Journal of Parkinson's Disease - Volume 12, issue 8

Authors: Bloem, Bastiaan R. | Kalia, Lorraine V.

Article Type: Editorial

DOI: 10.3233/JPD-229010

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2283-2286, 2022

Authors: McFarthing, Kevin

Article Type: Article Commentary

DOI: 10.3233/JPD-229007

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2287-2288, 2022

Authors: Richard, Edo | Bloem, Bastiaan R.

Article Type: Editorial

Keywords: Parkinson’s disease, alpha-synuclein, cinpanemab, prasinezumab

DOI: 10.3233/JPD-225032

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2289-2291, 2022

Authors: Brundin, Patrik | Svoboda, Hanno | Bonni, Azad | Pagano, Gennaro

Article Type: Article Commentary

DOI: 10.3233/JPD-229008

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2293-2296, 2022

Authors: Schootemeijer, Sabine | Darweesh, Sirwan K.L. | de Vries, Nienke M.

Article Type: Research Article

Abstract:  Converging lines of evidence suggest that aerobic exercise impacts Parkinson’s disease (PD) motor symptoms and might slow it’s progression. We provide an overview of the ongoing randomized clinical trials (RCTs) on aerobic exercise in PD. We found six RCTs with sample sizes between 28 and 370 and a follow-up between 8 weeks and 18 months. PD motor symptoms is mostly used as primary outcome while various secondary outcomes are reported. We need more trials that use both clinical endpoints and markers of neuroplasticity, and provide insight into the optimal exercise mode, duration and intensity.

DOI: 10.3233/JPD-229006

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2297-2306, 2022

Authors: Björklund, Anders | Nilsson, Fredrik | Mattsson, Bengt | Hoban, Deirdre B. | Parmar, Malin

Article Type: Review Article

Abstract: Injections of pre-formed α-synuclein fibrils (PFFs) or overexpression of α-synuclein using AAV vectors are commonly used as models of Parkinson-like synucleinopathy in rats and mice. In the modified method reviewed here, the “SynFib ” model, the PFFs and the AAV vector are administered together unilaterally into the substantia nigra. This approach combines the key features of these two models, i.e., the generation of toxic α-synuclein aggregates and Lewy body-like inclusions, in combination with the increased vulnerability caused by increased cellular levels of α-synuclein. The combined AAV/PFF delivery offers several advantages over the standard PFF model due to the enhanced and …accelerated α-synuclein pathology and microglial response induced by the PFF seeds in the presence of an elevated α-synuclein level. Injection of the AAV/PFF mixture into the substantia nigra makes it possible to target a larger proportion of the nigral dopamine neurons and obtain a level of dopamine cell loss (>60%) needed to induce significant impairments in drug-induced and spontaneous motor tests. The SynFib model shares attractive features of the standard 6-OHDA lesion model: a single unilateral stereotaxic intervention; pathology and cell loss developing over a short time span; and the possibility to monitor the degenerative changes using tests of motor behavior. Show more

Keywords: adeno-associated virus, disease modeling, inflammation, motor behavior, mouse, Parkinson’s disease, pre-formed fibrils, rat

DOI: 10.3233/JPD-223452

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2307-2320, 2022

Authors: Coleman, Colin | Martin, Ian

Article Type: Review Article

Abstract: Aging is the greatest risk factor for Parkinson’s disease (PD), suggesting that mechanisms driving the aging process promote PD neurodegeneration. Several lines of evidence support a role for aging in PD. First, hallmarks of brain aging such as mitochondrial dysfunction and oxidative stress, loss of protein homeostasis, and neuroinflammation are centrally implicated in PD development. Second, mutations that cause monogenic PD are present from conception, yet typically only cause disease following a period of aging. Third, lifespan-extending genetic, dietary, or pharmacological interventions frequently attenuate PD-related neurodegeneration. These observations support a central role for aging in disease development and suggest that …new discoveries in the biology of aging could be leveraged to elucidate novel mechanisms of PD pathophysiology. A recent rapid growth in our understanding of conserved molecular pathways that govern model organism lifespan and healthspan has highlighted a key role for metabolism and nutrient sensing pathways. Uncovering how metabolic pathways involving NAD+ consumption, insulin, and mTOR signaling link to the development of PD is underway and implicates metabolism in disease etiology. Here, we assess areas of convergence between nervous system aging and PD, evaluate the link between metabolism, aging, and PD and address the potential of metabolic interventions to slow or halt the onset of PD-related neurodegeneration drawing on evidence from cellular and animal models. Show more

Keywords: Aging, Parkinson’s disease, metabolism, mitochondria

DOI: 10.3233/JPD-223363

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2321-2338, 2022

Authors: Chan, Dennis G. | Ventura, Katelyn | Villeneuve, Ally | Du Bois, Paul | Holahan, Matthew R.

