scholarly journals Genetic Profile, Environmental Exposure, and Their Interaction in Parkinson’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Letizia Polito ◽  
Antonio Greco ◽  
Davide Seripa
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Exposure ◽  
Disease Onset ◽  
Genetic Profile ◽  
Environmental Toxicants ◽  
Susceptibility Factors ◽  
Increased Risk ◽  
Small Effect Size ◽  
The Impact

The discovery of causative mutations for Parkinson’s disease (PD) as well as their functional characterization in cellular and animal models has provided crucial insight into the pathogenesis of this disorder. Today, we know that PD pathogenesis involves multiple related processes including mitochondrial dysfunction, oxidative and nitrative stress, microglial activation and inflammation, and aggregation ofα-synuclein and impaired autophagy. However, with the exception of a few families with Mendelian inheritance, the cause of PD in most individuals is yet unknown and the identified genetic susceptibility factors have only small effect size. Epidemiologic studies have found increased risk of PD associated with exposure to environmental toxicants such as pesticides, organic solvents, metals, and air pollutants, while reduced risk of PD associated with smoking cigarettes and coffee consumption. The role of environmental exposure, as well as the contribution of single genetic risk factors, is still controversial. In most of PD cases, disease onset is probably triggered by a complex interplay of many genetic and nongenetic factors, each of which conveys a minor increase in the risk of disease. This review summarizes the current knowledge on causal mutation for PD, susceptibility factors increasing disease risk, and the genetic factors that modify the impact of environmental exposure.

scholarly journals Gut microbiome signatures of risk and prodromal markers of Parkinson’s disease

2019 ◽  
Author(s):  
Sebastian Heinzel ◽  
Velma T. E. Aho ◽  
Ulrike Suenkel ◽  
Anna-Katharina von Thaler ◽  
Claudia Schulte ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Gut Microbiome ◽  
Physical Inactivity ◽  
Disease Onset ◽  
Rem Sleep Behavior Disorder ◽  
Sleep Behavior ◽  
Microbiome Composition ◽  
Β Diversity ◽  
The Impact

AbstractObjectivesAlterations of the gut microbiome in Parkinson’s disease (PD) have been repeatedly demonstrated. However, little is known about whether such alterations precede disease onset and how they may be related to risk and prodromal markers of PD. We investigated associations of these features with gut microbiome composition.MethodsEstablished risk and prodromal markers of PD as well as factors related to diet/lifestyle, bowel function and medication were studied in relation to bacterial α-/β-diversity, enterotypes, and taxonomic composition in stool samples of 666 elderly TREND study participants.ResultsAmong risk and prodromal markers, physical inactivity, constipation and age showed associations with α- and β-diversity, and for both measures subthreshold parkinsonism and physical inactivity showed interaction effects. Moreover, male sex, possible REM-sleep behavior disorder (RBD), smoking as well as body-mass-index, antidiabetic and urate-lowering medication were associated with β-diversity. Physical inactivity and constipation severity were increased in individuals with the Firmicutes-enriched enterotype. Subthreshold parkinsonism was least frequently observed in individuals with the Prevotella-enriched enterotype. Differentially abundant taxa were linked to constipation, physical inactivity, possible RBD, and subthreshold parkinsonism. Substantia nigra hyperechogenicity, olfactory loss, depression, orthostatic hypotension, urinary/erectile dysfunction, PD family history and the overall prodromal PD probability showed no significant microbiome associations.InterpretationSeveral risk and prodromal markers of PD are associated with changes in gut microbiome composition. However, the impact of the gut microbiome on PD risk and potential microbiome-dependent subtypes in the prodrome of PD need further investigation based on prospective clinical and (multi)omics data in incident PD cases.

Molecular genetic pathways in Parkinson's disease: a review

2005 ◽  
Vol 109 (4) ◽  
pp. 355-364 ◽  
Author(s):  
Shushant Jain ◽  
Nicholas W. Wood ◽  
Daniel G. Healy
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Basis ◽  
Genetic Factors ◽  
Molecular Genetic ◽  
Mendelian Genetics ◽  
Susceptibility Factors ◽  
Increased Risk ◽  
Major Progress ◽  
Made In

