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1. Levodopa Response in Patients With Early Parkinson Disease: Further Observations of the LEAP Study

Author

Frequin, H.L., Schouten, J., Verschuur, C.V., Suwijn, S.R., Boel, J.A., Post, B., Bloem, B.R., Hilten, J.J. van, Laar, T. van, Tissingh, G., Munts, A.G., Dijk, J.M.C. van, Deuschl, G., Lang, A., Dijkgraaf, M.G.W., Haan, R.J. den, and Bie, R.M. de

Subjects
All institutes and research themes of the Radboud University Medical Center, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Abstract

Item does not contain fulltext BACKGROUND AND OBJECTIVES: The Levodopa in EArly Parkinson's Disease (LEAP) study enabled us to conduct post hoc analyses concerning the effects of levodopa in patients with early Parkinson disease. METHODS: The LEAP study was a double-blind, placebo-controlled, randomized, delayed-start trial in which patients with early Parkinson disease were randomized to receive levodopa/carbidopa 300/75 mg daily for 80 weeks (early-start group) or to placebo for 40 weeks followed by levodopa/carbidopa 300/75 mg daily for 40 weeks (delayed-start group). We analyzed the effect of levodopa with the Unified Parkinson's Disease Rating Scale on bradykinesia, rigidity, and tremor. At week 80, participants answered 3 questions regarding motor response fluctuations. RESULTS: A total of 222 patients were randomized to the early-start group (mean ± SD age at baseline 64.8 ± 8.7 years; 71% male) and 223 to the delayed-start group (mean ± SD age at baseline 65.5 ± 8.8 years; 69% male). The difference between the early- and delayed-start groups in mean change from baseline to week 4, expressed as Hedges g effect size, was -0.33 for bradykinesia, -0.29 for rigidity, and -0.25 for tremor (for all symptoms indicating a small effect in favor of the early-start group); from baseline to week 22, respectively, -0.49, -0.36, and -0.44 (small to medium effect); and from baseline to week 40, respectively, -0.32, -0.19, and -0.27 (small effect). At 80 weeks, fewer patients in the early-start group (46 of 205 patients, 23%) experienced motor response fluctuations than patients in the delayed-start group (81 of 211, 38%; p < 0.01). DISCUSSION: In patients with early Parkinson disease, levodopa improves bradykinesia, rigidity, and tremor to the same order of magnitude. For all 3 symptoms, effects were larger at 22 weeks compared with 4 weeks. At 80 weeks, there were fewer patients with motor response fluctuations in the group that had started levodopa earlier. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the effect of levodopa on bradykinesia, rigidity, and tremor is larger after 22 weeks compared with 4 weeks of treatment. TRIAL REGISTRATION INFORMATION: ISRCTN30518857, EudraCT number 2011-000678-72.

Published
2023

3. Patient-Related Factors Influencing Caregiver Burden in Parkinson's Disease Patients: Comparison of Effects Before and After Deep Brain Stimulation

Author

Hienen, M.M. van, Kuiper, R., Middelkoop, H.A.M., Hilten, J.J. van, Contarino, M.F., and Geraedts, V.J.

Subjects
Male, Cellular and Molecular Neuroscience, caregiver burden, Caregivers, quality of life, Parkinson's disease, Humans, Female, Parkinson Disease, epidemiology, Neurology (clinical), Aged, deep brain stimulation
Abstract

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

Published
2022

4. Differences in the Presentation and Progression of Parkinson's Disease by Sex

Author

Iwaki, H., Blauwendraat, C., Leonard, H.L., Makarious, M.B., Kim, J.J., Liu, G., Maple-Grødem, J., Corvol, J.C., Pihlstrøm, L., Nimwegen, M.L. van, Smolensky, L., Amondikar, N., Hutten, S.J., Frasier, M., Nguyen, K.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. Van, Hernandez, D.G., Gibbs, R.J., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O.A., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P.C. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., Nalls, M.A., Iwaki, H., Blauwendraat, C., Leonard, H.L., Makarious, M.B., Kim, J.J., Liu, G., Maple-Grødem, J., Corvol, J.C., Pihlstrøm, L., Nimwegen, M.L. van, Smolensky, L., Amondikar, N., Hutten, S.J., Frasier, M., Nguyen, K.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. Van, Hernandez, D.G., Gibbs, R.J., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O.A., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P.C. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., and Nalls, M.A.

Abstract

Item does not contain fulltext, BACKGROUND: Previous studies reported various symptoms of Parkinson's disease (PD) associated with sex. Some were conflicting or confirmed in only one study. OBJECTIVES: We examined sex associations to PD phenotypes cross-sectionally and longitudinally in large-scale data. METHODS: We tested 40 clinical phenotypes, using longitudinal, clinic-based patient cohorts, consisting of 5946 patients, with a median follow-up of 3.1 years. For continuous outcomes, we used linear regressions at baseline to test sex-associated differences in presentation, and linear mixed-effects models to test sex-associated differences in progression. For binomial outcomes, we used logistic regression models at baseline and Cox regression models for survival analyses. We adjusted for age, disease duration, and medication use. In the secondary analyses, data from 17 719 PD patients and 7588 non-PD participants from an online-only, self-assessment PD cohort were cross-sectionally evaluated to determine whether the sex-associated differences identified in the primary analyses were consistent and unique to PD. RESULTS: Female PD patients had a higher risk of developing dyskinesia early during the follow-up period, with a slower progression in activities of daily living difficulties, and a lower risk of developing cognitive impairments compared with male patients. The findings in the longitudinal, clinic-based cohorts were mostly consistent with the results of the online-only cohort. CONCLUSIONS: We observed sex-associated contributions to PD heterogeneity. These results highlight the necessity of future research to determine the underlying mechanisms and importance of personalized clinical management. © 2020 International Parkinson and Movement Disorder Society.

Published
2021

5. Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study. (Paper)

Author

Pogarell, O., Gasser, T., Hilten, J.J. Van, Spieker, S., Pollentier, S., Meier, D., and Oertel, W.H.

Subjects
Drug therapy, Physiological aspects, Parkinson disease -- Drug therapy, Dopamine agonists -- Physiological aspects, Drug resistance -- Physiological aspects -- Drug therapy, Parkinson's disease -- Drug therapy, Dopamine -- Agonists
Abstract

Objective: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease. Methods: Eighty four patients with [...]

Published
2002

6. Health related quality of life in Parkinson's disease: A systematic review of disease specific instruments. (Paper)

Author

Marinus, J., Ramaker, C., Hilten, J.J. Van, and Stiggelbout, A.M.

