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BACKGROUND: The A-allele of the catechol-O-methyltransferase (COMT) Val158Met polymorphism is associated with decreased enzymatic activity and higher dopamine availability. METHODS: We studied 219 patients with PD who were free of dyskinesias at baseline and underwent thorough annual examinations. RESULTS: The A-allele of the COMT Val158Met polymorphism was related to an increased risk of developing dyskinesias during follow-up, in a dose-dependent manner (adjusted hazard ratios for the AG and AA genotypes [compared to GG]: 2.09 [95% confidence interval (CI), 1.07-4.06] and 2.81 [CI, 1.43-5.54], respectively). CONCLUSIONS: This finding suggests that genetic factors may affect susceptibility to dyskinesias in PD. © 2011 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

An increased risk among siblings of probands with complex regional pain syndrome (CRPS) may be indicative of a genetic contribution. We calculated the sibling recurrence risk ratio (lambda(sibling)), a measure of familial aggregation. We surveyed 405 CRPS patients to collect information on the occurrence of CRPS in their siblings and compared this risk with the population risk to develop the syndrome. Information on disease status was collected from 1242 siblings, of which 24 were possibly affected according to their siblings. The diagnosis was confirmed in 16 patients, rejected in 2, and could not be verified in the remaining 6. Age-specific risk ratios were calculated for younger (<50 years) and older (>/=50 years) age groups. The strongest effects were seen in the younger age group, with a lambda(sibling) for possibly affected and confirmed cases of 5.6 (95% CI, 3.0 to 9.8) and 3.4 (95% CI, 1.5 to 6.8), respectively. We concluded that this study yielded no indications for an overall increased risk of developing CRPS for siblings of CRPS patients but that the risk was significantly increased in siblings younger than 50, which may indicate that genetic factors play a more pronounced role in this subgroup. PERSPECTIVE: We studied the risk of developing CRPS for siblings of patients with this syndrome. Although the overall risk for siblings was not increased compared with the population risk, the risk for younger siblings was elevated. To enhance chances of success, future genetic studies may consider restricting inclusion to younger-onset cases. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the presence and nature of patterns of coherency among the motor and non-motor domains in Parkinson's disease (PD) and to examine which clinical parameters are related to the potential patterns.Methods: A cohort of 397 patients with PD were randomly divided into two samples. Exploratory factor analysis (EFA) was performed on the motor and non-motor symptoms in PD in the first sample. Findings of the EFA were used to construct a model which was tested in the second sample by confirmatory factor analysis. Multiple regression analyses on the resulting factors were performed to evaluate the influence of clinical parameters on these factors.Results: Four factors were identified. The first and strongest factor (cognitive impairment, autonomic dysfunction, psychotic symptoms, depression, daytime sleepiness and axial symptoms) reflected advancing disease. Another factor largely reflected motor complications of therapy and was related to dopaminergic medication. The other two factors reflected sleep/depression and tremor/bradykinesia/rigidity, and were only marginally related to disease severity or medication.Conclusions: The motor and non-motor features in PD can be characterised by four distinct patterns of coherency, which provide insight into the contributions of the primary disease process and antiparkinsonian medication to the broad clinical spectrum of PD. One factor, consisting of predominantly non-motor symptoms together with axial features, clearly reflected disease severity and may provide a new basis for monitoring disease progression in PD. [ABSTRACT FROM AUTHOR]

There is a growing appreciation of the significant number of patients with complex regional pain syndrome suffer from movement disorders. [ABSTRACT FROM AUTHOR]

Purpose. To systematically evaluate and compare the clinical manifestations, disease course, risk factors and demographic characteristics of Complex Regional Pain Syndrome type 1 (CRPS), fibromyalgia (FM) and a-specific Repetitive Strain Injury (RSI). Method. A literature search was performed using terms related to the aforementioned topics and diseases. Only original clinical studies that included at least 20 subjects were eligible. Results. Fifty-nine studies on CRPS, 73 on FM and 7 on a-specific RSI were identified. The diseases show similarities in age distribution, male-female ratio, pain characteristics and sensory signs and symptoms. Motor, autonomic and trophic changes are frequently reported in CRPS, but only occasionally in FM and RSI. Systemic symptoms are found in patients with CRPS and FM, and in a subgroup of patients with RSI. In all three disorders, symptoms usually start locally, but may spread to other body regions later, which, in the case of FM, is a prerequisite for diagnosis. Disease onset is always, usually, or occasionally of traumatic origin in RSI, CRPS and FM, respectively. Anxiety and depression are more frequent in patients compared to controls, but probably not very different from patients with other pain conditions or chronic diseases. Conclusions. Apart from some obvious differences between CRPS, FM and RSI, the similarities are conspicuous. The common features of CRPS, FM and a-specific RSI may suggest that a common pathway is involved, but until patients with these type of symptoms are assessed with a uniform assessment procedure, a thorough comparison cannot be made. A systematic evaluation of patients with a suspected diagnosis of CRPS, FM or RSI, may lead to a better appreciation of the differences and similarities in these diseases and help to unravel the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Objective: To compare and contrast disease-specific quality of life instruments in Parkinson's disease and assess their clinimetric properties.Methods: Two reviewers independently evaluated both thoroughness and results of studies regarding clinimetric characteristics of identified scales.Results: Twenty studies were found reporting on the clinimetric properties of four scales. The content validity of the Parkinson's disease questionnaire-39 item version (PDQ-39), the Parkinson's disease quality of life questionnaire (PDQL), and the "Fragebogen Parkinson LebensQualität" (Parkinson Quality of Life questionnaire; PLQ) was adequate to good, but for the Parkinson's impact scale (PIMS) it was insufficient. Construct validity of both the PDQ-39 and the PDQL was good, but for the PLQ and the PIMS this was insufficiently evaluated. Internal consistency of all scale totals and of subscale totals of the PDQL were good, whereas for the social support subscale of the PDQ-39 and four subscales of the PLQ this was inadequate. Test-retest reliability was not evaluated for the PDQL and was adequate in the other scales. Responsiveness was partially established for the PDQ-39, and not assessed for the other scales. The number of available translations, as well as the number of studies in which these instruments were used, differed considerably.Conclusions: The selection of an instrument partially depends on the goal of the study. In many situations however, the PDQ-39 will probably be the most appropriate HRQoL instrument. The PDQL may be considered as an alternative, whereas the PLQ may be considered in studies involving German speaking patients with Parkinson's disease. Use of the PIMS should be considered only as a means of identifying areas of potential problems. [ABSTRACT FROM AUTHOR]

