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Beta-based adaptive Deep Brain Stimulation (aDBS) is effective in Parkinson's disease (PD), when assessed in the immediate post-implantation phase. However, the potential benefits of aDBS in patients with electrodes chronically implanted, in whom changes due to the microlesion effect have disappeared, are yet to be assessed. To determine the acute effectiveness and side-effect profile of aDBS in PD compared to conventional continuous DBS (cDBS) and no stimulation (NoStim), years after DBS implantation, 13 PD patients undergoing battery replacement were pseudo-randomised in a crossover fashion, into three conditions (NoStim, aDBS or cDBS), with a 2-min interval between them. Patient videos were blindly evaluated using a short version of the Unified Parkinson's Disease Rating Scale (subUPDRS), and the Speech Intelligibility Test (SIT). Mean disease duration was 16 years, and the mean time since DBS-implantation was 6.9 years. subUPDRS scores (11 patients tested) were significantly lower both in aDBS (p=<.001), and cDBS (p =.001), when compared to NoStim. Bradykinesia subscores were significantly lower in aDBS (p =.002), and did not achieve significance during cDBS (p =.08), when compared to NoStim. Two patients demonstrated re-emerging tremor during aDBS. SIT scores of patients who presented stimulation-induced dysarthria significantly worsened in cDBS (p =.009), but not in aDBS (p =.407), when compared to NoStim. Overall, stimulation was applied 48.8% of the time during aDBS. Beta-based aDBS is effective in PD patients with bradykinetic phenotypes, delivers less stimulation than cDBS, and potentially has a more favourable speech side-effect profile. Patients with prominent tremor may require a modified adaptive strategy. • The acute effect of beta-based aDBS in PD is effective in controlling bradykinesia. • Beta oscillations remain informative of the parkinsonian state 7 years after DBS. • aDBS did not lead to stimulation-induced dysarthria, compared to conventional DBS. • A minority of patients presented acute re-emerging tremor during aDBS. • Modified aDBS control strategies might be required in some patients with tremor. [ABSTRACT FROM AUTHOR]

Introduction: Continuous apomorphine infusion (CAI) is an advanced therapy in fluctuating Parkinson's disease (PD). The use of CAI is controversial in PD patients with cognitive dysfunction including visual hallucinations (VHs), and orthostatic hypotension (OH). This study was set-up to analyze the effectiveness and safety of CAI in elderly PD patients with cognitive dysfunction.Methods: This new-user cohort study identified fluctuating PD patients who started CAI treatment at the rehabilitation unit of Parkinson Expertise Center (RU-PEC) Groningen, from November 2004 until 2016. Efficacy and safety data included motor function, cognitive status, OH and VHs, and was analyzed retrospectively. Pre-existent non-motor symptoms were treated optimally before starting CAI.Results: Forty-five fluctuating PD patients (age: 70.9 ± 8.1 yrs, disease duration: 10.8 ± 4.8 yrs) were identified, with pre-existing cognitive dysfunction, VHs (71%), and OH (26%). During the stay at RU-PEC (median 52 days) apomorphine was successfully titrated without worsening of pre-existing VHs and OH. The mean daily apomorphine dose was 66 ± 28 mg, accompanied by a reduction of levodopa-equivalent daily dose (LEDD) with 17%. The duration of ON-time and OFF-time significantly improved with +2.36 h (25%) and -1.66 h (-45%), respectively, while dyskinesia duration did not change. During long-term follow-up (median of 26 months) VHs and OH worsened in 9 and 4 patients, which necessitated discontinuation in 4 cases.Conclusion: This study demonstrates that CAI is also an effective treatment in advanced PD patients with concomitant cognitive dysfunction including VHs and OH, provided that these comorbidities are treated adequately as well. [ABSTRACT FROM AUTHOR]

Objectives To determine whether objective (neuropsychological tests) and subjective measures (questionnaires) of executive functions (EFs) are associated in patients with Parkinson disease (PD), and to determine to what extent level of participation and quality of life (QoL) of patients with PD can be predicted by these measures of EFs. Design Correlational research design (case-control and prediction design). Setting Departments of neuropsychology of 3 medical centers. Participants A sample (N=136) of patients with PD (n=42) and their relatives, and controls without PD (n=94). Interventions Not applicable. Main Outcome Measures A test battery measuring EFs. In addition, patients, their relatives, and controls completed the Dysexecutive Questionnaire, Brock Adaptive Functioning Questionnaire, and Barkley Deficits in Executive Functioning Scale – time management questionnaires measuring complaints about EFs. Participation and QoL were measured with the Impact on Participation and Autonomy scale and the Parkinson's Disease Questionnaire-39, respectively. Results Patients with PD showed impairments in EFs on objective tests and reported significantly more complaints about EFs than did controls without PD. No associations were found between patients' performances on objective and subjective measures of EFs. However, both objective and subjective measures predicted patients' level of participation. In addition, subjective measures of EFs predicted QoL in patients with PD. Conclusions These findings show that objective and subjective measures of EFs are not interchangeable and that both approaches predict level of participation and QoL in patients with PD. However, within this context, sex needs to be taken into account. [ABSTRACT FROM AUTHOR]

