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The etiology of Parkinson's disease (PD) is multifactorial, with genetics, aging, and environmental agents all a part of the PD pathogenesis. Widespread aggregation of the α-synuclein protein in the form of Lewy bodies and Lewy neurites, and degeneration of substantia nigra dopamine neurons are the pathological hallmarks of PD. Inflammatory responses manifested by glial reactions, T cell infiltration, and increased expression of inflammatory cytokines, as well as other toxic mediators derived from activated glial cells, are currently recognized as prominent features of PD. Experimental, clinical and epidemiological data suggest that intestinal inflammation contributes to the pathogenesis of PD, and the increasing number of studies suggests that the condition may start in the gastrointestinal system years before any motor symptoms develop. Patients with inflammatory bowel disease (IBD) have a higher risk of developing PD compared with non-IBD individuals. Gene association study has found a genetic link between IBD and PD, and an evidence from animal studies suggests that gut inflammation, similar to that observed in IBD, may induce loss of dopaminergic neurons. Based on preclinical models of PD, it is suggested that the enteric microbiome changes early in PD, and gut infections trigger α-synuclein release and aggregation. In this paper, the possible link between IBD and PD is reviewed based on the available literature. Given the potentially critical role of gastrointestinal pathology in PD pathogenesis, there is reason to suspect that IBD or its treatments may impact PD risk. Thus, clinicians should be aware of PD symptoms in IBD patients. [ABSTRACT FROM AUTHOR]

Abstract Faecal microbiome transplantation (FMT) is an attractive technique, because the administration is relatively simple and in general has a mild adverse effect pattern. Moreover, FMT consists of a broad mixture, which could be beneficial, because at this moment it is not known what type of changes in the microbiome are needed. However, except from a few cases no clinical data in Parkinson's disease (PD) is available yet. There is some indication that FMT might be beneficial in severe constipated PD patients, but the clinical data to support this are very scarce. So, actually there are no good data in the public domain to support FMT at this moment in PD patients. FMT at this moment is a black box with too many unanswered questions, also with respect to safety concerns. Only the administration of species of Lactobacillus and Bifidobacterium over a time period of four to twelve weeks has repeatedly proven to be effective in treating constipation in PD. Also, no solid clinical data are available about the possible effects of probiotic treatment on motor symptoms or progression of PD. Therefore, also probiotic treatments in PD should wait until better clinical data become available, in order to select the right target populations and to have good estimates of the clinical effects to be expected. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a highly heterogeneous disorder, which probably consists of multiple subtypes. Aggregation of misfolded alpha-synuclein and propagation of these proteinacious aggregates through interconnected neural networks is believed to be a crucial pathogenetic factor. It has been hypothesized that the initial pathological alpha-synuclein aggregates originate in the enteric or peripheral nervous system (PNS) and invade the central nervous system (CNS) via retrograde vagal transport. However, evidence from neuropathological studies suggests that not all PD patients can be reconciled with this hypothesis. Importantly, a small fraction of patients do not show pathology in the dorsal motor nucleus of the vagus. Here, it is hypothesized that PD can be divided into a PNS-first and a CNS-first subtype. The former is tightly associated with REM sleep behavior disorder (RBD) during the prodromal phase and is characterized by marked autonomic damage before involvement of the dopaminergic system. In contrast, the CNS-first phenotype is most often RBD-negative during the prodromal phase and characterized by nigrostriatal dopaminergic dysfunction prior to involvement of the autonomic PNS. The existence of these subtypes is supported by in vivo imaging studies of RBD-positive and RBD-negative patient groups and by histological evidence— reviewed herein. The present proposal provides a fresh hypothesis-generating framework for future studies into the etiopathogenesis of PD and seems capable of explaining a number of discrepant findings in the neuropathological literature. [ABSTRACT FROM AUTHOR]

Increasing evidence is supporting the hypothesis of α-synuclein pathology spreading from the gut to the brain although the exact etiology of Parkinson's disease (PD) is unknown. Furthermore, it has been proposed that inflammation, via the gastrointestinal tract, potentially through infections, may contribute to α-synuclein pathogenesis, and thus to the risk of developing PD. Recently, many studies have shown that PD patients have an altered microbiota composition compared to healthy controls. Inflammation in the gut might drive microbiota alterations or vice versa. Many studies focused on the detection of biomarkers of the etiology, onset, or progression of PD however also report metabolites from bacterial origin. These metabolites might reflect the bacterial composition and as well play an important role in immune homeostasis, ultimately affecting the progression of PD. Besides the bacterial metabolites, pharmacological treatment of PD might play a crucial role during the progression and thus treatment of the disease on the immune system. This review aims to establish a link between the microbial composition with the observed alterations of bacterial metabolites and their impact on the immune system, which could have influential effect in onset, progression and etiology of PD. [ABSTRACT FROM AUTHOR]

