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Objective: We tested the hypothesis that there are 2 distinct phenotypes of Parkinson tremor, based on interindividual differences in the response of resting tremor to dopaminergic medication. We also investigated whether this pattern is specific to tremor by comparing interindividual differences in the dopamine response of tremor to that of bradykinesia., Methods: In this exploratory study, we performed a levodopa challenge in 76 tremulous patients with Parkinson tremor. Clinical scores (Movement Disorders Society-sponsored version of the Unified Parkinson's Disease Rating Scale part III) were collected "off" and "on" a standardized dopaminergic challenge (200/50 mg dispersible levodopa-benserazide). In both sessions, resting tremor intensity was quantified using accelerometry, both during rest and during cognitive coactivation. Bradykinesia was quantified using a speeded keyboard test. We calculated the distribution of dopamine-responsiveness for resting tremor and bradykinesia. In 41 patients, a double-blinded, placebo-controlled dopaminergic challenge was repeated after approximately 6 months., Results: The dopamine response of resting tremor, but not bradykinesia, significantly departed from a normal distribution. A cluster analysis on 3 clinical and electrophysiologic markers of tremor dopamine-responsiveness revealed 3 clusters: dopamine-responsive, intermediate, and dopamine-resistant tremor. A repeated levodopa challenge after 6 months confirmed this classification. Patients with dopamine-responsive tremor had greater disease severity and tended to have a higher prevalence of dyskinesia., Conclusion: Parkinson resting tremor can be divided into 3 partially overlapping phenotypes, based on the dopamine response. These tremor phenotypes may be associated with different underlying pathophysiologic mechanisms, requiring a different therapeutic approach., (© 2020 American Academy of Neurology.)

Background: Parkinson's Disease (PD) is a heterogeneous, progressive neurodegenerative disorder which is characterized by a variety of motor and non-motor symptoms. To date, no disease modifying treatment for PD exists. Here, the study protocol of the Dutch Parkinson Cohort (DUPARC) is described. DUPARC is a longitudinal cohort study aimed at deeply phenotyping de novo PD patients who are treatment-naïve at baseline, to discover and validate biomarkers for PD progression, subtypes and pathophysiology., Methods/design: DUPARC is a prospective cohort study in which 150 de novo PD subjects will be recruited through a collaborative network of PD treating neurologists in the northern part of the Netherlands (Parkinson Platform Northern Netherlands, PPNN). Participants will receive follow-up assessments after 1 year and 3 years, with the intention of an extended follow-up with 3 year intervals. Subjects are extensively characterized to primarily assess objectives within three major domains of PD: cognition, gastrointestinal function and vision. This includes brain magnetic resonance imaging (MRI); brain cholinergic PET-imaging with fluoroethoxybenzovesamicol (FEOBV-PET); brain dopaminergic PET-imaging with fluorodopa (FDOPA-PET); detailed neuropsychological assessments, covering all cognitive domains; gut microbiome composition; intestinal wall permeability; optical coherence tomography (OCT); genotyping; motor and non-motor symptoms; overall clinical status and lifestyle factors, including a dietary assessment; storage of blood and feces for additional analyses of inflammation and metabolic parameters. Since the start of the inclusion, at the end of 2017, over 100 PD subjects with a confirmed dopaminergic deficit on FDOPA-PET have been included., Discussion: DUPARC is the first study to combine data within, but not limited to, the non-motor domains of cognition, gastrointestinal function and vision in PD subjects over time. As a de novo PD cohort, with treatment naïve subjects at baseline, DUPARC provides a unique opportunity for biomarker discovery and validation without the possible confounding influences of dopaminergic medication., Trial Registration: NCT04180865; registered retrospectively, November 28th 2019.

