, medical professional societies, and research workgroups. Ethical issues must be considered as an integral part of the overall clinical and research approach to prodromal synucleinopathies.

Disruption of Brainstem Structural Connectivity in REM Sleep Behavior Disorder Using 7 Tesla Magnetic Resonance Imaging.

BACKGROUND: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is one of the earliest manifestations of α synucleinopathies. Brainstem pathophysiology underlying REM sleep behavior disorder has been described in animal models, yet it is understudied in living humans because of the lack of an in vivo brainstem nuclei atlas and to the limited magnetic resonance imaging (MRI) sensitivity. OBJECTIVE: To investigate brainstem structural connectivity changes in iRBD patients by using an in vivo probabilistic brainstem nuclei atlas and 7 Tesla MRI. METHODS: Structural connectivity of 12 iRBD patients and 12 controls was evaluated by probabilistic tractography. Two-sided Wilcoxon rank-sum test was used to compare the structural connectivity indices across groups. RESULTS: In iRBD, we found impaired (Z = 2.6, P < 0.01) structural connectivity in 14 brainstem nuclei, including the connectivity between REM-on (eg, subcoeruleus [SubC]) and REM sleep muscle atonia (eg, medullary reticular formation) areas. CONCLUSIONS: The brainstem nuclei diagram of impaired connectivity in human iRBD expands animal models and is a promising tool to study and possibly assess prodromal synucleinopathy stages. © 2021 International Parkinson and Movement Disorder Society.

THN 102 for Excessive Daytime Sleepiness Associated with Parkinson's Disease: A Phase 2a Trial.

BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.

Rapid eye movement sleep behaviour disorder: Past, present, and future.

This manuscript presents an overview of REM sleep behaviour disorder (RBD) with a special focus on European contributions. After an introduction examining the history of the disorder, we address the pathophysiological and clinical aspects, as well as the diagnostic issues. Further, implications of RBD diagnosis and biomarkers are discussed. Contributions of European researchers to this field are highlighted.

Rational Design of Novel Therapies for Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: This review highlights the recent scientific advances that have enabled rational design of novel clinical trials for pantothenate kinase-associated neurodegeneration (PKAN), a rare autosomal recessive neurogenetic disorder associated with progressive neurodegenerative changes and functional impairment. PKAN is caused by genetic variants in the PANK2 gene that result in dysfunction in pantothenate kinase 2 (PANK2) enzyme activity, with consequent disruption of coenzyme A (CoA) synthesis, and subsequent accumulation of brain iron. The clinical phenotype is varied and may include dystonia, rigidity, bradykinesia, postural instability, spasticity, loss of ambulation and ability to communicate, feeding difficulties, psychiatric issues, and cognitive and visual impairment. There are several symptom-targeted treatments, but these do not provide sustained benefit as the disorder progresses. OBJECTIVES: A detailed understanding of the molecular and biochemical pathogenesis of PKAN has opened the door for the design of novel rationally designed therapeutics that target the underlying mechanisms. METHODS: Two large double-blind phase 3 clinical trials have been completed for deferiprone (an iron chelation treatment) and fosmetpantotenate (precursor replacement therapy). A pilot open-label trial of pantethine as a potential precursor replacement strategy has also been completed, and a trial of 4-phosphopantetheine has begun enrollment. Several other compounds have been evaluated in pre-clinical studies, and additional clinical trials may be anticipated. CONCLUSIONS: Experience with these trials has encouraged a critical evaluation of optimal trial designs, as well as the development of PKAN-specific measures to monitor outcomes. PKAN provides a valuable example for understanding targeted drug development and clinical trial design for rare disorders. © 2021 International Parkinson and Movement Disorder Society.

Solriamfetol for Excessive Daytime Sleepiness in Parkinson's Disease: Phase 2 Proof-of-Concept Trial.