Objective To show the benefits of a continuous intrathecal baclofen (ITB) test infusion in a patient with hereditary spastic paraplegia (HSP), with an improved gait performance after ITB pump implantation. Design Case report. Setting University hospital. Participant A 49-year old man with HSP experiencing progressive walking difficulties because of lower extremity spasticity, which did not respond to oral spasmolytics. Interventions A prolonged, continuous ITB test infusion was started at a low dose and increased gradually, to provide a stable dose of ITB over a prolonged period. The gradual dose increase provided the patient enough time to experience the effects of ITB, because he feared that ITB therapy might cause functional loss. Main Outcome Measures Modified Ashworth Scale, electromyography, muscle strength, timed Up and Go tests, and the Patient Global Impression of Change. Gait performance before and after ITB pump implantation was assessed in a motion laboratory. Results During the test infusion, the ITB dose was gradually increased to a continuous dose of 108μg/d. This dose caused the spasticity to decrease, with maintenance of muscle strength. After pump implantation, gait performance was improved, resulting in increased knee flexion during the loading response and a doubled walking speed as compared with baseline. Conclusions Patients with HSP who have mild spasticity that does not respond to oral spasmolytics should receive a continuous ITB test infusion, to provide them with enough time to experience the delicate balance between spasmolysis and muscle strength. ITB administration is a suitable therapy to improve gait performance in patients with HSP. [ABSTRACT FROM AUTHOR]

Objective To review all pharmacological and physiological data available on intrathecal baclofen (ITB) therapy and to evaluate its use in clinical practice and future research. Data Sources PubMed was searched for relevant anatomic, physiological, and pharmacological data available on ITB. Study Selection All currently available data on ITB pharmacokinetics (PKs) and pharmacodynamics (PDs) in both human and animal studies were reviewed and combined with the anatomy and physiology of the intrathecal space and cerebrospinal fluid flow. Data Extraction Only 4 studies reported PK data on ITB in humans. More studies reported PD data on ITB; however, none were combined with PK data. More detailed data on PK could be gathered from studies using an animal model. Data Synthesis ITB does not spread equally over the intrathecal space after injection, but it diffuses according to a concentration gradient. ITB distribution can be influenced by the location of the catheter tip and by changing the infusion mode. Conclusions The pharmacological and physiological data on ITB can be used to support decisions in clinical practice concerning drug concentration, infusion regimens, localization of the catheter tip, and management of tolerance; however, some strategies have little evidence in humans. [ABSTRACT FROM AUTHOR]

Summary: Background: Patients with advanced Parkinson''s disease often have rapid swings between mobility and immobility, and many respond unsatisfactorily to adjustments in pharmacological treatment. We assessed whether globus pallidus pars interna (GPi) deep brain stimulation (DBS) gives greater functional improvement than does subthalamic nucleus (STN) DBS. Methods: We recruited patients from five centres in the Netherlands who were aged 18 years or older, had idiopathic Parkinson''s disease, and had, despite optimum pharmacological treatment, at least one of the following symptoms: severe response fluctuations, dyskinesias, painful dystonias, or bradykinesia. By use of a computer-generated randomisation sequence, we randomly assigned patients to receive either GPi DBS or STN DBS (1:1), applying a minimisation procedure according to drug use (levodopa equivalent dose <1000 mg vs ≥1000 mg) and treatment centre. Patients and study assessors (but not those who assessed adverse events) were masked to treatment allocation. We had two primary outcomes: functional health as measured by the weighted Academic Medical Center Linear Disability Scale (ALDS; weighted by time spent in the off phase and on phase) and a composite score for cognitive, mood, and behavioural effects up to 1 year after surgery. Secondary outcomes were symptom scales, activities of daily living scales, a quality-of-life questionnaire, the occurrence of adverse events, and drug use. We used the intention-to-treat principle for all analyses. This trial is registered with www.controlled-trials.com, number ISRCTN85542074. Findings: Between Feb 1, 2007, and March 29, 2011, we enrolled 128 patients, assigning 65 to GPi DBS and 63 to STN DBS. We found no statistically significant difference in either of our primary outcomes: mean change in weighted ALDS (3·0 [SD 14·5] in the GPi group vs 7·7 [23·2] in the STN group; p=0·28) and the number of patients with cognitive, mood, and behavioural side-effects (36 [58%] of 62 patients in the GPi group vs 35 [56%] of 63 patients in the STN group; p=0·94). Secondary outcomes showed larger improvements in off-drug phase in the STN group compared with the GPi group in the mean change in unified Parkinson''s disease rating scale motor examination scores (20·3 [16·3] vs 11·4 [16·1]; p=0·03), the mean change in ALDS scores (20·3 [27·1] vs 11·8 [18·9]; p=0·04), and medication (mean levodopa equivalent drug reduction: 546 [SD 561] vs 208 [521]; p=0·01). We recorded no difference in the occurrence of adverse events between the two groups. Other secondary endpoints showed no difference between the groups. Interpretation: Although there was no difference in our primary outcomes, our findings suggest that STN could be the preferred target for DBS in patients with advanced Parkinson''s disease. Funding: Stichting Internationaal Parkinson Fonds, Prinses Beatrix Fonds, and Parkinson Vereniging. [Copyright &y& Elsevier]

