Implications of the Gut Microbiome in Parkinson's Disease

Parkinson's disease is a common neurodegenerative disorder that presents with nonmotor and motor symptoms. The nonmotor manifestations of Parkinson's disease often begin years before the motor symptoms. Autopsy studies, including both Parkinson's disease patients and matched controls, demonstrated that α-synuclein aggregates in Parkinson's disease patients can be found in both the substantia nigra and the enteric nervous system. Therefore, it has been hypothesized that the pathological process that leads eventually to Parkinson's disease might initially take place in the enteric nervous system years before the appearance of motor features. The gut microbiome plays essential roles in the development and maintenance of different body systems. Dysbiosis of the normal gut microbiome is thought to be associated with pathophysiologic changes not only in the gastrointestinal system itself but also in the enteric and central nervous systems. These changes are thought to ultimately cause loss of dopaminergic neurons via various mechanisms including the release of neurotoxins into the systemic circulation, decreased production of neuroprotective factors, and triggering inflammatory and autoimmune responses. In this review, we review the gut microbiome changes in Parkinson's disease and discuss the mechanisms by which gut microbiome dysbiosis may be a contributing factor to the pathophysiology of Parkinson's disease. © 2020 International Parkinson and Movement Disorder Society     

The microbiome–gut–brain axis in epilepsy: pharmacotherapeutic target from bench evidence for potential bedside applications

The gut–brain axis augments the bidirectional communication between the gut and brain and modulates gut homeostasis and the central nervous system through the hypothalamic–pituitary–adrenal axis, enteroendocrine system, neuroendocrine system, inflammatory and immune pathways. Preclinical and clinical reports showed that gut dysbiosis might play a major regulatory role in neurological diseases such as epilepsy, Parkinson's, multiple sclerosis, and Alzheimer's disease. Epilepsy is a chronic neurological disease that causes recurrent and unprovoked seizures, and numerous risk factors are implicated in developing epilepsy. Advanced consideration of the gut–microbiota–brain axis can reduce ambiguity about epilepsy pathology, antiepileptic drugs, and effective therapeutic targets. Gut microbiota sequencing analysis reported that the level of Proteobacteria, Verrucomicrobia, Fusobacteria, and Firmicutes was increased and the level of Actinobacteria and Bacteroidetes was decreased in epilepsy patients. Clinical and preclinical studies also indicated that probiotics, ketogenic diet, faecal microbiota transplantation, and antibiotics can improve gut dysbiosis and alleviate seizure by enhancing the abundance of healthy biota. This study aims to give an overview of the connection between gut microbiota, and epilepsy, how gut microbiome changes may cause epilepsy, and whether gut microbiome restoration could be used as a treatment for epilepsy.     

The gut in Parkinson’s disease: Bottom‐up,top‐down,or neither?

The gut‐brain axis is a hot topic in Parkinson's disease. In an attempt to decipher its role in the disease pathogenesis, several animal models have been developed. Most of these models tried to reproduce Braak's hypothesis by showing that the pathological process could spread from the gut to the brain (bottom‐up scenario). Interestingly, others groups showed that a top‐down scenario could also occur and that 6‐hydroxydopamine‐induced nigrostriatal denervation was sufficient to induce significant changes in the gastrointestinal tract. Aside from this toxic approach, the article by O’Donovan and colleagues in this edition of Neurogastroenterology and Motility showed that bilateral nigral injection of adeno‐associated virus (AAV)‐alpha‐synuclein in rats was accompanied by changes in the enteric nervous system and the gut microbiota, which occurred without any apparent brain‐to‐gut spread of human injected alpha‐synuclein. Some changes observed in the gastrointestinal tract of animals injected with AAV‐alpha‐synuclein were in line with previous observations in Parkinson's disease patients, including increased expression of glial markers, swollen tyrosine hydroxylase‐positive varicosities in the submucosal plexus, and decreases in Faecalibacterium and Lachnospiraceae. These findings suggest that, in addition to gut‐brain pathways, the brain‐to‐gut communication may also be involved in Parkinson's disease pathophysiology. In this mini‐review, we describe the strengths and limitations of the existing studies on the gut‐brain axis in experimental models of parkinsonism and discuss an alternative hypothesis in which the central and enteric nervous system would evolve separately during disease progression.     