Diagnosing dementia with Lewy bodies (DLB) is challenging as symptoms are heterogenous and not specific to the disease. Here we present a clinicopathologic series of false-positive DLB cases. Patients were enrolled retrospectively from the Netherlands Brain Bank when they met the clinical criteria of probable DLB, but with a pathologic diagnosis other than DLB or Parkinson's disease dementia. Twenty-two false-positive cases were selected. Alzheimer disease with or without copathology was the most common (64%) pathologic diagnosis. Other pathologic diagnoses, such as frontotemporal dementia, multiple-system atrophy, Creutzfeldt-Jakob disease, and autoimmune encephalitis, were also encountered. Atypical clinical signs for DLB were present in almost half of the cases and could be a trigger to consider other diagnoses than DLB. Additional diagnostic examinations, feedback of pathologic diagnosis, and the creation of a set of clinical features that are indicative of other conditions, could reduce the amount of false-positive DLB cases.

The clinical diagnosis in patients with parkinsonian disorders can be challenging, and a definite diagnosis requires neuropathological confirmation. The aim of this study was to examine whether a clinical diagnosis of Parkinson's disease (PD) and atypical parkinsonian disorders predict the presence of Lewy pathology (LP) and concomitant neuropathological lesions.We included 293 donors with a history of parkinsonism without dementia at disease onset, collected by the Netherlands Brain Bank (NBB) from 1989 to 2015. We retrospectively categorized donors according the International Parkinson and Movement Disorder Society clinical diagnostic criteria for PD (MDS-PD criteria) as 'not PD', 'probable PD' or 'established PD'. We compared the final clinical diagnosis to presence of neuropathological lesions as defined by BrainNet Europe and National Institute on Aging - Alzheimer's Association guidelines.LP was present in 150 out of 176 donors (85%) with a clinical diagnosis of PD, in 8 out of 101 donors (8%) with atypical parkinsonian disorders and in 4 out of 16 donors (25%) without a definite clinical diagnosis. Independent from age at death, stages of amyloid-β, but not neurofibrillary tau or neuritic plaques, were higher in donors with LP compared to other types of pathology (p = 0.009). The MDS-PD criteria at a certainty level of 'probable PD' predicted presence of LP with a diagnostic accuracy of 89.3%. Among donors with LP, 'established PD' donors showed similar Braak α-synuclein stages and stages of amyloid-β, neurofibrillary tau and neuritic plaques compared to 'not PD' or 'probable PD' donors.In conclusion, both a clinical diagnosis of PD as well as MDS-PD criteria accurately predicted presence of LP in NBB donors. LP was associated with more widespread amyloid-β pathology, suggesting a link between amyloid-β accumulation and LP formation.

Background: Parkinson's disease (PD) is a chronic and neurodegenerative disease associated with a wide variety of symptoms. The risk of complications increases with progression of the disease. These complications have a tremendous impact on the quality of life of people with PD. The aim of this study was to examine health care professionals' experiences of potential barriers and facilitators in providing palliative care for people with PD in the Netherlands., Methods: This was a qualitative descriptive study. The data were collected from 10 individual in-depth interviews and three focus groups (n = 29) with health care professionals. Health care professionals were selected based on a positive answer to the question: "In the past 2 years, did you treat or support a person with PD who subsequently died?" The data were analyzed by thematic text analysis., Results: Health care professionals supported the development of a palliative care system for PD but needed to better understand the essence of palliative care. In daily practice, they struggled to identify persons' needs due to interfering PD-specific symptoms such as cognitive decline and communication deficits. Timely addressing the personal preferences for providing palliative care was identified as an important facilitator. Health care professionals acknowledged being aware of their lack of knowledge and of their little competence in managing complex PD. Findings indicate a perceived lack of care continuity, fragmentation of services, time pressure and information discontinuity., Conclusions: Health care professionals experienced several facilitators and barriers to the provision of palliative care to people with PD. There is a need to improve the knowledge on complex PD and the continuity of information, as well as optimize coordination and deliver care based on a persons' preferences. Additional training can help to become more knowledgeable and confident.