Luminal distention of the intestine can be aversive in humans and laboratory animals, and hypersensitivity to distention is found in functional gastrointestinal disorders. Current animal models either require anaesthesia or acute balloon intubation or use implanted balloons of irritant materials, for which the aversive quality of distention and physiological responses have not been well characterised. We report here that silicone balloon catheters implanted in the duodenum via the stomach have long patency without obvious tissue damage. Balloon inflation in freely moving rats caused passive avoidance learning and classic ‘pain’ postures, as well as graded cardiovascular responses which can be recorded telemetrically. The method should make long-lasting studies of pharmacological and environmental effects on visceral sensitivity more feasible. [Copyright &y& Elsevier]

Altered behavioural and physiological responsivity following a short session of foot shocks in the rat has proven to be a stable and clinically relevant model of stress-induced sensitisation. However, a number of key factors influencing effect size or direction have not previously been reported. Rats underwent a single, 15-min session of foot shocks and were exposed to a variety of novel stressful challenges 1 or 2 weeks later. Sensitised behavioural responses (increased immobility) in preshocked rats remained present over 3 days of repeated exposure to noise stress. In mild novel challenges (open field, empty cage), behavioural sensitisation and defecation was most clearly expressed at the beginning of the dark phase (evening). Higher-arousal challenges (prod, noise) caused increased behavioural inhibition in preshocked rats at all three time points (morning, afternoon, evening). Female preshocked rats showed a different pattern of behavioural and defecation sensitisation than preshocked males. The robustness of the model makes it suitable for further investigations into the mechanisms and vulnerability factors involved in the long-term consequences of stress. [Copyright &y& Elsevier]

Background: The supplementary motor area (SMA) is implicated in stereotypic multi-limb movements such as walking with arm swing. Gait difficulties in Parkinson's Disease (PD) include reduced arm swing, which is associated with reduced SMA activity.Objective: To test whether enhanced arm swing improves Parkinsonian gait and explore the role of the SMA in such an improvement.Methods: Cortical activity and gait characteristics were assessed by ambulant EEG, accelerometers and video recordings in 27 PD patients with self-reported gait difficulties and 35 healthy participants when walking normally. Within these two groups, 19 PD patients additionally walked with enhanced arm swing and 30 healthy participants walked without arm swing. Power changes across the EEG frequency spectrum were assessed by Event Related Spectral Perturbation analysis of recordings from Fz over the putative SMA and gait analysis was performed.Results: Baseline PD gait, characterized by reduced arm swing among other features, exhibited reduced within-step Event Related Desynchronization (ERD)/Synchronization (ERS) alternation (Fz; 20-50Hz), accompanied by a reduced step length and walking speed. All became similar to normal gait when patients walked with enhanced arm swing. When healthy controls walked without arm swing, their alternating ERD-ERS pattern decreased, mimicking baseline PD gait.Conclusion: Enhanced arm swing may serve as a driving force to overcome impaired gait control in PD patients by restoring reduced ERD-ERS alternation over the putative SMA. Accompanied by increased step length and walking speed, this provides a neural underpinning of arm swing as an effective rehabilitation concept for improving Parkinsonian gait. [ABSTRACT FROM AUTHOR]

In the course of Parkinson's disease (PD), oral medication may lose its effectiveness due to several reasons, like dysphagia, impaired absorption from the gastro-intestinal tract and delayed emptying of the stomach. If these problems occur, a non-oral therapy should be considered. Examples of non-oral therapies are transdermal patches, (e.g. rotigotine) which may overcome motor and nonmotor nighttime problems, and may serve as well to treat daytime response-fluctuations, if oral therapies fail to do so. Other options are injections with apomorphine to treat early morning dystonia and random off-periods during daytime, as well as continuously infused subcutaneous apomorphine for random fluctuations in PD patients. Low-dose apomorphine infusions also may be useful in the peri-operative phase, when PD patients may not be able to swallow oral medication. Finally, levodopa-carbidopa intestinal gel (LCIG) infusions or DBS have shown to be effective non-oral options to treat PD patients adequately, if they are not properly controlled by oral options. [ABSTRACT FROM AUTHOR]

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology. [ABSTRACT FROM AUTHOR]