Etiology and pathogenesis of Parkinson's disease

The past 25 years have seen a major expansion of knowledge concerning the cause of Parkinson's disease provided by an understanding of environmental and genetic factors that underlie the loss of nigral dopaminergic neurons. Based on the actions of toxins, postmortem investigations, and gene defects responsible for familial Parkinson's disease, there is now a general consensus about the mechanisms of cell death that contribute to neuronal loss in Parkinson's disease. Mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammatory change are considered to lead to cell dysfunction and death by apoptosis or autophagy. Ageing is the single most important risk factor for Parkinson's disease, and the biochemical changes that are a consequence of aging amplify these abnormalities in Parkinson's disease brain. What remains to be determined is the combination and sequence of events leading to cell death and whether this is identical in all brain regions where pathology occurs and in all individuals with Parkinson's disease. Focusing on those events that characterize Parkinson's disease, namely, mitochondrial dysfunction and Lewy body formation, may be the key to further advancing the understanding of pathogenesis and to taking these mechanisms forward as a means of defining targets for neuroprotection. © 2011 Movement Disorder Society     

Milestones in Parkinson's disease—Clinical and pathologic features

The identification of the widespread deposition of fibrillized α‐synuclein in Lewy bodies and Lewy neurites in the brains of patients with Parkinson's disease in 1997 has had a profound impact on how the disease is now conceptualized. The previous focus on the loss of the dopaminergic nigrostriatal system, the concept of subcortical dementia, and the idea that Parkinson's disease was dominated by motor impairment have all given way to research assessing more diverse brain regions, clinical symptoms, and phenotypes. It is now recognized that Parkinson's disease is more than just a loss of midbrain dopaminergic neurons in association with Lewy bodies. There are now several theories on how the disease develops and progresses currently being validated in a variety of studies, although many of these theories have yet to incorporate the phenotypic clinical and pathological changes associated with age. A particularly exciting new area of research involves the cell‐to‐cell transmission of pathogenic proteins. The recent consensus definition of Parkinson's disease dementia will allow its pathologic substrates to be determined. These advances have progressed to a stage where the preclinical stages of Parkinson's disease and its specific signs and symptoms are being predicted and tested clinically. Such strategies herald a future wave of preventive strategies for Parkinson's disease and its clinical symptoms. © 2011 Movement Disorder Society     

Potential role of gut microbiota and tissue barriers in Parkinson's disease and amyotrophic lateral sclerosis

Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases with pathophysiology that may be related to the gastrointestinal tract. It is well established that tissue barriers maintain homeostasis and health. Furthermore, gut microbiota may have an impact on brain activity through the gut-microbiota–brain axis under both physiological and pathological conditions. In this review, we highlight the current knowledge regarding the role of gut microbiota and tissue barriers in PD and ALS. To our knowledge, this is the first review of the key issues involving both the altered gut microbiota and impaired tissue barriers in the pathophysiology of PD and ALS.     

Review: The future of cell therapies and brain repair: Parkinson's disease leads the way

During the past 40 years brain tissue grafting techniques have been used both to study fundamental neurobiological questions and to treat neurological diseases. Motor symptoms of Parkinson's disease are largely due to degeneration of midbrain dopamine neurones. Because the nigrostriatal pathology is relatively focused anatomically, Parkinson's disease is considered the ideal candidate for brain repair by neural grafting and dopamine neurone transplantation for it has led the way in the neural transplantation research field. In this mini‐review, we briefly highlight four important areas of development. First, we describe marked functional benefits up to 18 years after transplantation surgery in patients with Parkinson's disease. This is proof‐of‐principle that, using optimal techniques and patient selection, grafted dopamine neurones can work in humans and the duration of the benefit exceeds placebo effects associated with surgery. Second, we describe that eventually protein aggregates containing α‐synuclein, identical to Lewy bodies, develop inside foetal dopamine neurones transplanted to patients with Parkinson's disease. This gives clues about pathogenetic mechanisms operating in Parkinson's disease, and also raises the question whether neural graft function will eventually decline as the result of the disease process. Third, we describe new emerging sources of transplantable dopamine neurones derived from pluripotent stem cells or reprogrammed adult somatic cells. Fourth, we highlight an important European Union‐funded multicentre clinical trial involving transplantation of foetal dopamine neurones in Parkinson's disease. We describe the design of this ongoing trial and how it can impact on the overall future of cell therapy in Parkinson's disease.     