Introduction: The instrumented-Timed-Up-and-Go test (iTUG) provides detailed information about the following movement patterns: sit-to-walk (siwa), straight walking, turning and walk-to-sit (wasi). We were interested in the relative contributions of respective iTUG sub-phases to specific clinical deficits most relevant for daily life in Parkinson's disease (PD). More specifically, we investigated which condition-fast speed (FS) or convenient speed (CS)-differentiates best between mild- to moderate-stage PD patients and controls, which parameters of the iTUG sub-phases are significantly different between PD patients and controls, and how the iTUG parameters associate with cognitive parameters (with particular focus on cognitive flexibility and working memory) and Health-Related-Quality of Life (HRQoL)., Methods: Twenty-eight PD participants (65.1 ± 7.1 years, H&Y stage 1-3, medication OFF state) and 20 controls (66.1 ± 7.5 years) performed an iTUG (DynaPort®, McRoberts BV, The Netherlands) under CS and FS conditions. The PD Questionnaire 39 (PDQ-39) was employed to assess HRQoL. General cognitive and executive functions were assessed using the Montreal Cognitive Assessment and the Trail Making Test., Results: The total iTUG duration and sub-phases durations under FS condition differentiated PD patients slightly better from controls, compared to the CS condition. The following sub-phases were responsible for the observed longer total duration PD patients needed to perform the iTUG: siwa, turn and wasi. None of the iTUG parameters correlated relevantly with general cognitive function. Turning duration and wasi maximum flexion velocity correlated strongest with executive function. Walking back duration correlated strongest with HRQoL., Discussion: This study confirms that mild- to moderate-stage PD patients need more time to perform the iTUG than controls, and adds the following aspects to current literature: FS may be more powerful than CS to delineate subtle movement deficits in mild- to moderate-stage PD patients; correlation levels of intra-individual siwa and wasi parameters may be interesting surrogate markers for the level of automaticity of performed movements; and sub-phases and kinematic parameters of the iTUG may have the potential to reflect executive functioning and HRQoL aspects of PD patients.

Objective: The objective of this study was to compare treatment profiles including both health outcomes and process characteristics in Parkinson disease using best-worst scaling (BWS), time trade-off (TTO), and visual analogue scales (VAS)., Methods: From the model comprising of seven attributes with three levels, six unique profiles were selected representing process-related factors and health outcomes in Parkinson disease. A Web-based survey (N = 613) was conducted in a general population to estimate process-related utilities using profile-based BWS (case 2), multiprofile-based BWS (case 3), TTO, and VAS. The rank order of the six profiles was compared, convergent validity among methods was assessed, and individual analysis focused on the differentiation between pairs of profiles with methods used., Results: The aggregated health-state utilities for the six treatment profiles were highly comparable for all methods and no rank reversals were identified. On the individual level, the convergent validity between all methods was strong; however, respondents differentiated less in the utility of closely related treatment profiles with a VAS or TTO than with BWS. For TTO and VAS, this resulted in nonsignificant differences in mean utilities for closely related treatment profiles., Conclusions: This study suggests that all methods are equally able to measure process-related utility when the aim is to estimate the overall value of treatments. On an individual level, such as in shared decision making, BWS allows for better prioritization of treatment alternatives, especially if they are closely related. The decision-making problem and the need for explicit trade-off between attributes should determine the choice for a method., (Copyright © 2016. Published by Elsevier Inc.)

Objectives: To assess the prevalence of (risk of) undernutrition in Dutch elder Parkinson's disease patients as well as it's risk factors., Design: Observational cross-sectional study., Setting: An outpatient clinic at the department Neurology of Medical Centre Leeuwarden, a large teaching hospital., Participants: 102 outpatients with Parkinson's disease aged 65 years and older were recruited., Measurements: Data regarding various aspects of undernutrition including socio-demographic aspect, disease characterisitics, nutritional status, appetite and overall-physical and psychological functioning were collected., Results: Undernutrition was diagnosed in 2.0% and 20.5% of the patients were categorized as being at risk of undernutrition. Care dependency and appetite were the two risk factors with the highest predictive value for an unfavorable nutritional status., Conclusion: Of Dutch elderly patients with Parkinson's Disease 22.5% had an unfavourable nutritional status. Dependency and appetite were the two risk factors with the highest predictive value fort his outcome. Because undernutrition can be regarded as a geriatric syndrome a comprehensive nutritional assessment should be done followed by nutritional interventions next to interventions focused on the risk factors. Further studies are needed to evaluate these interventions.

