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Flow chart: screening and examination process. Flow chart summarizing the number of cases starting with the list of 10 000 addresses from the registration office and ending with the number of completed baseline examinations
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Parkinson's disease is increasingly viewed as a complex disorder including a range of typical non-motor symptoms in addition to the cardinal motor signs. This cohort was set up in 2010 to investigate the specificity of non-motor symptoms for Parkinson's disease. For this, we included several control groups with decreasing contrast from Parkinson's...
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Citations
... We analyzed data from the first two visits of a prospective, population-based cohort to study non-motor symptoms in parkinsonism (EPIPARK) 23 . We recruited non-PD participants via a mailed survey sent to 10,000 inhabitants of Lübeck, Germany, aged 50-79 years. ...
Depressive symptoms in Parkinson’s disease (PD) are multifactorial and are partly linked to the underlying dopaminergic deficit.
However, at least a subset of PD patients may exhibit an unspecific depressive reaction to chronic illness. Here, we compared the
prevalence and severity of depressive symptoms in PD patients and disease controls (DC). PD patients reported depressive
symptoms at similar frequencies as DC but were on antidepressants, especially Mirtazapine, more frequently. Still, in both groups, a
high proportion of patients with clinically significant depressive symptoms was not receiving medication. Diagnosis and treatment
of depressive symptoms both in PD and DC should be improved.
... Patient recruitment for the Fox Insight Study has been previously described [21]. Data from a separate replication cohort of German iPD patients (EPIPARK) were used to test novel associations [22]. In the EPIPARK cohort, PD patients had a mean AAE of 67.7 ± 10.3 SD years (range 30.0-90.0 years) and a mean AAO of 54.8 ± 13.2 SD years (range 13.0-81.0 ...
... These results were additionally investigated in a multivariate linear regression model to predict AAO and revealed an association with aspirin intake when examined dichotomous as well as with aspirin intake duration, which was further validated after including more covariates and potential comorbidities. We further replicated our findings concerning aspirin in a separate German iPD cohort (EPIPARK) [22]. The effect on PD AAO was not extended to other NSAIDs in the Fox Insight cohort. ...
Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene–environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann–Whitney U test. Non-parametric Spearman’s correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. We found that smoking ( p < 0.0001), coffee drinking ( p < 0.0001) and aspirin intake ( p < 0.0001) show an exploratory association with AAO in PD, that was further supported by multivariate regression models. The association of aspirin with PD AAO was replicated in another cohort (EPIPARK) ( n = 237 patients with PD).
... The samples of two PD patient and control cohorts (Kiel PD, Luebeck PD) were recruited locally in Schleswig-Holstein, the northernmost federal state of Germany. EPIPARK is an additional prospective and longitudinal observational singlecenter study from Luebeck, focused upon the non-motor symptoms of PD patients [13]. DeNoPa is a prospective and longitudinal observational single-center study from Kassel in central Germany, aimed specifically at improving early diagnosis and prognosis of PD. ...
Idiopathic Parkinson’s disease (PD) is a complex multifactorial disorder caused by the interplay of both genetic and non-genetic risk factors. Polygenic risk scores (PRSs) are one way to aggregate the effects of a large number of genetic variants upon the risk for a disease like PD in a single quantity. However, reassessment of the performance of a given PRS in independent data sets is a precondition for establishing the PRS as a valid tool to this end. We studied a previously proposed PRS for PD in a separate genetic data set, comprising 1914 PD cases and 4464 controls, and were able to replicate its ability to differentiate between cases and controls. We also assessed theoretically the prognostic value of the PD-PRS, i.e., its ability to predict the development of PD in later life for healthy individuals. As it turned out, the PD-PRS alone can be expected to perform poorly in this regard. Therefore, we conclude that the PD-PRS could serve as an important research tool, but that meaningful PRS-based prognosis of PD at an individual level is not feasible.
... Patient recruitment for the Fox Insight Study has been previously described [25]. Data from a separate replication cohort of German iPD patients (EPIPARK) was used to test novel associations [26]. In the EPIPARK cohort, PD patients had a mean AAE of 67.7 10.3 SD years (range: 30.0-90.0 years) and a mean AAO of 54.8 13.2 SD years (range: 13.0-81.0 ...