Gut–brain axis and the spread of α‐synuclein pathology: Vagal highway or dead end?

Spread of α‐synuclein pathology from the peripheral to central nervous system may be an important etiological factor in Parkinson's disease, although there are some unanswered questions about its correlation with neuronal loss. Experimental evidence has highlighted the gastrointestinal tract as a potential starting point for aggregated α‐synuclein, with the vagus nerve acting as a “highway” by which pathology may be transmitted to the lower brain stem. This review begins by highlighting the key studies demonstrating that α‐synuclein pathology has the ability to spread from certain sites in the gastrointestinal tract to the brain (and vice versa). We go on to assess the recent epidemiological studies that have shown that vagotomy and appendectomy may have the potential to reduce the risk of developing Parkinson's disease. Finally, we discuss the factors in the gastrointestinal tract (such as dysbiosis of the gut microbiota, infection, and inflammation) that may trigger α‐synuclein aggregation in the first place, as well as other potential mechanisms underlying the distribution of α‐synuclein pathology in the brain. © 2019 International Parkinson and Movement Disorder Society     

Neural networks associated with quality of life in patients with Parkinson's disease

IntroductionThe neural underpinnings of health-related quality of life in Parkinson's disease remain unclear. This study was conducted to unravel which motor and non-motor symptoms in Parkinson's disease influence health-related quality of life and reveal neural networks most likely linked to it.MethodsComprehensive clinical assessments were conducted for 247 Parkinson's disease patients and image analyses were performed for 181 patients. Clinical scores commonly used to assess various symptoms related to health-related quality of life were investigated. Factor and resting-state functional magnetic resonance imaging analyses were reviewed to reveal health-related quality of life-associated brain networks.ResultsThe Spearman's rank correlation coefficient for the Parkinson's disease Questionnaire-39 summary index was high in the Activities-specific Balance Confidence Scale, Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part 2, Freezing of Gait Questionnaire, and Self-reported Autonomic Symptoms in Parkinson's disease. Multiple regression and Random Forest regression analyses indicated that health-related quality of life-associated factors were Movement Disorder Society-Sponsored Revision of the Unified Parkinson's Disease Rating Scale part 1, Depression Rating Scales, and the above-mentioned scales. The resting-state functional magnetic resonance imaging analysis revealed decreased functional connectivity between the anterior cingulate cortex and right temporo-parietal junction as health-related quality of life worsened.ConclusionFear of falling, daily living activities, gait freezing, and autonomic dysfunction have notable effects on health-related quality of life in Parkinson's disease. Brain networks consisting of the anterior cingulate cortex and temporo-parietal junction may be associated with the emotion-related and social factors of health-related quality of life in Parkinson's disease.     

Gastrointestinal dysfunction in Parkinson’s disease: molecular pathology and implications of gut microbiome,probiotics, and fecal microbiota transplantation

Journal of Neurology - Gastrointestinal symptoms and gut dysbiosis may occur before the onset of motor symptoms in Parkinson's disease (PD). Prediagnostic and prodromal features, such as...     

Chronobiology of Parkinson's disease: Past,present and future

Parkinson's disease is a neurodegenerative disorder predominately affecting midbrain dopaminergic neurons that results in a broad range of motor and non-motor symptoms. Sleep complaints are among the most common non-motor symptoms, even in the prodromal period. Sleep alterations in Parkinson's disease patients may be associated with dysregulation of circadian rhythms, intrinsic 24-h cycles that control essential physiological functions, or with side effects from levodopa medication and physical and mental health challenges. The impact of circadian dysregulation on sleep disturbances in Parkinson's disease is not fully understood; as such, we review the systems, cellular and molecular mechanisms that may underlie circadian perturbations in Parkinson's disease. We also discuss the potential benefits of chronobiology-based personalized medicine in the management of Parkinson's disease both in terms of behavioural and pharmacological interventions. We propose that a fuller understanding of circadian clock function may shed important new light on the aetiology and symptomatology of the disease and may allow for improvements in the quality of life for the millions of people with Parkinson's disease.     

