The importance of non-motor disturbances to quality of life in Parkinson's disease

The term health-related quality of life (HRQoL) refers to the consequences of the disease and treatment on the patients' life, as perceived and evaluated by patients themselves. Parkinson's disease is a complex disorder characterized by motor manifestations and an impressive diversity of non-motor symptoms (NMS) that may be simultaneously present in the same patient. Some of these non-motor symptoms (for example, depression, fatigue, or pain) have got evidence enough to be considered determinant factors of HRQoL. For others, evidence is incomplete or results of the studies are inconsistent. The availability of instruments for assessment of a wide set of NMS allows to evaluate the impact of NMS, as a whole and compared to the motor disorder, on the HRQoL. In that scenario, the whole NMS showed a close association with the quality of life deterioration, exceeding even the effects of the motor disorder.     

帕金森病疼痛机制研究进展

帕金森病是中老年人群常见的神经变性病,临床表现主要包括运动症状和非运动症状,疼痛是常见的非运动症状,因影响患者生活质量而倍受关注。然而目前关于帕金森病疼痛的发病机制仍不明确,尚待进一步研究。本文拟就可能的帕金森病疼痛发病机制进行阐述。     

帕金森病非运动症状研究进展

帕金森病(PD)是好发于中老年的神经系统变性疾病,PD不仅表现出核心的运动症状(MS),还表现出各种的非运动症状(NMS),NMS是PD发生频率很高且非常重要的症状,可以出现在PD的任何阶段。NMS能促进PD的早期诊断,也是引起PD患者日常生活能力及生命质量降低的重要原因。文中从感觉障碍、神经精神障碍、自主神经功能障碍、睡眠障碍、疲劳等方面对PD患者的NMS相关研究进展进行综述。     

The metric properties of a novel non-motor symptoms scale for Parkinson's disease: Results from an international pilot study.

Non-motor symptoms (NMS) in Parkinson's disease (PD) are common, significantly reduce quality of life and at present there is no validated clinical tool to assess the progress or potential response to treatment of NMS. A new 30-item scale for the assessment of NMS in PD (NMSS) was developed. NMSS contains nine dimensions: cardiovascular, sleep/fatigue, mood/cognition, perceptual problems, attention/memory, gastrointestinal, urinary, sexual function, and miscellany. The metric attributes of this instrument were analyzed. Data from 242 patients mean age 67.2 +/- 11 years, duration of disease 6.4 +/- 6 years, and 57.3% male across all stages of PD were collected from the centers in Europe, USA, and Japan. The mean NMSS score was 56.5 +/- 40.7, (range: 0-243) and only one declared no NMS. The scale provided 99.2% complete data for the analysis with the total score being free of floor and ceiling effect. Satisfactory scaling assumptions (multitrait scaling success rate >95% for all domains except miscellany) and internal consistency were reported for most of the domains (mean alpha, 0.61). Factor analysis supported the a prori nine domain structure (63% of the variance) while a small test-retest study showed satisfactory reproducibility (ICC > 0.80) for all domains except cardiovascular (ICC = 0.45). In terms of validity, the scale showed modest association with indicators of motor symptom severity and disease progression but a high correlation with other measures of NMS (NMSQuest) and health-related quality of life measure (PDQ-8) (both, rS = 0.70). In conclusion, NMSS can be used to assess the frequency and severity of NMS in PD patients across all stages in conjunction with the recently validated non-motor questionnaire.     

Animal models of the non-motor features of Parkinson's disease

The non-motor symptoms (NMS) of Parkinson's disease (PD) occur in roughly 90% of patients, have a profound negative impact on their quality of life, and often go undiagnosed. NMS typically involve many functional systems, and include sleep disturbances, neuropsychiatric and cognitive deficits, and autonomic and sensory dysfunction. The development and use of animal models have provided valuable insight into the classical motor symptoms of PD over the past few decades. Toxin-induced models provide a suitable approach to study aspects of the disease that derive from the loss of nigrostriatal dopaminergic neurons, a cardinal feature of PD. This also includes some NMS, primarily cognitive dysfunction. However, several NMS poorly respond to dopaminergic treatments, suggesting that they may be due to other pathologies. Recently developed genetic models of PD are providing new ways to model these NMS and identify their mechanisms. This review summarizes the current available literature on the ability of both toxin-induced and genetically-based animal models to reproduce the NMS of PD.     