The aim of the present study was to describe the occurrence of signs and symptoms in CRPS I patients meeting the IASP (Orlando) criteria, assess the occurrence of signs and symptoms in relation to disease duration and compare these to historical data based on a different diagnostic criteria set. Six hundred and ninety-two ambulatory patients meeting the IASP criteria for CRPS I referred to the outpatient clinics of five participating centers were included in this cross-sectional study. Characteristics were recorded in a standardized fashion and categorized according to the factor structure proposed by Bruehl/Harden. Subgroups were classified according to the duration of complaints and compared to historical data as described by Veldman et al. The Chi-square test corrected for multiple comparisons was used for statistical analysis. The prevalence of sensory signs was higher in patients with longer disease duration, especially for the allodynia's and hyperalgesia (all p<0.001). Signs in vasomotor (color difference; p=0.0007) and sudomotor (edema; p<0.0001) subgroups were less frequently present in patients with longer disease duration (i.e. >6months). Prevalences of signs in the motor subgroup were all higher (p<0.0001) in patients with longer disease duration, except for limited range of motion. Occurrence of signs was significantly lower (<0.001) than those reported by Veldman et al., except for hyperesthesia and dystonia. Occurrence rates may vary at different time points after onset of CRPS, which may be of influence for diagnosing patients with novel derived diagnostic criteria. We argue for a mechanism based description of CRPS I based on one set of uniform generally accepted diagnostic criteria in future studies. [ABSTRACT FROM AUTHOR]

