scholarly journals The Genetics of Parkinson’s Disease and Implications for Clinical Practice

Genes ◽  
2021 ◽  
Vol 12 (7) ◽  
pp. 1006
Author(s):  
Jacob Oliver Day ◽  
Stephen Mullin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Risk ◽  
High Frequency ◽  
Trial Design ◽  
Clinical Care ◽  
Clinical Trial Design ◽  
Pathogenic Variants ◽  
High Penetrance ◽  
Genetic Landscape

The genetic landscape of Parkinson’s disease (PD) is characterised by rare high penetrance pathogenic variants causing familial disease, genetic risk factor variants driving PD risk in a significant minority in PD cases and high frequency, low penetrance variants, which contribute a small increase of the risk of developing sporadic PD. This knowledge has the potential to have a major impact in the clinical care of people with PD. We summarise these genetic influences and discuss the implications for therapeutics and clinical trial design.

scholarly journals Electroceutically induced subthalamic high-frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson’s disease

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Musa Ozturk ◽  
Ashwin Viswanathan ◽  
Sameer A. Sheth ◽  
Nuri F. Ince
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pharmacological Treatment ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
High Frequency Oscillations ◽  
Stimulation Pulse ◽  
Main Challenge ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

AbstractDespite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by electrical stimulation of the subthalamic nucleus (STN) at therapeutic and non-therapeutic frequencies in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130–180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20 Hz) stimulation, the HFOs were induced only with therapeutic frequencies, and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA. We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

scholarly journals Feasibility Aspects of Exploring Exercise-Induced Neuroplasticity in Parkinson’s Disease: A Pilot Randomized Controlled Trial

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Hanna Johansson ◽  
Malin Freidle ◽  
Urban Ekman ◽  
Ellika Schalling ◽  
Breiffni Leavy ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dual Task ◽  
Trial Design ◽  
Controlled Trial ◽  
Recruitment Rate ◽  
Blood Sampling ◽  
Assessment Process ◽  
Control Group ◽  
Exercise Induced

Background. Recent studies indicate that exercise can induce neuroplastic changes in people with Parkinson’s disease (PwPD). Reports of feasibility outcomes from existing pilot trials however are, of date, insufficient to enable replication by others in larger definitive trials. Objective. To evaluate trial design for a definitive trial by exploring process and scientific feasibility. Methods. The trial design was a parallel-group RCT pilot with a 1 : 1 allocation ratio to either HiBalance or an active control group (HiCommunication). Both groups received one-hour sessions twice weekly, plus home exercises weekly, for 10 weeks. Participants with mild-to-moderate Parkinson’s disease (PD) were recruited via advertisement. Assessment included physical performance, structural and functional MRI, blood sampling, neuropsychological assessment, and speech/voice assessment. Process and scientific feasibility were monitored throughout the study. Process feasibility involved recruitment, participant acceptability of assessments and interventions, assessment procedures (focus on imaging, blood sampling, and dual-task gait analysis), and blinding procedures. Scientific feasibility involved trends in outcome response and safety during group training and home exercises. Data are presented in median, minimum, and maximum values. Changes from pre- to postintervention are reported descriptively. Results. Thirteen participants were included (4 women, mean age 69.7 years), with a recruitment rate of 31%. Attendance rates and follow-up questionnaires indicated that both groups were acceptable to participate. Image quality was acceptable; however, diplopia and/or sleepiness were observed in several participants during MRI. With regard to dual-task gait performance, there appeared to be a ceiling effect of the cognitive tasks with seven participants scoring all correct answers at pretest. Blinding of group allocation was successful for one assessor but was broken for half of participants for the other. Conclusions. The overall trial design proved feasible to perform, but further strengthening ahead of the definitive RCT is recommended, specifically with respect to MRI setup, cognitive dual-tasks during gait, and blinding procedures. This trial is registered with NCT03213873.

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 Intraoperative Characterization of Subthalamic Nucleus-to-Cortex Evoked Potentials in Parkinson’s Disease Deep Brain Stimulation

2021 ◽  
Vol 15 ◽  
Author(s):  
Lila H. Levinson ◽  
David J. Caldwell ◽  
Jeneva A. Cronin ◽  
Brady Houston ◽  
Steve I. Perlmutter ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Deep Brain Stimulation ◽  
Evoked Potentials ◽  
Subthalamic Nucleus ◽  
Brain Stimulation ◽  
High Frequency ◽  
Therapeutic Effects ◽  
Stn Dbs ◽  
Deep Brain

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is a clinically effective tool for treating medically refractory Parkinson’s disease (PD), but its neural mechanisms remain debated. Previous work has demonstrated that STN DBS results in evoked potentials (EPs) in the primary motor cortex (M1), suggesting that modulation of cortical physiology may be involved in its therapeutic effects. Due to technical challenges presented by high-amplitude DBS artifacts, these EPs are often measured in response to low-frequency stimulation, which is generally ineffective at PD symptom management. This study aims to characterize STN-to-cortex EPs seen during clinically relevant high-frequency STN DBS for PD. Intraoperatively, we applied STN DBS to 6 PD patients while recording electrocorticography (ECoG) from an electrode strip over the ipsilateral central sulcus. Using recently published techniques, we removed large stimulation artifacts to enable quantification of STN-to-cortex EPs. Two cortical EPs were observed – one synchronized with DBS onset and persisting during ongoing stimulation, and one immediately following DBS offset, here termed the “start” and the “end” EPs respectively. The start EP is, to our knowledge, the first long-latency cortical EP reported during ongoing high-frequency DBS. The start and end EPs differ in magnitude (p < 0.05) and latency (p < 0.001), and the end, but not the start, EP magnitude has a significant relationship (p < 0.001, adjusted for random effects of subject) to ongoing high gamma (80–150 Hz) power during the EP. These contrasts may suggest mechanistic or circuit differences in EP production during the two time periods. This represents a potential framework for relating DBS clinical efficacy to the effects of a variety of stimulation parameters on EPs.