Modulation of subthalamic alpha activity to emotional stimuli correlates with depressive symptoms in Parkinson's disease1

Background : Deep brain stimulation of the subthalamic nucleus is an effective treatment for patients with advanced Parkinson's disease. However, affective side effects following subthalamic deep brain stimulation have been reported. Here, we aim to elucidate the influence of affective state on emotional processing as indexed by local field potential activity and to identify neurophysiological markers in patients at risk of developing depressive symptoms during subthalamic deep brain stimulation. Methods : Subthalamic local field potentials were directly recorded via electrodes implanted for deep brain stimulation in 12 Parkinson's disease patients while viewing emotionally salient and neutral pictures. Parkinson's disease patients were assessed for depressive symptoms using the Beck depression inventory at the time of operation and 3 months after continuous subthalamic nucleus deep brain stimulation. Results : We found a significant event‐related desynchronization in the local alpha frequency band (8–12 Hz) for emotionally arousing but not neutral pictures. The the event‐related desynchronization (ERD) in the alpha frequency band was reduced for pleasant stimuli in patients with mild to moderate depressive symptoms compared with patients without depression. The alpha‐ERD to unpleasant stimuli showed the opposite pattern. Consistently, the index of event‐related alpha desynchronization (alpha ERD for pleasant stimuli minus alpha ERD for unpleasant stimuli) correlated with the Beck depression inventory at the time of the recordings and at 3 months after continuous deep brain stimulation. The alpha ERD to unpleasant pictures correlated significantly with the Beck depression inventory score at 3 months after chronic deep brain stimulation. Discusion : In conclusion, we found mood‐congruent stimulus processing in the subthalamic nucleus of Parkinson's disease patients. Electrophysiological markers such as event‐related desynchronization of subthalamic alpha activity reflect state‐dependent emotional processing and may potentially be used to predict depressive mood disturbances in Parkinson's disease patients with chronic subthalamic deep brain stimulation at an early stage. © 2011 Movement Disorder Society     

Invited Review: From nose to gut – the role of the microbiome in neurological disease

Inflammation and neurodegeneration are key features of many chronic neurological diseases, yet the causative mechanisms underlying these processes are poorly understood. There has been mounting interest in the role of the human microbiome in modulating the inflammatory milieu of the central nervous system (CNS) in health and disease. To date, most research has focussed on a gut‐brain axis, with other mucosal surfaces being relatively neglected. We herein take the novel approach of comprehensively reviewing the roles of the microbiome across several key mucosal interfaces – the nose, mouth, lung and gut – in health and in Parkinson's disease (PD), Alzheimer's disease (AD) and multiple sclerosis (MS). This review systematically appraises the anatomical and microbiological landscape of each mucosal surface in health and disease before considering relevant mechanisms that may influence the initiation and progression of PD, AD and MS. The cumulative effects of dysbiosis from the nose to the gut may contribute significantly to neurological disease through a wide variety of mechanisms, including direct translocation of bacteria and their products, and modulation of systemic or CNS‐specific immunity. This remains an understudied and exciting area for future research and may lead to the development of therapeutic targets for chronic neurological disease.     

Why psychosis is frequently associated with Parkinson's disease?