Background: Levodopa-induced dyskinesia (LID) is a common adverse effect of levodopa, one of the main therapeutics used to treat the motor symptoms of Parkinson's disease (PD). Previous evidence suggests a connection between LID and a disruption of the dopaminergic system as well as genes implicated in PD, including GBA1 and LRRK2., Objectives: Our goal was to investigate the effects of genetic variants on risk and time to LID., Methods: We performed a genome-wide association study (GWAS) and analyses focused on GBA1 and LRRK2 variants. We also calculated polygenic risk scores (PRS) including risk variants for PD and variants in genes involved in the dopaminergic transmission pathway. To test the influence of genetics on LID risk we used logistic regression, and to examine its impact on time to LID we performed Cox regression including 1612 PD patients with and 3175 without LID., Results: We found that GBA1 variants were associated with LID risk (odds ratio [OR] = 1.65; 95% confidence interval [CI], 1.21-2.26; P = 0.0017) and LRRK2 variants with reduced time to LID onset (hazard ratio [HR] = 1.42; 95% CI, 1.09-1.84; P = 0.0098). The fourth quartile of the PD PRS was associated with increased LID risk (OR fourth&#95;quartile  = 1.27; 95% CI, 1.03-1.56; P = 0.0210). The third and fourth dopamine pathway PRS quartiles were associated with a reduced time to development of LID (HR third&#95;quartile = 1.38; 95% CI, 1.07-1.79; P = 0.0128; HR fourth&#95;quartile = 1.38; 95% CI = 1.06-1.78; P = 0.0147)., Conclusions: This study suggests that variants implicated in PD and in the dopaminergic transmission pathway play a role in the risk/time to develop LID. Further studies will be necessary to examine how these findings can inform clinical care. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background and Objective: The Levodopa in EArly Parkinson's disease study showed no effect of earlier versus later levodopa initiation on Parkinson's disease (PD) progression over 80 weeks. We now report the effects over 5 years., Methods: The Levodopa in EArly Parkinson's disease study randomly assigned patients to levodopa/carbidopa 300/75 mg daily for 80 weeks (early start) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed start). Follow-up visits were performed 3 and 5 years after baseline. We assessed the between-group differences in terms of square root transformed total Unified Parkinson's Disease Rating Scale score at 3 and 5 years with linear regression. We compared the prevalence of dyskinesia, prevalence of wearing off, and the levodopa equivalent daily dose., Results: A total of 321 patients completed the 5-year visit. The adjusted square root transformed total Unified Parkinson's Disease Rating Scale did not differ between treatment groups at 3 (estimated difference, 0.17; standard error, 0.13; P = 0.18) and 5 years (estimated difference, 0.24; standard error, 0.13; P = 0.07). At 5 years, 46 of 160 patients in the early-start group and 62 of 161 patients in the delayed-start group experienced dyskinesia (P = 0.06). The prevalence of wearing off and the levodopa equivalent daily dose were not significantly different between groups., Conclusions: We did not find a difference in disease progression or in prevalence of motor complications between patients with early PD starting treatment with a low dose of levodopa 40 weeks earlier versus 40 weeks later over the subsequent 5 years. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The International Parkinson and Movement Disorder Society (MDS) created a task force (TF) to provide a critical overview of the Parkinson's disease (PD) subtyping field and develop a guidance on future research in PD subtypes. Based on a literature review, we previously concluded that PD subtyping requires an ultimate alignment with principles of precision medicine, and consequently novel approaches were needed to describe heterogeneity at the individual patient level. In this manuscript, we present a novel purpose-driven framework for subtype research as a guidance to clinicians and researchers when proposing to develop, evaluate, or use PD subtypes. Using a formal consensus methodology, we determined that the key purposes of PD subtyping are: (1) to predict disease progression, for both the development of therapies (use in clinical trials) and prognosis counseling, (2) to predict response to treatments, and (3) to identify therapeutic targets for disease modification. For each purpose, we describe the desired product and the research required for its development. Given the current state of knowledge and data resources, we see purpose-driven subtyping as a pragmatic and necessary step on the way to precision medicine. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Introduction: Experimental studies suggest a role of gut microbiota in the pathophysiology of Parkinson's disease (PD) via the gut-brain axis. The gut microbiota can also influence the metabolism of levodopa, which is the mainstay of treatment of PD. Therefore, modifying the gut microbiota by faecal microbiota transplantation (FMT) could be a supportive treatment strategy., Methods and Analysis: We have developed a study protocol for a single-centre, prospective, self-controlled, interventional, safety and feasibility donor-FMT pilot study with randomisation and double-blinded allocation of donor faeces. The primary objectives are feasibility and safety of FMT in patients with PD. Secondary objectives include exploring whether FMT leads to alterations in motor complications (fluctuations and dyskinesias) and PD motor and non-motor symptoms (including constipation), determining alterations in gut microbiota composition, assessing donor-recipient microbiota similarities and their association with PD symptoms and motor complications, evaluating the ease of the study protocol and examining FMT-related adverse events in patients with PD. The study population will consist of 16 patients with idiopathic PD that use levodopa and experience motor complications. They will receive FMT with faeces from one of two selected healthy human donors. FMT will be administered via a gastroscope into the duodenum, after treatment with oral vancomycin, bowel lavage and domperidone. There will be seven follow-up moments during 12 months., Ethics and Dissemination: This study was approved by the Medical Ethical Committee Leiden Den Haag Delft (ref. P20.087). Study results will be disseminated through publication in peer-reviewed journals and international conferences., Trial Registration Number: International Clinical Trial Registry Platform: NL9438., Competing Interests: Competing interests: Outside this work, MFC received travel support from Boston Scientific, she was in an advisory board of Medtronic (fees to institution), she was an independent consultant for research and/or educational issues (fees to institution) for Medtronic, Boston Scientific, Inbrain, and CHDR, she received speaking fees of Abbvie (CME activity) and ECMT (CME activity), she received research support from Medtronic (unrestricted educational grant to institution), Global Kinetics Corporation (research support in-kind) and Abbvie (grant support to institution). EMT and EJK of the NDFB report an unrestricted research grant of Vedanta Biosciences (https://www.vedantabio.com/), which was not specifically granted for this study. Outside this work, JJvH has received grants from the Alkemade-Keuls Foundation, Stichting Parkinson Fonds, Parkinson Vereniging, The Netherlands Organisation for Health Research and Development, Hersenstichting, AbbVie, Michael J Fox Foundation, and research support from the Centre of Human Drug Research. These funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: The Levodopa in EArly Parkinson's Disease (LEAP) study enabled us to conduct post hoc analyses concerning the effects of levodopa in patients with early Parkinson disease., Methods: The LEAP study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson's Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered 3 questions regarding motor response fluctuations., Results: A total of 222 patients were randomized to the early-start group (mean ± SD age at baseline 64.8 ± 8.7 years; 71% male) and 223 to the delayed-start group (mean ± SD age at baseline 65.5 ± 8.8 years; 69% male). The difference between the early- and delayed-start groups in mean change from baseline to week 4, expressed as Hedges g effect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22, respectively, -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40, respectively, -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p < 0.01)., Discussion: In patients with early Parkinson disease, levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all 3 symptoms, effects were larger at 22 weeks compared with 4 weeks. At 80 weeks, there were fewer patients with motor response fluctuations in the group that had started levodopa earlier., Classification of Evidence: This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity, and tremor is larger after 22 weeks compared with 4 weeks of treatment., Trial Registration Information: ISRCTN30518857, EudraCT number 2011-000678-72., (© 2022 American Academy of Neurology.)