Subjects
Psychological aspects, Evaluation, Measurement, Parkinson disease -- Psychological aspects -- Measurement, Quality of life -- Measurement -- Psychological aspects, Health status indicators -- Evaluation -- Measurement -- Psychological aspects, Parkinson's disease -- Psychological aspects -- Measurement
Abstract

Objective: To compare and contrast disease-specific quality of life instruments in Parkinson's disease and assess their clinimetric properties. Methods: Two reviewers independently evaluated both thoroughness and results of studies regarding [...]

Published
2002

7. Genomewide association study of Parkinson's disease clinical biomarkers in 12 longitudinal patients' cohorts

Author

Iwaki, H., Blauwendraat, C., Leonard, H.L., Kim, J.J., Liu, G.Q., Maple-Grodem, J., Corvol, J.C., Pihlstrom, L., Nimwegen, M. van, Hutten, S.J., Nguyen, K.D.H., Rick, J., Eberly, S., Faghri, F., Auinger, P., Scott, K.M., Wijeyekoon, R., Deerlin, V.M. van, Hernandez, D.G., Gibbs, J.R., Chitrala, K.N., Day-Williams, A.G., Brice, A., Alves, G., Noyce, A.J., Tysnes, O.B., Evans, J.R., Breen, D.P., Estrada, K., Wegel, C.E., Danjou, F., Simon, D.K., Andreassen, O., Ravina, B., Toft, M., Heutink, P., Bloem, B.R., Weintraub, D., Barker, R.A., Williams-Gray, C.H., Warrenburg, B.P. van de, Hilten, J.J. van, Scherzer, C.R., Singleton, A.B., Nalls, M.A., and Int Parkinson's Dis Genomics Cons

Subjects
Parkinson's disease, GBA, Apolipoprotein E, genomewide association study
Published
2019

8. Moving beyond neurons: the role of cell type-specific gene regulation in Parkinson's disease heritability

Author

Reynolds, R.H., Botia, J., Nalls, M.A., Hardy, J., Taliun, S.A.G., Ryten, M., Noyce, A.J., Nicolas, A., Cookson, M.R., Bandres-Ciga, S., Gibbs, J.R., Hernandez, D.G., Singleton, A.B., Reed, X., Leonard, H., Blauwendraat, C., Faghri, F., Bras, J., Guerreiro, R., Tucci, A., Kia, D.A., Houlden, H., Plun-Favreau, H., Mok, K.Y., Wood, N.W., Lovering, R., R'Bibo, L., Rizig, M., Chelban, V., Trabzuni, D., Tan, M., Morris, H.R., Middlehurst, B., Quinn, J., Billingsley, K., Holmans, P., Kinghorn, K.J., Lewis, P., Escott-Price, V., Williams, N., Foltynie, T., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Giri, A., Schulte, C., Brockmann, K., Simon-Sanchez, J., Heutink, P., Gasser, T., Rizzu, P., Sharma, M., Shulman, J.M., Robak, L., Lubbe, S., Mencacci, N.E., Finkbeiner, S., Lungu, C., Scholz, S.W., Gan-Or, Z., Rouleau, G.A., Krohan, L., Hilten, J.J. van, Marinus, J., Adarmes-Gomez, A.D., Bernal-Bernal, I., Bonilla-Toribio, M., Buiza-Rueda, D., Carrillo, F., Carrion-Claro, M., Mir, P., Gomez-Garre, P., Jesus, S., Labrador-Espinosa, M.A., Macias, D., Vargas-Gonzalez, L., Mendez-del-Barrio, C., Perinan-Tocino, T., Tejera-Parrado, C., Diez-Fairen, M., Aguilar, M., Alvarez, I., Boungiorno, M.T., Carcel, M., Pastor, P., Tartari, J.P., Alvarez, V., Gonzalez, M.M., Blazquez, M., Garcia, C., Suarez-Sanmartin, E., Barrero, F.J., Rezola, E.M., Yarza, J.A.B., Pagola, A.G., Arregui, A.L.D., Ruiz-Martinez, J., Cerdan, D., Duarte, J., Clarimon, J., Dols-Icardo, O., Infante, J., Marin, J., Kulisevsky, J., Pagonabarraga, J., Gonzalez-Aramburu, I., Rodriguez, A.S., Sierra, M., Duran, R., Ruz, C., Vives, F., Escamilla-Sevilla, F., Minguez, A., Camara, A., Compta, Y., Ezquerra, M., Marti, M.J., Fernandez, M., Munoz, E., Fernandez-Santiago, R., Tolosa, E., Valldeoriola, F., Garcia-Ruiz, P., Heredia, M.J.G., Errazquin, F.P., Hoenicka, J., Jimenez-Escrig, A., Martinez-Castrillo, J.C., Lopez-Sendon, J.L., Torres, I.M., Tabernero, C., Vela, L., Zimprich, A., Pihlstrom, L., Koks, S., Taba, P., Majamaa, K., Siitonen, A., Okubadejo, N.U., Ojo, O.O., Pitcher, T., Anderson, T., Bentley, S., Fowdar, J., Mellick, G., Dalrymple-Alford, J., Henders, A.K., Kassam, I., Montgomery, G., Sidorenko, J., Zhang, F.T., Xue, A.L., Vallerga, C.L., Wallace, L., Wray, N.R., Yang, J., Visscher, P.M., Gratten, J., Silburn, P.A., Halliday, G., Hickie, I., Kwok, J., Lewis, S., Kennedy, M., Pearson, J., Int Parkinsons Dis Genomics, and Syst Genomics Parkinsons Dis