scholarly journals Temporal Characteristics of High-Frequency Lower-Limb Oscillation during Freezing of Gait in Parkinson’s Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Don A. Yungher ◽  
Tiffany R. Morris ◽  
Valentina Dilda ◽  
James M. Shine ◽  
Sharon L. Naismith ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
High Frequency ◽  
Freezing Of Gait ◽  
Body Motion ◽  
High Frequency Oscillation ◽  
Frequency Oscillation ◽  
Timed Up And Go ◽  
Clinical Onset ◽  
Acceleration Data

A cardinal feature of freezing of gait (FOG) is high frequency (3–8 Hz) oscillation of the legs, and this study aimed to quantify the temporal pattern of lower-body motion prior to and during FOG. Acceleration data was obtained from sensors attached to the back, thighs, shanks, and feet in 14 Parkinson’s disease patients performing timed-up-and-go tasks, and clinical assessment of FOG was performed by two experienced raters from video. A total of 23 isolated FOG events, defined as occurring at least 5 s after gait initiation and with no preceding FOG, were identified from the clinical ratings. The corresponding accelerometer records were analyzed within a 4 s window centered at the clinical onset of freezing. FOG-related high-frequency oscillation (an increase in power in the 3–8 Hz band >3 SD from baseline) followed a distal to proximal onset pattern, appearing at the feet, shanks, thighs, and then back over a period of 250 ms. Peak power tended to decrease as the focus of oscillation moved from feet to back. There was a consistent delay (mean 872 ms) between the onset of high frequency oscillation at the feet and clinical onset of FOG. We infer that FOG is characterized by high frequency oscillation at the feet, which progresses proximally and is mechanically damped at the torso.

Electroceutically induced subthalamic high frequency oscillations and evoked compound activity may explain the mechanism of therapeutic stimulation in Parkinson's Disease

2020 ◽  
Author(s):  
Musa Ozturk ◽  
Ashwin Viswanathan ◽  
Sameer Sheth ◽  
Nuri Ince
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pharmacological Treatment ◽  
High Frequency ◽  
High Frequency Stimulation ◽  
High Frequency Oscillations ◽  
Stimulation Pulse ◽  
Main Challenge ◽  
Frequency Stimulation ◽  
Underlying Mechanisms

Abstract Despite having remarkable utility in treating movement disorders, the lack of understanding of the underlying mechanisms of high-frequency deep brain stimulation (DBS) is a main challenge in choosing personalized stimulation parameters. Here we investigate the modulations in local field potentials induced by therapeutic and non-therapeutic electrical stimulation of the subthalamic nucleus (STN) in Parkinson’s disease patients undergoing DBS surgery. We find that therapeutic high-frequency stimulation (130-180 Hz) induces high-frequency oscillations (~300 Hz, HFO) similar to those observed with pharmacological treatment. Along with HFOs, we also observed evoked compound activity (ECA) after each stimulation pulse. While ECA was observed in both therapeutic and non-therapeutic (20Hz) stimulation, the HFOs were induced only with therapeutic frequencies and the associated ECA were significantly more resonant. The relative degree of enhancement in the HFO power was related to the interaction of stimulation pulse with the phase of ECA.We propose that high-frequency STN-DBS tunes the neural oscillations to their healthy/treated state, similar to pharmacological treatment, and the stimulation frequency to maximize these oscillations can be inferred from the phase of ECA waveforms of individual subjects. The induced HFOs can, therefore, be utilized as a marker of successful re-calibration of the dysfunctional circuit generating PD symptoms.

scholarly journals Negative screening for 12 rare LRRK2 pathogenic variants in a cohort of Nigerians with Parkinson's disease

2020 ◽  
Author(s):  
Mie Rizig ◽  
Oluwadamilola O. Ojo ◽  
Alkyoni Athanasiou-Fragkouli ◽  
Osigwe P. Agabi ◽  
Olajumoke O. Oshinaike ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Pathogenic 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 The role of genetics in Parkinson’s disease: a large cohort study in Chinese mainland population

Brain ◽  
2020 ◽  
Vol 143 (7) ◽  
pp. 2220-2234 ◽  
Author(s):  
Yuwen Zhao ◽  
Lixia Qin ◽  
Hongxu Pan ◽  
Zhenhua Liu ◽  
Li Jiang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Chinese Population ◽  
Autosomal Recessive ◽  
Age At Onset ◽  
Mainland China ◽  
Mainland Chinese ◽  
Pathogenic Variants ◽  
Disease Associated Genes ◽  
Mainland Chinese Population

Abstract This study aimed to determine the mutational spectrum of familial Parkinson’s disease and sporadic early-onset Parkinson’s disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson’s disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson’s disease, 242 probands from families with autosomal-dominant Parkinson’s disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson’s disease-associated genes occurred more frequently in the autosomal-recessive Parkinson’s disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson’s disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson’s disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson’s disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson’s disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson’s disease-associated genes. Our data highlight the importance of genetic testing in Parkinson’s disease patients with age at onset &lt; 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

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