Gut microbiota have been studied in relation to the pathophysiology of Parkinson's disease (PD) due to the early gastrointestinal symptomatology and presence of alpha-synuclein pathology in the enteric nervous system, hypothesized to ascend via the vagal nerve to the central nervous system. Accordingly, sixteen human case-control studies have published gut microbiome composition changes in PD and reported over 100 differentially abundant taxa covering all taxonomic levels from phylum to genus or species, depending on methodology. While certain findings were replicated across several studies, various contradictory findings were reported. Here, differences in methodologies and the presence of possible confounders in the study populations are assessed for their potential to confound the results of gut microbiome studies in PD. Gut microbiome studies in PD exhibited considerable variability with respect to the study population, sample transport conditions, laboratory protocols and sequencing, bioinformatics pipelines, and biostatistical methods. To move from the current heterogeneous dataset towards clinically relevant biomarkers and the identification of putative therapeutic targets, recommendations are derived from the limitations of the available studies to increase the future comparability of microbiome studies in PD. In addition, integration of currently available data on the gut microbiome in PD is proposed to identify robust gut microbiome profiles in PD. Furthermore, expansion of the current dataset with atypical parkinsonism cohorts, prodromal and treatment-naïve de novo PD subjects, measurements of fecal microbial concentrations and multi-omics assessments are required to provide clinically relevant biomarkers and reveal therapeutic targets within the gut microbiome of PD. [ABSTRACT FROM AUTHOR]

The intestinal barrier, which primarily consists of epithelial cells stitched together with connecting proteins called tight junctions, plays a critical role in health and disease. It is in close contact with the gut microbiota on its luminal side and with the enteric neurons on the tissue side. Both microbiota and the enteric nervous system are regulatory housekeepers of the intestinal barrier. Therefore, the recently observed enteric neuropathology along with gut dysbiosis in Parkinson's disease have prompted research on intestinal permeability in this neurodegenerative disorder. In this mini-review we attempt to concisely summarize the current knowledge on intestinal barrier in Parkinson's disease. We envision future direction research that should be pursued in order to demonstrate its possible role in disease development and progression. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) has long been considered a brain disease, but studies now point to the gastrointestinal (GI) tract as a potential starting point for PD. In particular, the human vermiform appendix has been implicated in PD. The appendix is a tissue rich in immune cells, serving as part of the gut-associated lymphoid tissue and as a storehouse for the gut microbiome. The functions of the appendix converge with recent evidence demonstrating that gut inflammation and shifts in the microbiome are linked to PD. Some epidemiological studies have linked removal of the appendix to lowered PD risk, though there is controversy among these associations. What is apparent is that there is an abundance of aggregated forms of α-synuclein in the appendix relevant to PD pathology. α-Synuclein pathology is thought to propagate from gut to brain via the vagus nerve, which innervates GI tract locations, including the appendix. Remarkably, α-synuclein aggregates in the appendix occur not only in PD patients, but are also present in healthy individuals. This has led to the proposal that in the appendix α-synuclein aggregates are not unique to PD. Moreover, the molecular events leading to PD and the mechanisms by which α-synuclein aggregates transfers from gut to brain may be identifiable in the human appendix. The influence of the appendix on GI inflammation, autoimmunity, microbiome storage, and the lymphatic system may be yet unexplored mechanisms by which the appendix contributes to PD. Overall, the appendix represents a promising tissue site to advance our understanding of PD pathobiology. [ABSTRACT FROM AUTHOR]

The gastrointestinal (GI) tract is equipped with robust immune defenses which protect the organism from infection. Enteric nerves are front and center in this defensive network, even in the most primitive organisms. Neuropeptides exhibit potent antimicrobial activity in the vicinity of the nerve and attract the innate and adaptive immune systems to help confine the invading agent. Alpha-synuclein (αS) has many biophysical characteristics of antimicrobial peptides and binds small vesicles such as those carrying endocytosed viruses. It is induced in nerve cells in response to viral and bacterial infections. It renders the nerve cell resistant to viral infection and propagation. It signals the immune system by attracting neutrophils and macrophages, and by activating dendritic cells. Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates. Overproduction of αS in the enteric nervous system (ENS) and its chronic trafficking to the CNS may damage nerves and lead to Parkinson's disease. Targeting the formation of αS aggregates in the ENS may therefore slow the progression of the disease. [ABSTRACT FROM AUTHOR]