Published
2019

9. SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Author

Fernandez-Santiago, R., Martin-Flores, N., Antonelli, F., Cerquera, C., Moreno, V., Bandres-Ciga, S., Manduchi, E., Tolosa, E., Singleton, A.B., Moore, J.H., Noyce, A.J., Kaiyrzhanov, R., Middlehurst, B., Kia, D.A., Tan, M., Houlden, H., Morris, H.R., Plun-Favreau, H., Holmans, P., Hardy, J., Trabzuni, D., Bras, J., Quinn, J., Mok, K.Y., Kinghorn, K.J., Billingsley, K., Wood, N.W., Lewis, P., Schreglmann, S., Guerreiro, R., Lovering, R., R'Bibo, L., Manzoni, C., Rizig, M., Ryten, M., Guelfi, S., Escott-Price, V., Chelban, V., Foltynie, T., Williams, N., Morrison, K.E., Clarke, C., Brice, A., Danjou, F., Lesage, S., Corvol, J.C., Martinez, M., Schulte, C., Brockmann, K., Simoon-Saanchez, J., Heutink, P., Rizzu, P., Sharma, M., Gasser, T., Nicolas, A., Cookson, M.R., Blauwendraat, C., Craig, D.W., Faghri, F., Gibbs, J.R., Hernandez, D.G., Keuren-Jensen, K. van, Shulman, J.M., Iwaki, H., Leonard, H.L., Nalls, M.A., Robak, L., Lubbe, S., Finkbeiner, S., Mencacci, N.E., Lungu, C., Scholz, S.W., Reed, X., Alcalay, R.N., Gan-Or, Z., Rouleau, G.A., Krohn, L., Hilten, J.J. van, Marinus, J., Adarmes-Goomez, A.D., Aguilar, I., Alvarez, I., Alvarez, V., Barrero, F.J., Yarza, J.A.B., Bernal-Bernal, I., Blazquez, M., Bonilla-Toribio, M., Botia, J.A., Boungiorno, M.T., Buiza-Rueda, D., Camara, A., Carrillo, F., Carrion-Claro, M., Cerdan, D., Clarimon, J., Compta, Y., Casa, B. de la, Diez-Fairen, M., Dols-Icardo, O., Duarte, J., Duran, R., Escamilla-Sevilla, F., Ezquerra, M., Feliz, C., Fernandez, M., Garcia, C., Garcia-Ruiz, P., Gomez-Garre, P., Heredia, M.J.G., Gonzalez-Aramburu, I., Pagola, A.G., Hoenicka, J., Infante, J., Jesus, S., Jimenez-Escrig, A., Kulisevsky, J., Labrador-Espinosa, M.A., Lopez-Sendon, J.L., Arregui, A.L.D., Macias, D., Torres, I.M., Marin, J., Marti, M.J., Martinez-Castrillo, C., Mendez-del-Barrio, C., Gonzalez, M.M., Mata, M., Minguez, A., Mir, P., Rezola, E.M., Munoz, E., Pagonabarraga, J., Pascual-Sedano, B., Pastor, P., Errazquin, F.P., Perinan-Tocino, T., Ruiz-Martinez, J., Ruz, C., Rodriguez, A.S., Sierra, M., Suarez-Sanmartin, E., Tabernero, C., Tartari, J.P., Tejera-Parrado, C., Valldeoriola, F., Vargas-Gonzalez, L., Vela, L., Vives, F., Zimprich, A., Pihlstrom, L., Toft, M., Koks, S., Taba, P., Hassin-Baer, S., Malagelada, C., Int Parkinson's Dis Genomics Conso, Fundació La Marató de TV3, Michael J. Fox Foundation for Parkinson's Research, National Institutes of Health (US), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), and Ministerio de Ciencia, Innovación y Universidades (España)

Subjects
0301 basic medicine, epistasis, Male, Parkinson's disease, very elderly, alpha-synuclein, Alpha‐synuclein, regulatory associated protein of mTOR, Cohort Studies, 0302 clinical medicine, single nucleotide polymorphism, genetics, Age of Onset, Genetics, Aged, 80 and over, Polymorphism, Single Nucleoti, biology, TOR Serine-Threonine Kinases, target of rapamycin kinase, fchsd1 gene, Age at onset, Chromosome Mapping, glycogen synthase kinase 3beta, Parkinson Disease, Middle Aged, cohort analysis, LRRK2, priority journal, Neurology, chromosomal mapping, neuromodulation, mTOR, alpha-Synuclein, Female, age at onset, Signal Transduction, onset age, Adult, MTOR protein, human, protein kinase LKB1, gene locus, Genotype, multifactor dimensionality reduction, SNP, Single-nucleotide polymorphism, rps6ka2 gene, Polymorphism, Single Nucleotide, Risk Assessment, Article, brain function, 03 medical and health sciences, alpha synuclein, medicine, Humans, controlled study, Genetic Predisposition to Disease, human, ddc:610, SNCA protein, human, gene, Mechanistic target of rapamycin, PI3K/AKT/mTOR pathway, mammalian target of rapamycin, Aged, RPTOR, Epistasis, Genetic, Odds ratio, medicine.disease, major clinical study, nervous system diseases, 030104 developmental biology, mTOR signaling, biology.protein, Epistasis, pathology, Neurology (clinical), genetic predisposition, 030217 neurology & neurosurgery
Abstract

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

Published
2019
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10. Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease

Author

Verschuur, C.V., Suwijn, S.R., Boel, J.A., Post, B., Bloem, B.R., Hilten, J.J. van, Haan, R.J. de, Bie, R.M. de, Verschuur, C.V., Suwijn, S.R., Boel, J.A., Post, B., Bloem, B.R., Hilten, J.J. van, Haan, R.J. de, and Bie, R.M. de

Abstract

Contains fulltext : 201287.pdf (publisher's version ) (Open Access)

Published
2019

12. A Post Hoc Study on Gene Panel Analysis for the Diagnosis of Dystonia

Author

Egmond, M.E. van, Lugtenberg, C.H.A., Brouwer, O.F., Contarino, M.F., Fung, V.S.C., Heiner-Fokkema, M.R., Hilten, J.J. van, Hout, A.H. van der, Peall, K.J., Sinke, R.J., Roze, E., Verschuuren-Bemelmans, C.C., Willemsen, M.A., Wolf, N.I., Tijssen, M.A., and Koning, T.J. de

Subjects
gene panel analysis, diagnostic yield, cost, next-generation sequencing, dystonia, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3]
Abstract

Contains fulltext : 174078.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genetic disorders causing dystonia show great heterogeneity. Recent studies have suggested that next-generation sequencing techniques such as gene panel analysis can be effective in diagnosing heterogeneous conditions. The objective of this study was to investigate whether dystonia patients with a suspected genetic cause could benefit from the use of gene panel analysis. METHODS: In this post hoc study, we describe gene panel analysis results of 61 dystonia patients (mean age, 31 years; 72% young onset) in our tertiary referral center. The panel covered 94 dystonia-associated genes. As comparison with a historic cohort was not possible because of the rapidly growing list of dystonia genes, we compared the diagnostic workup with and without gene panel analysis in the same patients. The workup without gene panel analysis (control group) included theoretical diagnostic strategies formulated by independent experts in the field, based on detailed case descriptions. The primary outcome measure was diagnostic yield; secondary measures were cost and duration of diagnostic workup. RESULTS: Workup with gene panel analysis led to a confirmed molecular diagnosis in 14.8%, versus 7.4% in the control group (P = 0.096). In the control group, on average 3 genes/case were requested. The mean costs were lower in the gene panel analysis group (euro1822/case) than in the controls (euro2660/case). The duration of the workup was considerably shorter with gene panel analysis (28 vs 102 days). CONCLUSIONS: Gene panel analysis facilitates molecular diagnosis in complex cases of dystonia, with a good diagnostic yield (14.8%), a quicker diagnostic workup, and lower costs, representing a major improvement for patients and their families. (c) 2016 International Parkinson and Movement Disorder Society.