BACKGROUND: Solriamfetol is approved (US and EU) for excessive daytime sleepiness (EDS) in narcolepsy and obstructive sleep apnea. OBJECTIVES: Evaluate solriamfetol safety/efficacy for EDS in Parkinson's disease (PD). METHODS: Phase 2, double-blind, 4-week, crossover trial: adults with PD and EDS were randomized to sequence A (placebo, solriamfetol 75, 150, 300 mg/d), B (solriamfetol 75, 150, 300 mg/d, placebo), or C (placebo). Outcomes (safety/tolerability [primary]; Epworth Sleepiness Scale [ESS]; Maintenance of Wakefulness Test [MWT]) were assessed weekly. P values are nominal. RESULTS: Common adverse events (n = 66): nausea (10.7%), dizziness (7.1%), dry mouth (7.1%), headache (7.1%), anxiety (5.4%), constipation (5.4%), dyspepsia (5.4%). ESS decreased both placebo (-4.78) and solriamfetol (-4.82 to -5.72; P > 0.05). MWT improved dose-dependently with solriamfetol, increasing by 5.05 minutes with 300 mg relative to placebo (P = 0.0098). CONCLUSIONS: Safety/tolerability was consistent with solriamfetol's known profile. There were no significant improvements on ESS; MWT results suggest possible benefit with solriamfetol in PD. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Fosmetpantotenate Randomized Controlled Trial in Pantothenate Kinase-Associated Neurodegeneration.

BACKGROUND: Pantothenate kinase-associated neurodegeneration (PKAN) currently has no approved treatments. OBJECTIVES: The Fosmetpantotenate Replacement Therapy pivotal trial examined whether treatment with fosmetpantotenate improves PKAN symptoms and stabilizes disease progression. METHODS: This randomized, double-blind, placebo-controlled, multicenter study evaluated fosmetpantotenate, 300 mg oral dose three times daily, versus placebo over a 24-week double-blind period. Patients with pathogenic variants of PANK2, aged 6 to 65 years, with a score ≥6 on the PKAN-Activities of Daily Living (PKAN-ADL) scale were enrolled. Patients were randomized to active (fosmetpantotenate) or placebo treatment, stratified by weight and age. The primary efficacy endpoint was change from baseline at week 24 in PKAN-ADL. RESULTS: Between July 23, 2017, and December 18, 2018, 84 patients were randomized (fosmetpantotenate: n = 41; placebo: n = 43); all 84 patients were included in the analyses. Six patients in the placebo group discontinued treatment; two had worsening dystonia, two had poor compliance, and two died of PKAN-related complications (aspiration during feeding and disease progression with respiratory failure, respectively). Fosmetpantotenate and placebo group PKAN-ADL mean (standard deviation) scores were 28.2 (11.4) and 27.4 (11.5) at baseline, respectively, and were 26.9 (12.5) and 24.5 (11.8) at week 24, respectively. The difference in least square mean (95% confidence interval) at week 24 between fosmetpantotenate and placebo was -0.09 (-1.69 to 1.51; P = 0.9115). The overall incidence of treatment-emergent serious adverse events was similar in the fosmetpantotenate (8/41; 19.5%) and placebo (6/43; 14.0%) groups. CONCLUSIONS: Treatment with fosmetpantotenate was safe but did not improve function assessed by the PKAN-ADL in patients with PKAN. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effect of Urate-Elevating Inosine on Early Parkinson Disease Progression: The SURE-PD3 Randomized Clinical Trial.