Background: Patients with Parkinson's disease experience visual symptoms, partially originating from retinal changes. Since 2011, multiple case-control studies using spectral-domain OCT, which allows for studying individual retinal layers, have been published. The aim of this study was to substantiate the occurrence, extent, and location of retinal degeneration in Parkinson's by meta-analysis.Methods: Spectral-domain OCT case-control data were collected by performing a search in PubMed and Embase with terms: "optical coherence tomography" and "parkinson", up to November 5th, 2018. Studies with fewer than 10 patients or controls were excluded. We performed a random effects meta-analysis. Heterogeneity was evaluated with I2 statistics; publication bias with Egger's and Begg's tests.Results: Out of 77 identified studies, 36 were included, totaling 1916 patients and 2006 controls. A significant thinning of the peripapillary retinal nerve fiber layer (d = -0.42; 95% confidence interval -0.54 to -0.29) and the combined ganglion cell and inner plexiform layers (d = -0.40; -0.72, to -0.07) was found. The inner nuclear layer and outer plexiform layer did not show significant changes. Heterogeneity ranged from 3 to 92%; no publication bias was found.Conclusions: Parkinson's patients show significant thinning of the inner retinal layers, resembling changes found in glaucoma and other neurodegenerative diseases like Alzheimer's. Study of different cell layers in-vivo is possible by moving from time-to spectral domain OCT. Retinal degeneration may be affiliated with neurodegenerative pathology overall, and could serve as a biomarker in neurodegenerative disorders. Longitudinal research including clinical correlations is needed to determine usefulness in Parkinson's disease. [ABSTRACT FROM AUTHOR]

The MANAGE-PD tool may help general neurologists in deciding whether a patient with advanced Parkinson's disease should be referred for an advanced therapy. Although the development and clinical validation of MANAGE-PD would appear to serve an important need, we urge the reader to be aware of several methodological concerns. [ABSTRACT FROM AUTHOR]

Background: Visual hallucinations (VH) occur in the clinical course of Parkinson's disease (PD) and are predictive for PD dementia. The genesis of VH is related to impaired bottom-up and/or top-down visual processing which can be linked to cholinergic dysfunction and mono-amine imbalance. The risk of developing VH with oral dopamine agonists seems to increase with advancing disease, while in contrast some clinical studies suggest that apomorphine does not worsen VH, or might even improve VH.Methods: The aim of this study is to review the current evidence of apomorphine and its effects on VH in PD patients.Results: Apomorphine is well-tolerated in PD patients with VH, also in long-term follow-up studies. Apomorphine is also suggested to have the potential to alleviate VH. Some data suggest that the positive effect of apomorphine on VH is related to its piperidine moiety, part of many anti-psychotics. Irrespective this piperidine moiety, apomorphine has a high D1-like receptor affinity, and acts as a serotonin 5-HT2A receptor antagonist, which might explain the potential anti-hallucinogenic properties as well.Conclusion: The anecdotal evidence suggesting that apomorphine has a relatively low proclivity to induce VH in PD may be due to its capacity to reduce serotonergic activity in particular. Therefore apomorphine is still an option to consider in fluctuating PD patients with VH, if they are treated properly with respect to their cholinergic deficits and existing VH. [ABSTRACT FROM AUTHOR]

Introduction: Continuous apomorphine infusion (CAI) is an effective treatment in fluctuating Parkinson's disease (PD). However, long-term efficacy and safety data of CAI are scarce.Methods: We retrospectively reviewed long-term outcomes of CAI on motor and non-motor symptoms in a Dutch cohort of 125 PD patients.Results: Our cohort (age: 65.8 ± 9.8 years, disease duration: 11.9 ± 5.7 years) had a mean daily dose of apomorphine of 66 ± 30 mg, thereby reducing the levodopa-equivalent daily dose (LEDD) by 20%. The mean duration of treatment with apomorphine was 32.3 ± 31.9 months, ranging up to 139 months. Three-quarters of patients discontinued within the first four years. The main reason for discontinuation was a decreasing therapeutic effect. Patients who stopped apomorphine within four years had a lower LEDD reduction at hospital discharge and at last follow-up compared to patients who continued for a longer period. CAI showed good effects on motor fluctuations and dyskinesia, with better outcomes in patients with more pronounced LEDD reduction. CAI could be safely applied in patients with pre-existing visual hallucinations (30%).Conclusion: CAI showed beneficial effects on motor and several non-motor symptoms, whereas the magnitude of LEDD reduction seems to be a positive predictive factor on the duration of CAI. [ABSTRACT FROM AUTHOR]

Introduction: The postural instability gait difficulty motor subtype of patients with Parkinson's disease (PIGD-PD) has been associated with more severe cognitive pathology and a higher risk on dementia compared to the tremor-dominant subtype (TD-PD). Here, we investigated whether the microstructural integrity of the cholinergic projections from the nucleus basalis of Meynert (NBM) was different between these clinical subtypes.Methods: Diffusion-weighted imaging data of 98 newly-diagnosed unmedicated PD patients (44 TD-PD and 54 PIGD-PD subjects) and 10 healthy controls, were analysed using diffusion tensor imaging, focusing on the white matter tracts associated with cholinergic projections from the NBM (NBM-WM) as the tract-of-interest. Quantitative tract-based and voxel-based analyses were performed using FA and MD as the estimates of white matter integrity.Results: Voxel-based analyses indicated significantly lower FA in the frontal part of the medial and lateral NBM-WM tract of both hemispheres of PIGD-PD compared to TD-PD. Relative to healthy control, several clusters with significantly lower FA were observed in the frontolateral NBM-WM tract of both disease groups. Furthermore, significant correlations between the severity of the axial and gait impairment and NBM-WM FA and MD were found, which were partially mediated by NBM-WM state on subjects' attentional performance.Conclusions: The PIGD-PD subtype shows a loss of microstructural integrity of the NBM-WM tract, which suggests that a loss of cholinergic projections in this PD subtype already presents in de novo PD patients. [ABSTRACT FROM AUTHOR]