Published
2017

13. The significance of motor (A)symmetry in Parkinson's disease

Author

Marinus, J. and Hilten, J.J. van

Subjects
Male, medicine.medical_specialty, Parkinson's disease, motor distribution pattern, Excessive daytime sleepiness, Disease, Motor Activity, Audiology, Severity of Illness Index, Functional Laterality, Cohort Studies, Disease severity, cohort study, medicine, Humans, Aged, symmetry, Confounding, Parkinson Disease, Cognition, Middle Aged, medicine.disease, Neurology, Potential change, Disease Progression, Physical therapy, Female, Neurology (clinical), medicine.symptom, Psychology, Cohort study
Abstract

This study was undertaken to evaluate whether the predominant motor distribution pattern (ie, symmetric or asymmetric) observed in patients with Parkinson's disease (PD) contributes independently to disease severity and progression. We further examine whether this pattern is stable over time, and whether a potential change in pattern affects the course of the disease. We used data from the longitudinal PROPARK study (N > 400) to examine the association of the predominant motor distribution pattern with motor, cognitive, depressive, psychotic, and autonomic symptoms, and with excessive daytime sleepiness. We found that a symmetrical distribution of motor features was associated with poorer performance on nearly all domains, but that this was entirely explained by confounding, in particular by higher age and longer disease duration. We also found that greater asymmetry was associated with younger age, younger age at onset, and shorter disease duration. We further observed a clear tendency to develop a more symmetric distribution pattern as the disease advanced. Conversion to a symmetric pattern was associated with more severe disease, but this conversion did not contribute independently to the less favorable disease course. With increasing age and disease duration comes a clear tendency to develop a more symmetric distribution of motor features in PD. Although this change in distribution pattern is associated with more severe disease as compared with nonconvertors, this pattern change did not contribute independently to the less favorable course. We discuss these findings in light of the evidence from the literature. © 2014 International Parkinson and Movement Disorder Society

Published
2014
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14. Oral Health of Parkinson's Disease Patients: A Case-Control Study.

Author

Stiphout, M.A.E. van, Marinus, J., Hilten, J.J. van, Lobbezoo, F., Baat, C. de, Stiphout, M.A.E. van, Marinus, J., Hilten, J.J. van, Lobbezoo, F., and Baat, C. de

Abstract

Contains fulltext : 193399.pdf (publisher's version ) (Open Access), The aim of the study was to examine the oral health status of Parkinson's disease (PD) patients, to compare their oral health status to that of a control group, and to relate it to the duration and severity of PD. Materials and Methods. 74 PD patients and 74 controls were interviewed and orally examined. Among PD patients, the duration and the Hoehn and Yahr stage (HY) of the disease were registered. Results. More PD patients than controls reported oral hygiene care support as well as chewing/biting problems, taste disturbance, tooth mobility, and xerostomia, whereas dentate patients had more teeth with carious lesions, tooth root remnants, and biofilm. Both longer duration and higher HY were associated with more chewing problems and, in dentates, more teeth with restorations. In dentates, longer duration of the disease was associated with higher number of mobile teeth. Higher HY was associated with more oral hygiene care support as well as biting problems and, in dentates, more teeth with carious lesions and tooth root remnants. Conclusions. Comparatively, PD patients had weakened oral health status and reduced oral hygiene care. Both duration and severity of the disease were associated with more oral health and hygiene care problems.

Published
2018

17. Associated and predictive factors of depressive symptoms in patients with Parkinson’s disease

Author

Zhu, K.D., Hilten, J.J. van, and Marinus, J.

Abstract

Depression is one of the most common non-motor symptoms in Parkinson's disease (PD). A thorough understanding of factors associated with depressive symptomatology may facilitate early detection and guide future intervention strategies. The objective of the study was to determine associated and predictive factors of depression in patients with PD. Analyses were performed in data of the SCOPA-PROPARK cohort, a 5-year hospital-based longitudinal cohort of over 400 PD patients who have been examined annually. Linear mixed models using data of all patients were used to identify factors associated with longitudinal changes in Beck Depression Inventory (BDI) scores. A survival analysis using data of patients without depression at baseline was performed to identify risk factors for future depression (i.e. BDI ≥ 15). The proportion of patients with depression was approximately 20 % and remained stable during follow-up, with approximately half of cases showing a persistent course. Female gender, more severe disability, more severe motor fluctuations, autonomic and cognitive dysfunction, poorer nighttime sleep and daytime sleepiness were independently associated with higher BDI scores over time. Higher baseline BDI score, daytime sleepiness and a higher levodopa dosage were risk factors for future depression. Depression is common in PD, where it may follow a persistent or non-persistent course. Apart from motor fluctuations and levodopa dose, depressive symptoms in PD are mainly associated with factors of non-dopaminergic origin. This suggests that depression in PD is an inherent consequence of the progressive pathobiology of the disease, which may render its treatment with currently available treatment options difficult.

Published
2016

19. Force modulation deficits in complex regional pain syndrome: A potential role for impaired sense of force production

Author

Bank, P.J.M., Rooijen, D.E. van, Marinus, J., Reilmann, R., Hilten, J.J. van, Movement Behavior, and Kinesiology

Subjects
SDG 3 - Good Health and Well-being
Abstract

Background Compelling evidence points at both impaired proprioception and disturbed force control in patients with chronic complex regional pain syndrome (CRPS). Because force modulation at least partly relies on proprioception, we evaluated if impaired sense of force production contributes to disturbances of force control in patients with CRPS. Methods Characteristics of voluntary force modulation were examined in the affected upper extremity in 28 CRPS patients with abnormal postures, in 12 CRPS patients without abnormal postures, and in 32 healthy controls. Isometric grip-force matching was compared between conditions with and without visual feedback to identify potential deficits in the sense of force production in terms of force reproduction errors. Results Voluntary force modulation was impaired in CRPS patients, but more so in patients with abnormal postures. In particular, CRPS patients with abnormal postures were characterized by reduced maximum force, reduced ability to increase force output according to task instructions, higher variability of force output and less adequate correction of deviations from the target force. Although effects of visual feedback removal appeared largely similar for the two patient groups and controls, our findings with respect to force reproduction errors suggested that an impaired sense of force production may contribute to the motor dysfunction in CRPS. Conclusions CRPS patients, in particular those with abnormal postures, showed impaired voluntary force control and an impaired sense of force production. This suggests that therapeutic strategies aimed at restoration of proprioceptive impairments, possibly using online visual feedback, may promote the recovery of motor function in CRPS. © 2014 European Pain Federation - EFIC®.