Major progress has been made in the last decade in understanding the genetic basis of PD (Parkinson's disease) with five genes unequivocally associated with disease. As a result, multiple pathways have been implicated in the pathogenesis of PD, including proteasome impairment and mitochondrial dysfunction. Although Mendelian genetics has been successful in establishing a genetic predisposition for familial PD, this has not been reiterated in the sporadic form. In fact no genetic factors have been unequivocally associated with increased risk for sporadic PD. The difficulty in identifying susceptibility factors in PD has not only been because of numerous underpowered studies, but we have been unable to dissect out the genetic component in a multifactorial disease. This review aims to summarize the genetic findings within PD.

scholarly journals Astrocytic Oxidative/Nitrosative Stress Contributes to Parkinson’s Disease Pathogenesis: The Dual Role of Reactive Astrocytes

Antioxidants ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 265 ◽  
Author(s):  
Asha Rizor ◽  
Edward Pajarillo ◽  
James Johnson ◽  
Michael Aschner ◽  
Eunsook Lee
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Nitrosative Stress ◽  
Critical Role ◽  
Substantia Nigra Pars Compacta ◽  
Environmental Toxicants ◽  
Oxidative And Nitrosative Stress ◽  
Reactive Astrogliosis ◽  
The Impact

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide; it is characterized by dopaminergic neurodegeneration in the substantia nigra pars compacta, but its etiology is not fully understood. Astrocytes, a class of glial cells in the central nervous system (CNS), provide critical structural and metabolic support to neurons, but growing evidence reveals that astrocytic oxidative and nitrosative stress contributes to PD pathogenesis. As astrocytes play a critical role in the production of antioxidants and the detoxification of reactive oxygen and nitrogen species (ROS/RNS), astrocytic oxidative/nitrosative stress has emerged as a critical mediator of the etiology of PD. Cellular stress and inflammation induce reactive astrogliosis, which initiates the production of astrocytic ROS/RNS and may lead to oxidative/nitrosative stress and PD pathogenesis. Although the cause of aberrant reactive astrogliosis is unknown, gene mutations and environmental toxicants may also contribute to astrocytic oxidative/nitrosative stress. In this review, we briefly discuss the physiological functions of astrocytes and the role of astrocytic oxidative/nitrosative stress in PD pathogenesis. Additionally, we examine the impact of PD-related genes such as α-synuclein, protein deglycase DJ-1( DJ-1), Parkin, and PTEN-induced kinase 1 (PINK1) on astrocytic function, and highlight the impact of environmental toxicants, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, manganese, and paraquat, on astrocytic oxidative/nitrosative stress in experimental models.

scholarly journals Impact of Progression of Parkinson's Disease and Various Other Factors on Generalized Anxiety Disorder

2018 ◽  
Vol 09 (03) ◽  
pp. 287-290 ◽  
Author(s):  
Abdul Qayyum Rana ◽  
Hamza Ansari ◽  
Abdul Rehman M. Qureshi ◽  
Eraad Rahman
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Anxiety Disorder ◽  
Generalized Anxiety Disorder ◽  
Ethnically Diverse ◽  
Influential Factors ◽  
Generalized Anxiety ◽  
Increased Risk ◽  
The Impact ◽  
The Relationship

ABSTRACT Objective: While much research has been conducted toward understanding the relationship between prevalence of Parkinson's disease (PD) and generalized anxiety, little has been done considering additional influential factors in the relationship by means of a large ethnically diverse sample. Our study strives to fulfill these deficits in the literature as we set out to determine the impact of progression of PD, age, gender, and Hoehn and Yahr (H and Y) staging of PD on generalized anxiety. Methods: A retrospective chart review analysis was performed on PD patients who were regularly examined in a community-based PD and movement disorders center from 2005 to 2010. Results: This study consisted of 310 patients with PD among whom 12% had generalized anxiety. Neither age nor gender was significant onset predictors at P = 0.05. The impact of progression of H and Y Stages 2–3 and 2–4 increased the odds of generalized anxiety disorder (GAD) prevalence though it was statistically insignificant at P = 0.05. Conclusions: Clinicians should not expect the risk of developing anxiety to depend on gender nor change as a function of age though it may increase with symptomatic progression of PD as outlined by H and Y. To the best of our knowledge, this is the largest and most ethnically diverse prevalence study with a focus on generalized anxiety and PD. Significant Outcomes and Limitations: The symptomatic progression of PD, but not age or gender, may be associated with an increased risk for GAD. This study lacked adjustment for potential confounders such as depression and PD medications.

scholarly journals Inflammasomes: An Emerging Mechanism Translating Environmental Toxicant Exposure Into Neuroinflammation in Parkinson’s Disease

