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.     

Cognitive dysfunction and depression in Parkinson's disease: what can be learned from rodent models?

Parkinson's disease (PD) has for decades been considered a pure motor disorder and its cardinal motor symptoms have been attributed to the loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta and to nigral Lewy body pathology. However, there has more recently been a shift in the conceptualization of the disease, and its pathological features have now been recognized as involving several other areas of the brain and indeed even outside the central nervous system. There are a corresponding variety of intrinsic non-motor symptoms such as autonomic dysfunction, cognitive impairment, sleep disturbances and neuropsychiatric problems, which cannot be explained exclusively by nigral pathology. In this review, we will focus on cognitive impairment and affective symptoms in PD, and we will consider whether, and how, these deficits can best be modelled in rodent models of the disorder. As only a few of the non-motor symptoms respond to standard DA replacement therapies, the quest for a broader therapeutic approach remains a major research effort, and success in this area in particular will be strongly dependent on appropriate rodent models. In addition, better understanding of the different models, as well as the advantages and disadvantages of the available behavioural tasks, will result in better tools for evaluating new treatment strategies for PD patients suffering from these neuropsychological 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。     

Autonomic symptoms in idiopathic REM behavior disorder: a multicentre case–control study

Patients with idiopathic REM sleep behavior disorder (iRBD) are at very high risk of developing neurodegenerative synucleinopathies, which are disorders with prominent autonomic dysfunction. Several studies have documented autonomic dysfunction in iRBD, but large-scale assessment of autonomic symptoms has never been systematically performed. Patients with polysomnography-confirmed iRBD (318 cases) and controls (137 healthy volunteers and 181 sleep center controls with sleep diagnoses other than RBD) were recruited from 13 neurological centers in 10 countries from 2008 to 2011. A validated scale to study the disorders of the autonomic nervous system in Parkinson's disease (PD) patients, the SCOPA-AUT, was administered to all the patients and controls. The SCOPA-AUT consists of 25 items assessing the following domains: gastrointestinal, urinary, cardiovascular, thermoregulatory, pupillomotor, and sexual dysfunction. Our results show that compared to control subjects with a similar overall age and sex distribution, patients with iRBD experience significantly more problems with gastrointestinal, urinary, and cardiovascular functioning. The most prominent differences in severity of autonomic symptoms between our iRBD patients and controls emerged in the gastrointestinal domain. Interestingly, it has been reported that an altered gastrointestinal motility can predate the motor phase of PD. The cardiovascular domain SCOPA-AUT score in our study in iRBD patients was intermediate with respect to the scores reported in PD patients by other authors. Our findings underline the importance of collecting data on autonomic symptoms in iRBD. These data may be used in prospective studies for evaluating the risk of developing neurodegenerative disorders.     

帕金森病直立性低血压的研究进展

帕金森病(PD)是一种常见的神经系统变性疾病。PD患者除表现为典型的运动症状外,还具有一些非运动症状,如认知、情绪和睡眠等方面的改变。大部分PD患者在病程中会出现自主神经功能障碍,如便秘、排尿异常、性功能障碍、多汗、直立性低血压等。直立性低血压在PD患者中有较高的发生率,影响患者生活质量,文中就PD患者直立性低血压的诊断、病理生理机制及相关研究做一综述。     

Wpływ głębokiej stymulacji mózgowej jądra niskowzgórzowego na objawy autonomiczne obserwowane w chorobie Parkinsona

Dysfunctions of the autonomic nervous system (DA) are common in Parkinson's disease (PD). DA appear in the premotor phase of PD and may antedate cardinal motor symptoms by years or decades. DA significantly impair quality of life in the majority of PD patients. DA are related to accumulation of Lewy bodies in the central and peripheral nervous system. Progression of neurodegeneration and chronic dopaminergic therapy may increase DA as well. It is accepted that bilateral deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in PD. The effect of STN DBS on DA, such as cardiovascular symptoms and urinary, gastrointestinal and sexual dysfunction in PD, is not clear. STN DBS ameliorates some DA, but others might deteriorate at the same time.     