Published
2014
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24. Is TOR1A a risk factor in adult-onset primary torsion dystonia?

Author

Groen, J.L., Ritz, K., Tanck, M.W., Warrenburg, B.P. van de, Hilten, J.J. van, Aramideh, M., Baas, F., and Tijssen, M.A.J.

Subjects
meta-analysis, focal dystonia, DCN MP - Plasticity and memory, complex disease, otorhinolaryngologic diseases, association study, TOR1A, nervous system diseases
Abstract

Item does not contain fulltext BACKGROUND: Studies of genetic association between TOR1A and adult-onset primary torsion dystonia have contradictory results. METHODS: The authors genotyped TOR1A single nucleotide polymorphisms rs1801968, rs2296793, rs1182 and rs3842225 in a cohort of clinically well characterized cervical dystonia patients (n=367) and constructed haplotypes. The authors systematically reviewed the published case-control TOR1A association studies in adult-onset primary torsion dystonia. RESULTS: In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance. However, in a selection of familial cases the functional variant p.Asp216His (rs1801968) was associated with increased dystonia risk (odds ratio 1.43; 95%CI 1.01-2.02). CONCLUSIONS: Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases. (c) 2013 Movement Disorder Society.

Published
2013

27. A two-stage meta-analysis identifies several new loci for Parkinson's disease

Author

Plagnol, V., Nalls, M.A., Bras, J.M., Hernandez, D., Sharma, M., Sheerin, U.M., Saad, M., Simon-Sanchez, J., Schulte, C., Lesage, S., Sveinbjornsdottir, S., Amouyel, P., Arepalli, S., Band, G., Barker, R.A., Bellinguez, C., Ben-Shlomo, Y., Berendse, H.W., Berg, D., Bhatia, K.P., Bie, R.M. de, Biffi, A., Bloem, B.R., Bochdanovits, Z., Bonin, M., Brockmann, K., Brooks, J., Burn, D.J., Charlesworth, G., Chen, H., Chinnery, P.F., Chong, S., Clarke, C.E., Cookson, M.R., Cooper, J.M., Corvol, J.C., Counsell, J., Damier, P., Dartigues, J.F., Deloukas, P., Deuschl, G., Dexter, D.T., Dijk, K.D. van, Dillman, A., Durif, F., Durr, A., Edkins, S., Evans, J.R., Foltynie, T., Freeman, C., Gao, J., Gardner, M., Gibbs, J.R., Goate, A., Gray, E., Guerreiro, R., Gustafsson, O., Harris, C., Hellenthal, G., Hilten, J.J. van, Hofman, A., Hollenbeck, A., Holton, J.L., Hu, M., Huang, X., Huber, H, Hudson, G., Hunt, S.E., Huttenlocher, J., Illig, T., Jonsson, P.V., Langford, C., Lees, A.J., Lichtner, P., Limousin, P., Lopez, G., McNeill, A., Moorby, C., Moore, M., Morris, H.A., Morrison, K.E., Mudanohwo, E., O'Sullivan, S.S, Pearson, J., Pearson, R., Perlmutter, J., Petursson, H., Pirinen, M., Polnak, P., Post, B., Potter, S.C., Ravina, B., Revesz, T., Riess, O., Rivadeneira, F., Rizzu, P., Ryten, M., Sawcer, S.J., Schapira, A., Scheffer, H., Shaw, K., Shoulson, I., Sidransky, E., Silva, R. de, Smith, C., Spencer, C.C., Stefansson, H., Steinberg, S., Stockton, J.D., Strange, A., Su, Z., Talbot, K., Tanner, C.M., Tashakkori-Ghanbaria, A., Tison, F., Trabzuni, D., Traynor, B.J., Uitterlinden, A.G., Vandrovcova, J., Velseboer, D., Vidailhet, M., Vukcevic, D., Walker, R., Warrenburg, B.P.C. van de, Weale, M.E., Wickremaratchi, M., Williams, N., Williams-Gray, C.H., Winder-Rhodes, S., Stefansson, K., Martinez, M., Donnelly, P., Singleton, A.B., Hardy, J., Heutink, P., Brice, A., Gasser, T., and Wood, N.W.

Subjects
Functional Neurogenomics Human Movement & Fatigue [DCN 2], Genomic disorders and inherited multi-system disorders Functional Neurogenomics [IGMD 3], Functional Neurogenomics [DCN 2]
Abstract

Contains fulltext : 97597.pdf (Publisher’s version ) (Open Access) A previous genome-wide association (GWA) meta-analysis of 12,386 PD cases and 21,026 controls conducted by the International Parkinson's Disease Genomics Consortium (IPDGC) discovered or confirmed 11 Parkinson's disease (PD) loci. This first analysis of the two-stage IPDGC study focused on the set of loci that passed genome-wide significance in the first stage GWA scan. However, the second stage genotyping array, the ImmunoChip, included a larger set of 1,920 SNPs selected on the basis of the GWA analysis. Here, we analyzed this set of 1,920 SNPs, and we identified five additional PD risk loci (combined p

Published
2011

28. Distribution of signs and symptoms of complex regional pain syndrome type 1 in patients meeting the diagnostic criteria of the international association of the study of pain

Author

Boer, R.D.H. de, Marinus, J., Hilten, J.J. van, Huygen, F.J., Eijs, F. van, Kleef, M. van, Bauer, M.C.R., Gestel, M. van, Zuurmond, W.W.A., and Perez, R.S.G.M.

Abstract

The aim of the present study was to describe the occurrence of signs and symptoms in CRPS I patients meeting the IASP (Orlando) criteria, assess the occurrence of signs and symptoms in relation to disease duration and compare these to historical data based on a different diagnostic criteria set. Six hundred and ninety-two ambulatory patients meeting the IASP criteria for CRPS I referred to the outpatient clinics of five participating centers were included in this cross-sectional study. Characteristics were recorded in a standardized fashion and categorized according to the factor structure proposed by Bruehl/Harden. Subgroups were classified according to the duration of complaints and compared to historical data as described by Veldman et al. The Chi-square test corrected for multiple comparisons was used for statistical analysis. The prevalence of sensory signs was higher in patients with longer disease duration, especially for the allodynia's and hyperalgesia (all p 6 months). Prevalences of signs in the motor subgroup were all higher (p

Published
2011

29. Distribution of signs and symptoms of Complex Regional Pain Syndrome type I in patients meeting the diagnostic criteria of the international association for the study of pain

Author

Boer, R.D.H. de, Marinus, J., Hilten, J.J. van, Huygen, F.J., Eijs, F. van, Kleef, M. van, Bauer, M.C.R., Gestel, M. van, Zuurmond, W.W.A., Perez, R.S.G.M., Anesthesiology, and EMGO - Musculoskeletal health