Non-motor symptoms of Parkinson's disease: diagnosis and management

The clinical diagnosis of Parkinson's disease rests on the identification of the characteristics related to dopamine deficiency that are a consequence of degeneration of the substantia nigra pars compacta. However, non-dopaminergic and non-motor symptoms are sometimes present before diagnosis and almost inevitably emerge with disease progression. Indeed, non-motor symptoms dominate the clinical picture of advanced Parkinson's disease and contribute to severe disability, impaired quality of life, and shortened life expectancy. By contrast with the dopaminergic symptoms of the disease, for which treatment is available, non-motor symptoms are often poorly recognised and inadequately treated. However, attention is now being focused on the recognition and quantitation of non-motor symptoms, which will form the basis of improved treatments. Some non-motor symptoms, including depression, constipation, pain, genitourinary problems, and sleep disorders, can be improved with available treatments. Other non-motor symptoms can be more refractory and need the introduction of novel non-dopaminergic drugs. Inevitably, the development of treatments that can slow or prevent the progression of Parkinson's disease and its multicentric neurodegeneration provides the best hope of curing non-motor symptoms.     

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。     

Quantitation of non-motor symptoms in Parkinson's disease

Background:  Disabling non-motor symptoms (NMS) associated with Parkinson's disease (PD), such as dementia and loss of balance, do not respond well to levodopa therapy and can lead to eventual death in patients with the disease. In 2006, a multidisciplinary group of experts and patient representatives developed an NMS screening questionnaire (NMSQuest) and a unified Non-Motor Symptoms Scale (NMSS) to address the need for simple identification and comprehensive assessment of NMS in patients with PD.
Methods and Results:  An international pilot study of 96 healthy controls and 123 patients with various stages of treated and untreated PD was conducted to demonstrate that the NMSQuest is a feasible, valid, and accepted tool.
Conclusion:  The majority of patients and caregivers felt that the questionnaire was clear and relevant to their daily lives. Data from 242 PD patients with no dementia were analysed in a pilot study on the clinimetric validation of NMSS. Similar to the NMSQuest study, the NMSS study revealed a significant correlation between progression of PD and increasing NMS burden. These studies suggest that the NMSQuest accurately detects the NMS, and that the NMSS closely correlates with quality of life for PD patients.     

Gender-related differences in the burden of non-motor symptoms in Parkinson’s disease

Differences in the expression of non-motor symptoms (NMS) by Parkinson's disease (PD) patients may have important implications for their management and prognosis. Gender is a basic epidemiological variable that could influence such expression. The present study evaluated the prevalence and severity of NMS by gender in an international sample of 951 PD patients, 62.63% males, using the non-motor symptoms scale (NMSS). Assessments for motor impairment and complications, global severity, and health state were also applied. All disease stages were included. No significant gender differences were found for demographic and clinical characteristics. For the entire sample, the most prevalent symptoms were Nocturia (64.88%) and Fatigue (62.78%) and the most prevalent affected domains were Sleep/Fatigue (84.02%) and Miscellaneous (82.44%). Fatigue, feelings of nervousness, feelings of sadness, constipation, restless legs, and pain were more common and severe in women. On the contrary, daytime sleepiness, dribbling saliva, interest in sex, and problems having sex were more prevalent and severe in men. Regarding the NMSS domains, Mood/Apathy and Miscellaneous problems (pain, loss of taste or smell, weight change, and excessive sweating) were predominantly affected in women and Sexual dysfunction in men. No other significant differences by gender were observed. To conclude, in this study significant differences between men and women in prevalence and severity of fatigue, mood, sexual and digestive problems, pain, restless legs, and daytime sleepiness were found. Gender-related patterns of NMS involvement may be relevant for clinical trials in PD.     