Importance: Urate elevation, despite associations with crystallopathic, cardiovascular, and metabolic disorders, has been pursued as a potential disease-modifying strategy for Parkinson disease (PD) based on convergent biological, epidemiological, and clinical data. Objective: To determine whether sustained urate-elevating treatment with the urate precursor inosine slows early PD progression. Design, Participants, and Setting: Randomized, double-blind, placebo-controlled, phase 3 trial of oral inosine treatment in early PD. A total of 587 individuals consented, and 298 with PD not yet requiring dopaminergic medication, striatal dopamine transporter deficiency, and serum urate below the population median concentration (<5.8 mg/dL) were randomized between August 2016 and December 2017 at 58 US sites, and were followed up through June 2019. Interventions: Inosine, dosed by blinded titration to increase serum urate concentrations to 7.1-8.0 mg/dL (n = 149) or matching placebo (n = 149) for up to 2 years. Main Outcomes and Measures: The primary outcome was rate of change in the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS; parts I-III) total score (range, 0-236; higher scores indicate greater disability; minimum clinically important difference of 6.3 points) prior to dopaminergic drug therapy initiation. Secondary outcomes included serum urate to measure target engagement, adverse events to measure safety, and 29 efficacy measures of disability, quality of life, cognition, mood, autonomic function, and striatal dopamine transporter binding as a biomarker of neuronal integrity. Results: Based on a prespecified interim futility analysis, the study closed early, with 273 (92%) of the randomized participants (49% women; mean age, 63 years) completing the study. Clinical progression rates were not significantly different between participants randomized to inosine (MDS-UPDRS score, 11.1 [95% CI, 9.7-12.6] points per year) and placebo (MDS-UPDRS score, 9.9 [95% CI, 8.4-11.3] points per year; difference, 1.26 [95% CI, -0.59 to 3.11] points per year; P = .18). Sustained elevation of serum urate by 2.03 mg/dL (from a baseline level of 4.6 mg/dL; 44% increase) occurred in the inosine group vs a 0.01-mg/dL change in serum urate in the placebo group (difference, 2.02 mg/dL [95% CI, 1.85-2.19 mg/dL]; P<.001). There were no significant differences for secondary efficacy outcomes including dopamine transporter binding loss. Participants randomized to inosine, compared with placebo, experienced fewer serious adverse events (7.4 vs 13.1 per 100 patient-years) but more kidney stones (7.0 vs 1.4 stones per 100 patient-years). Conclusions and Relevance: Among patients recently diagnosed as having PD, treatment with inosine, compared with placebo, did not result in a significant difference in the rate of clinical disease progression. The findings do not support the use of inosine as a treatment for early PD. Trial Registration: ClinicalTrials.gov Identifier: NCT02642393.

Circadian alterations in patients with neurodegenerative diseases: Neuropathological basis of underlying network mechanisms.

Circadian organization of physiology and behavior is an important biological process that allows organisms to anticipate and prepare for daily changes and demands. Disruptions in this system precipitates a wide range of health issues. In patients with neurodegenerative diseases, alterations of circadian rhythms are among the most common and debilitating symptoms. Although a growing awareness of these symptoms has occurred during the last decade, their underlying neuropathophysiological circuitry remains poorly understood and consequently no effective therapeutic strategies are available to alleviate these health issues. Recent studies have examined the neuropathological status of the different neural components of the circuitry governing the generation of circadian rhythms in neurodegenerative diseases. In this review, we will dissect the potential contribution of dysfunctions in the different nodes of this circuitry to circadian alterations in patients with neurodegenerative diseases. A deeper understanding of these mechanisms will provide not only a better understanding of disease neuro-pathophysiology, but also hold the promise for developing effective and mechanisms-based therapies.

Clinical trials in REM sleep behavioural disorder: challenges and opportunities.

The rapid eye movement sleep behavioural disorder (RBD) population is an ideal study population for testing disease-modifying treatments for synucleinopathies, since RBD represents an early prodromal stage of synucleinopathy when neuropathology may be more responsive to treatment. While clonazepam and melatonin are most commonly used as symptomatic treatments for RBD, clinical trials of symptomatic treatments are also needed to identify evidence-based treatments. A comprehensive framework for both disease-modifying and symptomatic treatment trials in RBD is described, including potential treatments in the pipeline, cost-effective participant recruitment and selection, study design, outcomes and dissemination of results. For disease-modifying treatment clinical trials, the recommended primary outcome is phenoconversion to an overt synucleinopathy, and stratification features should be used to select a study population at high risk of phenoconversion, to enable more rapid clinical trials. For symptomatic treatment clinical trials, objective polysomnogram-based measurement of RBD-related movements and vocalisations should be the primary outcome measure, rather than subjective scales or diaries. Mobile technology to enable objective measurement of RBD episodes in the ambulatory setting, and advances in imaging, biofluid, tissue, and neurophysiological biomarkers of synucleinopathies, will enable more efficient clinical trials but are still in development. Increasing awareness of RBD among the general public and medical community coupled with timely diagnosis of these diseases will facilitate progress in the development of therapeutics for RBD and associated neurodegenerative disorders.

Risk and predictors of dementia and parkinsonism in idiopathic REM sleep behaviour disorder: a multicentre study.