Neuropathology of autonomic dysfunction in synucleinopathies

The synucleinopathies—Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, and pure autonomic failure—result from distinct patterns of abnormal α‐synuclein aggregation throughout the nervous system. Autonomic dysfunction in these disorders results from variable involvement of the central and peripheral autonomic networks. The major pathologic hallmark of Parkinson's disease and dementia with Lewy bodies is Lewy bodies and Lewy neurites; of multiple system atrophy, oligodendroglial cytoplasmic inclusions; and of pure autonomic failure, peripheral neuronal cytoplasmic inclusions. Clinical manifestations include orthostatic hypotension, thermoregulatory dysfunction, gastrointestinal dysmotility, and urogenital dysfunction with neurogenic bladder and sexual dysfunction. Strong evidence supports isolated idiopathic rapid eye movement sleep disorder as a significant risk factor for the eventual development of synucleinopathies with autonomic and/or motor involvement. In contrast, some neurologically normal elderly individuals have Lewy‐related pathology. Future work may reveal protective or vulnerability factors that allow some patients to harbor Lewy pathology without overt autonomic dysfunction. © 2018 International Parkinson and Movement Disorder Society     

Features associated with the development of non-motor manifestations in Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder, predominantly characterized by the presence of motor symptoms. However, the non motor manifestations (NMM) are a frequent complaint in the PD patients. There is a lack of information about the risk factors associated with the NMM in these patients. The aim of this study is to evaluate the prevalence of the more common NMM in a population of PD patients and to determine the features associated with its development. We studied 124 ambulatory PD patients. NMM were defined by the presence of neuropsychiatric manifestations, cognitive disorder, autonomic dysfunction or sleep related problems. In a multivariate analysis we found that the years of evolution of the PD and the presence of cognitive dysfunction are the risk factors for the neuropsychiatric and autonomic manifestations, whereas axial impairment is a risk factor for cognitive disorders and dyskinesias is for sleep related problems. In conclusion, this study shows that the features related to the PD progression appear as the main risk factors associated with NMM.     

Neurotransmission in Parkinson’s disease: beyond dopamine

Parkinson’s disease (PD) is most frequently associated with characteristic motor symptoms that are known to arise with degeneration of dopaminergic neurons. However, patients with this disease also experience a multitude of non‐motor symptoms, such as sleep disturbances, fatigue, apathy, anxiety, depression, cognitive impairment, dementia, olfactory dysfunction, pain, sweating and constipation, some of which can be at least as debilitating as the movement disorders and have a major impact on patients’ quality of life. Many of these non‐motor symptoms may be evident prior to the onset of motor dysfunction. The neuropathology of PD has shown that complex, interconnected neuronal systems, regulated by a number of different neurotransmitters in addition to dopamine, are involved in the aetiology of motor and non‐motor symptoms. This review focuses on the non‐dopaminergic neurotransmission systems associated with PD with particular reference to the effect that their modulation and interaction with dopamine has on the non‐motor symptoms of the disease. PD treatments that focus on the dopaminergic system alone are unable to alleviate both motor and non‐motor symptoms, particularly those that develop at early stages of the disease. The development of agents that interact with several of the affected neurotransmission systems could prove invaluable for the treatment of this disease.     

An exploration of central dysregulation of erectile function as a contributing cause of diabetic impotence

Diabetic impotence is generally presumed to be secondary to peripheral abnormalities of the vascular or autonomic nervous system, although central nervous control of the autonomic nervous system has not previously been studied. Measures of rapid eye movement (REM) sleep as potential indicators of central autonomic dysfunction were studied along with sleep-related tumescence for 10 impotent diabetics, nine psychogenically impotent men, and 10 men whose impotence was secondary to pelvic trauma. Low REM density was found in the diabetics with REM density correlating with measures of tumescence. These results suggest that central autonomic dysfunction may be a contributing factor in the impotence of diabetic men. A metabolic disturbance in the central nervous system of diabetics which might alter both sleep and autonomic nervous system activity is proposed to explain these results and may help in the understanding of other observed abnormalities in both the sleep and autonomic dysfunction of diabetics.     