Psychosis is a common non-motor symptom of Parkinson’s disease whose pathogenesis remains poorly understood.Parkinson’s disease in conjunction with psychosis has been shown to induce injury to extracorticospinal tracts as well as within some cortical areas.In this study,Parkinson’s disease patients with psychosis who did not receive antipsychotic treatment and those without psychosis underwent diffusion tensor imaging.Results revealed that in Parkinson’s disease patients with psychosis,damage to the left frontal lobe,bilateral occipital lobe,left cingulated gyrus,and left hippocampal white-matter fibers were greater than damage to the substantia nigra or the globus pallidus.Damage to white-matter fibers in the right frontal lobe and right cingulate gyrus were also more severe than in the globus pallidus,but not the substantia nigra.Damage to frontal lobe and cingulate gyrus white-matter fibers was more apparent than that to occipital or hippocampal fiber damage.Compared with Parkinson’s disease patients without psychosis,those with psychosis had significantly lower fractional anisotropy ratios of left frontal lobe,bilateral occipital lobe,left cingulated gyrus,and left hippocampus to ipsilateral substantia nigra or globus pallidus,indicating more severe damage to white-matter fibers.These results suggest that psychosis associated with Parkinson’s disease is probably associated with an imbalance in the ratio of white-matter fibers between brain regions associated with psychiatric symptoms(frontal lobe,occipital lobe,cingulate gyrus,and hippocampus) and those associated with the motor symptoms of Parkinson’s disease(the substantia nigra and globus pallidus).The relatively greater damage to white-matter fibers in psychiatric symptom-related brain regions than in extracorticospinal tracts might explain why psychosis often occurs in Parkinson’s disease patients.     

Motor and non-motor features of Parkinson's disease that predict persistent drug-induced Parkinsonism

BackgroundDrug-induced Parkinsonism is common, causes significant morbidity, and can be clinically indistinguishable from idiopathic Parkinson's disease. Additionally, drug-induced Parkinsonism may, in some cases, represent “unmasking” of incipient Parkinson's disease. Clinical features or tests that distinguish degenerative from pharmacologic Parkinsonism are needed.MethodsWe performed a retrospective case-control study of 97 drug-induced Parkinsonism subjects and 97 age-matched patients with Parkinson's disease. We compared the frequency of subjective motor and non-motor complaints, objective motor findings (Unified Parkinson's Disease Rating Scale Part III) and, where available, objective olfactory tests. We also performed a nested case-control study wherein we compared these same features between drug-induced Parkinsonism patients based on whether or not they recovered after changing the offending agent.ResultsNon-motor symptoms including constipation and sexual dysfunction were more common in Parkinson's disease than in drug-induced Parkinsonism. While total motor scores were similar between groups, Postural Instability-Gait Difficulty scores were also higher in Parkinson's disease. Features that were significantly different or showed a trend towards significance in both comparisons included subjective loss of facial expression, dream-enactment behavior, autonomic complaints and Postural Instability-Gait Difficulty scores. Hyposmia was more common in Parkinson's disease and was strongly predictive of persistent drug-induced Parkinsonism after therapy change (odds ratio 30.3, 95% confidence interval: 1.5–500, p = 0.03).ConclusionsA constellation of motor and non-motor features may differentiate unmasked Parkinson's disease from drug-induced Parkinsonism. In particular, olfactory testing may offer a simple and inexpensive method to help predict outcomes in drug-induced Parkinsonism and, potentially, identify a cohort of pre-motor Parkinson's disease.     

Neurosurgery in Parkinson＇s disease： Social adjustment, quality of life and coping strategies

Subthalamic nucleus deep brain stimulation has become a standard neurosurgical therapy for ad- vanced Parkinson＇s disease. Subthalamic nucleus deep brain stimulation can dramatically improve the motor symptoms of carefully selected patients with this disease. Surprisingly, some specific dimensions of quality of life, ＂psychological＂ aspects and social adjustment do not always improve, and they could sometimes be even worse. Patients and their families should fully understand that subthalamic nucleus deep brain stimulation can alter the motor status and time is needed to readapt to their new postoperative state and lifestyles. This paper reviews the literatures regarding effects of bilateral subthalamic nucleus deep brain stimulation on social adjustment, quality of life and coping strategies in patients with Parkinson＇s disease. The findings may help to understand the psychoso-cial maladjustment and poor improvement in quality of life in some Parkinson＇s disease patients.     

