scholarly journals O6E.4 Metabolome and exposome profiling: new opportunities to study risk factors for parkinson’s disease

2019 ◽  
Vol 76 (Suppl 1) ◽  
pp. A60.1-A60
Author(s):  
Susan Peters ◽  
Douglas Walker ◽  
Gary Miller ◽  
Marc Chadeau-Hyam ◽  
Paolo Vineis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
High Resolution Mass Spectrometry ◽  
Association Studies ◽  
Disease Onset ◽  
Incidence Density ◽  
Exogenous Compounds ◽  
Nested Case Control

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is imposing an increasing social and economic burden in ageing populations. Although the role of environmental factors has been recognised, few established risk factors have been consistently identified. Evidence that exposure to pesticides, herbicides and metals increase PD risk is suggestive, but further research is needed to identify specific compounds that may play a causal role.Large established prospective population studies offer an important opportunity for investigating risk factors in relatively rare diseases such as PD. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, 734 incident PD cases have been ascertained, for whom pre-diagnostic blood has been stored. A nested case-control study will be conducted, where one control per case will be selected by incidence density sampling matched by age at recruitment, sex and study centre.Untargeted metabolomics can simultaneously characterize thousands of endogenous and exogenous compounds within a biological sample: the metabolome. Metabolome wide association studies (MWAS) have identified significant differences in the metabolomic profile of older adults with and without PD. We will employ an innovative approach combining liquid and gas phase chromatography with ultra-high-resolution mass spectrometry (LC/GC-UHRMS), to identify exogenous chemical exposures (e.g. pollutants, pesticides and medications), the exposome, in addition to the metabolome.Disease specific variability in blood metabolite compositions may signify the presence of mechanistic aberrations contributing to PD pathogenesis. The combination of metabolome and exposome profiling provides a measure of the continuum from exposure to disease. Allowing previously unavailable richness and depth for characterizing the metabolome and exposome upon which novel discoveries in PD can be made.The EPIC cohort allows us to perform a to study the metabolome and exposome well before disease onset, to eliminate possible effects of levodopa medication or disease-related processes.

scholarly journals Differences in MTHFR and LRRK2 variant’s association with sporadic Parkinson’s disease in Mexican Mestizos correlated to Native American ancestry

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Elizabeth Romero-Gutiérrez ◽  
Paola Vázquez-Cárdenas ◽  
Hortensia Moreno-Macías ◽  
José Salas-Pacheco ◽  
Teresa Tusié-Luna ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Native American ◽  
Neurodegenerative Disorder ◽  
European Ancestry ◽  
Native American Ancestry ◽  
Risk Effect ◽  
Mexican Mestizos ◽  
Shared Risk

AbstractParkinson’s disease (PD), a common neurodegenerative disorder, has a complex etiology where environmental and genetic factors intervene. While a number of genes and variants have been identified in recent decades as causative or protective agents of this condition, a limited number of studies have been conducted in mixed populations, such as Mexican Mestizos. The historical convergence of two founding groups and three ethnicities, and the increasing north-to-south gradient of Native American ancestry in Mexico resulted in a subpopulation structure with considerable genetic diversity. In this work, we investigate the influence of 21 known susceptibility variants for PD. Our case–control study, with a cohort of 311 Mexican Mestizo subjects, found a significant risk association for the variant rs1491942 in LRRK2. However, when stratification by ancestry was performed, a risk effect for MTHFR rs1801133 was observed only in the group with the highest percentage of European ancestry, and the PD risk effect for LRRK2 rs1491942 was significant in subjects with a higher ratio of Native American ancestry. Meta-analyses of these SNP revealed the effect of LRRK2 rs1491942 to be even more significant than previously described in populations of European descent. Although corroboration is necessary, our findings suggest that polymorphism rs1491942 may be useful as a risk marker of PD in Mexican Mestizos with greater Native American ancestry. The absence of associations with the remaining known risk factors is, in itself, a relevant finding and invites further research into the shared risk factors’ role in the pathophysiological mechanisms of this neurodegenerative disorder.

scholarly journals Gene4PD: A Comprehensive Genetic Database of Parkinson’s Disease

2021 ◽  
Vol 15 ◽  
Author(s):  
Bin Li ◽  
Guihu Zhao ◽  
Qiao Zhou ◽  
Yali Xie ◽  
Zheng Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Association Studies ◽  
Age At Onset ◽  
Genetic Data ◽  
Genome Wide Association Studies ◽  
Onset Age ◽  
Loss Of Function

