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- Zago, E, et al.
(author)
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Early downregulation of hsa-miR-144-3p in serum from drug-naïve Parkinson's disease patients
- 2022
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 1330-
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Journal article (peer-reviewed)abstract
- Advanced age represents one of the major risk factors for Parkinson’s Disease. Recent biomedical studies posit a role for microRNAs, also known to be remodelled during ageing. However, the relationship between microRNA remodelling and ageing in Parkinson’s Disease, has not been fully elucidated. Therefore, the aim of the present study is to unravel the relevance of microRNAs as biomarkers of Parkinson’s Disease within the ageing framework. We employed Next Generation Sequencing to profile serum microRNAs from samples informative for Parkinson’s Disease (recently diagnosed, drug-naïve) and healthy ageing (centenarians) plus healthy controls, age-matched with Parkinson’s Disease patients. Potential microRNA candidates markers, emerging from the combination of differential expression and network analyses, were further validated in an independent cohort including both drug-naïve and advanced Parkinson’s Disease patients, and healthy siblings of Parkinson’s Disease patients at higher genetic risk for developing the disease. While we did not find evidences of microRNAs co-regulated in Parkinson’s Disease and ageing, we report that hsa-miR-144-3p is consistently down-regulated in early Parkinson’s Disease patients. Moreover, interestingly, functional analysis revealed that hsa-miR-144-3p is involved in the regulation of coagulation, a process known to be altered in Parkinson’s Disease. Our results consistently show the down-regulation of hsa-mir144-3p in early Parkinson’s Disease, robustly confirmed across a variety of analytical and experimental analyses. These promising results ask for further research to unveil the functional details of the involvement of hsa-mir144-3p in Parkinson’s Disease.
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- Chaudhuri, K Ray, et al.
(author)
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King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation.
- 2015
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In: Movement Disorders. - : Wiley. - 0885-3185. ; 30:12, s. 1623-1631
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Journal article (peer-reviewed)abstract
- Pain is a key unmet need and a major aspect of non-motor symptoms of Parkinson's disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross-sectional, open, multicenter, one-point-in-time evaluation with retest study of the first PD-specific pain scale, the King's PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0-3) multiplied by frequency (0-4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy-eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29-85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non-PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median King's PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the King's PD Pain Scale, explaining 57% of the variance (Kaiser-Mayer-Olkin, 0.73; sphericity test). Cronbach's alpha was 0.78, item-total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the King's PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD-Motor, Non-Motor Symptoms Scale total score, and quality of life measures was high. The King's PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD. © 2015 International Parkinson and Movement Disorder Society.
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- Martinez-Martin, P., et al.
(author)
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First comprehensive tool for screening pain in Parkinson's disease : the King's Parkinson's Disease Pain Questionnaire
- 2018
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In: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 25:10, s. 1255-1261
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Journal article (peer-reviewed)abstract
- Background and purpose: Pain is highly prevalent in Parkinson's disease (PD), impacting patients’ ability, mood and quality of life. Detecting the presence of pain in its multiple modalities is necessary for adequate personalized management of PD. A 14-item, PD-specific, patient-based questionnaire (the King's Parkinson's Disease Pain Questionnaire, KPPQ) was designed corresponding to the rater-based KPP Scale (KPPS). The present multicentre study was aimed at testing the validity of this screening tool. Methods: First, a comparison between the KPPQ scores of patients and matched controls was performed. Next, convergent validity, reproducibility (test–retest) and diagnostic performance of the questionnaire were analysed. Results: Data from 300 patients and 150 controls are reported. PD patients declared significantly more pain symptoms than controls (3.96 ± 2.56 vs. 2.17 ± 1.39; P < 0.0001). The KPPQ convergent validity was high with KPPS total score (rS = 0.80) but weak or moderate with other pain assessments. Test–retest reliability was satisfactory with kappa values ≥0.65 except for item 5, Dyskinetic pains (κ = 0.44), and the intraclass correlation coefficient (ICC) for the KPPQ total score was 0.98. After the scores of the KPPS were adapted for screening (0, no symptom; ≥1, symptom present), a good agreement was found between the KPPQ and the KPPS (ICC = 0.88). A strong correlation (rS = 0.80) between the two instruments was found. The diagnostic parameters of the KPPQ were very satisfactory as a whole, with a global accuracy of 78.3%–98.3%. Conclusions: These results suggest that the KPPQ is a useful, reliable and valid screening instrument for pain in PD to advance patient-related outcomes.
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| 11. |
- Mollenhauer, B., et al.
