Clinical Significance of REM Sleep Behavior Disorders and Other Non-motor Symptoms of Parkinsonism

Rapid eye movement sleep behavior disorder (RBD) is one of the most common non-motor symptoms of parkinsonism, and it may serve as a prodromal marker of neurodegenerative disease. The mechanism underlying RBD is unclear. Several prospective studies have reported that specific non-motor symptoms predict a conversion risk of developing a neurodegenerative disease, including olfactory dysfunction, abnormal color vision, autonomic dysfunction, excessive daytime sleepiness, depression, and cognitive impairment. Parkinson’s disease (PD) with RBD exhibits clinical heterogeneity with respect to motor and non-motor symptoms compared with PD without RBD. In this review, we describe the main clinical and pathogenic features of RBD, focusing on its association with other non-motor symptoms of parkinsonism.     

帕金森病非运动症状研究现状

帕金森病(Parkinson’s disease,PD)是一种中枢神经系统退行性病变,临床上通常以静止性震颤、运动迟缓、齿轮样肌僵直、姿势反射障碍等运动障碍为主要临床表现。一直以来针对帕金森病的治疗方案是以改善患者的运动症状为主要目标,但PD患者通常还会出现感觉障碍(疼痛等)、睡眠障碍(日间过度睡眠等)、自主神经功能异常及精神神经症状(抑郁、躁狂及情感障碍)等,称之为非运动症状(non-motor symptoms,NMS)。有资料显示PD的某些非运动症状与年龄、疾病的严重程度密切相关,对患者生活质量的影响较运动症状更加明显。一些非运动症状,如嗅觉障碍、便秘、抑郁、快速眼动期睡眠行为紊乱(RBD)等,可在疾病早期甚至运动症状出现之前出现,可能对PD的早期诊断有所帮助。非运动症状对患者造成的负担可远远超过运动障碍对患者日常生活和幸福感的影响,深入了解非运动症状,对于PD的预防、治疗及远期预后具有积极意义。本文总结近年来文献并以上述非运动症状的病理、常见临床表现、常用的临床评估及治疗方案为阐述架构,展现近年来PDNMS的研究进展。为了提供一种可以量化的工具,研究者还发明了非运动症状评价量表(NMSS)作为PD非运动症状的临床评价,对严重程度和发作频率进行评估,包含9个方面:心血管、睡眠/疲劳、情绪/认知、感知障碍、注意力/记忆、胃肠道症状、泌尿系统症状、性功能及混合症状,可为临床评价非运动症状的严重程度及治疗提供帮助。     

How specific are non-motor symptoms in the prodrome of Parkinson's disease compared to other movement disorders?

The clinical diagnosis of Parkinson's disease (PD) based on motor signs is often preceded by several non-motor symptoms that can indicate early prodromal neurodegenerative processes. Such prodromal symptoms can aid the early detection of PD, but their specificity for prodromal PD in comparison to prodromes of other movement disorders is still largely unclear. We here aim to give a first insight into the published evidence of prodromal non-motor symptoms in PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), Huntington's disease (HD), progressive supranuclear palsy (PSP) and spinocerebellar ataxia (SCA). REM-sleep behavior disorder (RBD) and autonomic dysfunction have been observed in the prodromes of PD, MSA, DLB and SCA. Depression and cognitive decline have been reported for prodromal PD, DLB, HD, SCA, and PSP. Olfactory loss has only been described in prodromal PD/DLB. However, estimating the specificity of prodromal non-motor symptoms in PD is so far complicated by scarce prospective evidence and study limitations. Information on marker specificity is a prerequisite for an accurate early (differential) diagnosis of prodromal diseases, as well as specific recruitment for targeted neuroprotective interventions. We here would like to raise awareness of these issues and encourage further prospective research of prodromal non-motor symptoms in neurodegenerative movement disorders and other diseases.     

Microstructural changes in patients with Parkinson disease and REM sleep behavior disorder: depressive symptoms versus non-depressed

Search for Parkinson’s disease (PD) progression biomarkers has led to the identification of both motor and non-motor symptoms relevant of prodromal PD that could be eye-opening to the spreading underlying Lewy body pathogenesis. One most robust predictor of PD is the REM sleep behavior disorder (RBD), and one most common early non-motor symptom of PD is depression. With RBD, frequently coexisting with clinical depression and both predicting dopamine transmission dysfunction, we aimed to survey structural associates of depressive symptoms in early PD patients with comorbid RBD. Through diffusion MRI connectometry, we tracked fiber differences comparing DWI images obtained from 14 patients with depressive symptoms and 18 without depression from a group with comorbid RBD and PD. DWI images and patients were recruited from the Parkinson’s Progression Markers Initiative database. PD-RBD patients with depressive symptoms showed pathways with significantly reduced connectivity in the right cingulum, left and right fornix, left inferior longitudinal fasciculus, right corticospinal tract, left middle cerebellar peduncle and genu of corpus callosum (FDR = 0.0228). Diffusivity alteration of the mentioned fibers in depressed, early PD patients with RBD might reflect underlying PD pathology and serve as common structural DWI signatures for early PD diagnosis.     

