scholarly journals Genetic Risk Profiling in Parkinson’s Disease and Utilizing Genetics to Gain Insight into Disease-Related Biological Pathways

2020 ◽  
Vol 21 (19) ◽  
pp. 7332 ◽  
Author(s):  
Ashley Hall ◽  
Sara Bandres-Ciga ◽  
Monica Diez-Fairen ◽  
John P. Quinn ◽  
Kimberley J. Billingsley
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Large Scale ◽  
Biological Pathways ◽  
Risk Scores ◽  
Potential Contribution ◽  
Genetic Profiling ◽  
Gwa Studies ◽  
Insight Into

Parkinson’s disease (PD) is a complex disorder underpinned by both environmental and genetic factors. The latter only began to be understood around two decades ago, but since then great inroads have rapidly been made into deconvoluting the genetic component of PD. In particular, recent large-scale projects such as genome-wide association (GWA) studies have provided insight into the genetic risk factors associated with genetically ‘’complex’’ PD (PD that cannot readily be attributed to single deleterious mutations). Here, we discuss the plethora of genetic information provided by PD GWA studies and how this may be utilized to generate polygenic risk scores (PRS), which may be used in the prediction of risk and trajectory of PD. We also comment on how pathway-specific genetic profiling can be used to gain insight into PD-related biological pathways, and how this may be further utilized to nominate causal PD genes and potentially druggable therapeutic targets. Finally, we outline the current limits of our understanding of PD genetics and the potential contribution of variation currently uncaptured in genetic studies, focusing here on uncatalogued structural variants.

scholarly journals Parkinson’s disease determinants, prediction and gene–environment interactions in the UK Biobank

2020 ◽  
Vol 91 (10) ◽  
pp. 1046-1054 ◽  
Author(s):  
Benjamin Meir Jacobs ◽  
Daniel Belete ◽  
Jonathan Bestwick ◽  
Cornelis Blauwendraat ◽  
Sara Bandres-Ciga ◽  
...  
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Family History ◽  
Genetic Risk ◽  
Positive Family History ◽  
Risk Scores ◽  
Uk Biobank ◽  
Gene Environment ◽  
History Of

ObjectiveTo systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson’s disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores.MethodsWe identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene–environment interactions and compare predictive models for PD.ResultsStrong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes.InterpretationHere, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene–environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

scholarly journals Interactions of COMT and ALDH2 Genetic Polymorphisms on Symptoms of Parkinson’s Disease

2021 ◽  
Vol 11 (3) ◽  
pp. 361
Author(s):  
Rwei-Ling Yu ◽  
Shao-Ching Tu ◽  
Ruey-Meei Wu ◽  
Pei-An Lu ◽  
Chun-Hsiang Tan
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Detrimental Effect ◽  
Personal Hygiene ◽  
Nucleotide Polymorphisms ◽  
Monoamine Neurotransmitters ◽  
Single Nucleotide ◽  
Detrimental Impact ◽  
Reduced Activity ◽  
Insight Into

(1) Background: Monoamine neurotransmitters play essential roles in the normal functioning of our nervous system. However, the metabolism of monoamine neurotransmitters is accompanied by the production of neurotoxic metabolites, and inefficient removal of the metabolites has been suggested to cause neurodegeneration. (2) Methods: To examine the effect of reduced activity of catechol-O-methyltransferase (COMT) and aldehyde dehydrogenase 2 (ALDH2) conferred by single nucleotide polymorphisms COMT rs4680(A) and ALDH2 rs671(A) on the symptoms of patients with Parkinson’s disease (PD), a total of 114 PD patients were recruited cross-sectionally and received genotyping for rs4680 and rs671 along with MDS-UPDRS evaluation. (3) Results: We found that patients carrying rs4680(A) had more severe bradykinesia in the upper extremity and rest tremor. Besides, patients carrying rs671(A) had more difficulty maintaining personal hygiene, while patients with genotype rs671(GG) had higher scores in the item “depressed mood.” More importantly, we found the effect of rs4680 to be moderated by rs671 SNP for the symptom of “hand movements.” The detrimental impact of rs4680(A) is more pronounced in the presence of genotype rs671(GG). (4) Conclusions: This study facilitates a deeper understanding of the detrimental effect of reduced activity of COMT and ALDH2 conferred by genetic variation and provides novel insight into the interactions between enzymes metabolizing monoamine neurotransmitters in the pathogenesis of PD.

scholarly journals Restless legs syndrome in Parkinson's disease and increased cardiovascular risk

2018 ◽  
Vol 76 (11) ◽  
pp. 731-735 ◽  
Author(s):  
Maren de Moraes e Silva ◽  
Cezar Henrique Lorenzi ◽  
Blenda Barreto Schneider ◽  
Catherine Enk Fischer Seidel ◽  
Isabela Salomé ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cardiovascular Risk ◽  
Restless Legs Syndrome ◽  
Protective Factor ◽  
Risk Scores ◽  
Dopaminergic Transmission ◽  
Restless Legs ◽  
Cardiovascular Comorbidities ◽  
Framingham Risk