(author)
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Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression
- 2020
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In: Movement Disorders. - : Wiley. - 0885-3185 .- 1531-8257. ; 35:11, s. 1999-2008
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Journal article (peer-reviewed)abstract
- Background The objective of this study was to assess neurofilament light chain as a Parkinson's disease biomarker. Methods We quantified neurofilament light chain in 2 independent cohorts: (1) longitudinal cerebrospinal fluid samples from the longitudinal de novo Parkinson's disease cohort and (2) a large longitudinal cohort with serum samples from Parkinson's disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers. Results In the Parkinson's Progression Marker Initiative cohort, mean baseline serum neurofilament light chain was higher in Parkinson's disease patients (13 +/- 7.2 pg/mL) than in controls (12 +/- 6.7 pg/mL),P= 0.0336. Serum neurofilament light chain increased longitudinally in Parkinson's disease patients versus controls (P< 0.01). Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores showed a negative association. Conclusions Neurofilament light chain in serum samples is increased in Parkinson's disease patients versus healthy controls, increases over time and with age, and correlates with clinical measures of Parkinson's disease severity. Although the specificity of neurofilament light chain for Parkinson's disease is low, it is the first blood-based biomarker candidate that could support disease stratification of Parkinson's disease versus other cognate/neurodegenerative disorders, track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of neurofilament light chain as a biomarker of response to neuroprotective interventions remains to be assessed. (c) 2020 The Authors.Movement Disorderspublished by Wiley Periodicals LLC. on behalf of International Parkinson and Movement Disorder Society.
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| 12. |
- Ferreira, J. J., et al.
(author)
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Summary of the recommendations of the EFNS/MDS-ES review on therapeutic management of Parkinson's disease
- 2013
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In: European Journal of Neurology. - : Wiley. - 1351-5101. ; 20:1, s. 5-15
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Journal article (peer-reviewed)abstract
- Objective: To summarize the 2010 EFNS/MDS-ES evidence-based treatment recommendations for the management of Parkinson's disease (PD). This summary includes the treatment recommendations for early and late PD. Methods: For the 2010 publication, a literature search was undertaken for articles published up to September 2009. For this summary, an additional literature search was undertaken up to December 2010. Classification of scientific evidence and the rating of recommendations were made according to the EFNS guidance. In cases where there was insufficient scientific evidence, a consensus statement ('good practice point') is made. Results and Conclusions:: For each clinical indication, a list of therapeutic interventions is provided, including classification of evidence.
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| 13. |
- Luk, C., et al.
(author)
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Development and assessment of sensitive immuno-PCR assays for the quantification of cerebrospinal fluid three- and four-repeat tau isoforms in tauopathies
- 2012
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In: Journal of Neurochemistry. - : Wiley. - 0022-3042. ; 123:3, s. 396-405
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Journal article (peer-reviewed)abstract
- Characteristic tau isoform composition of the insoluble fibrillar tau inclusions define tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal dementia with parkinsonism linked to chromosome 17/frontotemporal lobar degeneration-tau (FTDP-17/FTLD-tau). Exon 10 splicing mutations in the tau gene, MAPT, in familial FTDP-17 cause elevation of tau isoforms with four microtubule-binding repeat domains (4R-tau) compared to those with three repeats (3R-tau). On the basis of two well-characterised monoclonal antibodies against 3R- and 4R-tau, we developed novel, sensitive immuno-PCR assays for measuring the trace amounts of these isoforms in CSF. This was with the aim of assessing if CSF tau isoform changes reflect the pathological changes in tau isoform homeostasis in the degenerative brain and if these would be relevant for differential clinical diagnosis. Initial analysis of clinical CSF samples of PSP (n = 46), corticobasal syndrome (CBS; n = 22), AD (n = 11), Parkinson's disease with dementia (PDD; n = 16) and 35 controls revealed selective decreases of immunoreactive 4R-tau in CSF of PSP and AD patients compared with controls, and lower 4R-tau levels in AD compared with PDD. These decreases could be related to the disease-specific conformational masking of the RD4-binding epitope because of abnormal folding and/or aggregation of the 4R-tau isoforms in tauopathies or increased sequestration of the 4R-tau isoforms in brain tau pathology.
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| 14. |
- Jost, Stefanie T., et al.