Potential impact of self-perceived prodromal symptoms on the early diagnosis of Parkinson’s disease

The detection of Parkinson’s disease (PD) at stages earlier than current diagnostic criteria allow for may increase the efficacy of disease-modifying therapies. Here we studied the relationship between retrospectively reported prodromal non-motor and motor features of PD, their pre-diagnostic presentation to physicians, and the extrapolated potential of an earlier diagnosis of PD considering early diagnostic markers detected at presence. One hundred and fifteen PD patients (41 women; age 63.2 ± 8.6 years) underwent a structured face-to-face interview on 22 prediagnostic symptoms. Present olfactory function, motor symptoms, and substantia nigra hyperechogenicity (SN-h) were assessed using standardized tools. Most frequently self-perceived symptoms in the early and very early prediagnostic phase (>2, >7 years prior to diagnosis) were hyposmia (23, 10 %), musculoskeletal pain (21, 9 %), and depression/anxiety (14, 11 %). In the late prediagnostic phase (≤2 years) mild motor signs, especially asymmetric bradykinesia and rest tremor, increasingly dominated the self-perception. In the prediagnostic phase, 99 % of patients consulted a physician because of motor symptoms but only 36 % with non-motor symptoms, mostly pain (20 %), depression/anxiety (9 %), constipation, bladder urgency, insomnia, REM sleep behaviour disorder, sexual dysfunction, and malignant melanoma (each, <6 %). Assuming the potential detectability of present hyposmia, asymmetric motor slowing and SN-h, a triad highly specific for PD, as early as 5 years prior to diagnosis, up to 84 (73 %) patients could have been identified in the prediagnostic phase using their or their physicians’ awareness of early symptoms. We conclude that educating the general population and physicians on the importance of distinct prodromal features and applying symptom-specific diagnostic programs can improve the early detection of PD.     

Identifying prodromal Parkinson's disease: pre-motor disorders in Parkinson's disease

Increasing recognition that Parkinson's disease (PD) may start outside of the substantia nigra has led to a rapidly expanding effort to define prodromal stages of PD, before motor signs permit classical diagnosis. Many of these efforts center around the identification of clinical non-motor symptoms and signs of disease. There is now direct evidence that olfaction, rapid eye movement (REM) sleep behavior disorder (RBD), constipation, and depression can be present in prodromal PD. In addition, there is suggestive evidence that visual changes, other autonomic symptoms, and subtle cognitive changes may also be present at prodromal stages. A critical issue in utility of these prodromal markers will be assessment of sensitivity, specificity, and positive and negative predictive values. Although these have yet to be fully defined, olfactory deficits, some visual changes, and autonomic symptoms occur in the majority of PD patients at diagnosis, suggesting good potential sensitivity. However, with the exception of RBD and perhaps some specific autonomic measures, specificity, and positive predictive value of these markers may be insufficient to be used alone as identifiers of prodromal disease. The evidence for the utility of olfaction, RBD, autonomic markers, visual changes, mood disorders, and cognitive loss as markers of prodromal PD and the potential sensitivity and specificity of these markers are summarized.     

Zellersatz und adulte Neurogenese beim idiopathischen Parkinson-Syndrom

Parkinson’s disease (PD) is the most common age-related movement disorder and characterized by slowly progressive neurodegeneration resulting in motor symptoms, such as bradykinesia, rigidity, tremor and postural instability. Moreover, non-motor symptoms, such as hyposmia, anxiety and depression reduce the quality of life in PD. Motor symptoms are associated with a distinct striatal dopaminergic deficit resulting from axonal dysfunction and neuronal loss in the substantia nigra (SN). Recent progress in stem cell technology allows the optimization of cellular transplantation strategies in order to alleviate the motor deficit, which potentially leads to a reactivation of this therapeutic strategy. Besides neurodegenerative processes impaired adult neurogenesis and consequentially reduced endogenous cellular plasticity may play an important role in PD. This article discusses the notion that non-motor symptoms in PD may partly be explained by reduced adult neurogenesis in the olfactory bulb and hippocampus.     