Background/Objective: Idiopathic REM sleep behavior disorder (iRBD) often precedes Parkinson's disease (PD) and other alpha-synucleinopathies. The aim of the study is to investigate brain glucose metabolism of patients with RBD and PD by means of a multidimensional scaling approach, using18F-FDG-PET as a biomarker of synaptic function. Methods: Thirty-six iRBD patients (64.1±6.5 y, 32 M), 72 PD patients, and 79 controls (65.6±9.4 y, 53 M) underwent brain 18F-FDG-PET. PD patients were divided according to the absence (PD, 32 subjects; 68.4±8.5 y, 15 M) or presence (PDRBD, 40 subjects; 71.8±6.6 y, 29 M) of RBD. 18F-FDG-PET scans were used to independently discriminate subjects belonging to four categories: controls (RBD no, PD no), iRBD (RBD yes, PD no), PD (RBD no, PD yes) and PDRBD (RBD yes, PD yes). Results: The discriminant analysis was moderately accurate in identifying the correct category. This is because the model mostly confounds iRBD and PD, thus the intermediate classes. Indeed, iRBD, PD and PDRBD were progressively located at increasing distance from controls and are ordered along a single dimension (principal coordinate analysis) indicating the presence of a single flux of variation encompassing both RBD and PD conditions. Conclusion: Data-driven approach to brain 18F-FDG-PET showed only moderate discrimination between iRBD and PD patients, highlighting brain glucose metabolism heterogeneity among such patients. iRBD should be considered as a marker of an ongoing condition that may be picked-up in different stages across patients and thus express different brain imaging features and likely different clinical trajectories. [ABSTRACT FROM AUTHOR]

Introduction: Continuous apomorphine infusion (CAI) is an advanced therapy in fluctuating Parkinson's disease (PD). The use of CAI is controversial in PD patients with cognitive dysfunction including visual hallucinations (VHs), and orthostatic hypotension (OH). This study was set-up to analyze the effectiveness and safety of CAI in elderly PD patients with cognitive dysfunction.Methods: This new-user cohort study identified fluctuating PD patients who started CAI treatment at the rehabilitation unit of Parkinson Expertise Center (RU-PEC) Groningen, from November 2004 until 2016. Efficacy and safety data included motor function, cognitive status, OH and VHs, and was analyzed retrospectively. Pre-existent non-motor symptoms were treated optimally before starting CAI.Results: Forty-five fluctuating PD patients (age: 70.9 ± 8.1 yrs, disease duration: 10.8 ± 4.8 yrs) were identified, with pre-existing cognitive dysfunction, VHs (71%), and OH (26%). During the stay at RU-PEC (median 52 days) apomorphine was successfully titrated without worsening of pre-existing VHs and OH. The mean daily apomorphine dose was 66 ± 28 mg, accompanied by a reduction of levodopa-equivalent daily dose (LEDD) with 17%. The duration of ON-time and OFF-time significantly improved with +2.36 h (25%) and -1.66 h (-45%), respectively, while dyskinesia duration did not change. During long-term follow-up (median of 26 months) VHs and OH worsened in 9 and 4 patients, which necessitated discontinuation in 4 cases.Conclusion: This study demonstrates that CAI is also an effective treatment in advanced PD patients with concomitant cognitive dysfunction including VHs and OH, provided that these comorbidities are treated adequately as well. [ABSTRACT FROM AUTHOR]

Tremor, bradykinesia, and rigidity are incapacitating motor symptoms that can be suppressed with stereotactic neurosurgical treatment like deep brain stimulation (DBS) and ablative surgery (e.g., thalamotomy, pallidotomy). Traditionally, clinicians rely on clinical rating scales for intraoperative evaluation of these motor symptoms during awake stereotactic neurosurgery. However, these clinical scales have a relatively high inter-rater variability and rely on experienced raters. Therefore, objective registration (e.g., using movement sensors) is a reasonable extension for intraoperative assessment of tremor, bradykinesia, and rigidity. The main goal of this scoping review is to provide an overview of electronic motor measurements during awake stereotactic neurosurgery. The protocol was based on the PRISMA extension for scoping reviews. After a systematic database search (PubMed, Embase, and Web of Science), articles were screened for relevance. Hundred-and-three articles were subject to detailed screening. Key clinical and technical information was extracted. The inclusion criteria encompassed use of electronic motor measurements during stereotactic neurosurgery performed under local anesthesia. Twenty-three articles were included. These studies had various objectives, including correlating sensor-based outcome measures to clinical scores, identifying optimal DBS electrode positions, and translating clinical assessments to objective assessments. The studies were highly heterogeneous in device choice, sensor location, measurement protocol, design, outcome measures, and data analysis. This review shows that intraoperative quantification of motor symptoms is still limited by variable signal analysis techniques and lacking standardized measurement protocols. However, electronic motor measurements can complement visual evaluations and provide objective confirmation of correct placement of the DBS electrode and/or lesioning. On the long term, this might benefit patient outcomes and provide reliable outcome measures in scientific research. [ABSTRACT FROM AUTHOR]