Levodopa infusion therapies for Parkinson disease.

PURPOSE OF REVIEW: to review recent progress in the development and use of continuous levodopa therapies in Parkinson disease (PD). RECENT FINDINGS: Levodopa/Carbidopa intestinal gel (LCIG) is a continuous levodopa therapy which is widely used in the United States, Europe and other countries and is effective at reducing 'off' time. Recent work has shown that LCIG can be useful in managing dyskinesias and can improve nonmotor symptoms and quality of life. Several studies have shown good long-term effectiveness of LCIG. Recent data support the cost-effectiveness of this treatment strategy. Subcutaneous (SC) delivery of levodopa is a newer strategy that avoids the need for a surgically placed gastric tube. Two different products enabling SC delivery of levodopa are in development: ND0612 and foslevodopa/foscarbidopa. Both have recently been shown to reduce 'off' time in randomized, double-blind trials. Adverse effects of SC levodopa are primarily related to skin reactions at the infusion site. SUMMARY: Continuous levodopa therapies can be used to treat Parkinson disease motor fluctuations that cannot be managed with standard oral therapies. They may also improve nonmotor symptoms, and improve overall quality of life in patients with advanced PD.

Identification of genetic risk loci and causal insights associated with Parkinson's disease in African and African admixed populations: a genome-wide association study.

BACKGROUND: An understanding of the genetic mechanisms underlying diseases in ancestrally diverse populations is an important step towards development of targeted treatments. Research in African and African admixed populations can enable mapping of complex traits, because of their genetic diversity, extensive population substructure, and distinct linkage disequilibrium patterns. We aimed to do a comprehensive genome-wide assessment in African and African admixed individuals to better understand the genetic architecture of Parkinson's disease in these underserved populations. METHODS: We performed a genome-wide association study (GWAS) in people of African and African admixed ancestry with and without Parkinson's disease. Individuals were included from several cohorts that were available as a part of the Global Parkinson's Genetics Program, the International Parkinson's Disease Genomics Consortium Africa, and 23andMe. A diagnosis of Parkinson's disease was confirmed clinically by a movement disorder specialist for every individual in each cohort, except for 23andMe, in which it was self-reported based on clinical diagnosis. We characterised ancestry-specific risk, differential haplotype structure and admixture, coding and structural genetic variation, and enzymatic activity. FINDINGS: We included 197 918 individuals (1488 cases and 196 430 controls) in our genome-wide analysis. We identified a novel common risk factor for Parkinson's disease (overall meta-analysis odds ratio for risk of Parkinson's disease 1·58 [95% CI 1·37-1·80], p=2·397 × 10-14) and age at onset at the GBA1 locus, rs3115534-G (age at onset ß=-2·00 [SE=0·57], p=0·0005, for African ancestry; and ß=-4·15 [0·58], p=0·015, for African admixed ancestry), which was rare in non-African or non-African admixed populations. Downstream short-read and long-read whole-genome sequencing analyses did not reveal any coding or structural variant underlying the GWAS signal. The identified signal seems to be associated with decreased glucocerebrosidase activity. INTERPRETATION: Our study identified a novel genetic risk factor in GBA1 in people of African ancestry, which has not been seen in European populations, and it could be a major mechanistic basis of Parkinson's disease in African populations. This population-specific variant exerts substantial risk on Parkinson's disease as compared with common variation identified through GWAS and it was found to be present in 39% of the cases assessed in this study. This finding highlights the importance of understanding ancestry-specific genetic risk in complex diseases, a particularly crucial point as the Parkinson's disease field moves towards targeted treatments in clinical trials. The distinctive genetics of African populations highlights the need for equitable inclusion of ancestrally diverse groups in future trials, which will be a valuable step towards gaining insights into novel genetic determinants underlying the causes of Parkinson's disease. This finding opens new avenues towards RNA-based and other therapeutic strategies aimed at reducing lifetime risk of Parkinson's disease. FUNDING: The Global Parkinson's Genetics Program, which is funded by the Aligning Science Across Parkinson's initiative, and The Michael J Fox Foundation for Parkinson's Research.

Metagenomics of Parkinson's disease implicates the gut microbiome in multiple disease mechanisms.