Subjects
Complex Regional Pain Syndrome, Diagnosis, Symptoms, Disease course, Signs
Published
2011
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30. Reliability and Validity of the Range of Motion Scale (ROMS) in Patients with Abnormal Postures

Author

Rooijen, D.E. van, Lalli, S., Marinus, J., Maihofner, C., McCabe, C.S., Munts, A.G., Plas, A.A. van der, Tijssen, M.A.J., Warrenburg, B.P.C. van de, Albanese, A., Hilten, J.J. van, Rooijen, D.E. van, Lalli, S., Marinus, J., Maihofner, C., McCabe, C.S., Munts, A.G., Plas, A.A. van der, Tijssen, M.A.J., Warrenburg, B.P.C. van de, Albanese, A., and Hilten, J.J. van

Abstract

Item does not contain fulltext, OBJECTIVE: Sustained abnormal postures (i.e., fixed dystonia) are the most frequently reported motor abnormalities in complex regional pain syndrome (CRPS), but these symptoms may also develop after peripheral trauma without CRPS. Currently, there is no valid and reliable measurement instrument available to measure the severity and distribution of these postures. The range of motion scale (ROMS) was therefore developed to assess the severity based on the possible active range of motion of all joints (arms, legs, trunk, and neck), and the present study evaluates its reliability and validity. METHODS: Inter- and intra-rater reliability of the ROMS was determined in 16 patients with abnormal sustained postures, who were videotaped following a standard video protocol in a university hospital. The recordings were rated by a panel of international experts. In addition, 30 patients were clinically tested with both the Burke-Fahn-Marsden (BFM) scale as well as the ROMS to assess construct validity. RESULTS: Inter-rater reliability for total ROMS scores showed an intra-class correlation coefficient (ICC) of 0.85. The majority of the scores for the separate joints (13 out of 18) demonstrated an almost perfect agreement with ICCs ranging from 0.81 to 0.94; of the other items, one showed fair, one moderate, and three substantial agreement. The ICCs for the intra-rater reliability ranged from moderate to almost perfect (0.68-0.98). Spearman's correlation coefficients between corresponding body areas as measured with the ROMS or BFM were all above 0.82. CONCLUSION: The ROMS is a reliable and valid instrument to evaluate the severity and distribution of sustained abnormal postures.

Published
2015

31. Protocol of a randomised delayed-start double-blind placebo-controlled multi-centre trial for Levodopa in EArly Parkinson's disease: the LEAP-study

Author

Verschuur, C.V., Suwijn, S.R., Post, B., Dijkgraaf, M., Bloem, B.R., Hilten, J.J. van, Laar, T. van, Tissingh, G., Deuschl, G., Lang, A.E., Haan, R.J. de, Bie, R.M. de, Verschuur, C.V., Suwijn, S.R., Post, B., Dijkgraaf, M., Bloem, B.R., Hilten, J.J. van, Laar, T. van, Tissingh, G., Deuschl, G., Lang, A.E., Haan, R.J. de, and Bie, R.M. de

Abstract

Contains fulltext : 152630.pdf (publisher's version ) (Open Access), BACKGROUND: The aim of this study is to investigate if early treatment with levodopa has a beneficial disease modifying effect on Parkinson's disease (PD) symptoms and functional health, improves the ability to (maintain) work, and reduces the use of (informal) care, caregiver burden, and costs. Additionally, cost-effectiveness and cost-utility of early levodopa treatment will be assessed. METHODS: To differentiate between the direct symptomatic effects and possible disease modifying effects of levodopa, we use a randomised delayed-start double-blind placebo-controlled multi-centre trial design. Patients with early stage PD whose functional health does not yet necessitate initiation of PD-medication will be randomised to either 40 weeks of treatment with levodopa/carbidopa 100/25 mg TID including 2 weeks of dose escalation or to 40 weeks placebo TID. Subsequently, all patients receive levodopa/carbidopa 100/25 mg TID for 40 weeks. There are 8 assessments: at baseline and at 4, 22, 40, 44, 56, 68, and 80 weeks. The primary outcome measure is the difference in the mean total Unified Parkinson's Disease Rating Scale scores between the early- and delayed-start groups at 80 weeks. Secondary outcome measures are rate of progression, the AMC Linear Disability Score, side effects, perceived quality of life with the Parkinson's Disease Questionnaire-39, the European Quality of Life-5 Dimensions (EQ-5D), ability to (maintain) work, the use of (informal) care, caregiver burden, and costs. 446 newly diagnosed PD patients without impaired functional health need to be recruited in order to detect a minimal clinical relevant difference of 4 points on the total UPDRS at 80 weeks. DISCUSSION: The LEAP-study will provide insights into the possible disease modifying effects of early levodopa. TRIAL REGISTRATION: ISRCTN30518857 , EudraCT number 2011-000678-72.

Published
2015

32. Movement Disorders in Complex Regional Pain Syndrome

Author

Hilten, J.J. van

Subjects
Complex Regional Pain Syndrome (CRPS) Dystonia reflex sympathetic dystrophy inflammatory response tonic dystonia substance-p spinal-cord symptoms pathophysiology plasticity gain hand
Abstract

About 25% of the patients with complex regional pain syndrome (CRPS) suffer movement disorders, including loss of voluntary control, bradykinesia, dystonia, myoclonus, and tremor. These movement disorders are generally difficult to manage and add considerably to the disease burden. Over the last years, interesting findings have emerged that show how tissue or nerve injury may induce spinal plasticity (central sensitization), which alters sensory transmission and sensorimotor processing in the spinal cord and is associated with disinhibition. These changes, in turn, set the stage for the development of movement disorders seen in CRPS. There are no randomized control studies on the treatment of movement disorders in CRPS but findings from fundamental and clinical research suggest that strategies that enhance the central inhibitory state may benefit these patients.

Published
2010

34. No mutations in the voltage-gated Na(V)1.7 sodium channel alpha 1 subunit gene SCN9A in familial complex regional pain syndrome

Author

Rooij, A.M. de, Gosso, M.F., Alsina-Sanchis, E., Marinus, J., Hilten, J.J. van, and Maagdenberg, A.M.J.M. van den

Subjects
familial CRPS mutation analysis SCN9A gene reflex sympathetic dystrophy inflammatory pain disorder erythromelalgia erythermalgia dystonia sensitivity nociception mechanisms symptoms
Abstract

Background: Mutations in the voltage-gated Na(V)1.7 Na+ channel alpha 1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder. Both show clinical overlap with complex regional pain syndrome (CRPS), a condition that is characterized by pain in association with combinations of vasomotor, sudomotor, sensory, and motor disturbances. Therefore, we here investigated the involvement of the SCN9A gene in familial CRPS. Methods: We performed a mutation analysis of the SCN9A gene in four index cases of families with CRPS. All 26 coding exons and adjacent sequences of the SCN9A gene were analyzed for mutations using direct sequencing analysis. Results: No causal gene mutations were identified in the SCN9A gene in any of the patients. Conclusions: Despite the fact that the SCN9A gene is an excellent candidate, we did not find evidence that it plays a major role in familial CRPS.