Disorders of the autonomic nervous system: Part 1. Pathophysiology and clinical features

Autonomic dysfunction may result from diseases that affect primarily either the central nervous system or the peripheral autonomic nervous system. The most common pathogenesis of disturbed autonomic function in central nervous system diseases is degeneration of the intermediolateral cell columns (progressive autonomic failure) or disease or damage to descending pathways that synapse on the intermediolateral column cells (spinal cord lesions, cerebrovascular disease, brainstem tumors, multiple sclerosis). The peripheral autonomic nervous system may be damaged in isolation in the acute and subacute autonomic neuropathies or in association with a generalized peripheral neuropathy. The peripheral neuropathies most likely to cause severe autonomic disturbance are those in which small myelinated and unmyelinated fibers are damaged in the baroreflex afferents, the vagal efferents to the heart, and the sympathetic efferent pathways to the mesenteric vascular bed. Acute demyelination of the sympathetic and parasympathetic nerves in the Guillain-Barré syndrome may also cause acute autonomic dysfunction. Although autonomic disturbances may occur in other types of peripheral neuropathy, they are rarely clinically important.     

PD-related psychosis: pathophysiology with therapeutical strategies

Parkinson's disease (PD) is a chronic, neurodegenerative disease with degeneration of the central dopaminergic neurons in the substantia nigra, leading to a depletion of dopamine (DA) in the striatum. This depletion causes the clinical hallmarks of this disease: bradykinesia, hypokinesia, rigidity, tremor and postural instability. Besides these well known motor symptoms, non-motor symptoms may develop, such as hyposmia, sleep disorders, autonomic disturbances, depression, cognitive impairment and psychosis. Pathophysiological mechanisms underlying these symptoms not only comprise Lewy body pathology in the central dopaminergic system, but also in the noradrenergic, serotinergic and cholinergic transmittersystems. Indeed, in Parkinson's disease, about 30-40% of the patients suffers fluctuating psychotic symptoms, mainly paranoid delusions and/or visual or acoustic hallucinations, symptoms considered to represent major contributors to patient and caregiver distress and nursing home placement. Endogenous (related to the disease process itself) as well as exogenous (related to therapeutical interventions) psychotogenic factors may contribute to the development of psychotic symptoms in PD. Therapeutical strategies, therefore, are aimed to reduce both endogenous and exogenous factors. To reduce endogenous psychotogenic factors, cholinesterase inhibitors, suggested to reduce cognitive deterioration, now seem to be the drugs of choice. In exogenously induced psychotic symptoms, atypical antipsychotics are considered the most effective. However, as psychotic symptoms in PD are often influenced by both endogenous and exogenous factors, a combination of both strategies may be preferred.     

Diffusion alterations associated with Parkinson's disease symptomatology: A review of the literature

Parkinson's disease (PD) is a heterogeneous neurological disorder with a variety of motor and non-motor symptoms. The underlying mechanisms of these symptoms are not fully understood. An increased interest in structural connectivity analyses using diffusion tensor imaging (DTI) in PD has led to an expansion of our understanding of the impact of abnormalities in diffusivity on phenotype. This review outlines the contribution of these abnormalities to symptoms of PD including bradykinesia, tremor and non-tremor phenotypes, freezing of gait, cognitive impairment, mood, sleep disturbances, visual hallucinations and olfactory dysfunction. Studies have shown that impairments in cognitive functioning are related to diffusion abnormalities in frontal and parietal regions, as well as in the corpus callosum and major fibres connecting midbrain and subcortical structures with the neocortex. However, the impact of diffusion alterations on motor, mood and other symptoms of PD are less well understood. The findings presented here highlight the challenges faced and the potential areas of future research avenues where DTI may be beneficial. Larger cohort studies and standardized imaging protocols are required to investigate current promising preliminary findings.     