Introduction: Although continuous subcutaneous apomorphine infusion (CSAI) is an effective therapy for Parkinson's disease (PD) with motor fluctuations, data from Asian cohorts is limited. The therapy is often discontinued due to the complexity of its delivery.Methods: Fifty-one PD patients undergoing CSAI as an add-on therapy were enrolled in the Thai Apomorphine Registry, an electronic database that recorded clinical characteristics and parameters during the 14-consecutive-day titration and long-term follow-up. Factors at the time of titration were documented in order to identify predictors of long-term discontinuation.Results: Following initiation, PD patients were administered a mean CSAI dose of 5.89 mg/h (SD 1.36) over a mean time of 12.28 h (SD 1.90) each day. The mean follow-up period was 626.2 days (SD 619.17). Significant reductions in UPDRS-I, II, III, and IV scores, total NMSQ score, PDQ-8 score, daily off and dyskinesia hours, Timed Up and Go test, walking step test, levodopa-equivalent daily dose, number of times a day the levodopa was taken versus pre-CSAI values were observed (p < 0.05, each). Thirty-five (68.6%) patients discontinued during the follow-up period. Relative risks of variables recorded at the time of titration that determined discontinuation of CSAI therapy were an absence of full-time caregivers, achieving a daily off hours reduction <3.5 h, and NMSQ scores at the time of CSAI titration ≥9.5 points.Conclusion: Identifying factors that predict discontinuation of CSAI at the time of its initiation may help physicians to better understand the patient's drug response and how to manage them long-term. [ABSTRACT FROM AUTHOR]

Short-latency afferent inhibition (SAI) is a relatively cheap and non-invasive method that has been proposed as a cholinergic marker in Parkinson's disease (PD). We aim to verify the clinical feasibility of SAI as a cholinergic marker in PD using positron emission tomography (PET) with the tracer (2R,3R)-5-(2-[18F]fluoroethoxy)benzovesamicol ([18F]FEOBV) as a reference. We examined relations between SAI and [18F]FEOBV PET using linear regression analysis, with the primary motor cortex (M1) as primary region of interest. Additionally, we examined relations of both measures with clinical features. 30 PD patients with varying degrees of cognitive dysfunction and 10 healthy controls (HC) were included in the analysis. SAI was not related to tracer uptake in M1 in the PD group (p =.291) or the HC group (p =.206). We could not replicate the previously published relations between SAI and cholinergic symptoms, such as cognition, psychotic experiences and olfactory function. SAI was not related to [18F]FEOBV imaging parameters, nor to clinical measures of cholinergic dysfunction. Therefore, SAI may not be feasible as a clinically applied cholinergic marker in PD. • Short-latency afferent inhibition was not related to cortical cholinergic tracer uptake in Parkinson's disease. • We could not replicate published relations between short-latency afferent inhibition and cholinergic symptoms. • Short-latency afferent inhibition may not be a clinically feasible marker for central cholinergic activity. [ABSTRACT FROM AUTHOR]

Introduction: The randomized, double-blind phase (DBP) of the TOLEDO study confirmed the efficacy of apomorphine infusion (APO) in reducing OFF time in PD patients with persistent motor fluctuations despite optimized oral/transdermal therapy. Here we report safety and efficacy results including the 52-week open-label phase (OLP).Methods: All patients completing the 12-week DBP (including those switching early to open-label treatment) were offered OLP entry. The primary objective was the evaluation of long-term safety of APO.Results: Eighty-four patients entered the OLP (40 previously on APO, 44 on placebo) and 59 patients (70.2%) completed the study. The safety profile of APO was consistent with experience from extensive clinical use. Common treatment-related adverse events (AEs) were mild or moderate infusion site nodules, somnolence and nausea. Fourteen (16.7%) patients discontinued the OLP due to AEs, those involving >1 patient were infusion site reactions (n = 4) and fatigue (n = 2); hemolytic anemia occurred in one case. Reduction in daily OFF time and improvement in ON time without troublesome dyskinesia were sustained for up to 64 weeks. Pooled data for week 64 (n = 55) showed a mean (SD) change from DBP baseline in daily OFF time of -3.66 (2.72) hours and in ON time without troublesome dyskinesia of 3.31 (3.12) hours. Mean (±SD) daily levodopa-equivalent dose decreased from DBP baseline to week 64 by 543 mg (±674) and levodopa dose by 273 mg (±515).Conclusions: The safety and efficacy of APO infusion were demonstrated with long-term use for persistent motor fluctuations, allowing substantial reductions in oral PD medication. [ABSTRACT FROM AUTHOR]