2018 ◽  
Vol 166 (1) ◽  
pp. 3-15 ◽  
Author(s):  
Faith L Anderson ◽  
Madeleine M Coffey ◽  
Brent L Berwin ◽  
Matthew C Havrda
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Exposure ◽  
Strong Association ◽  
Cellular Damage ◽  
Common Mechanism ◽  
Inflammasome Activation ◽  
Environmental Toxicants ◽  
Environmental Toxicant ◽  
Toxicant Exposure

Abstract Evidence indicates that complex gene-environment interactions underlie the incidence and progression of Parkinson’s disease (PD). Neuroinflammation is a well-characterized feature of PD widely believed to exacerbate the neurodegenerative process. Environmental toxicants associated with PD, such as pesticides and heavy metals, can cause cellular damage and stress potentially triggering an inflammatory response. Toxicant exposure can cause stress and damage to cells by impairing mitochondrial function, deregulating lysosomal function, and enhancing the spread of misfolded proteins. These stress-associated mechanisms produce sterile triggers such as reactive oxygen species (ROS) along with a variety of proteinaceous insults that are well documented in PD. These associations provide a compelling rationale for analysis of sterile inflammatory mechanisms that may link environmental exposure to neuroinflammation and PD progression. Intracellular inflammasomes are cytosolic assemblies of proteins that contain pattern recognition receptors, and a growing body of evidence implicates the association between inflammasome activation and neurodegenerative disease. Characterization of how inflammasomes may function in PD is a high priority because the majority of PD cases are sporadic, supporting the widely held belief that environmental exposure is a major factor in disease initiation and progression. Inflammasomes may represent a common mechanism that helps to explain the strong association between exposure and PD by mechanistically linking environmental toxicant-driven cellular stress with neuroinflammation and ultimately cell death.

scholarly journals Memantine for the Patients with Mild Cognitive Impairment in Parkinson’s Disease: A Pharmacological fMRI Study

2021 ◽  
Author(s):  
Shoji Kawashima ◽  
Noriyuki Matsukawa ◽  
RCIP-Nagoya Study Group
Keyword(s):  
Parkinson’S Disease ◽  
Working Memory ◽  
Parkinson's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Spatial Working Memory ◽  
Clinical Status ◽  
Visuospatial Working Memory ◽  
Increased Risk ◽  
The Impact

Abstract Background:Mild cognitive impairment of Parkinson’s disease (PD-MCI) represents increased risk of future cognitive decline. The characteristics of PD-MCI are impairments in executive function and visuospatial recognition. The visuospatial n-back test has a merit that it can assess both cognitive domains. Concerning the treatment of PD-MCI and dementia in PD (PDD), many studies have reported efficacy of cholinesterase inhibitors. Similarly, some studies reported efficacy of memantine for PDD, showing that it improved clinical status or behavioral symptoms. However, therapeutic evidence of memantine for PD-MCI has not been unestablished. Methods: We aimed to investigate whether memantine can alter brain function of the patients with PD-MCI, using functional MRI. In comparison between memantine and placebo, we explored the difference in regions associated with visuospatial n-back test. The 0-back test reflects visuospatial recognition, and the 1-back and 2-back tests reflect visuospatial working memory. This study followed a randomized double-blind crossover design. Patients in the memantine group were given memantine at 5 mg/day in the first week, and the dose was increased by 5 mg/day per week, with the final dose of 20 mg/day. The patients in the placebo group were given a placebo following the same regimen. The population in this study constitutes 10 patients who completed follow-up. During maximum dose administration, fMRI scanning and neuropsychological tests were performed. Group comparisons between memantine and placebo were performed.Results: There were no significant regions enhanced by memantine comparing with placebo at any load of n-back tests. In contrast, exploring regions reduced by memantine, we found significant reduction of activations within right lingual gyrus and left superior frontal gyrus in comparison between 2-back and 0-back test. A number of correct answers of the 2-back test and time to complete Trail Making Test-A were worse at memantine intervention. Reduced brain activations were associated with worse visuo-spatial working memory caused by memantine.Conclusions:This study reports memantine did not improve visuospatial working memory of the patients with PD-MCI. Treatment of PD should be planned carefully considering the impact for cognitive function. Further study is needed to establish new therapeutic strategy of the patients with PD-MCI.