Mitochondria are a culprit in the onset of Parkinson's disease, but their role during disease progression is unclear. Here we used Cox proportional hazards models to exam the effect of variation in the mitochondrial genome on longitudinal cognitive and motor progression over time in 4064 patients with Parkinson's disease. Mitochondrial macro-haplogroup was associated with reduced risk of cognitive disease progression in the discovery and replication population. In the combined analysis, patients with the super macro-haplogroup J, T, U# had a 41% lower risk of cognitive progression with P = 2.42 × 10-6 compared to those with macro-haplogroup H. Exploratory analysis indicated that the common mitochondrial DNA variant, m.2706A>G, was associated with slower cognitive decline with a hazard ratio of 0.68 (95% confidence interval 0.56-0.81) and P = 2.46 × 10-5. Mitochondrial haplogroups were not appreciably linked to motor progression. This initial genetic survival study of the mitochondrial genome suggests that mitochondrial haplogroups may be associated with the pace of cognitive progression in Parkinson's disease over time., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Standardized screening for subthalamic deep brain stimulation (STN DBS) in Parkinson's disease (PD) patients is crucial to determine eligibility, but its utility to predict postoperative outcomes in eligible patients is inconclusive. It is unknown whether wearable data can contribute to this aim., Objective: To evaluate the utility of universal components incorporated in the DBS screening, complemented by a wearable sensor, to predict motor outcomes and Quality of life (QoL) one year after STN DBS surgery., Methods: Consecutive patients were included in the OPTIMIST cohort study from two DBS centers. Standardized assessments included a preoperative Levodopa Challenge Test (LCT), and questionnaires on QoL and non-motor symptoms including cognition, psychiatric symptoms, impulsiveness, autonomic symptoms, and sleeping problems. Moreover, an ambulatory wearable sensor (Parkinson Kinetigraph (PKG)) was used. Postoperative assessments were similar and also included a Stimulation Challenge Test to determine DBS effects on motor function., Results: Eighty-three patients were included (median (interquartile range) age 63 (56-68) years, 36% female). Med-OFF (Stim-OFF) motor severity deteriorated indicating disease progression, but patients significantly improved in terms of Med-ON (Stim-ON) motor function, motor fluctuations, QoL, and most non-motor domains. Motor outcomes were not predicted by preoperative tests, including covariates of either LCT or PKG. Postoperative QoL was predicted by better preoperative QoL, lower age, and more preoperative impulsiveness scores in multivariate models., Conclusion: Data from the DBS screening including wearable data do not predict postoperative motor outcome at one year. Post-DBS QoL appears primarily driven by non-motor symptoms, rather than by motor improvement.

External visual cueing is a well-known means to target freezing of gait (FOG) in Parkinson's disease patients. Holocue is a wearable visual cueing application that allows the HoloLens 1 mixed-reality headset to present on-demand patient-tailored action-relevant 2D and 3D holographic visual cues in free-living environments. The aim of this study involving 24 Parkinson's disease patients with dopaminergic "ON state" FOG was two-fold. First, to explore unfamiliarity and habituation effects associated with wearing the HoloLens on FOG. Second, to evaluate the potential immediate effect of Holocue on alleviating FOG in the home environment. Three sessions were conducted to examine (1) the effect of wearing the unfamiliar HoloLens on FOG by comparing walking with and without the HoloLens, (2) habituation effects to wearing the HoloLens by comparing FOG while walking with HoloLens over sessions, and (3) the potential immediate effect of Holocue on FOG by comparing walking with HoloLens with and without Holocue. Wearing the HoloLens (without Holocue) did significantly increase the number and duration of FOG episodes, but this unfamiliarity effect disappeared with habituation over sessions. This not only emphasizes the need for sufficient habituation to unfamiliar devices, but also testifies to the need for research designs with appropriate control conditions when examining effects of unfamiliar wearable cueing devices. Holocue had overall no immediate effect on FOG, although objective and subjective benefits were observed for some individuals, most notably those with long and/or many FOG episodes. Our participants raised valuable opportunities to improve Holocue and confirmed our assumptions about current and anticipated future design choices, which supports ongoing Holocue development for and with end users., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. After this study was accepted for publication, VU signed a collaboration agreement with Strolll.co as part of a joint ongoing EUreka Eurostars project (115506 MAGIC CUE, start date December 1, 2021), including transfer of IP and technology related to holographic cueing from VU to Strolll.co., (Copyright © 2022 Geerse, Coolen, van Hilten and Roerdink.)

Background: Caregivers of Parkinson's disease (PD) patients provide important support during the pre- and postoperative phase of deep brain stimulation (DBS). High levels of caregiver burden have been reported after DBS. However, a comparison between preoperative and postoperative burden and associated factors has been insufficiently studied., Objective: To investigate the influence of DBS on caregiver burden, and to identify the differential impact of patient-related factors on caregiver burden before and after DBS., Methods: Consecutive patients referred for DBS eligibility screening or during one-year follow-up assessments were included. Caregiver burden was measured with the short Zarit Burden Interview (ZBI-12). Inverse Probability Weighting (IPW) was used to compare caregiver burden between preoperative and postoperative assessments., Results: We included 47 patients (24 screening, 23 follow-up) (median age 65 years, 29.4% female sex). DBS did not impact caregiver burden (screening: median ZBI-12 9.5 (IQR 3.25, 16.75); follow-up median ZBI-12 6 (IQR 4, 14); IPW-coefficient 0.57 (95% CI -2.75, 3.89)). Worse caregiver burden during DBS screening was associated with worse patient-related scores on depressive symptoms, anxiety, QoL, and impulsiveness. Worse scores on depressive symptoms, anxiety, apathy, postural-instability-gait-disorder, and QoL were associated with worse caregiver burden at one-year follow-up., Conclusion: DBS appears not associated with changes in caregiver burden. Various symptoms are valued differently between screening and follow-up assessments in terms of caregiver burden. Early recognition of caregivers "at risk" may improve guidance of patient-caregiver dyads throughout the DBS process.