Objectives: To determine the prevalence of nonmotor symptoms (NMS) in nursing home (NH) residents with Parkinson's disease (PD) and to establish the association with quality of life., Design: Cross-sectional., Setting: Nursing homes in the southeast of the Netherlands., Participants: Nursing home residents with PD and a Mini-Mental State Examination score of 18 or greater (N = 73; mean age 78.7, disease duration 10 years, mainly Hoehn and Yahr Stages 4 (38%) and 5 (49%)) underwent detailed examination to determine the prevalence of NMS., Measurements: Validated instruments for PD-related NMS were used to examine the NH residents with PD. The overall burden of NMS, and autonomic problems in particular, were measured using the Non-Motor Symptoms Scale (NMSS). Depression, neuropsychiatric symptoms, sleep problems, cognitive dysfunction, and motor impairments were focused on in further detail using established clinimetric tests. Linear regression analysis was used to examine the relationship between these symptoms and quality of life, which was measured using the Parkinson's Disease Questionnaire (PDQ-8)., Results: The NMSS revealed a mean of nearly 13 different NMS per resident. Autonomic problems (constipation, urinary urgency) were particularly prevalent (48-75% of residents). Depressive symptoms were present in 45%. The most prevalent neuropsychiatric symptoms other than depression were irritability and apathy. The most common sleep problems were overall poor nighttime sleep quality, daytime sleepiness, and nocturia. Cognitive problems were highly prevalent, and 77% of the residents met the criteria for PD-related dementia. High scores were also obtained for motor impairments. Mean PDQ-8 score was high, indicating poor quality of life. Poor quality of life was most strongly associated with the prevalence and severity of overall NMS burden (coefficient of determination = 0.45)., Conclusion: Nonmotor symptoms were highly prevalent in NH residents with PD. Quality of life was poor, largely because of NMS. Because many NMS are potentially treatable, diagnosis and treatment of these severely affected individuals deserve more attention., (© 2013, Copyright the Authors Journal compilation © 2013, The American Geriatrics Society.)

Background: A multidisciplinary approach is thought to be the best way to manage the motor and non-motor symptoms of Parkinson's disease, but how such care should be delivered is unknown. To address this gap in knowledge, we assessed the effectiveness of an integrated multidisciplinary approach compared with usual care., Methods: We recruited patients for our non-randomised controlled trial from six community hospitals in the Netherlands (two in regions where the integrated care intervention was available and four in control regions that administered usual care). Eligible patients were those with Parkinson's disease, aged 20-80 years, and without severe cognitive impairment or comorbidity. Patients in the intervention group were offered an individually tailored comprehensive assessment in an expert tertiary referral centre and subsequent referrals to a regional network of allied health professionals specialised in Parkinson's disease. Primary outcomes were activities of daily living (Academic Medical Center linear disability score [ALDS]) and quality of life (Parkinson's disease quality of life questionnaire [PDQL]) measured at 4, 6, and 8 months. Secondary outcomes included motor functioning (unified Parkinson's disease rating scale, part III [UPDRS III], at 4 months), caregiver burden (belastungsfragebogen Parkinson angehörigen-kurzversion [BELA-A-k] at 4 and 8 months), and costs (during whole study period). Primary analysis was by intention to treat and included scores over 4, 6, and 8 months, with correction for baseline score. The trial is registered at Clinicaltrials.gov, number NCT00518791., Findings: We recruited 301 patients (150 patients in the intervention group and 151 in the control group) between August, 2007, and December, 2009, of whom 285 completed follow-up (last follow-up was July, 2010). 101 (67%) patients in the intervention group visited the expert centre; 49 (33%) opted not to visit the expert centre. The average ALDS score from months 4, 6, and 8, with correction for baseline score, was greater in the intervention group than in the control group (difference 1·3 points, 95% CI -2·1 to 2·8; corresponding raw logit score difference 0·1, 95% CI 0·003 to 0·2) as was the average PDQL score (difference 3·0 points, 0·4 to 5·6). Secondary analysis with correction for baseline disease severity showed no differences between groups for ALDS (difference 0·9 points, 95% CI -0·6 to 2·4; corresponding raw logit score difference 0·1, -0·02 to 0·3) or PDQL (difference 1·7 points, -1·2 to 4·6). Secondary outcomes did not differ between groups (UPDRS III score difference 0·6 points, 95% CI -1·4 to 2·6; BELA-A-k score difference 0·8 points, -0·2 to 1·8; cost difference €742, -€489 to €1950)., Interpretation: This integrated care approach offered only small benefits to patients with Parkinson's disease, and these disappeared after correction for baseline disease severity. These results suggest that different approaches are needed to achieve more substantial health benefits., Funding: NutsOhra Foundation, Stichting Parkinson Nederland, National Parkinson Foundation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: It has been suggested that ergoline dopamine agonists can cause ischemic complications. The effect of dopamine agonists in general on the prevalence of ischemic events in patients with Parkinson's disease (PD) has not been studied., Objective: Our aim was to investigate the association between the use of dopamine agonists and hospitalization due to ischemic events in patients with PD., Methods: We performed a nested case-control study using the PHARMO Institute for Drug Outcome Research database. All patients issued at least one prescription for levodopa after the age of 55 years between 1994 and 2006 were initially identified. Cases were patients who were hospitalized for the first time after November 1997 for an ischemic event and were matched to as many as four controls. Exposure to dopamine agonists during the year preceding the index date was identified., Results: The study population consisted of 542 cases and 2,155 controls. The mean effect of dopamine agonist use 1 year prior to the index date on ischemic events requiring hospitalization is shown with 95% probability in the 0.95-1.49 range. Stratified results according to the type of dopamine agonist showed no risk differences between ergoline and nonergoline agonists., Conclusions: This study does not support an association between dopamine agonist use and an increased risk of ischemic events requiring hospitalization.