There is some evidence to suggest an association between ambient air pollution and development of Parkinson's disease (PD). However, the small number of studies published to date has reported inconsistent findings. To assess the association between long-term exposure to ambient air pollution constituents and the development of PD. Air pollution exposures (particulate matter with aerodynamic diameter <10 μm [PM 10 ] , <2.5 μm [PM 2.5 ], between 2.5 μm and 10 μm [PM coarse ], black carbon, and nitrogen oxides [NO 2 and NO x ]) were predicted based on land-use regression models developed within the "European Study for Air Pollution Effects" (ESCAPE) study, for a Dutch PD case-control study. A total of 1290 subjects (436 cases and 854 controls). were included and 16 years of exposure were estimated (average participant starting age: 53). Exposures were categorized and conditional logistic regression models were applied to evaluate the association between ambient air pollution and PD. Overall, no significant, positive relationship between ambient air pollutants and PD was observed. The odds ratio (OR) for PD associated with an increase from the first quartile of NO 2 (<22.8 μg/m3) and the fourth (>30.4 μg/m3) was 0.87 (95% CI: 0.54, 1.41). For PM 2.5 where the contrast in exposure was more limited, the OR associated with an increase from the first quartile PM 2.5 (<21.2 μg/m3) to the fourth (>22.3 μg/m3) was 0.50 (95% CI: 0.24, 1.01). In a subset of the population with long-term residential stability (n = 632), an increased risk of PD was observed (e.g. OR for Q4 vs Q1 NO 2 :1.37, 95% CI: 0.71, 2.67). We found no clear association between 16 years of residential exposure to ambient air pollution and the development of PD in The Netherlands. • The role of air pollution in Parkinson's disease (PD) is poorly understood. • We examined 16 years of air pollution and PD in a case-control study of 1290 people. • No positive relationship between air pollution in the 16 years and PD was observed. [ABSTRACT FROM AUTHOR]

Background: Subcutaneous apomorphine infusion is a clinically established therapy for patients with Parkinson's disease with motor fluctuations not optimally controlled by oral medication. Open-label studies have shown that apomorphine infusion is effective in reducing off time (periods when antiparkinsonian drugs have no effect), dyskinesias, and levodopa dose, but confirmatory evidence from double-blind, controlled studies is lacking. We aimed to investigate the efficacy and safety of apomorphine infusion compared with placebo in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal treatment.Methods: In this randomised, placebo-controlled, double-blind, multicentre trial, we enrolled patients at 23 European hospitals who had been diagnosed with Parkinson's disease more than 3 years previously and had motor fluctuations not adequately controlled by medical treatment. Patients were randomly assigned (1:1) with a computer-generated randomisation code, stratified by site, to receive 3-8 mg/h apomorphine or placebo saline infusion during waking hours (16 h a day [range 14-18 was acceptable]) for 12 weeks. The flow rate of the study drug and other oral medications could be adjusted during the first 4 weeks on the basis of individual efficacy and tolerability, after which patients entered an 8-week maintenance period. The primary endpoint was the absolute change in daily off time based on patient's diaries, and was assessed in the full analysis set, which was defined as all patients who received at least one dose of allocated study drug and had efficacy data available at any timepoint post-baseline. Safety was assessed in all patients who received at least one dose of apomorphine or placebo. All study participants and investigators were masked to treatment assignment. Both the 12-week double-blind phase and the 52-week open-label phase of this study are now complete; this paper reports results for the double-blind phase only. This study is registered with ClinicalTrials.gov (NCT02006121).Findings: Between March 3, 2014, and March 1, 2016, 128 patients were screened for eligibility and 107 were randomly assigned, of whom 106 were included in the full analysis set (n=53 in both groups). Apomorphine infusion (mean final dose 4·68 mg/h [SD 1·50]) significantly reduced off time compared with placebo (-2·47 h per day [SD 3·70] in the apomorphine group vs -0·58 h per day [2·80] in the placebo group; difference -1·89 h per day, 95% CI -3·16 to -0·62; p=0·0025). Apomorphine was well tolerated without any unexpected safety signals. Six patients in the apomorphine group withdrew from the study because of treatment-related adverse events.Interpretation: Apomorphine infusion results in a clinically meaningful reduction in off time in patients with Parkinson's disease with persistent motor fluctuations despite optimised oral or transdermal therapy.Funding: Britannia Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) is a new potential treatment for Parkinson's Disease dementia (PDD) and other types of dementia. To get a better understanding of this structure, its local neurophysiological properties and cortical connectivity patterns were studied.Methods: We simultaneously recorded DBS local field potentials (LFPs) and electroencephalography (EEG) in two patients with PDD. Both patients had DBS electrodes in the internal globus pallidus (GPi) with one or more distal contacts close to or inside the NBM. Measurements were obtained during routine battery replacement. The distance of DBS contacts to the NBM were calculated using CT-MRI fusion.Results: Delta (1-4 Hz) oscillations were more prominently present in the NBM region than in its vicinity, whereas temporal coherence in the theta (4-8 Hz) range was less outspoken.Conclusion: These neurophysiological characteristics, if also proven in larger cohorts, might help to map the NBM more precisely during electrode implantation. [ABSTRACT FROM AUTHOR]