Fatigue in Parkinson's disease: The contribution of cerebral metabolic changes

Fatigue is a common and disabling non‐motor symptom in Parkinson's disease associated with a feeling of overwhelming lack of energy. The aim of this study was to identify the neural substrates that may contribute to the development of fatigue in Parkinson's disease. Twenty‐three Parkinson's disease patients meeting UK Brain Bank criteria for the diagnosis of idiopathic Parkinson's disease were recruited and completed the 2‐[¹⁸F]fluoro‐2‐deoxy‐D‐glucose (FDG)‐PET scan. The metabolic activities of Parkinson's disease patients with fatigue were compared to those without fatigue using statistical parametric mapping analysis. The Parkinson's disease group exhibiting higher level of fatigue showed anti‐correlated metabolic changes in cortical regions associated with the salience (i.e., right insular region) and default (i.e., bilateral posterior cingulate cortex) networks. The metabolic abnormalities detected in these brain regions displayed a significant correlation with level of fatigue and were associated with a disruption of the functional correlations with different cortical areas. These observations suggest that fatigue in Parkinson's disease may be the expression of metabolic abnormalities and impaired functional interactions between brain regions linked to the salience network and other neural networks. Hum Brain Mapp 38:283–292, 2017. © 2016 Wiley Periodicals, Inc.     

Impulsive and compulsive behaviors among Danish patients with Parkinson's disease: Prevalence,depression, and personality

IntroductionDopaminergic medication administered to ameliorate motor symptoms of Parkinson's disease is associated with impulse control disorders, such as pathological gambling, hypersexuality, compulsive buying, and binge eating. Studies indicate a prevalence of impulse control disorders in Parkinson's disease of 6–16%.ObjectiveTo estimate the prevalence of impulsive and compulsive behaviors among Danish patients with Parkinson's disease and to explore the relation of such behavioral disorders to depression and personality.Methods490 patients with Parkinson's disease (303 males), identified through the National Danish Patient Registry, were evaluated with: 1) the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease; 2) the Geriatric Depression Scale; and 3) the NEO-Personality Inventory.Results176 (35.9%) patients reported impulsive and compulsive behaviors sometime during Parkinson's disease (current symptoms in 73, 14.9%). Hereof, 114 (23.3%) reported multiple behavioral symptoms. Patients with behavioral symptoms were significantly younger, were younger at PD onset, had longer disease duration, displayed more motor symptoms, and received higher doses of dopaminergic medication than patients without behavioral symptoms. Furthermore, they reported significantly more depressive symptoms and scored significantly higher on neuroticism and lower on both agreeableness and conscientiousness than patients without behavioral symptoms.ConclusionA history of impulsive and compulsive behaviors are common in Danish patients with Parkinson's disease and have clinical correlates that may allow identification of patients at risk for developing these behaviors.     

A tale on animal models of Parkinson's disease

Parkinson's disease is a neurodegenerative disorder whose cardinal manifestations are due primarily to a profound deficit in brain dopamine. Since the 1980s, several therapeutic strategies have been discovered to treat the symptoms of this neurological disorder, but as of yet, none halts or retards the neurodegenerative process. In an attempt to shed light on the neurobiology of Parkinson's disease, a number of experimental models have been developed, especially during the last 25 years. They come essentially in 3 flavors: pharmacological (eg, reserpine), toxic (eg, 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine), and genetic (eg, transgenic synuclein mice). These models can also be recast as etiologic, pathogenic, and symptomatic/pathophysiologic, as each may contribute to our understanding of the cause, the mechanisms, and the treatment of Parkinson's disease. In this review, we will discuss the question of Parkinson's disease models, starting from the period when this journal was born to today. During this journey of 25 years, we will discuss both the significant contributions of the Parkinson's disease models and hurdles that remain to be overcome to one day cure this neurological disease. © 2011 Movement Disorder Society     

Functional movement disorder comorbidity in Parkinson's disease: Unraveling the web

Functional movement disorders are commonly seen in neurology services and may coexist with other neurological diseases. This combination is known as “functional overlay” and an increasing interest on this topic has emerged in the past decade as the field of functional neurological disorders has moved forward. Some neurological diseases may be more prone to develop “functional overlay” than others, and within the field of movement disorders, most studies have focused on patients with Parkinson's disease. This review comprehensively summarizes the current body of knowledge on this topic and provides an expert opinion to equip clinicians with a pragmatic approach to recognize functional movement disorders in patients with Parkinson's disease, to communicate the diagnosis and to become familiar with potential therapies in this complex clinical scenario. Potential underlying mechanisms and risk factors that may play a role in increasing the vulnerability of Parkinson's disease patients to develop functional movement disorder comorbidity are also discussed within the framework of modern neurobiological theories of brain functioning.