Objective: To determine clinical heterogeneity in newly diagnosed Parkinson's disease using cluster analysis and to describe the subgroups in terms of impairment, disability, perceived quality of life, and use of dopaminergic therapy., Methods: We conducted a k-means cluster analysis in a prospective hospital based cohort of 133 patients with newly diagnosed Parkinson's disease. Variables selected for the cluster analysis were age of disease onset, age at the moment of examination, rate of disease progression, levodopa responsive PD symptoms and levodopa non-responsive PD symptoms, cognition (mini-mental state examination) and emotional functioning (hospital anxiety depression scale). In addition, the homogeneous subgroups identified were clinically validated using descriptive statistics., Results: Cluster analysis with a two-cluster solution identified a younger and older age group. The three-cluster solution identified an intermediate group with respect to age. In both cluster solutions the older the onset group, the higher the progression rate and the level of motor impairments. The intermediate older onset group in the three cluster solution was characterized by more anxiety and depressive symptoms. Increasing age at disease onset was significantly associated with higher Hoehn and Yahr stages, level of disability and lower perceived quality of life., Conclusions: We hypothesize there are three distinct subgroups in patients with newly diagnosed PD: a younger onset group, an intermediate older onset group with more anxiety and depressive symptoms and an oldest onset group with more motor impairment and higher rate of progression.

Drooling is a well known problem in patients with Parkinson's disease (PD). The aim of this study was to investigate the severity and consequences of drooling in PD. A comprehensive drooling questionnaire was sent to 105 PD outpatients, who had volunteered drooling during a previous questionnaire (n = 216). Among 63 patients who responded and confirmed drooling, 27% experienced severe saliva loss. Social and emotional consequences were reported by 17% to 77% of patients, and significantly more often by those with severe drooling. We conclude that drooling is a frequent, disabling and apparently undertreated symptom of PD. History taking ought to be detailed and specific to understand the full impact of drooling for an individual patient. Therapeutic options should be evaluated more intensively.

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.