The success of levodopa and other classes of drugs have meant that most people with Parkinson's disease enjoy a good quality of life for many years. However, despite the availability of several drugs and formulations that can be used as monotherapy and in combination, there are a number of disease features that the current therapies are unable to address. The disease continues to progress despite treatment, patients suffer from a myriad of motor and non-motor symptoms, and a neuroprotective therapy is urgently required. To move forward with medical and surgical management, it is important to consider new insights that recent research offers and in this review we examine how a better understanding of the disease pathology and progression might improve and enrich our daily clinical practice. It is also timely to consider the service provision changes that will increasingly be needed to effectively manage the needs of the aging population. [ABSTRACT FROM AUTHOR]

Background Exposure to pesticides has been linked to Parkinson's disease (PD), although associations between specific pesticides and PD have not been well studied. Residents of rural areas can be exposed through environmental drift and volatilization of agricultural pesticides. Objectives Our aim was to investigate the association between lifetime environmental exposure to individual pesticides and the risk of PD, in a national case-control study. Methods Environmental exposure to pesticides was estimated using a spatio-temporal model, based on agricultural crops around the residential address. Distance up to 100 m from the residence was considered most relevant, considering pesticide drift potential of application methods used in the Netherlands. Exposure estimates were generated for 157 pesticides, used during the study period, of which four (i.e. paraquat, maneb, lindane, benomyl) were considered a priori relevant for PD. Results A total of 352 PD cases and 607 hospital-based controls were included. No significant associations with PD were found for the a priori pesticides. In a hypothesis generating analysis, including 153 pesticides, increased risk of PD was found for 21 pesticides, mainly used on cereals and potatoes. Results were suggestive for an association between bulb cultivation and PD. Conclusions For paraquat, risk estimates for the highest cumulative exposure tertile were in line with previously reported elevated risks. Increased risk of PD was observed for exposure to (a cluster of) pesticides used on rotating crops. High correlations limited our ability to identify individual pesticides responsible for this association. This study provides some evidence for an association between environmental exposure to specific pesticides and the risk of PD, and generates new leads for further epidemiological and mechanistic research. [ABSTRACT FROM AUTHOR]

Timely referral of Parkinson's disease (PD) patients to specialized centers for treatment with device-aided therapies (DAT) is suboptimal. To develop a screening tool for timely referral for DAT in PD and to compare the tool with the published 5-2-1 criteria. A cross-sectional, observational study was performed in 8 hospitals in the catchment area of a specialized movement disorder center in the Northern part of the Netherlands. The target population comprised PD patients not yet on DAT visiting the outpatient clinic of participating hospitals. The primary outcome was apparent eligibility for referral for DAT based on consensus by a panel of 5 experts in the field of DAT. Multivariable logistic regression modelling was used to develop a screening tool for eligibility for referral for DAT. Potential predictors were patient and disease characteristics as observed by attending neurologists. In total, 259 consecutive PD patients were included, of whom 17 were deemed eligible for referral for DAT (point prevalence: 6.6%). Presence of response fluctuations and troublesome dyskinesias were the strongest independent predictors of being considered eligible. Both variables were included in the final model, as well as levodopa equivalent daily dose. Decision curve analysis revealed the new model outperforms the 5-2-1 criteria. A simple chart was constructed to provide guidance for referral. Discrimination of this simplified scoring system proved excellent (AUC after bootstrapping: 0.97). Awaiting external validation, the developed screening tool already appears promising for timely referral and subsequent treatment with DAT in patients with PD. • The estimated prevalence of eligibility for referral for DAT is relatively low (6.6%). • Patient and treatment characteristics are predictive of eligibility for referral. • A new screening tool was composed encompassing three patient factors. • The new tool can accurately screen for eligibility for referral for DAT. • The tool outperforms other tools by having a high positive-predictive value. [ABSTRACT FROM AUTHOR]

Objective Functional movement disorders (FMDs) fall within the broader category called functional neurological symptom disorder (FNSD). New DSM-5 criteria for FNSD no longer require the presence of a ‘psychological conflict’ suggesting that some patients with FMD may not have obvious psychological comorbidity. We studied patients with FMD in comparison to patients with a neurological movement disorder (MD) and healthy controls (HC) to identify whether there is a subgroup of patients with FMD who have normal psychological test scores. Methods We assessed self-rated measures of depression/anxiety (SCL-90), dissociation and personality disorder (PDQ-4) in patients attending neurological clinics and healthy controls. The proportion of patients scoring within normal ranges was determined, and the levels of somatic and psychological symptoms were compared between the three groups. Results Among the FMD group, 39% (20/51) scored within the normal range for all measures compared to 38% (13/34) of MD subjects and 89% (47/53) of healthy controls. There were no differences in overall scores in the SCL-90 and PDQ-4 between FMD and MD patients. FMD patients also did not differ from controls on a self-rated measure of personality pathology. Conclusion Our data show that a substantial proportion of patients with FMD score within the normal range in psychological questionnaires, lending some support to the new DSM-5 criteria. [ABSTRACT FROM AUTHOR]