... We found an association between the general intake of aspirin, intake duration and number of pills per week with later AAO. We further replicated our findings concerning aspirin in a separate German iPD cohort (EPIPARK) [26]. However, in a linear regression model to predict AAO, aspirin diminished as independent predictor, raising the question that aspirin may possibly be confounded. ...
Parkinson's disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene-environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) and clinical severity in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann-Whitney U test. Non-parametric Spearman correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. Reported p-values remain descriptive because they are not corrected for multiple testing and results are exploratory. We found that smoking (r=0.08, p<0.0001), coffee drinking (r=0.69, p<0.0001) and aspirin intake (r=0.23, p<0.0001) show an exploratory association with AAO in iPD. However, the effect of aspirin diminished as an independent predictor after including comorbidities (heart diseases and arthritis). Smoking was associated with higher (more severe) motor scores, while coffee drinking was linked to lower (less severe) motor scores (p<0.05). In addition, smokers reported anxiety, depression and other non-motor symptoms such as unexplained pains and problems remembering (p<0.05). The association of aspirin with PD AAO was replicated in another cohort (EPIPARK) (n=237 patients with PD), although again the effect diminished after including age in the regression model. Future longitudinal studies are warranted to investigate the clinical severity over time.
... Forty-seven patients with PD and 53 age-and sex-matched healthy controls (HCs) were enrolled after written informed consent was obtained. We enrolled study participants from the EPIPARK cohort, 29 our Movement Disorders outpatient clinics, and our PD medical rehabilitation ward. We confirmed the diagnosis of clinically established PD following the Movement Disorders Society Clinical Diagnostic Criteria 30 including the presence of at least 2 supportive criteria (e.g., clear and dramatic beneficial response to dopaminergic therapy), the absence of absolute exclusion criteria (e.g., downward vertical supranuclear gaze palsy), and the absence of any red flags (e.g., severe autonomic failure within the first 5 years of the disease course). ...
Objective
To investigate the contribution of substantia nigra (SN) and locus coeruleus (LC) pathology to clinical signs and symptoms in Parkinson’s disease (PD) by applying neuromelanin-weighted imaging.
Methods
Forty-seven patients with PD and 53 matched controls underwent motor assessment, a neuropsychological test battery and neuromelanin-weighted MRI. Patients with PD have been enrolled after fulfilling the criteria for ‘clinically established PD’ as defined by the Movement Disorders Society Clinical Diagnostic Criteria. Two independent raters identified SN and LC and calculated the contrast-to-noise ratio (CNR).
Results
The intra-rater reliability demonstrated a good reliability between raters with an intraclass correlation coefficient of .88 (p<.001) and an inter-rater reliability of .80 (p<.001). Both, SN and LC CNRs were lower in patients with PD (p≤.001) compared to controls. The CNR of SN but not of LC was strongly correlated with disease duration (p≤.001). Neuromelanin pathology of the pars compacta-containing dorso-lateral SN correlated with MDS-UPDRS I, II and III but not cognitive functions. In contrast, neuromelanin pathology of LC was associated with cognitive functions in all tested domains but not with motor impairment or activities of daily living. No such associations were present in controls.
Conclusions
Neuromelanin imaging of the SN and LC is well-suited to map neurodegeneration in PD. Neuromelanin pathology of the SN correlates with motor dysfunction whereas LC pathology is related to cognitive impairment. Neuromelanin-weighted imaging of the LC could thus serve as an imaging marker of executive and other cognitive dysfunctions in PD.
Classification of Evidence
This study provides Class I evidence that neuromelanin-weighted imaging was associated with the severity of various signs and symptoms in patients with PD.
... Participants. Participants were selected from a large epidemiological, longitudinal study on nonmotor symptoms in PD, the EPIPARK study (Epidemiology of nonmotor symptoms in Parkinson's disease: frequency, characteristics, specificity, and course) 20 . All participants were selected according to the following exclusion criteria: age < 18 years, a high-grade visual loss, known macular disease or glaucoma, history of intraocular surgery (all participants), evidence for atypical or secondary parkinsonism, concurrent neurodegenerative diseases, known structural brain lesions, Hoehn and Yahr stage 5 (PD patients), and any neurological disease (controls). ...