Parkinson's disease is a slowly progressive and irreversible disorder of the nervous system. Drooling is listed as a secondary symptom of Parkinson's disease. Its cause is insufficiently clear. In the literature 2 possible causes are described: hypersalivation and swallowing abnormalities. These parameters have not been measured in a single study before. This article presents a review of the literature on the subject and describes the design for a future clinical study. The aim of this clinical study is to gain an insight into the cause and the prevalence of drooling in Parkinson's patients. A group of 50 Parkinson's patients will be compared to a group of 50 controls. The objectives of this comparative study comprise the assessment of salivary flow volumes, swallowing capacity, subjective experiences with drooling and an objective observation of drooling, the drooling quotient. Finally, the possibilities for treatment will be described.

Background: Currently, there is a lot of interest in the flexible framework offered by item banks for measuring patient relevant outcomes. However, there are few item banks, which have been developed to quantify functional status, as expressed by the ability to perform activities of daily life. This paper examines the measurement properties of the Academic Medical Center linear disability score item bank in a mixed population., Methods: This paper uses item response theory to analyse data on 115 of 170 items from a total of 1002 respondents. These were: 551 (55%) residents of supported housing, residential care or nursing homes; 235 (23%) patients with chronic pain; 127 (13%) inpatients on a neurology ward following a stroke; and 89 (9%) patients suffering from Parkinson's disease., Results: Of the 170 items, 115 were judged to be clinically relevant. Of these 115 items, 77 were retained in the item bank following the item response theory analysis. Of the 38 items that were excluded from the item bank, 24 had either been presented to fewer than 200 respondents or had fewer than 10% or more than 90% of responses in the category 'can carry out'. A further 11 items had different measurement properties for younger and older or for male and female respondents. Finally, 3 items were excluded because the item response theory model did not fit the data., Conclusion: The Academic Medical Center linear disability score item bank has promising measurement characteristics for the mixed patient population described in this paper. Further studies will be needed to examine the measurement properties of the item bank in other populations.

Background: Most prognostic studies on Parkinson disease have been hospital based or have applied register-based case-finding methods. Potential under-representation of mild cases may have given biased results., Objective: To evaluate whether Parkinson disease is associated with an increased risk of dementia and death., Design: Population-based cohort study. Parkinson disease and dementia were assessed through in-person examination at baseline (1990-1993) and 2 follow-up visits (1993-1994 and 1997-1999). Computerized linkage to medical and municipality records provided additional information on disease outcomes and mortality., Setting: General population., Participants: A total of 6969 participants, including 99 prevalent and 67 incident cases of Parkinson disease., Main Outcome Measures: Incident dementia and death. Adjusted hazard ratios were calculated through Cox proportional hazards regression analysis., Results: Patients with Parkinson disease had an increased risk of dementia (hazard ratio, 2.8; 95% confidence interval, 1.8-4.4), which was especially pronounced in participants carrying at least 1 apolipoprotein E gene (APOE) epsilon2 allele (13.5; 4.5-40.6). Parkinson disease was associated with an increased mortality risk (1.8; 1.5-2.3). The association consistently diminished when analyses were sequentially restricted to patients with shorter disease duration and after adjustment for the occurrence of dementia., Conclusions: Especially patients with Parkinson disease who carry an APOE epsilon2 allele have an increased risk of developing dementia. Increased mortality risk in Parkinson disease is dependent on disease duration and is only modest in the absence of dementia.

The incidence and some risk factors of Parkinson's disease were investigated in a study performed in The Netherlands. The study was based on a disease register of the Sentinel Stations, which provide a complete ascertainment of new patients with Parkinson's disease in 60 general practices in The Netherlands. The incidence rate of Parkinson's disease in The Netherlands is estimated to be 11/100,000 person-years for men and 12/100,000 person-years for women. Risk factors for Parkinson's disease were investigated in a case-control study in which 86 cases, with the diagnosis of Parkinson's disease confirmed by a neurologist, were compared with 172 reference subjects, matched for age and gender. Cigarette smoking was associated with a lower risk of Parkinson's disease (relative risk 0.6, 95% confidence interval 0.3-1.0). No association was observed between Parkinson's disease and severe head trauma with loss of consciousness, or surgery with total anaesthesia.