Idiopathic REM sleep behaviour disorder (iRBD) is a powerful early sign of Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. This provides an unprecedented opportunity to directly observe prodromal neurodegenerative states, and potentially intervene with neuroprotective therapy. For future neuroprotective trials, it is essential to accurately estimate phenoconversion rate and identify potential predictors of phenoconversion. This study assessed the neurodegenerative disease risk and predictors of neurodegeneration in a large multicentre cohort of iRBD. We combined prospective follow-up data from 24 centres of the International RBD Study Group. At baseline, patients with polysomnographically-confirmed iRBD without parkinsonism or dementia underwent sleep, motor, cognitive, autonomic and special sensory testing. Patients were then prospectively followed, during which risk of dementia and parkinsonsim were assessed. The risk of dementia and parkinsonism was estimated with Kaplan-Meier analysis. Predictors of phenoconversion were assessed with Cox proportional hazards analysis, adjusting for age, sex, and centre. Sample size estimates for disease-modifying trials were calculated using a time-to-event analysis. Overall, 1280 patients were recruited. The average age was 66.3 ± 8.4 and 82.5% were male. Average follow-up was 4.6 years (range = 1-19 years). The overall conversion rate from iRBD to an overt neurodegenerative syndrome was 6.3% per year, with 73.5% converting after 12-year follow-up. The rate of phenoconversion was significantly increased with abnormal quantitative motor testing [hazard ratio (HR) = 3.16], 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 DAT scan (HR = 1.98), colour vision abnormalities (HR = 1.69), constipation (HR = 1.67), REM atonia loss (HR = 1.54), and age (HR = 1.54). There was no significant predictive value of sex, daytime somnolence, insomnia, restless legs syndrome, sleep apnoea, urinary dysfunction, orthostatic symptoms, depression, anxiety, or hyperechogenicity on substantia nigra ultrasound. Among predictive markers, only cognitive variables were different at baseline between those converting to primary dementia versus parkinsonism. Sample size estimates for definitive neuroprotective trials ranged from 142 to 366 patients per arm. This large multicentre study documents the high phenoconversion rate from iRBD to an overt neurodegenerative syndrome. Our findings provide estimates of the relative predictive value of prodromal markers, which can be used to stratify patients for neuroprotective trials.

The FOsmetpantotenate Replacement Therapy (FORT) randomized, double-blind, Placebo-controlled pivotal trial: Study design and development methodology of a novel primary efficacy outcome in patients with pantothenate kinase-associated neurodegeneration.

BACKGROUND/AIMS: Pantothenate kinase-associated neurodegeneration is a rare neurodegenerative disease with a variable clinical phenotype. Fosmetpantotenate is in clinical development as a replacement therapy that targets the underlying cause of pantothenate kinase-associated neurodegeneration. The FOsmetpantotenate Replacement Therapy pivotal trial-an ongoing phase 3, randomized, double-blind, placebo-controlled, multicenter trial-examines the efficacy and safety of fosmetpantotenate in patients with pantothenate kinase-associated neurodegeneration aged 6-65 years. The FOsmetpantotenate Replacement Therapy trial required the development and validation of a novel patient-reported outcome measure specifically relevant to pantothenate kinase-associated neurodegeneration. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to assess activities of daily living related to motor functioning in patients with pantothenate kinase-associated neurodegeneration to evaluate clinically meaningful change as the primary efficacy endpoint in clinical trials. This article describes the design of the FOsmetpantotenate Replacement Therapy pivotal trial and the development of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale. METHODS: A systematic, iterative process consistent with the US Food and Drug Administration guidance and advice from the Committee for Medicinal Products for Human Use at the European Medicines Agency was used to evaluate and adapt or remove scale items of an existing widely used instrument for movement disorders to be pantothenate kinase-associated neurodegeneration-specific, and to create new items. Modification of scale items was based on input from international experts, patient advocacy leaders, and primary caregivers. A clinimetric study of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale conducted in patients with pantothenate kinase-associated neurodegeneration or their caregivers (N = 40 at first assessment; N = 39 at second assessment) demonstrated high content and construct validity and excellent test-retest reliability over an approximately 2-week period. The Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale was developed to be broadly useful within clinical and research settings in the examination of patient response to pantothenate kinase-associated neurodegeneration therapies. RESULTS: Approximately 82 patients will be enrolled in the ongoing FOsmetpantotenate Replacement Therapy pivotal trial. Change from baseline in Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living score over the 24-week double-blind period is the primary efficacy endpoint for the FOsmetpantotenate Replacement Therapy trial. Treatment effect will be evaluated using a mixed model for repeated measures analysis to assess data from all visits simultaneously. CONCLUSION: The development and implementation of the Pantothenate Kinase-Associated Neurodegeneration-Activities of Daily Living scale in the FOsmetpantotenate Replacement Therapy trial illustrates the feasibility and potential patient benefit of putting into practice the current regulatory guidance on the use of patient-reported outcomes in clinical trials. These processes can be broadly applied to clinical trial methodology that requires newly created or revised patient-reported outcome measures to evaluate outcome change as a primary efficacy endpoint. The goal of such measures in patients with pantothenate kinase-associated neurodegeneration is to facilitate development of disease-modifying therapeutics in multiple drug development programs.