帕金森病患者非运动症状的发生及对日常生活能力的影响

目的 研究帕金森病(PD)患者非运动症状(NMS)的发生情况,及其对PD患者日常生活能力(ADL)的影响.方法 对107例PD患者进行NMS问卷(NMS Quest)调查,分析NMS的分布状况及临床特征,并采用统一PD评定量表(UPDRS)、Hoehn-Yahr分期、左旋多巴等效剂量、ADL问卷、MMSE评分进行评估,采用多元逐步线性回归探讨NMS对ADL的影响.结果 97.2%(104/107)的PD患者伴发不同程度的NMS,其发生数平均(8±5)个,其中尿频、便秘、记忆力下降最常见,发生率均超过50%;UPDRS-Ⅲ评分(28.0±16.4)分,能解释ADL总分变化的48.1%(R~2=0.481,P=0.000),引入NMS分值后,ADL分值可被解释的部分增加到51.1%.结论 PD患者普遍伴发NMS,而影响患者的ADL.PD可能是由NMS和运动症状共同组成的多系统神经变性疾病.PD患者的NMS在临床上应引起同样的重视,运动症状与NMS同治,才能提高疗效和ADL.     

Neuropsychological correlates of olfactory dysfunction in Parkinson's disease

Olfactory impairment is a common early non-motor manifestation in Parkinson's disease that has garnered interest as a clinical biomarker for early "pre-motor" diagnosis and prediction of associated clinical phenotypes. Whether olfactory impairment correlates well with motor symptoms is not yet clear, and recent interest has focused on the relationship between hyposmia and other non-motor symptoms. In this paper, we will review emerging evidence for a relationship between hyposmia and neuropsychiatric manifestations, discussing the potential pathophysiology together with challenges and opportunities for future research.     

帕金森病非运动症状及其治疗的流行病学调查

目的 调查帕金森病(Parkinson’s Disease, PD)非运动症状(Non-motor symptom, NMS)的发生率、严重程度、持续时间、治疗情况及其对生活质量的影响。方法 2014年1月～2016年4月对139例PD患者和87例健康成人(对照组)运用非运动症状评分(Non-Motor Symptoms Scale,NMSS)调查NMS,运用帕金森病生活质量问卷39项(39-item Parkinson’s Disease Questionnaire,PDQ-39)评估生活质量,运用Hoehn& Yahr(H-Y)分级评定PD患者运动症状的严重程度,并记录研究对象的一般情况和治疗情况,分析PD患者生活质量的影响因素。结果 98.6%的PD患者存在NMS,平均NMSS总分[(61.46±41.92),(0～208)]。在PD患者中发生率超过50%的NMS依次如下:夜尿、便秘、不宁腿、性欲下降、性功能障碍、失眠、乏力; 平均NMSS≥3分的NMS依次如下:便秘、性欲下降、性功能障碍、乏力、失眠、不宁腿、尿频、夜尿; 平均持续时间≥2年的NMS依次如下:便秘、性欲改变、夜尿、勃起障碍、快速动眼睡眠行为异常(REM Sleep Behavior Disorder Questionnaire,RBD)、嗅觉障碍。PD患者中通便药、安眠药、抗抑郁药和排尿困难药的使用率分别为47.8%(43/90)、19.7%(13/66)、2.7%(2/74)、2.6%(2/76)。PD患者中通便药使用率显著多于正常人群(P<0.0001),2组安眠药使用率比较无明显差异(P=0.736),对照组无人使用改善情绪和排尿困难的药物。多重线性回归分析发现,调查时年龄、H-Y分级和NMS总分是PD患者日常生活质量的预测因素。结论 NMS几乎见于每例PD患者,自主神经功能紊乱、嗅觉障碍和RBD等NMS可用于辅助PD早期诊断,NMS降低PD患者的生活质量,需要加强对NMS的关注。     

Link between non-motor symptoms and cognitive dysfunctions in de novo, drug-naive PD patients