Beyond tremor and rigidity: non-motor features of Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease and primarily considered as a movement disorder defined by the presence of motor symptoms, such as bradykinesia, tremor and rigidity. However, it is nowadays widely accepted that PD is associated with a wide variety of non-motor features, which affect the vast majority of patients during the course of the disease and may even precede the onset of motor symptoms. The spectrum of these non-motor disturbances is very broad and comprises neuropsychiatric conditions, such as depression, dementia and hallucinations, as well as autonomic, sensory and sleep disorders. Physicians need to be aware of these non-motor features, since they have substantial impact on the health-related quality of life of PD patients, even ahead of motor symptoms. This article aims to provide an overview of frequently observed non-motor features in PD and discusses prospects and limitations of currently available options for symptomatic treatment of these disturbances.     

REM sleep behavior disorder in Japanese patients with Parkinson’s disease: a multicenter study using the REM sleep behavior disorder screening questionnaire

REM sleep behavior disorder (RBD) is known to be observed more frequently in patients with an α-synucleinopathy such as Parkinson's disease (PD) than in the general population. The precise prevalence of RBD in Japanese PD patients is not known. Therefore, we investigated the prevalence and the clinical characteristics of patients with RBD in a large population of Japanese patients with PD. We investigated various clinical features and employed the Japanese version of the RBD screening questionnaire on 469 non-demented Japanese PD patients in this multicenter study. Probable or possible RBD was detected in 146 patients (31.1%) and was significantly associated with longer PD duration, higher Hoehn and Yahr stage, higher Unified Parkinson's Disease Rating Scale part III subscale (7 items), more motor fluctuations, and a higher levodopa-equivalent daily dose (p < 0.01). As to the major autonomic dysfunctions, severe constipation was significantly more frequent in PD patients with RBD than in those without it (p < 0.01). The RBD symptoms of 53 patients (39.0%) preceded the onset of PD motor symptoms. The median interval from the onset of RBD symptoms to PD motor symptoms was 17.5 years, and 3 patients had intervals of over 50 years. This large-scale multicenter study revealed that RBD is a frequent non-motor symptom in Japanese patients with PD, which may precede the onset of motor symptoms. Moreover, RBD that increases with the duration and severity of PD may be associated with autonomic dysfunction.     

早期帕金森病患者快速眼动睡眠期行为障碍研究

目的探讨早期帕金森病患者快速眼动睡眠期行为障碍发生情况,以及帕金森病运动症状、非运动症状和快速眼动睡眠期行为障碍特点。方法共60例原发性帕金森病患者,采用统一帕金森病评价量表第二和第三部分(UPDRSⅡ和UPDRSⅢ)以及Hoehn-Yahr分期评价帕金森病非运动症状和运动症状,蒙特利尔认知评价量表评价认知功能,汉密尔顿焦虑量表和汉密尔顿抑郁量表评价焦虑和抑郁症状;中文版快速眼动睡眠期行为障碍筛查量表判断是否伴快速眼动睡眠期行为障碍,Epworth嗜睡量表(ESS)评价白天过度嗜睡程度;多导睡眠图监测睡眠障碍特征,包括下颌位相性肌电活动密度和快速眼动睡眠期肌肉失弛缓。结果 60例帕金森病患者中42例(70%)伴快速眼动睡眠期行为障碍(PD+RBD组),多导睡眠图监测其异常行为主要表现为上肢伸展抓握、肢体震颤抽搐、发笑、喊叫和怒骂等非暴力动作,仅2例出现暴力击打、蹬踢等异常行为。PD+RBD组患者年龄(P=0.024)、病程8年比例(P=0.000)、UPDRSⅡ(P=0.005)和UPDRSⅢ(P=0.001)评分、Hoehn-Yahr分期2级比例(P=0.007)、焦虑障碍(P=0.044)和抑郁障碍(P=0.001)比例,以及下颌位相性肌电活动密度(P=0.000)和快速眼动睡眠期肌肉失弛缓比例(P=0.000)均高于对照组,其中,PD+RBD组有16例(38.10%)快速眼动睡眠期行为障碍症状早于帕金森样症状5.20(3.91,6.51)年。结论年龄大、病程长、运动症状和非运动症状严重的帕金森病患者易伴发快速眼动睡眠期行为障碍,快速眼动睡眠期行为障碍可能是帕金森病的早期表现。多导睡眠图监测对早期帕金森病伴快速眼动睡眠期行为障碍的诊断有重要参考价值。     