Biomarkers for the early detection of Parkinson's and Alzheimer's disease

In the aging population of many countries in the world, neurodegenerative diseases like Parkinson's disease (PD) are becoming an increasing burden. Therefore, early therapy and ultimately disease prevention is essential, which is only possible with an early diagnosis. Besides a genetic predisposition, a number of biomarkers are being discussed to indicate vulnerability to PD, some of them many years before disease manifestation. These include hyperechogenicity of the substantia nigra as well as premotor symptoms like olfactory and autonomic dysfunction, depression, REM sleep behavior disorder, and neuropsychological impairment. Moreover, first signs of affection of the substantia nigra like PET and SPECT abnormalities and slight motor signs can be included, as they may be detected before a definite diagnosis according to motor symptoms can be made. Interestingly, other frequent neurodegenerative disorders like Alzheimer's disease (AD) are also characterized by a long preclinical period, with several biomarkers discussed as indicative for disease vulnerability including cerebrospinal fluid, serum, and neuroimaging biomarkers, olfactory dysfunction as well as subtle neuropsychological deficits. However, future studies are necessary, which establish the predictive value of these markers singularly and in combination to detect a subgroup of the population at risk for PD and AD not only to accelerate research on etiology and pathophysiology but also to promote testing for neuroprotective strategies.     

Autonomic dysfunction according to disease progression in Parkinson's disease

BackgroundAlthough autonomic dysfunction is common in patients with Parkinson’s disease (PD), few data are available regarding its pattern and quantitative severity with increasing Hoehn and Yahr (H&Y) stage. We conducted autonomic function tests to quantify autonomic dysfunction in PD patients and to elucidate its possible relationship with disease progression.MethodsWe performed autonomic function tests including Valsalva ratio, heart rate response to deep breathing, quantitative sudomotor axon reflex test, and head-up tilt test in 66 patients with PD. We compared clinical characteristics and results of autonomic function tests between stages, and correlated the proportion of abnormal patients in each test with their H&Y stage. In addition, logistic regression analyses were conducted to examine the contribution of increasing H&Y stage to impairments of each domain of the autonomic nervous system.ResultsWe found that PD patients with higher disease stage tended to have impairments in cardiovagal and sudomotor domains of the autonomic nervous system. Cardiovagal function was the domain most influenced by disease progression. Our findings also demonstrated that the pattern of sudomotor impairment in PD was similar to that in patients with peripheral autonomic neuropathy.ConclusionsOur study demonstrates that autonomic dysfunction is not only common in early stage PD but it increases in severity with increasing disease stage. Given that the patterns of sudomotor impairments in PD are similar to those in peripheral neuropathy, our data support a previous hypothesis that pathophysiology of PD involves both the central and peripheral nervous systems.     

Olfactory dysfunction in Parkinson disease

Olfactory dysfunction is among the earliest nonmotor features of Parkinson disease (PD). Such dysfunction is present in approximately 90% of early-stage PD cases and can precede the onset of motor symptoms by years. The mechanisms responsible for olfactory dysfunction are currently unknown. As equivalent deficits are observed in Alzheimer disease, Down syndrome, and the Parkinson-dementia complex of Guam, a common pathological substrate may be involved. Given that olfactory loss occurs to a lesser extent or is absent in disorders such as multiple system atrophy, corticobasal degeneration, and progressive supranuclear palsy, olfactory testing can be useful in differential diagnosis. The olfactory dysfunction in PD and a number of related diseases with smell loss correlates with decreased numbers of neurons in structures such as the locus coeruleus, the raphe nuclei, and the nucleus basalis of Meynart. These neuroanatomical findings, together with evidence for involvement of the autonomic nervous system in numerous PD-related symptoms, suggest that deficits in cholinergic, noradrenergic and serotonergic function may contribute to the olfactory loss. This Review discusses the current understanding of olfactory dysfunction in PD, including factors that may be related to its cause.     