Parkinson’s disease (PD) is a complex neurodegenerative disorder with a strong genetic component. A growing number of variants and genes have been reported to be associated with PD; however, there is no database that integrate different type of genetic data, and support analyzing of PD-associated genes (PAGs). By systematic review and curation of multiple lines of public studies, we integrate multiple layers of genetic data (rare variants and copy-number variants identified from patients with PD, associated variants identified from genome-wide association studies, differentially expressed genes, and differential DNA methylation genes) and age at onset in PD. We integrated five layers of genetic data (8302 terms) with different levels of evidences from more than 3,000 studies and prioritized 124 PAGs with strong or suggestive evidences. These PAGs were identified to be significantly interacted with each other and formed an interconnected functional network enriched in several functional pathways involved in PD, suggesting these genes may contribute to the pathogenesis of PD. Furthermore, we identified 10 genes were associated with a juvenile-onset (age ≤ 30 years), 11 genes were associated with an early-onset (age of 30–50 years), whereas another 10 genes were associated with a late-onset (age > 50 years). Notably, the AAOs of patients with loss of function variants in five genes were significantly lower than that of patients with deleterious missense variants, while patients with VPS13C (P = 0.01) was opposite. Finally, we developed an online database named Gene4PD (http://genemed.tech/gene4pd) which integrated published genetic data in PD, the PAGs, and 63 popular genomic data sources, as well as an online pipeline for prioritize risk variants in PD. In conclusion, Gene4PD provides researchers and clinicians comprehensive genetic knowledge and analytic platform for PD, and would also improve the understanding of pathogenesis in PD.

PINK1 polymorphism IVS1−7 A→G, exposure to environmental risk factors and anticipation of disease onset in Brazilian patients with early-onset Parkinson's Disease

2010 ◽  
Vol 469 (1) ◽  
pp. 155-158 ◽  
Author(s):  
Clecio Godeiro ◽  
Patricia M. de Carvalho Aguiar ◽  
Andre C. Felício ◽  
Orlando G.P. Barsottini ◽  
Sonia M.A. Silva ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Environmental Risk ◽  
Early Onset ◽  
Disease Onset ◽  
Environmental Risk Factors ◽  
Early Onset Parkinson’S Disease

scholarly journals Spectrum of impulse control behaviours in Parkinson’s disease: pathophysiology and management

2020 ◽  
Vol 91 (7) ◽  
pp. 703-711
Author(s):  
Mark John Kelly ◽  
Fahd Baig ◽  
Michele Tao-Ming Hu ◽  
David Okai
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Impulse Control ◽  
Association Studies ◽  
Management Strategies ◽  
Brain Regions ◽  
Vulnerability Factors ◽  
Pharmacological Management ◽  
Functional Changes

Impulse control behaviours (ICBs) are a range of behaviours linked by their reward-based, repetitive natures. They can be precipitated in Parkinson’s disease (PD) by dopamine replacement therapy, often with detrimental consequences for patients and caregivers. While now a well-recognised non-motor feature of treated PD, much remains unknown about the influence of risk factors, pathophysiological mechanisms, vulnerability factors for specific types of behaviour and the optimal management strategies. Imaging studies have identified structural and functional changes in striatal and prefrontal brain regions, among others. Gene association studies indicate a role for genetic predisposition to PD-ICB. Clinical observational studies have identified potential modifiable and non-modifiable risk factors. Psychological studies shed light on the neurocognitive domains implicated in PD-ICBs and identify psychosocial determinants that may perpetuate the cycle of impulsive and harm-avoidance behaviours. Based on these results, a range of pharmacological and non-pharmacological management strategies have been trialled in PD-ICBs with varying success. The purpose of this review is to update clinicians on the evidence around the pathophysiology of PD-ICB. We aim to translate our findings into an interpretable biopsychosocial model that can be applied to the clinical assessment and management of individual cases of PD-ICB.

scholarly journals Machine Learning Prediction of Parkinson's Disease Onset and Subtype Using Germline Variants

2021 ◽  
Author(s):  
Saya R Dennis ◽  
Tanya Simuni ◽  
Yuan Luo
Keyword(s):  
Machine Learning ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
The United States ◽  
Machine Learning Algorithms ◽  
Progression Rate ◽  
High Importance ◽  
Germline Variants