Non-motor dysfunction in Parkinson's disease

In the field of neurology, Parkinson's disease (PD) is commonly perceived to be a disorder affecting only the (extrapyramidal) motor system, characteristically manifesting as bradykinesia, rigidity, tremor and postural instability. Although non-motor symptoms such as behavioural abnormalities, dysautonomia, sleep disturbances and sensory dysfunctions are also common and quite disabling manifestations of the disease, they are often not formally assessed and thus are frequently misdiagnosed and/or under diagnosed. For this reason, in this review we have concentrated on the pathophysiological and clinical basis of non-motor involvement such as olfactory dysfunction, depression, dementia, dysautonomia and sleep disorders in PD. The early recognition of these symptoms may well perhaps lead to an earlier diagnosis of PD, but in any case should lead to more prompt and effective treatment of the relatively unrecognized non-motor problems associated with PD.     

Management of non-motor symptoms in advanced Parkinson disease

Progress in pharmacology has markedly improved the treatment of early Parkinson's disease. The management of advanced Parkinson's symptoms, however, remains a challenge. These symptoms are divided into motor and non-motor symptoms. Non-motor symptoms may appear early or late in the disease and sometimes even before the onset of the first motor symptoms confirming the diagnosis. The spectrum of non-motor symptoms encompasses autonomic dysfunctions, sleep disorders, mood disorders, impulse control disorders, cognitive dysfunction, dementia, paranoia and hallucinations. They are often less appreciated than motor symptoms but are important sources of disability for many PD patients. This review describes these non-motor symptoms and their managements.     

Magnetic resonance imaging markers for early diagnosis of Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by selective and progressive degeneration, as well as loss of dopaminergic neurons in the substantia nigra. In PD, approximately 60-70% of nigrostriatal neurons are degenerated and 80% of content of the striatal dopamine is reduced before the diagnosis can be established according to widely accepted clinical diagnostic criteria. This condition describes a stage of disease called "prodromal", where non-motor symptoms, such as olfactory dysfunction, constipation, rapid eye movement behaviour disorder, depression, precede motor sign of PD. Detection of prodromal phase of PD is becoming an important goal for determining the prognosis and choosing a suitable treatment strategy. In this review, we present some non-invasive instrumental approaches that could be useful to identify patients in the prodromal phase of PD or in an early clinical phase, when the first motor symptoms begin to be apparent. Conventional magnetic resonance imaging (MRI) and advanced MRI techniques, such as magnetic resonance spectroscopy imaging, diffusion-weighted and diffusion tensor imaging and functional MRI, are useful to differentiate early PD with initial motor symptoms from atypical parkinsonian disorders, thus, making easier early diagnosis. Functional MRI and diffusion tensor imaging techniques can show abnormalities in the olfactory system in prodromal PD.     

Hyposmia: a possible biomarker of Parkinson’s disease

Hyposmia, identified as reduced sensitivity to odor, is a common non-motor symptom of Parkinson’s disease (PD) that antedates the typical motor symptoms by several years. It occurs in ～90% of early-stage cases of PD. In addition to the high prevalence, the occurrence of hyposmia may also predict a higher risk of PD. Investigations into hyposmia and its relationship with PD may help elucidate the underlying pathogenic mechanisms. This review provides an update of olfactory dysfunction in PD and its potential as a biomarker for this devastating disease.     

Neuroimaging of nonmotor features of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms that respond to dopaminergic therapy. However, there is increasing interest in nonmotor PD features such as hyposmia, sleep disorders, dementia, depression, and psychoses. We review neuroimaging studies in nonmotor symptoms of PD and the use of dopaminergic imaging to support screening of nonmotor symptoms for early PD. Neuroimaging data document nonmotor pathophysiologic involvement of systems beyond the nigrostriatal dopaminergic pathway. These neuroimaging studies support a broader view of PD with early involvement in time and wider involvement of monoamine and cortical systems that may provide targets for novel therapies for nonmotor symptoms.     

Impaired olfaction and other prodromal features in the Parkinson At-Risk Syndrome Study