ABSTRACT Restless legs syndrome (RLS) is a disorder commonly found in patients with Parkinson's disease, with descriptions for both conditions impairing dopaminergic transmission in central nervous system. Previous studies in varied populations indicate an association between the presence of RLS and increased cardiovascular risk and, so far, there are no consistent studies of this association in Parkinson's disease. Objective: To analyze the influence of RLS on cardiovascular risk in patients with Parkinson's disease. Methods: We reviewed the medical records of 202 patients diagnosed with Parkinson's disease and verified the presence of RLS, cardiovascular comorbidities, blood pressure measurements, lipid profiles and Framingham Risk Scores. Results: Statistically significant higher values of total cholesterol were found for the RLS group (mean 216.6 mg/dL), as well as for LDL cholesterol (mean 145 mg/dL). No statistical difference was found among the other factors. Conclusion: Patients with Parkinson's disease and RLS have a higher prevalence of dyslipidemia than patients without RLS, suggesting a correlation between restless legs and hyperlipidemia. It is questioned whether the dopaminergic substrate is the main factor in the genesis of the syndrome, as even with the use of dopaminergic agonists by both groups, it was possible to observe differences between groups. The hypothesis of the real interference of the syndrome treatment as a protective factor for cardiovascular risk was generated.

scholarly journals Dermal fibroblasts from patients with Parkinson’s disease have normal GCase activity and autophagy compared to patients with PD and GBA mutations

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1751 ◽  
Author(s):  
Lucy M Collins ◽  
Janelle Drouin-Ouellet ◽  
Wei-Li Kuan ◽  
Timothy Cox ◽  
Roger A Barker
Keyword(s):  
Risk Factors ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
Gaucher Disease ◽  
Dermal Fibroblasts ◽  
Skin Fibroblasts ◽  
Autophagic Flux ◽  
Clinical Progression ◽  
Gba Mutations

Background: Recently, the development of Parkinson’s disease (PD) has been linked to a number of genetic risk factors, of which the most common is glucocerebrosidase (GBA) mutations. Methods: We investigated PD and Gaucher Disease (GD) patient derived skin fibroblasts using biochemistry assays. Results: PD patient derived skin fibroblasts have normal glucocerebrosidase (GCase) activity, whilst patients with PD and GBA mutations have a selective deficit in GCase enzyme activity and impaired autophagic flux. Conclusions: This data suggests that only PD patients with a GBA mutation have altered GCase activity and autophagy, which may explain their more rapid clinical progression.

scholarly journals A selective effect of dopamine on information-seeking

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Valentina Vellani ◽  
Lianne P de Vries ◽  
Anne Gaule ◽  
Tali Sharot
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Information Seeking ◽  
Selective Effect ◽  
Reward Seeking ◽  
The Impact ◽  
The Brain ◽  
Insight Into ◽  
Primary Reward

Humans are motivated to seek information from their environment. How the brain motivates this behavior is unknown. One speculation is that the brain employs neuromodulatory systems implicated in primary reward-seeking, in particular dopamine, to instruct information-seeking. However, there has been no causal test for the role of dopamine in information-seeking. Here, we show that administration of a drug that enhances dopamine function (dihydroxy-L-phenylalanine; L-DOPA) reduces the impact of valence on information-seeking. Specifically, while participants under Placebo sought more information about potential gains than losses, under L-DOPA this difference was not observed. The results provide new insight into the neurobiology of information-seeking and generates the prediction that abnormal dopaminergic function (such as in Parkinson’s disease) will result in valence-dependent changes to information-seeking.

scholarly journals Pilot Study of Mindfulness Training on the Self-Awareness of Motor Symptoms in Parkinson’s Disease – A Randomized Controlled Trial

2021 ◽  
Vol 12 ◽  
Author(s):  
Timo Marcel Buchwitz ◽  
Franziska Maier ◽  
Andrea Greuel ◽  
Franziska Thieken ◽  
Kenan Steidel ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Control Group ◽  
Motor Symptoms ◽  
Self Awareness ◽  
Disease Symptoms ◽  
Waitlist Control ◽  
Sleeping Problems ◽  
Waitlist Control Group ◽  
Insight Into

Objective: This study aims to evaluate feasibility and effects of a newly developed mindfulness intervention tailored to specific needs of patients with Parkinson’s disease (PD).Background: The phenomenon of impaired self-awareness of motor symptoms (ISAm) in PD might be reduced by increasing patients’ mindfulness. A PD-specific mindfulness intervention has been developed and evaluated as a potential treatment option: IPSUM (“Insight into Parkinson’s Disease Symptoms by using Mindfulness”).Methods: IPSUM’s effectiveness is evaluated by comparing an intervention with a waitlist-control group. Applying a pre-post design, patients were assessed before, directly after and 8weeks after treatment. The primary outcome was the change in a quantitative ISAm score from baseline to post-assessment. Secondary outcome measures were PD-related affective changes and neuropsychological test performance. Feasibility was evaluated via feedback forms.Results: In total, 30 non-depressed and non-demented PD patients were included (intervention: n=14, waitlist-control: n=16). ISAm score did not change significantly, but the training group showed greater performance in sustained attention and language tasks over time. Additional changes included greater mindfulness as well as less sleeping problems and anxiety. Cognitive disturbances, apathy, and sleeping problems worsened only in the waitlist-control group. Patients’ feedback regarding the training concept and material was excellent.Conclusion: Insight into Parkinson’s Disease Symptoms by using Mindfulness has not been capable of reducing ISAm in PD patients but appears to be a feasible and effective concept to, among others, support mental health in the mid-term. It has to be noted though that the study was stopped beforehand because of the SARS CoV-2 pandemic. The lack of findings might therefore be caused by a lack of statistical power. The need for further research to better understand the mechanisms of ISAm and its connection to mindfulness in PD is highlighted.

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