Objectives The aim of this study was to investigate the potential association between occupational exposure to solvents, metals and/or welding fumes and risk of developing Parkinson's disease (PD). Methods Data of a hospital based case-control study including 444 PD patients and 876 age and sex matched controls was used. Occupational histories and lifestyle information of cases and controls were collected in a structured telephone interview. Exposures to aromatic solvents, chlorinated solvents and metals were estimated by linking the ALOHA+ job-exposure matrix to the occupational histories. Exposure to welding fumes was estimated using self-reported information on welding activities. Results No statistically significant associations with any of the studied metal and solvent exposures were found. However, for self-reported welding activities we observed non-statistically significant reduced risk estimates (third tertile cumulative exposure: OR = 0.51 (95% CI: 0.21–1.24)). Conclusions The results of our study did not provide support for an increased chance on developing PD after occupational exposure to aromatic solvents, chlorinated solvents or exposure to metals. The results showed reduced risk estimates for welding, which is in line with previous research, but no clear explanation for these findings is available. [ABSTRACT FROM AUTHOR]

Visual hallucinations (VH) are common in Parkinson''s Disease (PD). Both deficits of perception and attention seem to play a role in the pathogenesis of VH in PD. However, the possible coexistence of impairments in attention and visual perception in PD with VH is not known. This study investigated both attention and visual perception in non-demented PD patients with VH, compared to PD patients without VH and healthy controls. Fourteen participants were included in each group. All patients were assessed with sustained visual attention and object and space perception tests. Only PD patients with VH showed impairments on object and space perception. In addition, PD patients with and without VH showed impairments on sustained visual attention, being more severely affected in PD patients with VH. Only in PD patients with VH sustained visual attention was associated with a decreased object and space perception. The results of our study thus suggest that in PD patients with VH an impairment of object and space perception, possibly in association with a decreased sustained visual attention, might play a role in the pathogenesis of VH. [Copyright &y& Elsevier]

Abstract: Objective of the present study was to evaluate the possible pathophysiology and clinical characteristics of dystonia in patients with the 18p deletion syndrome by describing a new case and reviewing the literature. Dystonia in patients with the 18p deletion syndrome seems to present heterogeneously with a variable age of onset and distribution of symptoms. It may be accompanied with white matter lesions on the MRI. Deletion of 2 known dystonia loci on chromosome 18p, DYT7 and DYT15, or the deletion of another dystonia gene just above the centromere of chromosome 18p may be the cause of dystonia in patients with the 18p deletion syndrome. However, dystonia may also be secondary to structural brain changes often seen in patients with the 18p deletion syndrome. [Copyright &y& Elsevier]

Background Deep brain stimulation (DBS) is an established treatment for refractory essential tremor (ET). Initially, the target of choice was the thalamic ventralis intermedius nucleus (VIM). However, the zona incerta (ZI) has been suggested as a superior target. Both targets are considered safe and effective, but a direct comparison between these targets is lacking. Methods We analyzed a single-center cohort of 44 patients with ET treated with DBS between 1998 and 2017, targeting the VIM and/or ZI. Patient-reported outcome on the Washington Heights–Inwood Genetic Study of Essential Tremor rating scale, adverse events, and stimulation-induced side effects were assessed. Results Patient-reported outcome of ZI DBS (−2.2 ± 1.2; 18 patients with 28 electrodes) was superior to VIM DBS (−1.2 ± 1.4; 10 patients with 19 electrodes) ( P < 0.01). There was no difference in adverse events between implantations in VIM (45%) and ZI (46%). Dysarthria stimulation-induced side effects were significantly more often reported after VIM DBS ( P = 0.01), whereas visual stimulation-induced side effects occurred more often after ZI DBS ( P = 0.04). Conclusions In this study, ZI DBS was superior to VIM DBS in terms of patient-reported effectiveness. There was a comparable number of complications between both targets. This finding further supports ZI over VIM as the principal DBS target in essential tremor. [ABSTRACT FROM AUTHOR]

Optimal care of Parkinson's disease (PD) patients should involve a multidisciplinary team (MDT) of which a PD nurse specialist (PDNS) is a key member. The role of a PDNS is particularly prominent in the care of advanced PD patients suitable for apomorphine because, in addition to nursing skills, apomorphine treatment requires liaison, training, interaction and coordination with patients, caregivers and other members of the MDT as well as the interface with primary care physicians. The therapeutic success of apomorphine therapy depends not only upon the pharmacologic drug response, but also on how well the patient understands his/her disease and how to handle the therapy. In this respect, a PDNS is a vital member of the MDT who provides education and training, support, and is available for consultation when problems arise. In this article, we review the literature on the contribution of PDNSs in both continuous subcutaneous apomorphine infusion and intermittent subcutaneous apomorphine injection and highlight the various beneficial aspects of PDNS care, supported by scientific evidence when available. Despite a low level of published evidence, there is strong clinical evidence that the impact of PDNSs on the management of apomorphine therapy is vital and indispensable for the success of this treatment. [ABSTRACT FROM AUTHOR]