Parkinson's Disease is the second most common neurodegenerative disorder in the United States, and is characterized by a largely irreversible worsening of motor and non-motor symptoms as the disease progresses. A prominent characteristic of the disease is its high heterogeneity in manifestation as well as the progression rate. For sporadic Parkinson's Disease, which comprises ~90% of all diagnoses, the relationship between the patient genome and disease onset or progression subtype remains largely elusive. Machine learning algorithms are increasingly adopted to study the genomics of diseases due to their ability to capture patterns within the vast feature space of the human genome that might be contributing to the phenotype of interest. In our study, we develop two machine learning models that predict the onset as well as the progression subtype of Parkinson's Disease based on subjects' germline mutations. Our best models achieved an ROC of 0.77 and 0.61 for disease onset and subtype prediction, respectively. To the best of our knowledge, our models present state-of-the-art prediction performances of PD onset and subtype solely based on the subjects' germline variants. The genes with high importance in our best-performing models were enriched for several canonical pathways related to signaling, immune system, and protein modifications, all of which have been previously associated with PD symptoms or pathogenesis. These high-importance gene sets provide us with promising candidate genes for future biomedical and clinical research.

scholarly journals Engaging cognitive circuits to promote motor recovery in degenerative disorders. exercise as a learning modality

2016 ◽  
Vol 52 (1) ◽  
pp. 35-51 ◽  
Author(s):  
Michael W. Jakowec ◽  
Zhou Wang ◽  
Daniel Holschneider ◽  
Jeff Beeler ◽  
Giselle M. Petzinger
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Wide Spectrum ◽  
Disease Onset ◽  
Short Review ◽  
Motor Recovery ◽  
Adult Brain ◽  
Brain Disorders ◽  
Dopamine Depletion

AbstractExercise and physical activity are fundamental components of a lifestyle essential in maintaining a healthy brain. This is primarily due to the fact that the adult brain maintains a high degree of plasticity and activity is essential for homeostasis throughout life. Plasticity is not lost even in the context of a neurodegenerative disorder, but could be maladaptive thus promoting disease onset and progression. A major breakthrough in treating brain disorders such as Parkinson’s disease is to drive neuroplasticity in a direction to improve motor and cognitive dysfunction. The purpose of this short review is to present the evidence from our laboratories that supports neuroplasticity as a potential therapeutic target in treating brain disorders. We consider that the enhancement of motor recovery in both animal models of dopamine depletion and in patients with Parkinson’s disease is optimized when cognitive circuits are engaged; in other words, the brain is engaged in a learning modality. Therefore, we propose that to be effective in treating Parkinson’s disease, physical therapy must employ both skill-based exercise (to drive specific circuits) and aerobic exercise (to drive the expression of molecules required to strengthen synaptic connections) components to select those neuronal circuits, such as the corticostriatal pathway, necessary to restore proper motor and cognitive behaviors. In the wide spectrum of different forms of exercise, learning as the fundamental modality likely links interventions used to treat patients with Parkinson’s disease and may be necessary to drive beneficial neuroplasticity resulting in symptomatic improvement and possible disease modification.

scholarly journals Prediction of Parkinson’s Disease Risk Based on Genetic Profile and Established Risk Factors

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1278
Author(s):  
Paraskevi P. Chairta ◽  
Andreas Hadjisavvas ◽  
Andrea N. Georgiou ◽  
Maria A. Loizidou ◽  
Kristia Yiangou ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Regression Analysis ◽  
Environmental Factors ◽  
Stepwise Regression ◽  
Neurodegenerative Disorder ◽  
Environmental Data ◽  
Genetic Profile ◽  
Polygenic Risk Score

Background: Parkinson’s disease (PD) is a neurodegenerative disorder, and literature suggests that genetics and lifestyle/environmental factors may play a key role in the triggering of the disease. This study aimed to evaluate the predictive performance of a 12-Single Nucleotide Polymorphisms (SNPs) polygenic risk score (PRS) in combination with already established PD-environmental/lifestyle factors. Methods: Genotypic and lifestyle/environmental data on 235 PD-patients and 464 controls were obtained from a previous study carried out in the Cypriot population. A PRS was calculated for each individual. Univariate logistic-regression analysis was used to assess the association of PRS and each risk factor with PD-status. Stepwise-regression analysis was used to select the best predictive model for PD combining genetic and lifestyle/environmental factors. Results: The 12-SNPs PRS was significantly increased in PD-cases compared to controls. Furthermore, univariate analyses showed that age, head injury, family history, depression, and Body Mass Index (BMI) were significantly associated with PD-status. Stepwise-regression suggested that a model which includes PRS and seven other independent lifestyle/environmental factors is the most predictive of PD in our population. Conclusions: These results suggest an association between both genetic and environmental factors and PD, and highlight the potential for the use of PRS in combination with the classical risk factors for risk prediction of PD.

scholarly journals Olfaction and Colour Vision: What Can They Tell Us about Parkinson’s Disease?