To evaluate the significance of motion artifacts in optical coherence tomography angiography (OCTA) images of patients with Parkinson’s disease (PD) and healthy controls. In this prospective, cross-sectional study subjects with medicated PD (ON) and healthy, age- and gender-matched volunteers were recruited. Participants underwent specific ophthalmological examinations, including OCTA. Angiograms of the superficial retinal capillary plexus were evaluated for the type and frequency of artifacts using a validated motion artifact score (MAS). A total of 30 PD patients (60 eyes), average disease duration of 9.61 ± 5.55 years, and 30 matched, healthy controls (60 eyes) were recruited. Twenty percent of all eyes had an eye disease, unknown to the participant, with a significant impact on OCTA results. After cleansing the dataset by excluding subjects with confounding ocular comorbidities 42 eyes of 28 PD patients and 53 eyes of 29 healthy controls were further evaluated. Overall MAS and all five subtypes of motion artifacts were comparable without significant differences between groups. OCTA can be used in treated PD patients (ON) without a significant increase in motion artifacts. Nevertheless, special attention should be paid to image quality during the acquisition of OCTA data, for which an experienced OCTA operator is useful.
... In the context of the present cross-sectional study, participants were recruited at tertiary movement disorder referral centres in Lü beck, Tü bingen (Germany), and Pavia/Rome (Italy). Samples from the University of Lü beck were collected within the SysMedPD study, the EPIPARK cohort (Kasten et al., 2012), and the Transregional Collaborative Research Center 134. All participants gave written informed consent, and the local ethics committees approved the study. ...
There is increasing evidence for a role of inflammation in Parkinson's disease. Recent research in murine models suggests that parkin and PINK1 deficiency leads to impaired mitophagy, which causes the release of mitochondrial DNA (mtDNA), thereby triggering inflammation. Specifically, the CGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon genes) pathway mitigates activation of the innate immune system, quantifiable as increased interleukin-6 (IL6) levels. However, the role of IL6 and circulating cell-free mtDNA in unaffected and affected individuals harbouring mutations in PRKN/PINK1 and idiopathic Parkinson's disease patients remain elusive. We investigated IL6, C-reactive protein, and circulating cell-free mtDNA in serum of 245 participants in two cohorts from tertiary movement disorder centres. We performed a hypothesis-driven rank-based statistical approach adjusting for multiple testing. We detected (i) elevated IL6 levels in patients with biallelic PRKN/PINK1 mutations compared to healthy control subjects in a German cohort, supporting the concept of a role for inflammation in PRKN/PINK1-linked Parkinson's disease. In addition, the comparison of patients with biallelic and heterozygous mutations in PRKN/PINK1 suggests a gene dosage effect. The differences in IL6 levels were validated in a second independent Italian cohort; (ii) a correlation between IL6 levels and disease duration in carriers of PRKN/PINK1 mutations, while no such association was observed for idiopathic Parkinson's disease patients. These results highlight the potential of IL6 as progression marker in Parkinson's disease due to PRKN/PINK1 mutations; (iii) increased circulating cell-free mtDNA serum levels in both patients with biallelic or with heterozygous PRKN/PINK1 mutations compared to idiopathic Parkinson's disease, which is in line with previous findings in murine models. By contrast, circulating cell-free mtDNA concentrations in unaffected heterozygous carriers of PRKN/PINK1 mutations were comparable to control levels; and (iv) that circulating cell-free mtDNA levels have good predictive potential to discriminate between idiopathic Parkinson's disease and Parkinson's disease linked to heterozygous PRKN/PINK1 mutations, providing functional evidence for a role of heterozygous mutations in PRKN or PINK1 as Parkinson's disease risk factor. Taken together, our study further implicates inflammation due to impaired mitophagy and subsequent mtDNA release in the pathogenesis of PRKN/PINK1-linked Parkinson's disease. In individuals carrying mutations in PRKN/PINK1, IL6 and circulating cell-free mtDNA levels may serve as markers of Parkinson's disease state and progression, respectively. Finally, our study suggests that targeting the immune system with anti-inflammatory medication holds the potential to influence the disease course of Parkinson's disease, at least in this subset of patients.