Disturbances of Sleep and Alertness in Parkinson's Disease.

PURPOSE OF REVIEW: Parkinson's disease (PD) is the second most common neurodegenerative disorder. Sleep dysfunction is one of the most common non-motor manifestations of PD that has gained significant interest over the past two decades due to its impact on the daily lives of PD patients, poorly understood mechanisms, and limited treatment options. In this review, we discuss the most common sleep disorders in PD and present recent investigations that have broadened our understanding of the epidemiology, clinical manifestations, diagnosis, and treatment of disturbed sleep and alertness in PD. RESENT FINDINGS: The etiology of impaired sleep-wake cycles in PD is multifactorial. Sleep dysfunction in PD encompasses insomnia, REM sleep behavior disorder, sleep-disordered breathing, restless legs syndrome, and circadian dysregulation. Despite the high prevalence of sleep dysfunction in PD, evidence supporting the efficacy of treatment strategies is limited. We are at the opportune time to advance our understanding of sleep dysfunction in PD, which will hopefully lead to mechanisms-driven interventions for better sleep and allow us to approach sleep as a modifiable therapeutic target for other non-motor and motor manifestations in PD.

Longitudinal assessment of excessive daytime sleepiness in early Parkinson's disease.

BACKGROUND: Excessive daytime sleepiness (EDS) is common and disabling in Parkinson's disease (PD). Predictors of EDS are unclear, and data on biological correlates of EDS in PD are limited. We investigated clinical, imaging and biological variables associated with longitudinal changes in sleepiness in early PD. METHODS: The Parkinson's Progression Markers Initiative is a prospective cohort study evaluating progression markers in participants with PD who are unmedicated at baseline (n=423) and healthy controls (HC; n=196). EDS was measured with the Epworth Sleepiness Scale (ESS). Clinical, biological and imaging variables were assessed for associations with EDS for up to 3 years. A machine learning approach (random survival forests) was used to investigate baseline predictors of incident EDS. RESULTS: ESS increased in PD from baseline to year 3 (mean±SD 5.8±3.5 to 7.55±4.6, p<0.0001), with no change in HC. Longitudinally, EDS in PD was associated with non-tremor dominant phenotype, autonomic dysfunction, depression, anxiety and probable behaviour disorder, but not cognitive dysfunction or motor severity. Dopaminergic therapy was associated with EDS at years 2 and 3, as dose increased. EDS was also associated with presynaptic dopaminergic dysfunction, whereas biofluid markers at year 1 showed no significant associations with EDS. A predictive index for EDS was generated, which included seven baseline characteristics, including non-motor symptoms and cerebrospinal fluid phosphorylated-tau/total-tau ratio. CONCLUSIONS: In early PD, EDS increases significantly over time and is associated with several clinical variables. The influence of dopaminergic therapy on EDS is dose dependent. Further longitudinal analyses will better characterise associations with imaging and biomarkers.

Management of sleep disorders in Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and multiple system atrophy (MSA) are disorders associated with α synuclein-related neurodegeneration. Nonmotor symptoms are common hallmarks of these disorders, and disturbances of the sleep-wake cycle are among the most common nonmotor symptoms. It is only recently that sleep disturbances have received the attention of the medical and research community. Significant progress has been made in understanding the pathophysiology of sleep and wake disruption in alphasynucleinopathies during the past few decades. Despite these advancements, treatment options are limited and frequently associated with problematic side effects. Further studies that center on the development of novel treatment approaches are very much needed. In this article, the author discusses the current state of the management of disturbed sleep and alertness in PD and MSA. © 2017 International Parkinson and Movement Disorder Society.