Article Type: Review Article

Abstract: The contribution of the microbiota to induce gastrointestinal inflammation is hypothesized to be a key component of alpha-synuclein (aSyn) aggregation within the gastrointestinal (GI) tract in the pathological progression of Parkinson’s disease (PD). The function of the GI tract is governed by a system of neurons that form part of the enteric nervous system (ENS). The ENS hosts  100–500 million nerve cells within two thin layers lining the GI tract. The gut-brain axis (GBA) is the major communication pathway between the ENS and the central nervous system. It has become increasingly clear that the microbiota in the gut are key …regulators of GBA function and help to maintain homeostasis in the immune and endocrine systems. The GBA may act as a possible etiological launching pad for the pathogenesis of age-related neurodegenerative diseases, such as PD, because of an imbalance in the gut microbiota. PD is a multi-faceted illness with multiple biological, immunological, and environmental factors contributing to its pathological progression. Interestingly, individuals with PD have an altered gut microbiota compared to healthy individuals. However, there is a lack of literature describing the relationship between microbiota composition in the gut and symptom progression in PD patients. This review article examines how the pathology and symptomology of PD may originate from dysregulated signaling in the ENS. We then discuss by targeting the imbalance within the gut microbiota such as prebiotics and probiotics, some of the prodromal symptoms might be alleviated, possibly curtailing the pathological spread of aSyn and ensuing debilitating motor symptoms. Show more

Keywords: Microbiome, Parkinson’s disease, alpha-synuclein, prodromal symptoms, probiotics, prebiotics, fecal microbiota transplantation, gastrointestinal tract

DOI: 10.3233/JPD-223461

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2339-2352, 2022

Authors: Kolicheski, Ana | Turcano, Pierpaolo | Tamvaka, Nicole | McLean, Pamela J. | Springer, Wolfdieter | Savica, Rodolfo | Ross, Owen A.

Article Type: Review Article

Abstract: Parkinson’s disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different …forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk. Show more

Keywords: Parkinson’s disease, early-onset Parkinson’s disease, genetics, environment, risk factors

DOI: 10.3233/JPD-223380

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2353-2367, 2022

Authors: Mitchell, Eleanor | Chohan, Harneek | Bestwick, Jonathan P. | Noyce, Alastair J.

Article Type: Systematic Review

Abstract: Background: A substantial body of research has examined the relationship between alcohol consumption and risk of Parkinson’s disease (PD). Objective: To provide an updated systematic review and meta-analysis of observational studies examining the relationship between alcohol consumption and risk of PD. Methods: Eligible studies comparing PD risk in ever vs. never alcohol drinkers were sourced from six databases. Outcomes were pooled using standard meta-analysis techniques. Separate female and male estimates were generated from studies reporting sex-specific data. Additionally, cohort studies stratifying participants by quantity of alcohol intake were integrated in a dose-response analysis. Results: …52 studies were included, totaling 63,707 PD patients and 9,817,924 controls. Our meta-analysis supported a statistically significant overrepresentation of never drinkers among PD subjects; odds ratio (OR) for ever drinking alcohol 0.84 (95% confidence interval (CI) 0.76 – 0.92). A subgroup analysis revealed similar effect estimates in females and males. A further synthesis of seven cohort studies suggested a negative, dose-dependent association between alcohol and risk of PD. Conclusion: In the absence of a known neuroprotective pathway, there may be reason to doubt a true biological effect. The role of survivor bias, selection and recall bias, misclassification, and residual confounding requires consideration. Alternatively, observations might be attributable to reverse causation if those predestined for PD alter their alcohol habits during the preclinical phase. Major limitations of our study include high between-study heterogeneity (I2  = 93.2%) and lack of adjustment for key confounders, namely smoking status. Show more

Keywords: Parkinson’s disease, alcohols, ethanol, alcohol drinking, alcoholic beverages, systematic review, meta-analysis

DOI: 10.3233/JPD-223522

Citation: Journal of Parkinson's Disease, vol. 12, no. 8, pp. 2369-2381, 2022