... Today, we still do not know what relationship exists between the progression of motor symptoms and non-motor symptoms in the long term. Different longitudinal studies with prospective followup of patients have provided an understanding of the development of motor complications and their relationship with the type of symptomatic therapy initially used [68][69][70], cognitive impairment and/or dementia [71][72][73][74], the course following a given intervention (e.g., deep brain stimulation) [75,76] or other data on the course of the disease [77][78][79][80][81][82][83][84][85][86]. There are other promising studies currently underway with a fundamental objective of identifying a disease progression biomarker [87]. ...
Background and objective:
In Parkinson's disease (PD), the course of the disorder is highly variable between patients. Well-designed, prospective studies for identifying PD progression biomarkers are necessary. Our aim is to show the results of baseline evaluations of an ongoing global PD Project, COPPADIS-2015 (COhort of Patient's with PArkinson's DIsease in Spain, 2015).
Methods:
Observational, descriptive, nationwide study (Spain). The recruitment period ended in October 2017. Baseline evaluation included more than 15 validated scales and complementary studies in a subgroup of participants.
Results:
1,174 subjects from 35 centers were considered valid for baseline analysis: 694 patients (62.6 ± 8.9 years old, 60.3% males), 273 caregivers (58.5 ± 11.9 years old, 31.8% males), and 207 controls (61 ± 8.3 years old, 49.5% males). The mean disease duration was 5.5 ± 4.4 years. Hoehn&Yahr stage was 1 or 2 in 90.7% of the patients while 33.9% and 18.1% of them presented motor fluctuations and dyskinesias, respectively. Mean Non-Motor Symptoms Scale (NMSS) total score was 45.4 ± 38.1, and 30.4% of the patients presented cognitive impairment, 16.1% major depression, 12.7% impulse control disorder and 7.2% compulsive behaviour, 57.2% pain, and 13.2% falls. Compared to the control group, PD patients presented a significantly higher burden of non-motor symptoms and a worse quality of life. More than 300 subjects conducted complementary studies (serum biomarkers, genetic and neuroimaging).
Conclusions:
PD is a complex disorder and different NMS are frequently present and are more prevalent than in controls. In real clinical practice is important to ask for them. This article is protected by copyright. All rights reserved.
... The patient has a revised diagnosis of Progressive Supranuclear Palsy (PSP). Patients with idiopathic Parkinson's who met the UK Parkinson's Disease Society Brain Bank (UKPDBB) criteria for the diagnosis of probable idiopathic PD (Hughes et al., 1992) on examination by a neurologist were recruited from ongoing cohort studies at the University of Oxford (UK) and the University of Lubeck (Germany) (Kasten et al., 2013). Patients with secondary parkinsonism due to head trauma or medication use, or features of atypical parkinsonism syndromes, were excluded (Szewczyk-Krolikowski et al., 2014). ...
... The patient has a revised diagnosis of Progressive Supranuclear Palsy (PSP). Patients with idiopathic Parkinson's who met the UK Parkinson's Disease Society Brain Bank (UKPDBB) criteria for the diagnosis of probable idiopathic PD (Hughes et al., 1992) on examination by a neurologist were recruited from ongoing cohort studies at the University of Oxford (UK) and the University of Lubeck (Germany) (Kasten et al., 2013). Patients with secondary parkinsonism due to head trauma or medication use, or features of atypical parkinsonism syndromes, were excluded (Szewczyk-Krolikowski et al., 2014). ...
Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson's disease (PD), but neuronal cultures are confounded by asynchronous and heterogeneous appearance of disease phenotypes in vitro. Using high-resolution, single-cell transcriptomic analyses of iPSC-derived dopamine neurons carrying the GBA-N370S PD risk variant, we identified a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Pseudotime analysis of genes differentially expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with HDAC4-modulating compounds upregulated genes early in the DE axis and corrected PD-related cellular phenotypes. Our study demonstrates how single-cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.