Little is known about the relationship between cognitive dysfunctions and the non-motor complex in subjects with newly diagnosed untreated Parkinson's disease (PD). The aim of this study was to explore the association between non-motor symptoms (NMS) and cognitive dysfunctions in an incident cohort of de novo, drug-naive, PD patients. Sixty-six non-demented, early, untreated PD patients completed a semi-structured interview on NMS and a battery of neuropsychological tests that assess verbal memory, visuospatial abilities, and attention/executive functions. Scores were age- and education-corrected. Patients who failed at least two tests for each cognitive domain were diagnosed as having mild cognitive impairment (MCI). All but three (95.4%) PD patients complained of at least one NMS. A total of 37.8% was diagnosed with MCI. There was a relationship between sleep-NMS and cognitive dysfunctions. Specifically, both REM behavioral sleep disorders (RBD) and insomnia were associated with lower scores on several cognitive tests. Moreover, RBD was closely related to MCI. NMS and MCI are very common even in the early phase of PD, before patients are treated. Given the correlation between sleep disturbances and cognitive impairment, it is possible that sleep symptoms in PD patients might be considered as an early marker of dementia.     

Non-dopaminergic treatments in development for Parkinson's disease

Non-dopaminergic treatments are increasingly being recognised as part of the therapeutic armamentarium for Parkinson's disease (PD). Clinical and pathological studies have shown that the disease extends beyond the substantia nigra pars compacta and involves various non-dopaminergic neurotransmitter systems that mediate both motor and non-motor symptoms that characterise PD. To date, several therapeutic strategies have been proposed to treat such symptoms. However, despite the significant morbidity associated with these symptoms, particularly non-motor symptoms, research into and drug development for problems such as mood and autonomic dysfunction remain scarce. Here, we review novel non-dopaminergic approaches that are in at least phase II clinical development for the treatment of PD.     

Cognitive function and other non-motor features in non-demented Parkinson’s disease motor subtypes

Among patients with Parkinson’s disease (PD), a wide range of non-motor symptoms (NMS) are evident. We assessed markers of NMS and explored their behavioral correlates with the tremor-dominant (TD) and postural instability gait difficulty (PIGD) subtypes. 110 non-demented patients with PD were evaluated and stratified into the PIGD and TD subtypes and, using stricter criteria, into predominant subgroups: p-PIGD (n = 31) and p-TD (n = 32). Non-motor signs that were assessed included cognitive function (pen and paper and a computerized battery), autonomic function (NMSQest and SCOPA-AUT), mood, and sleep. Health-related quality of life was evaluated using the PDQ-39. The p-PIGD subgroup had a higher score on the NMSQest (p = 0.033) and a higher score (i.e., worse) on the PDQ-39 (p-PIGD: 26.28 ± 12.47; p-TD: 16.93 ± 12.22; p = 0.004), compared to the p-TD subgroup, while these measures did not differ in the larger PIGD and TD group. The p-PIGD subgroup used more sleep medications compared to the p-TD subgroup (1.0 ± 1.39 vs. 0.41 ± 0.94, p = 0.05, respectively). Most cognitive scores were similar in both subgroups; however, the visuospatial components of the Montreal Cognitive Assessment and the computerized catch game were significantly worse among the p-PIGD subgroup. Mild associations were found between certain non-motor symptoms, but not cognitive function, and the PIGD score. Non-demented patients from the PIGD subtype experience more non-motor symptoms and poorer quality of life compared to the TD subtype. These findings suggest that the clinical management of non-motor and motor symptoms in patients with PD may be enhanced by a personalized approach.     

帕金森病患者非运动症状发生及相关影响因素的研究

目的 研究帕金森病(PD)非运动症状的发生和分布情况及其与多种相关因素的关系。方法 对68例原发性PD患者使用统一PD评分量表(uPDRs)、PD非运动症状30问卷量表(the PD NMS questionnaire,NMSQuest)、日常生活能力量表(ADL)和简易智能量表(MMsE)进行评分,并对非运动症状进行评估。结果 所有PD患者各个时期病程均有非运动症状的出现,平均每个PD患者出现9项左右不同的非运动症状,并且非运动症状的发生与PD疾病的进展相关,与Hoehn and yahr(H-Y)分级呈正相关(P<0.01),与UPDRsⅢ运动评分呈正相关(P<0.01),且影响患者的生活质量,与ADL评分呈负相关P<0.05),而与年龄、性别、PD发病类型和左旋多巴每日治疗量无关(P>0.05)。结论 非运动症状的发生在PD中很普遍,各项发生率随PD患者的临床特点及病程进展的情况变化,NMS发生数与PD的疾病严重程度呈正相关,对患者生活质量产生严重影响,需要全面认识和及时干预。     