Background: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start)., Objective: This paper reports the results of the economic evaluation performed alongside the LEAP-study., Methods: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up., Results: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of € 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated., Conclusion: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.

Background: It is currently unknown whether results from intraoperative test stimulation of two types of Deep Brain Stimulation (DBS), either during awake pallidal (GPi) or thalamic (Vim), are comparable to the results generated by chronic stimulation through the definitive lead. Objective: To determine whether side-effects-thresholds from intraoperative test stimulation are indicative of postoperative stimulation findings. Methods: Records of consecutive patients who received GPi or Vim were analyzed. Thresholds for the induction of either capsular or non-capsular side-effects were compared at matched depths and at group-level. Results: Records of fifty-two patients were analyzed (20 GPis, 75 Vims). The induction of side-effects was not significantly different between intraoperative and postoperative assessments at matched depths, although a large variability was observed (capsular: GPi DBS: p = 0.79; Vim DBS: p = 0.68); non-capsular: GPi DBS: p = 0.20; and Vim DBS: p = 0.35). Linear mixed-effect models revealed no differences between intraoperative and postoperative assessments, although the Vim had significantly lower thresholds (capsular side-effects p = 0.01, non-capsular side-effects p < 0.01). Unpaired survival analyses demonstrated lower intraoperative than postoperative thresholds for capsular side-effects in patients under GPi DBS ( p = 0.01), while higher intraoperative thresholds for non-capsular side-effects in patients under Vim DBS ( p = 0.01). Conclusion: There were no significant differences between intraoperative and postoperative assessments of GPi and Vim DBS, although thresholds cannot be directly extrapolated at an individual level due to high variability., Competing Interests: Unrelated to this study, JH reports grants from The Netherlands Organisation for Health Research and Development, The Netherlands Organisation for Scientific Research, Hoffmann-La Roche, AbbVie, Lundbeck, Hersenstichting, Stichting Parkinson Fonds, Alkemade-Keuls Foundation, and Centre of Human Drug Research. AM reports travel support from Boston Scientific. CH reports travel support from Boston Scientific. NG reports travel support from Boston Scientific. MC reports support for advisory board from Medtronic (fees to institution), consultancy fees: Medtronic (fees to institution), CHDR (fees to institution), research support: Medtronic (to institution), AbbVie (to institution), research support in kind from Global Kinetics Corporation, travel support: Boston Scientific. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Geraedts, van Ham, van Hilten, Mosch, Hoffmann, van der Gaag and Contarino.)

Purpose: The ability to adapt walking is important for safe ambulation. Assessments of impairments in walking adaptability with the Interactive Walkway may aid in the development of individualized therapy strategies of stroke patients. The Interactive Walkway is an overground walkway with Kinect v2 sensors for a markerless registration of full-body kinematics, which can be augmented with (gait-dependent) visual context to assess walking adaptability. This study aims to evaluate the potential of the Interactive Walkway as a new technology for assessing walking adaptability in stroke patients. Materials and methods: 30 stroke patients and 30 controls performed clinical tests, quantitative gait assessments and various walking-adaptability tasks on the Interactive Walkway. Outcome measures were compared between stroke patients and controls to examine known-groups validity. Pearson's correlation coefficients were calculated to assess the relationship between walking-adaptability outcomes and commonly used clinical test scores of walking ability and spatiotemporal gait parameters of unconstrained walking. Results: Good known-groups validity for walking-adaptability outcomes was demonstrated. In addition, the vast majority of walking-adaptability outcomes did not or only moderately correlate with clinical test scores of walking ability and unconstrained walking parameters. Conclusion: Interactive Walkway walking-adaptability outcomes have good known-groups validity and complement standard clinical tests and spatiotemporal gait parameters.IMPLICATIONS FOR REHABILITATIONThe Interactive Walkway allows for a comprehensive walking-adaptability assessment.Good known-groups validity for walking-adaptability tasks was demonstrated and walking-adaptability tasks complemented clinical tests and gait parameters.The Interactive Walkway has potential for monitoring recovery of walking after stroke.Assessments of walking adaptability may contribute to individualized interventions.