Parkinson's disease (PD) may start in the gut and spread to the brain. To investigate the role of gut microbiome, we conducted a large-scale study, at high taxonomic resolution, using uniform standardized methods from start to end. We enrolled 490 PD and 234 control individuals, conducted deep shotgun sequencing of fecal DNA, followed by metagenome-wide association studies requiring significance by two methods (ANCOM-BC and MaAsLin2) to declare disease association, network analysis to identify polymicrobial clusters, and functional profiling. Here we show that over 30% of species, genes and pathways tested have altered abundances in PD, depicting a widespread dysbiosis. PD-associated species form polymicrobial clusters that grow or shrink together, and some compete. PD microbiome is disease permissive, evidenced by overabundance of pathogens and immunogenic components, dysregulated neuroactive signaling, preponderance of molecules that induce alpha-synuclein pathology, and over-production of toxicants; with the reduction in anti-inflammatory and neuroprotective factors limiting the capacity to recover. We validate, in human PD, findings that were observed in experimental models; reconcile and resolve human PD microbiome literature; and provide a broad foundation with a wealth of concrete testable hypotheses to discern the role of the gut microbiome in PD.

Dysregulation of the Adaptive Immune System in Patients With Early-Stage Parkinson Disease.

OBJECTIVE: To determine the activation status and cytokine profiles of CD4+ T cells, CD8+ T cells, and CD19+ B cells from patients with early-stage Parkinson disease (PD) compared with healthy controls (HCs). METHODS: Peripheral blood samples from 41 patients with early-stage PD and 40 HCs were evaluated. Peripheral blood mononuclear cells were analyzed by flow cytometry for surface markers and intracellular cytokine production. Correlations of immunologic changes and clinical parameters were analyzed. RESULTS: Adaptive immunity plays a role in the pathogenesis of PD, yet the contribution of T cells and B cells, especially cytokine production by these cells, is poorly understood. We demonstrate that naive CD4+ and naive CD8+ T cells are significantly decreased in patients with PD, whereas central memory CD4+ T cells are significantly increased in patients with PD. Furthermore, IL-17-producing CD4+ Th17 cells, IL-4-producing CD4+ Th2 cells, and IFN-γ-producing CD8+ T cells are significantly increased in patients with PD. Regarding B cells, we observed a decrease in naive B cells and an increase in nonswitched memory and double-negative B cells. As well, TNF-α-producing CD19+ B cells were significantly increased in patients with PD. Notably, some of the changes observed in CD4+ T cells and B cells were associated with clinical motor disease severity. CONCLUSIONS: These findings suggest that alterations in the adaptive immune system may promote clinical disease in PD by skewing to a more proinflammatory state in the early-stage PD patient cohort. Our study may shed light on potential immunotherapies targeting dysregulated CD4+ T cells, CD8+ T cells, and CD19+ B cells in patients with PD.

Characterizing dysbiosis of gut microbiome in PD: evidence for overabundance of opportunistic pathogens.

In Parkinson's disease (PD), gastrointestinal features are common and often precede the motor signs. Braak and colleagues proposed that PD may start in the gut, triggered by a pathogen, and spread to the brain. Numerous studies have examined the gut microbiome in PD; all found it to be altered, but found inconsistent results on associated microorganisms. Studies to date have been small (N = 20 to 306) and are difficult to compare or combine due to varied methodology. We conducted a microbiome-wide association study (MWAS) with two large datasets for internal replication (N = 333 and 507). We used uniform methodology when possible, interrogated confounders, and applied two statistical tests for concordance, followed by correlation network analysis to infer interactions. Fifteen genera were associated with PD at a microbiome-wide significance level, in both datasets, with both methods, with or without covariate adjustment. The associations were not independent, rather they represented three clusters of co-occurring microorganisms. Cluster 1 was composed of opportunistic pathogens and all were elevated in PD. Cluster 2 was short-chain fatty acid (SCFA)-producing bacteria and all were reduced in PD. Cluster 3 was carbohydrate-metabolizing probiotics and were elevated in PD. Depletion of anti-inflammatory SCFA-producing bacteria and elevated levels of probiotics are confirmatory. Overabundance of opportunistic pathogens is an original finding and their identity provides a lead to experimentally test their role in PD.