Progress in defining the premotor phase of Parkinson's disease

Several studies have suggested that a variety of non-motor symptoms (NMS) frequently antedate the development of the classical motor symptoms in Parkinson's disease (PD). Some of these premotor symptoms are well known, like REM sleep behaviour disorder, smell loss and constipation and can precede the motor symptoms by years or even decades. The appearance of these symptoms seems to correlate with the neuropathological changes occurring during Braaks stages I to III. Also studies of the nigrostriatal dopaminergic pathways with neuroimaging show that substantia nigra degeneration occurs before motor symptoms onset. Studies on the premotor phase of PD are important for our understanding of when and where does PD start and how it evolves in these initial stages. Several ongoing studies combine clinical, genetic and neuroimaging investigations to study the premotor phase in subjects at high risk for developing such as hyposmic individuals (PARS study) or nonmanifesting carriers of LRRK2 mutations (ASAP Study). The diagnosis of premotor PD remains still elusive but the information becoming available on premotor PD should guide the search for predictive biomarkers and the identification of risk or protective factors for PD.     

The management of gastrointestinal symptoms in Parkinson's disease

The involvement of the autonomic nervous system in Parkinson's disease causes many non-motor symptoms, among which gastrointestinal complaints are prominent. Drooling, dyspepsia, constipation, abdominal pain and fecal incontinence are frequently a source of patient distress. Dysphagia is recognized as causing both discomfort and increased risk of serious complications. Although a diagnosis can often be established based on the reports of patients and/or caregivers, and additional testing is seldom required, these diagnoses are clearly under recognized in clinical practice. These symptoms respond to the same treatment measures used in the general population, although certain drugs with a potential to increase parkinsonian symptoms should be avoided. Increased and early identification of these symptoms can result in a significant improvement in the quality of life of Parkinson's disease patients.     

原发性震颤患者的非运动症状

目的 研究原发性震颤(essential tremor,ET)患者嗅觉障碍等非运动症状的发生情况.方法 对62例ET患者应用震颤评分量表(Falm-Tolosa-Matin Tremor Rating Scale,TRS)、帕金森病非运动症状30问卷量表(Parkinson's disease non-motor symptoms questionnaire,NMS Quest)和MMSE进行评分,T&T标准嗅觉测试液检测嗅觉功能,并与60名健康体检者进行对照.结果 ET患者的嗅觉障碍发生率为51.6%(32/62),明显高于健康对照组(30.0%,18/60,x~2=12.371,P<0.05);平均每例ET患者出现5项左右不同的非运动症状,以对近期发生的事情记忆有困难或忘记做一些事情、嗅觉障碍、令人紧张或害怕的梦或生动梦境的发生率较高.嗅觉障碍等非运动症状的发生与ET患者的病程、病情严重程度、治疗与否没有明显的相关性.结论 除姿势性震颤或动作性震颤外,ET患者还会出现嗅觉障碍等非运动症状,需要全面认识和及时干预.     

The PRIAMO study: background, methods and recruitment

PRIAMO (PaRkinson And non Motor symptOms) is an epidemiology study aimed to assess the prevalence and incidence of non-motor symptoms (NMS) in patients with parkinsonism. PRIAMO consists of two phases: (1) a transversal assessment of the prevalence of NMS and (2) a longitudinal observation with two follow-up visits at 12 and 24 months to establish the incidence of NMS. A secondary aim of PRIAMO is to study the relationship between NMS and quality of life. Patients with parkinsonism have been evaluated in 59 Neurology Centres widely distributed throughout Italy. PRIAMO has analysed a total of 1307 patients (out of 1325 initially enrolled). We expect that PRIAMO will substantially help to quantify the burden of NMS in patients with parkinsonism.