To test the association between impaired olfaction and other prodromal features of PD in the Parkinson At-Risk Syndrome Study. The onset of olfactory dysfunction in PD typically precedes motor features, suggesting that olfactory testing could be used as a screening test. A combined strategy that uses other prodromal nonmotor features, along with olfactory testing, may be more efficient than hyposmia alone for detecting the risk of PD. Individuals with no neurological diagnosis completed a mail survey, including the 40-item University of Pennsylvania Smell Identification Test, and questions on prodromal features of PD. The frequency of reported nonmotor features was compared across individuals with and without hyposmia. A total of 4,999 subjects completed and returned the survey and smell test. Of these, 669 were at or below the 15th percentile based on age and gender, indicating hyposmia. Hyposmics were significantly more likely to endorse nonmotor features, including anxiety and depression, constipation, and rapid eye movement sleep behavior disorder symptoms, and to report changes in motor function. Twenty-six percent of subjects with combinations of four or more nonmotor features were hyposmic, compared to 12% for those reporting three or fewer nonmotor features (P < 0.0001). Hyposmia is associated with other nonmotor features of PD in undiagnosed individuals. Further assessment of hyposmic subjects using more specific markers for degeneration, such as dopamine transporter imaging, will evaluate whether combining hyposmia and other nonmotor features is useful in assessing the risk of future neurodegeneration.     

Smoking and age-at-onset of both motor and non-motor symptoms in Parkinson's disease

IntroductionSeveral evidence suggest that smoking may decrease the risk of Parkinson's disease and is associated with an older age-at-onset of motor signs. The relation between smoking and age-at-onset of non-motor symptoms has never been analyzed. Objective of the study is to evaluate whether smoking habit and pack-years of smoking are associated with a delay of age-at-onset of motor signs, and of some non-motor symptoms.MethodsThe study population consisted of 262 consecutive parkinsonian patients. Information on relevant demographic/clinical data focused on motor signs, REM sleep behavior disorder, constipation, depression, and hyposmia. Patients were stratified according to smoking habit (ever-versus never-smoker) and number of pack-years of smoking was computed. Repeatability of data on age-at-onset was checked 6 months after the initial interview in a randomly recruited subsample.ResultsSmoking habit and number of pack-years smoked were associated with an older in age-at-onset of motor signs, REM sleep behavior disorder and depression. By contrast, smoking did not affect age-at-onset of hyposmia and constipation.Conclusioninformation from this study confirms that smoking may be associated with an older age-at-onset of motor signs, and that a similar effect can be observed on some non-motor symptoms like REM sleep behavior and depression.     

Sleep alterations in an environmental neurotoxin-induced model of parkinsonism

Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD.     

Clinical features associated with REM sleep behavior disorder symptoms in the early stages of Parkinson’s disease

We aimed to characterize the clinical features associated with REM sleep behaviour disorder (RBD) in early stage Parkinson’s disease (PD). Presence of clinical RBD was determined according to ICSD minimal clinical criteria and a validated RBD questionnaire. We registered time of appearance of RBD symptoms in relation to PD onset and the occurrence of RBD symptoms in the past in non-RBD patients. RBD and non-RBD groups were compared in terms of motor and cognitive dysfunction. The same comparisons were made between patients who reported RBD symptoms at some point in time (including those non-RBD patients that reported occurrence of RBD symptoms in the past) and those who did not (RBDS and non-RBDS, respectively). We assessed 75 patients. Forty-one (55%) patients presented with RBD, 19 beginning before PD onset. Five non-RBD patients reported having had RBD symptoms in the past. There were no significant differences between RBD and non-RBD patients. RBDS group presented a significantly higher proportion of non-tremor motor sub-type compared to non-RBDS patients. Our results suggest that RBD is very frequent in the early stages of PD. In some patients, RBD symptoms could have disappeared before or in the first years after motor disturbance onset. Non-tremor motor sub-type was related to RBD symptoms history, rather than to the presence of RBD clinical criteria at time of evaluation, suggesting that the physiopathological changes that cause the association with motor status could remain, in spite of symptom fluctuation.     

Anxiety and self-perceived health status in Parkinson's disease

Both anxiety and depression are associated with lower self-perceived health status (HS) in persons with Parkinson's disease (PD). Given the high co-morbidity with depression and other non-motor symptoms, it is unclear whether anxiety disorders, in general, versus specific anxiety subtypes have an independent effect on HS in PD. To examine this question, comprehensive assessments of motor and non-motor symptoms from 249 subjects with idiopathic PD followed in three community-based movement disorders neurology practices were analyzed. HS was measured using the 8-item PD Questionnaire (PDQ-8). Psychiatric diagnoses were established by consensus using a panel of six psychiatrists with expertise in geriatric psychiatry and movement disorders. Stepwise multiple regression analyses were used, with the PDQ-8 score as the dependent variable, to identify independent predictors of HS among motor, psychiatric, and other non-motor variables. Among the anxiety disorders, only anxiety associated with motor fluctuations was an independent predictor of HS after accounting for co-morbid depression and other clinical features. In addition, depressive disorders were also an independent predictor of lower HS. Prevention or treatment of state-dependent anxiety may improve HS in persons with PD.