Published
2010

35. The Identification of Parkinson's Disease Subtypes Using Cluster Analysis: A Systematic Review

Author

Rooden, S.M. van, Heiser, W.J., Kok, J.N., Verbaan, D., Hilten, J.J. van, and Marinus, J.

Subjects
systematic review Parkinson's disease subtype subgroup cluster analysis data-driven approach neuropsychiatric symptoms heterogeneity dementia psychopathology prevalence
Abstract

The clinical variability between patients with Parkinson's disease (PD) may point at the existence of subtypes of the disease. Identification of subtypes is important, since a focus on homogeneous groups may enhance the chance of success of research on mechanisms of disease and may also lead to tailored treatment strategies. Cluster analysis (CA) is an objective method to classify patients into subtypes. We systematically reviewed the methodology and results of CA studies in PD to gain a better understanding of the robustness of identified subtypes. We found seven studies that fulfilled the inclusion criteria. Studies were limited by incomplete reporting and methodological limitations. Differences between studies rendered comparisons of the results difficult. However, it appeared that studies which applied a comparable design identified similar subtypes. The cluster profiles "old age-at-onset and rapid disease progression" and "young age-at-onset and slow disease progression" emerged from the majority of studies. Other cluster profiles were less consistent across studies. Future studies with a rigorous study design that is standardized with respect to the included variables, data processing, and CA technique may advance the knowledge on subtypes in PD. (C) 2010 Movement Disorder Society

Published
2010

38. 'Nieuwe' middelen voor de behandeling van de ziekte van Parkinson

Author

Hovestadt, A., Berendse, H.W., Bloem, B.R., Boon, A.J., Hilten, J.J. van, Koning-Tijssen, M.A. de, Laar, T. van, Nijssen, P.C., and Weber, W.E.

Subjects
Human Movement & Fatigue [NCEBP 10], Cognitive neurosciences [UMCN 3.2], Functional Neurogenomics [DCN 2]
Abstract

Item does not contain fulltext

Published
2007

40. Normal eyeblink classical conditioning in patients with fixed dystonia

Author

Janssen, S., Veugen, L.C.E., Hoffland, B.S., Kassavetis, P., Rooijen, D.E. van, Stegeman, D.F., Edwards, M.J., Hilten, J.J. van, Warrenburg, B.P.C. van de, Janssen, S., Veugen, L.C.E., Hoffland, B.S., Kassavetis, P., Rooijen, D.E. van, Stegeman, D.F., Edwards, M.J., Hilten, J.J. van, and Warrenburg, B.P.C. van de

Abstract

Item does not contain fulltext, Fixed dystonia without evidence of basal ganglia lesions or neurodegeneration typically affects young women following minor peripheral trauma. We use eyeblink classical conditioning (EBCC) to study whether cerebellar functioning is abnormal in patients with fixed dystonia, since this is part of the pathophysiology of primary dystonia. An auditory tone (conditioning stimulus) was paired with a supraorbital nerve stimulus (unconditioned stimulus) with a delay of 400 ms in order to yield conditioned responses. We recruited 11 fixed dystonia patients of whom six used medication and seven age-matched healthy controls. Non-medicated patients with fixed dystonia performed as well as healthy controls, while medicated patients showed fewer conditioned responses. We found an influence of medication and possibly extent of dystonic features and/or co-occurrence of complex regional pain syndrome (CRPS) on EBCC performance. Our study argues against abnormal cerebellar function in non-medicated, fixed dystonia patients without CRPS or spread of symptoms.

Published
2014

41. Cervical dystonia and genetic common variation in the dopamine pathway

Author

Groen, J.L., Simon-Sanchez, J., Ritz, K., Bochdanovits, Z., Fang, Y., Hilten, J.J. van, Aramideh, M., Warrenburg, B.P.C. van de, Boon, A.J., Baas, F., Heutink, P., Tijssen, M.A., Groen, J.L., Simon-Sanchez, J., Ritz, K., Bochdanovits, Z., Fang, Y., Hilten, J.J. van, Aramideh, M., Warrenburg, B.P.C. van de, Boon, A.J., Baas, F., Heutink, P., and Tijssen, M.A.

Abstract

Item does not contain fulltext, Cervical dystonia, a late onset focal dystonia, has a complex genetic background. Multiple lines of evidence point to a role for aberrant dopamine levels in dystonia. We assessed whether common variation within genes that regulate brain dopamine levels and in key genes of the dopamine metabolic pathway, modulate the risk for cervical dystonia. DNA was collected from 363 Dutch CD patients and a cohort of Dutch control individuals. Haplotype-tagging single nucleotide polymorphisms (SNPs) complemented with selected variants of functional importance in COMT, DAT, TH, MAO-A and -B, DDC and DBH were investigated. We tested the 143 markers in single-SNP, haplotype and epistasis analyses. We did not find an association with any of the selected 143 SNPs in these key dopamine genes. Our data shows that common variations in key genes of the dopamine pathway do not contribute to dystonia risk in the Dutch population. Possibly, risk alleles in this pathway may be rarer than detectable in this study, or might be located in downstream dopamine signaling pathway. Alternatively, found dopamine level changes are secondary to the dystonia disease processes.

Published
2013

42. Mutational analysis of TARDBP in Parkinson's disease

Author

Blitterswijk, M. van, Es, M.A. van, Verbaan, D., Hilten, J.J. van, Scheffer, H., Warrenburg, B.P.C. van de, Veldink, J.H., Berg, L.H. van den, Blitterswijk, M. van, Es, M.A. van, Verbaan, D., Hilten, J.J. van, Scheffer, H., Warrenburg, B.P.C. van de, Veldink, J.H., and Berg, L.H. van den

Abstract

Item does not contain fulltext, Mutations in TAR DNA-binding protein (TARDBP) are associated with heterogenic phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and Parkinson's disease. In this study, we investigated the presence of TARDBP mutations in a cohort of 429 Dutch patients with Parkinson's disease. Though we detected 1 silent mutation, p.S332S, no missense mutations were present in our cohort. Our findings, therefore, demonstrate that TARDBP mutations do not appear to contribute to the pathogenesis of Parkinson's disease in The Netherlands.