Background: Subthalamic deep brain stimulation (STN DBS) may relieve refractory motor complications in Parkinson's disease (PD) patients. Despite careful screening, it remains difficult to determine severity of alpha-synucleinopathy involvement which influences the risk of postoperative complications including cognitive deterioration. Quantitative electroencephalography (qEEG) reflects cognitive dysfunction in PD and may provide biomarkers of postoperative cognitive decline., Objective: To develop an automated machine learning model based on preoperative EEG data to predict cognitive deterioration 1 year after STN DBS., Methods: Sixty DBS candidates were included; 42 patients had available preoperative EEGs to compute a fully automated machine learning model. Movement Disorder Society criteria classified patients as cognitively stable or deteriorated at 1-year follow-up. A total of 16,674 EEG-features were extracted per patient; a Boruta algorithm selected EEG-features to reflect representative neurophysiological signatures for each class. A random forest classifier with 10-fold cross-validation with Bayesian optimization provided class-differentiation., Results: Tweny-five patients were classified as cognitively stable and 17 patients demonstrated cognitive decline. The model differentiated classes with a mean (SD) accuracy of 0.88 (0.05), with a positive predictive value of 91.4% (95% CI 82.9, 95.9) and negative predictive value of 85.0% (95% CI 81.9, 91.4). Predicted probabilities between classes were highly differential (hazard ratio 11.14 [95% CI 7.25, 17.12]); the risk of cognitive decline in patients with high probabilities of being prognosticated as cognitively stable (>0.5) was very limited., Conclusions: Preoperative EEGs can predict cognitive deterioration after STN DBS with high accuracy. Cortical neurophysiological alterations may indicate future cognitive decline and can be used as biomarkers during the DBS screening. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Cortical atrophy is a common manifestation in Parkinson's disease (PD), particularly in advanced stages of the disease. To elucidate the molecular underpinnings of cortical thickness changes in PD, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and patterns of cortical thickness based on T1-weighted anatomical MRI data of 149 PD patients and 369 controls. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of PD. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in PD are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in PD and possibly influence motor and cognitive functions., Competing Interests: The authors declare that this study received funding from AbbVie, Hoffmann-La-Roche, and Lundbeck. The funders were not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication., (Copyright © 2021 Keo, Dzyubachyk, van der Grond, van Hilten, Reinders and Mahfouz.)

Objective: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide 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., Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 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., Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%)., Interpretation: 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 cases 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 female patients. ANN NEUROL 2021;90:41-48., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance across a population. We examined the transcriptomic signature of such anatomical networks in the healthy brain using postmortem microarray data from the Allen Human Brain Atlas. A previous study revealed that a posterior cingulate network and anterior cingulate network showed decreased gray matter in brains of Parkinson's disease patients. Therefore, we examined these two anatomical networks to understand the underlying molecular processes that may be involved in Parkinson's disease. Whole brain transcriptomics from the healthy brain revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS-signaling pathways. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a functional role. Finally, both networks were enriched for genes associated with neuropsychiatric disorders that overlap with Parkinson's disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinson's disease., (© 2021 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

A key driver of patients' well-being and clinical trials for Parkinson's disease (PD) is the course that the disease takes over time (progression and prognosis). To assess how genetic variation influences the progression of PD over time to dementia, a major determinant for quality of life, we performed a longitudinal genome-wide survival study of 11.2 million variants in 3,821 patients with PD over 31,053 visits. We discover RIMS2 as a progression locus and confirm this in a replicate population (hazard ratio (HR) = 4.77, P = 2.78 × 10 -11 ), identify suggestive evidence for TMEM108 (HR = 2.86, P = 2.09 × 10 -8 ) and WWOX (HR = 2.12, P = 2.37 × 10 -8 ) as progression loci, and confirm associations for GBA (HR = 1.93, P = 0.0002) and APOE (HR = 1.48, P = 0.001). Polygenic progression scores exhibit a substantial aggregate association with dementia risk, while polygenic susceptibility scores are not predictive. This study identifies a novel synaptic locus and polygenic score for cognitive disease progression in PD and proposes diverging genetic architectures of progression and susceptibility.

Objective: A downside of Deep Brain Stimulation (DBS) for Parkinson's Disease (PD) is that cognitive function may deteriorate postoperatively. Electroencephalography (EEG) was explored as biomarker of cognition using a Machine Learning (ML) pipeline., Methods: A fully automated ML pipeline was applied to 112 PD patients, taking EEG time-series as input and predicted class-labels as output. The most extreme cognitive scores were selected for class differentiation, i.e. best vs. worst cognitive performance (n = 20 per group). 16,674 features were extracted per patient; feature-selection was performed using a Boruta algorithm. A random forest classifier was modelled; 10-fold cross-validation with Bayesian optimization was performed to ensure generalizability. The predicted class-probabilities of the entire cohort were compared to actual cognitive performance., Results: Both groups were differentiated with a mean accuracy of 0.92; using only occipital peak frequency yielded an accuracy of 0.67. Class-probabilities and actual cognitive performance were negatively linearly correlated (β = -0.23 (95% confidence interval (-0.29, -0.18)))., Conclusions: Particularly high accuracies were achieved using a compound of automatically extracted EEG biomarkers to classify PD patients according to cognition, rather than a single spectral EEG feature., Significance: Automated EEG assessment may have utility for cognitive profiling of PD patients during the DBS screening., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study., Objectives: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data., Methods: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD., Results: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort., Conclusions: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Background: Caregivers of patients with Parkinson's Disease (PD) often provide important support in the pre- and postoperative phase of Deep Brain Stimulation (DBS). DBS-associated changes of patient-functioning may affect caregiver wellbeing and impact the support system. Factors influencing caregiver-wellbeing under these circumstances are incompletely known., Objective: to systematically review studies of sufficient methodological quality on the impact of DBS on caregivers of PD patients., Methods: using PRISMA guidelines, major databases were searched up to May 2020. Five subcategories were identified: Caregiver burden, Caregiver cognitive and psychiatric functioning, Caregiver Quality of Life (QoL), Marital Satisfaction/Conflicts, and Caregiver Satisfaction. Quality was assessed using an in-house checklist., Results: 293 studies were identified; 12 were ultimately included. Caregiver burden, psychiatric and cognitive functioning and QoL remained relatively unchanged. Results on marital satisfaction/conflicts were contrasting: an increase in marital conflicts despite improved relationship quality scores DBS. Caregiver satisfaction with surgery was low with 50-58% of caregivers being disappointed with DBS outcomes. Concerning caregiver related factors: a higher preoperative caregiver QoL, younger age, lower scores on psychiatric rating scales, and more favourable preoperative relationship quality scores, were associated with better caregiver wellbeing. A favourable patient-profile includes younger age and age-at-onset, shorter disease duration, lower medication requirements, and lower scores on psychiatric rating scales., Conclusion: Although most patient- and caregiver-related subdomains remained unchanged after DBS, dissatisfaction among caregivers and marital problems may constitute a large risk for a well-functioning patient-caregiver dyad. Early recognition of potential problem situations may improve post-DBS care for both patients and caregivers., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: No funding is applicable to this article. The authors report no competing interests.