(author)
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Levodopa Dose Equivalency in Parkinson's Disease : Updated Systematic Review and Proposals
- 2023
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In: Movement Disorders. - 0885-3185. ; 38:7, s. 1236-1252
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Journal article (peer-reviewed)abstract
- Background: To compare drug regimens across clinical trials in Parkinson's disease (PD) conversion formulae between antiparkinsonian drugs have been developed. These are reported in relation to levodopa as the benchmark drug in PD pharmacotherapy as ‘levodopa equivalent dose’ (LED). Currently, the LED conversion formulae proposed in 2010 by Tomlinson et al. based on a systematic review are predominantly used. However, new drugs with established and novel mechanisms of action and novel formulations of longstanding drugs have been developed since 2010. Therefore, consensus proposals for updated LED conversion formulae are needed. Objectives: To update LED conversion formulae based on a systematic review. Methods: The MEDLINE, CENTRAL, and Embase databases were searched from January 2010 to July 2021. Additionally, in a standardized process according to the GRADE grid method, consensus proposals were issued for drugs with scarce data on levodopa dose equivalency. Results: The systematic database search yielded 3076 articles of which 682 were eligible for inclusion in the systematic review. Based on these data and the standardized consensus process, we present proposals for LED conversion formulae for a wide range of drugs that are currently available for the pharmacotherapy of PD or are expected to be introduced soon. Conclusions: The LED conversion formulae issued in this Position Paper will serve as a research tool to compare the equivalence of antiparkinsonian medication across PD study cohorts and facilitate research on the clinical efficacy of pharmacological and surgical treatments as well as other non-pharmacological interventions in PD.
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| 15. |
- Mollenhauer, B., et al.
(author)
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Monitoring of 30 marker candidates in early Parkinson disease as progression markers
- 2016
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In: Neurology. - 0028-3878. ; 87:2, s. 168-177
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Journal article (peer-reviewed)abstract
- Objective: This was a longitudinal single-center cohort study to comprehensively explore multimodal progression markers for Parkinson disease (PD) in patients with recently diagnosed PD (n 123) and age-matched, neurologically healthy controls (HC; n 106). Methods: Thirty tests at baseline and after 24 months covered nonmotor symptoms (NMS), cognitive function, and REM sleep behavior disorder (RBD) by polysomnography (PSG), voxel-based morphometry (VBM) of the brain by MRI, and CSF markers. Linear mixed-effect models were used to estimate differences of rates of change and to provide standardized effect sizes (d) with 95% confidence intervals (CI). Results: A composite panel of 10 informative markers was identified. Significant relative worsening (PD vs HC) was seen with the following markers: the Unified Parkinson's Disease Rating Scale I (d 0.39; CI 0.09-0.70), the Autonomic Scale for Outcomes in Parkinson's Disease (d 0.25; CI 0.06-0.46), the Epworth Sleepiness Scale (d 0.47; CI 0.24-0.71), the RBD Screening Questionnaire (d 0.44; CI 0.25-0.64), and RBD by PSG (d 0.37; CI 0.19-0.55) as well as VBM units of cortical gray matter (d -0.2; CI -0.3 to -0.09) and hippocampus (d -0.15; CI -0.27 to -0.03). Markers with a relative improvement included the Nonmotor Symptom (Severity) Scale (d -0.19; CI -0.36 to -0.02) and 2 depression scales (Beck Depression Inventory d -0.18; CI -0.36 to 0; Montgomery-Åsberg Depression Rating Scale d -0.26; CI -0.47 to -0.04). Unexpectedly, cognitive measures and select laboratory markers were not significantly changed in PD vs HC participants. Conclusions: Current CSF biomarkers and cognitive scales do not represent useful progression markers. However, sleep and imaging measures, and to some extent NMS, assessed using adequate scales, may be more informative markers to quantify progression. © 2016 American Academy of Neurology.
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- Sixel-Doering, F., et al.
(author)
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Apomorphin zur subkutanen Dauerinfusion bei fortgeschrittenem Morbus Parkinson: Effektivität, Verträglichkeit und Patientenzufriedenheit im Langzeitverlauf
- 2011
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In: Aktuelle Neurologie. - : Georg Thieme Verlag KG. - 0302-4350 .- 1438-9428. ; 38:Suppl. 1, s. 27-33
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Research review (peer-reviewed)abstract
- Subcutaneous continuous infusion of apomorphine has been shown to effectively reduce off-time and dyskinesias in Parkinson's disease (PD). In this multicentre observational cohort study we investigated motor effectivity, tolerability and patient satisfaction with subcutaneous apomorphine infusion therapy over a follow-up period of 2 years. 62 PD patients were included (34 women, 28 men; median age 67.7 years). 33 of 62 patients (53%) continued therapy throughout the study period, showing a 79% reduction of daily off-time at the end of the observation period as compared to baseline. A third of these patients reported a lasting, subjective improvement of dyskinesias. At the end of the 2 years 75.8% of patients for final evaluation rated their satisfaction with subcutaneous apomorphine infusions as good". Altogether 29 patients (47%) stopped apomorphine infusions in the course of the study, most of them during the 3(rd) and 12(th) month of therapy. 8 cases stated adverse effects and 4 cases insufficient efficacy as reasons for discontinuation of therapy. 4 patients died during the observation period, 3 patients as a result of concomitant disease most likely not related to apomorphine, and 1 patient due to insufficiently treated medication-induced paranoid psychosis probably related to apomorphine. 6 patients were lost to follow-up. Conclusion Apomorphine therapy was effective with patient satisfaction rated as good in 53% of patients over a period of 2 years. Besides adverse events, low acceptance of long-term pump therapy as well as disease progression may be possible reasons for stopping apomorphine infusions. Physicians caring for PD patients with apomorphine therapy should be trained in the use of the substance to ensure safety and best possible therapy management.