2018 ◽  
Vol 119 (2-3) ◽  
pp. 85-96 ◽  
Author(s):  
Irene Dall’Antonia ◽  
Karel Šonka ◽  
Petr Dušek
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Colour Vision ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Alpha Synuclein ◽  
Nerve Tissue ◽  
Clinical Markers ◽  
Motor Abnormalities ◽  
Non Motor Symptoms

Parkinson’s disease is a neurodegenerative disorder with the pathological accumulation of alpha synuclein in the brain and peripheral nerve tissue. Early stages of synucleinopathies, often present clinically with rapid eye movement (REM) sleep disorder (RBD). Clinical markers that indicate early progression from RBD to manifest synucleinopathies include abnormal dopamine transporter (DAT) imaging, motor and non-motor symptoms. Despite the high diagnostic strength of DAT imaging and motor abnormalities, they are not the earliest biomarkers. Non-motor signs of neurodegeneration such as colour vision and olfaction abnormalities are detectable by clinical examination as early as 20 years before disease onset. Detailed analysis of olfactory and colour vision dysfunction can provide valuable information regarding brain pathologies, further specifying clinical phenotypes, and giving clues to underlying pathophysiological mechanisms in Parkinson’s disease and related disorders.

scholarly journals Investigation of Autosomal Genetic Sex Differences in Parkinson’s disease

2021 ◽  
Author(s):  
Cornelis Blauwendraat ◽  
Hirotaka Iwaki ◽  
Mary B. Makarious ◽  
Sara Bandres-Ciga ◽  
Hampton Leonard ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Genome Wide Association Studies ◽  
Disease Etiology ◽  
Male And Female ◽  
Y Chromosomes ◽  
Genome Wide

AbstractParkinson’s disease (PD) is a complex neurodegenerative disorder. Males are on average ∼1.5 times more likely to develop PD compared to females. Over the years genome-wide association studies (GWAS) have identified numerous genetic risk factors for PD, however it is unclear whether genetics contribute to disease etiology in a sex-specific manner.In an effort to study sex-specific genetic factors associated with PD, we explored two large genetic datasets from the International Parkinson’s Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.In total 19 genome-wide significant regions were identified, and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was identified (rg=0.877) and heritability estimates were identical between male and female PD cases (∼20%).We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females.

scholarly journals Neuroprotective mechanisms of red clover and soy isoflavones in Parkinson’s disease models

2020 ◽  
Author(s):  
Aurélie de Rus Jacquet ◽  
Abeje Ambaw ◽  
Mitali Arun Tambe ◽  
Sin Ying Ma ◽  
Michael Timmers ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Trifolium Pratense ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Red Clover ◽  
Antioxidant Response ◽  
Motor Dysfunction ◽  
Neuroprotective Effects ◽  
Dietary Polyphenols

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by nigrostriatal degeneration and the spreading of aggregated forms of the presynaptic protein α-synuclein (aSyn) throughout the brain. PD patients are currently only treated with symptomatic therapies, and strategies to slow or stop the progressive neurodegeneration underlying the disease’s motor and cognitive symptoms are greatly needed. The time between the first neurobiochemical alterations and the initial presentation of symptoms is thought to span several years, and early neuroprotective dietary interventions could delay the disease onset or slow PD progression. This study aimed at characterizing the neuroprotective effects of isoflavones, a class of dietary polyphenols found in soy products and in the medicinal plant red clover (Trifolium pratense). We found that isoflavone-rich extracts and individual isoflavones rescued the loss of dopaminergic neurons and the shortening of neurites in primary mesencephalic cultures exposed to two PD-related insults, the environmental toxin rotenone and an adenovirus encoding the A53T aSyn mutant. The extracts and individual isoflavones also activated the Nrf2-mediated antioxidant response in astrocytes via a mechanism involving inhibition of the ubiquitin-proteasome system, and they alleviated deficits in mitochondrial respiration. Furthermore, an isoflavone-enriched soy extract reduced motor dysfunction exhibited by rats lesioned with the PD-related neurotoxin 6-OHDA. These findings suggest that plant-derived isoflavones could serve as dietary supplements to delay PD onset in at-risk individuals and mitigate neurodegeneration in the brains of patients.

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