Background: The most common genetic risk factor for Parkinson's disease known is a damaging variant in the GBA1 gene. The entire GBA1 gene has rarely been studied in a large cohort from a single population. The objective of this study was to assess the entire GBA1 gene in Parkinson's disease from a single large population., Methods: The GBA1 gene was assessed in 3402 Dutch Parkinson's disease patients using next-generation sequencing. Frequencies were compared with Dutch controls (n = 655). Family history of Parkinson's disease was compared in carriers and noncarriers., Results: Fifteen percent of patients had a GBA1 nonsynonymous variant (including missense, frameshift, and recombinant alleles), compared with 6.4% of controls (OR, 2.6; P < 0.001). Eighteen novel variants were detected. Variants previously associated with Gaucher's disease were identified in 5.0% of patients compared with 1.5% of controls (OR, 3.4; P < 0.001). The rarely reported complex allele p.D140H + p.E326K appears to likely be a Dutch founder variant, found in 2.4% of patients and 0.9% of controls (OR, 2.7; P = 0.012). The number of first-degree relatives (excluding children) with Parkinson's disease was higher in p.D140H + p.E326K carriers (5.6%, 21 of 376) compared with p.E326K carriers (2.9%, 29 of 1014); OR, 2.0; P = 0.022, suggestive of a dose effect for different GBA1 variants., Conclusions: Dutch Parkinson's disease patients display one of the largest frequencies of GBA1 variants reported so far, consisting in large part of the mild p.E326K variant and the more severe Dutch p.D140H + p.E326K founder allele. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.)

Background: Several studies suggested an important role of the gut microbiota in the pathophysiology of neurological disorders, implying that alteration of the gut microbiota might serve as a treatment strategy. Fecal microbiota transplantation (FMT) is currently the most effective gut microbiota intervention and an accepted treatment for recurrent Clostridioides difficile infections. To evaluate indications of FMT for patients with neurological disorders, we summarized the available literature on FMT. In addition, we provide suggestions for future directions. Methods: In July 2019, five main databases were searched for studies and case descriptions on FMT in neurological disorders in humans or animal models. In addition, the ClinicalTrials.gov website was consulted for registered planned and ongoing trials. Results: Of 541 identified studies, 34 were included in the analysis. Clinical trials with FMT have been performed in patients with autism spectrum disorder and showed beneficial effects on neurological symptoms. For multiple sclerosis and Parkinson's disease, several animal studies suggested a positive effect of FMT, supported by some human case reports. For epilepsy, Tourette syndrome, and diabetic neuropathy some studies suggested a beneficial effect of FMT, but evidence was restricted to case reports and limited numbers of animal studies. For stroke, Alzheimer's disease and Guillain-Barré syndrome only studies with animal models were identified. These studies suggested a potential beneficial effect of healthy donor FMT. In contrast, one study with an animal model for stroke showed increased mortality after FMT. For Guillain-Barré only one study was identified. Whether positive findings from animal studies can be confirmed in the treatment of human diseases awaits to be seen. Several trials with FMT as treatment for the above mentioned neurological disorders are planned or ongoing, as well as for amyotrophic lateral sclerosis. Conclusions: Preliminary literature suggests that FMT may be a promising treatment option for several neurological disorders. However, available evidence is still scanty and some contrasting results were observed. A limited number of studies in humans have been performed or are ongoing, while for some disorders only animal experiments have been conducted. Large double-blinded randomized controlled trials are needed to further elucidate the effect of FMT in neurological disorders., (Copyright © 2020 Vendrik, Ooijevaar, de Jong, Laman, van Oosten, van Hilten, Ducarmon, Keller, Kuijper and Contarino.)

The molecular mechanisms underlying caudal-to-rostral progression of Lewy body pathology in Parkinson's disease remain poorly understood. Here, we identified transcriptomic signatures across brain regions involved in Braak Lewy body stages in non-neurological adults from the Allen Human Brain Atlas. Among the genes that are indicative of regional vulnerability, we found known genetic risk factors for Parkinson's disease: SCARB2, ELOVL7, SH3GL2, SNCA, BAP1, and ZNF184. Results were confirmed in two datasets of non-neurological subjects, while in two datasets of Parkinson's disease patients we found altered expression patterns. Co-expression analysis across vulnerable regions identified a module enriched for genes associated with dopamine synthesis and microglia, and another module related to the immune system, blood-oxygen transport, and endothelial cells. Both were highly expressed in regions involved in the preclinical stages of the disease. Finally, alterations in genes underlying these region-specific functions may contribute to the selective regional vulnerability in Parkinson's disease brains.