A further update on the role of excitotoxicity in the pathogenesis of Parkinson’s disease

Increased levels of extracellular glutamate and hyperactivation of glutamatergic receptors in the basal ganglia trigger a critical cascade of events involving both intracellular pathways and cell-to-cell interactions that affect cell viability and promote neuronal death. The ensemble of these glutamate-triggered events is responsible for excitotoxicity, a phenomenon involved in several pathological conditions affecting the central nervous system, including a neurodegenerative disease such as Parkinson’s disease (PD). PD is an age-related disorder caused by the degeneration of dopaminergic neurons within the substantia nigra pars compacta, with a miscellaneous pathogenic background. Glutamate-mediated excitotoxicity may be involved in a lethal vicious cycle, which critically contributes to the exacerbation of nigrostriatal degeneration in PD. Since excitotoxicity is a glutamate-receptor-mediated phenomenon, growing interest and work have been dedicated to the research for modulators of glutamate neurotransmission that might enable new therapeutic interventions to slow down the neurodegenerative process and ameliorate PD motor symptoms.     

Prodromal non-motor symptoms of Parkinson’s disease

The motor symptoms of Parkinson’s disease (PD), bradykinesia, muscular rigidity, and tremor depend upon degeneration of the dopaminergic neurons in the substantia nigra pars compacta. Recent neuropathological studies show that the Lewy bodies, the intraneuronal landmark of PD, accumulate in several neuronal cell types in the brain. An ascending gradient of pathological involvement, from the medulla oblongata to neocortical areas has been reported. Thus the original view of PD as a disease characterized by selective damage of the dopaminergic neurons in the mesencephalon should be updated into the concept of a severe multisystemic neurodegenerative disorder. Additionally, the neuropathological alterations outside the substantia nigra are soundly correlated with the non-motor symptoms of PD. As a result of these findings, interest is growing in the identification of prodromal non-motor symptoms of PD. Indeed, data from the literature suggest that autonomic disturbances, olfactory dysfunctions, depression and sleep disorders (in particular REM-sleep behavior disorder) may represent prodromal non-motor symptoms of PD. Several tests are available to detect most of these symptoms. Thus, the identification of prodromal non-motor symptoms may contribute to the precocious diagnosis of PD, and might be useful in the future to test the efficacy of neuroprotective agents.     

Early phenotypic differences between Parkinson's disease patients with and without freezing of gait

BackgroundPrevious studies have associated freezing of gait in Parkinson's disease with the presence of specific phenotypic features such as mood disturbances, REM sleep behavior disorder and selective cognitive impairments. However, it is not clear whether these features are present in the earlier stages of disease or simply represent a more general pattern of progression. To investigate this issue, the current study evaluated motor, cognitive, affective and autonomic features as well as REM sleep behavior disorder in Parkinson's disease patients in the early stages of the condition.MethodsThirty-eight freezers and fifty-three non-freezers with disease duration of less than five years and a Hoehn and Yahr stage of less than three were included in this study. The groups were matched on a number of key disease features including age, disease duration, motor severity and dopamine dose equivalence. Furthermore, patients were assessed on measures of motor, cognitive, affective and autonomic features, as well as REM sleep behavior disorder.ResultsCompared to non-freezers, patients with freezing of gait had significantly more non-tremor symptoms and a selective impairment on executive functions, such as set-shifting ability and working memory. Freezers and non-freezers did not differ on measures of tremor, autonomic function, REM sleep behavior disorder, mood or more general cognition.ConclusionThese results suggest the pathophysiological mechanisms underlying freezing of gait in the early clinical stages of Parkinson's disease are likely to be related to specific changes in the frontostriatal pathways rather than being due to brainstem or more diffuse neuropathology.