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| 18. |
- Trenkwalder, C., et al.
(author)
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Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: Results from a multi-center, randomized, active controlled trial
- 2007
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In: Mov Disord. - : Wiley. - 0885-3185. ; 22:5, s. 696-703
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Journal article (peer-reviewed)abstract
- We report the first large-scale double-blind, randomly assigned study to compare two active dopaminergic therapies for Restless Legs Syndrome (RLS), the dopamine agonist cabergoline (CAB) and levodopa/benserazide (levodopa). Patients with idiopathic RLS were treated with fixed daily doses of 2 or 3 mg CAB or 200 or 300 mg levodopa for 30 weeks. Efficacy was assessed by changes in the IRLS (International RLS Severity Scale) and by time to discontinuation of treatment due to loss of efficacy or augmentation. 361 of 418 screened patients (age 58 +/- 12 years, 71% females) were randomly assigned and treated (CAB: n = 178; levodopa: n = 183) in 51 centers of four European countries. Baseline IRLS total score was 25.7 +/- 6.8. The baseline-adjusted mean change from baseline to week 6 in IRLS sum score was d = -16.1 in the CAB group and d = -9.5 in the levodopa group (d = -6.6, P < 0.0001). More patients in the levodopa group (24.0%) than in the CAB group (11.9%, P = 0.0029, log-rank test) discontinued because of loss of efficacy (14.2% vs. 7.9%, P = 0.0290) or augmentation (9.8% vs. 4.0%, P = 0.0412). Adverse events (AEs) occurred in 83.1% of the CAB group and in 77.6% of the levodopa group. In both groups, most frequent AEs were gastrointestinal symptoms (CAB: 55.6%, levodopa: 30.6%, P < 0.0001). This first large-scale active controlled study in RLS showed superior efficacy of cabergoline versus levodopa after a 30-week long-term therapy. Tolerability was found more favorable with levodopa than with cabergoline. (c) 2007 Movement Disorder Society.
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| 19. |
- Trenkwalder, Teresa, et al.
(author)
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Effects of the coronary artery disease associated LPA and 9p21 loci on risk of aortic valve stenosis
- 2019
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In: International Journal of Cardiology. - : Elsevier BV. - 0167-5273 .- 1874-1754. ; 276, s. 212-217
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Journal article (peer-reviewed)abstract
- Background: Aortic valve stenosis (AVS) and coronary artery disease (CAD) have a significant genetic contribution and commonly co-exist. To compare and contrast genetic determinants of the two diseases, we investigated associations of the LPA and 9p21 loci, i.e. the two strongest CAD risk loci, with risk of AVS. Methods: We genotyped the CAD-associated variants at the LPA (rs10455872) and 9p21 loci (rs1333049) in the GeneCAST (Genetics of Calcific Aortic STenosis) Consortium and conducted a meta-analysis for their association with AVS. Cases and controls were stratified by CAD status. External validation of findings was undertaken in five cohorts including 7880 cases and 851,152 controls. Results: In the meta-analysis including 4651 cases and 8231 controls the CAD-associated allele at the LPA locus was associated with increased risk of AVS (OR 1.37; 95%CI 1.24–1.52, p = 6.9 × 10−10) with a larger effect size in those without CAD (OR 1.53; 95%CI 1.31–1.79) compared to those with CAD (OR 1.27; 95%CI 1.12–1.45). The CAD-associated allele at 9p21 was associated with a trend towards lower risk of AVS (OR 0.93; 95%CI 0.88–0.99, p = 0.014). External validation confirmed the association of the LPA risk allele with risk of AVS (OR 1.37; 95%CI 1.27–1.47), again with a higher effect size in those without CAD. The small protective effect of the 9p21 CAD risk allele could not be replicated (OR 0.98; 95%CI 0.95–1.02). Conclusions: Our study confirms the association of the LPA locus with risk of AVS, with a higher effect in those without concomitant CAD. Overall, 9p21 was not associated with AVS.
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