Background and Purpose: Subthalamic deep brain stimulation (STN DBS) is an effective therapy against medication-refractory motor complications in patients with Parkinson's disease. However, it remains difficult to predict which baseline patient characteristics are associated with quality of life (QoL) after surgery. The objective was to identify preoperative factors associated with QoL after STN DBS by systematically reviewing publications of sufficient methodological quality., Methods: Main databases were systematically searched up to March 2019 to identify studies that investigated factors associated with QoL after STN DBS in patients with idiopathic Parkinson's disease., Results: In all, 869 studies were identified, of which 18 fulfilled the inclusion criteria. Higher QoL after DBS appears to be associated with a large preoperative difference between ON and OFF motor function in some studies, although there was no clear association of severity of motor function or motor complications with postoperative QoL. Lower severity of dyskinesias was associated with greater postoperative QoL improvement but has been insufficiently studied. Higher baseline QoL was suggestive of higher postoperative QoL. Four studies suggested that older age at surgery is associated with a lower improvement, although six other studies reported no association. No or limited evidence was found for cognitive impairment or psychiatric dysfunction., Conclusion: Various relative contraindications for STN DBS such as cognitive impairment and psychiatric dysfunction appear to be unrelated to postoperative QoL. However, the lack of clear correlations with disease-related variables suggests that QoL may be individually influenced by other factors, indicating that an ideal preoperative patient profile with regard to QoL improvement cannot be readily provided., (© 2019 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions., (Published by Oxford University Press on behalf of the Guarantors of Brain 2019. This work is written by US Government employees and is in the public domain in the US.)

Background: Several reports have identified different patterns of Parkinson's disease progression in individuals carrying missense variants in GBA or LRRK2 genes. The overall contribution of genetic factors to the severity and progression of Parkinson's disease, however, has not been well studied., Objectives: To test the association between genetic variants and the clinical features of Parkinson's disease on a genomewide scale., Methods: We accumulated individual data from 12 longitudinal cohorts in a total of 4093 patients with 22,307 observations for a median of 3.81 years. Genomewide associations were evaluated for 25 cross-sectional and longitudinal phenotypes. Specific variants of interest, including 90 recently identified disease-risk variants, were also investigated post hoc for candidate associations with these phenotypes., Results: Two variants were genomewide significant. Rs382940(T>A), within the intron of SLC44A1, was associated with reaching Hoehn and Yahr stage 3 or higher faster (hazard ratio 2.04 [1.58-2.62]; P value = 3.46E-8). Rs61863020(G>A), an intergenic variant and expression quantitative trait loci for α-2A adrenergic receptor, was associated with a lower prevalence of insomnia at baseline (odds ratio 0.63 [0.52-0.75]; P value = 4.74E-8). In the targeted analysis, we found 9 associations between known Parkinson's risk variants and more severe motor/cognitive symptoms. Also, we replicated previous reports of GBA coding variants (rs2230288: p.E365K; rs75548401: p.T408M) being associated with greater motor and cognitive decline over time, and an APOE E4 tagging variant (rs429358) being associated with greater cognitive deficits in patients., Conclusions: We identified novel genetic factors associated with heterogeneity of Parkinson's disease. The results can be used for validation or hypothesis tests regarding Parkinson's disease. © 2019 International Parkinson and Movement Disorder Society., (© 2019 International Parkinson and Movement Disorder Society.)

Objective: Although subthalamic Deep Brain Stimulation (STN DBS) is proven effective in improving symptoms of Parkinson's Disease (PD), previous literature demonstrates a discrepancy between objective improvement and patients' perception thereof. We aimed to examine whether postoperative stimulation challenge tests (SCT) alters patients' satisfaction after STN DBS for PD., Methods: Fifty-four PD patients underwent preoperative levodopa challenge tests and were routinely invited for SCT 1-2 years postoperatively. SEverity of predominantly Nondopaminergic Symptoms in PD (SENS-PD) scores quantified non-dopaminergic disease severity. Motor functioning was quantified using Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III scores; a ratio between conditions ON and OFF (preoperative Med-ON vs. Med-OFF, and postoperative Med-ON/Stim-ON vs. Med-OFF/Stim-OFF) reflected treatment benefit. 'Global Impression of Change' (GIC) and 'Global Satisfaction with Surgery' (GSS) Likert scales were filled out before and immediately after SCT., Results: Postoperative Med-ON/Stim-ON severity was lower than preoperative ON severity. Disease severity scores were not different between assessments. GIC and GSS scores were higher after SCT versus before (GIC: Z = -3.80, r = 0.37, subjects indicating maximum scores before SCT: 32.1%, after SCT: 57.1%; GSS: Z = -3.69, r = 0.35, maximum scores before SCT: 25.0%, after SCT: 46.4%). Higher non-dopaminergic disease severity was associated with lower GIC and GSS scores (GIC: OR 1.2 (95%CI 1.0-1.3); GSS: OR 1.2 (95%CI 1.1-1.3), while motor-scores and magnitude of DBS-effects were not., Conclusion: SCT improves patients' satisfaction and is recommended especially in case of suboptimal subjective valuations. This information should be considered in clinical practice and in the context of clinical trials., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)