Coexistent Osteoarthritis and Parkinson’s Disease: Data from the Parkinson’s Foundation Outcomes Project

2020 ◽  
Vol 10 (4) ◽  
pp. 1601-1610
Author(s):  
Jaimie A. Roper ◽  
Abigail C. Schmitt ◽  
Hanzhi Gao ◽  
Ying He ◽  
Samuel Wu ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Study Data ◽  
Functional Mobility ◽  
Quality Improvement Initiative ◽  
Timed Up And Go ◽  
Mobility Performance ◽  
Risk Of Mortality ◽  
The Impact

Background: The impact of concurrent osteoarthritis on mobility and mortality in individuals with Parkinson’s disease is unknown. Objective: We sought to understand to what extent osteoarthritis severity influenced mobility across time and how osteoarthritis severity could affect mortality in individuals with Parkinson’s disease. Methods: In a retrospective observational longitudinal study, data from the Parkinson’s Foundation Quality Improvement Initiative was analyzed. We included 2,274 persons with Parkinson’s disease. The main outcomes were the effects of osteoarthritis severity on functional mobility and mortality. The Timed Up and Go test measured functional mobility performance. Mortality was measured as the osteoarthritis group effect on survival time in years. Results: More individuals with symptomatic osteoarthritis reported at least monthly falls compared to the other groups (14.5% vs. 7.2% without reported osteoarthritis and 8.4% asymptomatic/minimal osteoarthritis, p = 0.0004). The symptomatic group contained significantly more individuals with low functional mobility (TUG≥12 seconds) at baseline (51.5% vs. 29.0% and 36.1%, p < 0.0001). The odds of having low functional mobility for individuals with symptomatic osteoarthritis was 1.63 times compared to those without reported osteoarthritis (p < 0.0004); and was 1.57 times compared to those with asymptomatic/minimal osteoarthritis (p = 0.0026) after controlling pre-specified covariates. Similar results hold at the time of follow-up while changes in functional mobility were not significant across groups, suggesting that osteoarthritis likely does not accelerate the changes in functional mobility across time. Coexisting symptomatic osteoarthritis and Parkinson’s disease seem to additively increase the risk of mortality (p = 0.007). Conclusion: Our results highlight the impact and potential additive effects of symptomatic osteoarthritis in persons with Parkinson’s disease.

A New Series Of 1,3-Dimethylxanthine Based Adenosine A2a Receptor Antagonists As A Non-Dopaminergic Treatment Of Parkinson’s Disease

2020 ◽  
Vol 17 ◽  
Author(s):  
Suman Rohilla ◽  
Ranju Bansal ◽  
Puneet Chauhan ◽  
Sonja Kachler ◽  
Karl-Norbert Klotz
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Molecular Docking ◽  
Binding Affinity ◽  
Docking Studies ◽  
Binding Modes ◽  
Molecular Docking Studies ◽  
In Silico Docking ◽  
Adenosine A2a Receptor Antagonists ◽  
The Impact

Background: Adenosine receptors (AR) have emerged as competent and innovative nondopaminergic targets for the development of potential drug candidates and thus constitute an effective and safer treatment approach for Parkinson’s disease (PD). Xanthine derivatives are considered as potential candidates for the treatment Parkinson’s disease due to their potent A2A AR antagonistic properties. Objective: The objectives of the work are to study the impact of substituting N7-position of 8-m/pchloropropoxyphenylxanthine structure on in vitro binding affinity of compounds with various AR subtypes, in vivo antiparkinsonian activity and binding modes of newly synthesized xanthines with A2A AR in molecular docking studies. Methods: Several new 7-substituted 8-m/p-chloropropoxyphenylxanthine analogues have been prepared. Adenosine receptor binding assays were performed to study the binding interactions with various subtypes and perphenazine induced rat catatonia model was used for antiparkinsonian activity. Molecular docking studies were performed using Schrödinger molecular modeling interface. Results: 8-para-substituted xanthine 9b bearing an N7-propyl substituent displayed the highest affinity towards A2A AR (Ki = 0.75 µM) with moderate selectivity versus other AR subtypes. 7-Propargyl analogue 9d produced significantly longlasting antiparkinsonian effects and also produced potent and selective binding affinity towards A2A AR. In silico docking studies further highlighted the crucial structural components required to develop xanthine derived potential A2A AR ligands as antiparkinsonian agents. Conclusion: A new series of 7-substituted 8-m/p-chloropropoxyphenylxanthines having good affinity for A2A AR and potent antiparkinsonian activity has been developed.

Sign in / Sign up

Export Citation Format

Share Document