Published
2013

43. Association of BDNF Met66Met polymorphism with arm tremor in cervical dystonia.

Author

Groen, J.L., Ritz, K., Velseboer, D.C., Aramideh, M., Hilten, J.J. van, Boon, A.J., Warrenburg, B.P.C. van de, Baas, F., Tijssen, M.P., Groen, J.L., Ritz, K., Velseboer, D.C., Aramideh, M., Hilten, J.J. van, Boon, A.J., Warrenburg, B.P.C. van de, Baas, F., and Tijssen, M.P.

Abstract

1 mei 2012, Item does not contain fulltext

Published
2012

44. Phenotypes and genetic architecture of focal primary torsion dystonia.

Author

Groen, J.L., Kallen, M.C., Warrenburg, B.P.C. van de, Speelman, J.D., Hilten, J.J. van, Aramideh, M., Boon, A.J., Klein, C., Koelman, J.H., Langeveld, T.P., Baas, F., Tijssen, M.A., Groen, J.L., Kallen, M.C., Warrenburg, B.P.C. van de, Speelman, J.D., Hilten, J.J. van, Aramideh, M., Boon, A.J., Klein, C., Koelman, J.H., Langeveld, T.P., Baas, F., and Tijssen, M.A.

Abstract

01 oktober 2012, Item does not contain fulltext, BACKGROUND: The focal primary torsion dystonias (FPTDs) form a group of clinical heterogeneous syndromes and can be considered a genetic complex disease; it is thought to be primed by genetic variants with variable impact and triggered by non-genetic factors. Thorough clinical description of FPTDs cohorts is sparse but essential for further progress in genetic research. OBJECTIVE: To establish suggested relations between age at onset (AaO), site and family history in a large focal dystonias cohort and gain more insight into familial clustering for genetic research. PATIENTS AND METHODS: A prospective cohort study between March 2008 and March 2011, including 676 FPTD patients attending the botulinum toxin outpatient clinics of six Dutch movement disorder centres. RESULTS AND CONCLUSIONS: Of all of the FPTD patients, 25% had a familial predisposition; in 2.4% a Mendelian inheritance pattern was noted. With a stronger family history, a significantly lower AaO was seen in all focal dystonias. In both the sporadic and familial focal dystonia groups, AaO had an effect on the distribution of dystonia, with a caudal to cranial tendency. In all focal dystonia forms, women were more frequently affected, except for writer's cramp. Careful clinical characterisation will allow the formation of phenotype subgroups. We suggest that genetic research into FPTDs will benefit from this approach and discuss genetic research strategies to decipher the complex background of focal dystonias.

Published
2012

45. Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis.

Author

Es, M.A. van, Schelhaas, H.J., Vught, P.W. van, Ticozzi, N., Andersen, P.M., Groen, E.J., Schulte, C., Blauw, H.M., Koppers, M., Diekstra, F.P., Fumoto, K., Leclerc, A.L., Keagle, P., Bloem, B.R., Scheffer, H., Nuenen, B.F.L. van, Blitterswijk, M. van, Rheenen, W. van, Wills, A.M., Lowe, P.P., Hu, G.F., Yu, W., Kishikawa, H., Wu, D., Folkerth, R.D., Mariani, C., Goldwurm, S., Pezzoli, G., Damme, P. van, Lemmens, R., Dahlberg, C., Birve, A., Fernandez-Santiago, R., Waibel, S., Klein, C., Weber, M., Kooi, A.J. van der, Visser, M. de, Verbaan, D., Hilten, J.J. van, Heutink, P., Hennekam, E.A., Cuppen, E., Berg, D., Brown, R.H. Jr., Silani, V., Gasser, T., Ludolph, A.C., Robberecht, W., Ophoff, R.A., Veldink, J.H., Pasterkamp, R.J., Bakker, P.I. de, Landers, J.E., Warrenburg, B.P.C. van de, Berg, L.H. van den, Es, M.A. van, Schelhaas, H.J., Vught, P.W. van, Ticozzi, N., Andersen, P.M., Groen, E.J., Schulte, C., Blauw, H.M., Koppers, M., Diekstra, F.P., Fumoto, K., Leclerc, A.L., Keagle, P., Bloem, B.R., Scheffer, H., Nuenen, B.F.L. van, Blitterswijk, M. van, Rheenen, W. van, Wills, A.M., Lowe, P.P., Hu, G.F., Yu, W., Kishikawa, H., Wu, D., Folkerth, R.D., Mariani, C., Goldwurm, S., Pezzoli, G., Damme, P. van, Lemmens, R., Dahlberg, C., Birve, A., Fernandez-Santiago, R., Waibel, S., Klein, C., Weber, M., Kooi, A.J. van der, Visser, M. de, Verbaan, D., Hilten, J.J. van, Heutink, P., Hennekam, E.A., Cuppen, E., Berg, D., Brown, R.H. Jr., Silani, V., Gasser, T., Ludolph, A.C., Robberecht, W., Ophoff, R.A., Veldink, J.H., Pasterkamp, R.J., Bakker, P.I. de, Landers, J.E., Warrenburg, B.P.C. van de, and Berg, L.H. van den

Abstract

1 december 2011, Contains fulltext : 95644.pdf (publisher's version ) (Closed access), OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973.

Published
2011

46. Genome-wide association study confirms extant PD risk loci among the Dutch

Author

Simon-Sanchez, J., Hilten, J.J. van, Warrenburg, B.P.C. van de, Post, B., Berendse, H.W., Arepalli, S., Hernandez, D.G., Bie, R.M. de, Velseboer, D., Scheffer, H., Bloem, B.R., Dijk, K.D. van, Rivadeneira, F., Hofman, A., Uitterlinden, A.G., Rizzu, P., Bochdanovits, Z., Singleton, A.B., Heutink, P., Simon-Sanchez, J., Hilten, J.J. van, Warrenburg, B.P.C. van de, Post, B., Berendse, H.W., Arepalli, S., Hernandez, D.G., Bie, R.M. de, Velseboer, D., Scheffer, H., Bloem, B.R., Dijk, K.D. van, Rivadeneira, F., Hofman, A., Uitterlinden, A.G., Rizzu, P., Bochdanovits, Z., Singleton, A.B., and Heutink, P.

Abstract

Item does not contain fulltext, In view of the population-specific heterogeneity in reported genetic risk factors for Parkinson's disease (PD), we conducted a genome-wide association study (GWAS) in a large sample of PD cases and controls from the Netherlands. After quality control (QC), a total of 514,799 SNPs genotyped in 772 PD cases and 2024 controls were included in our analyses. Direct replication of SNPs within SNCA and BST1 confirmed these two genes to be associated with PD in the Netherlands (SNCA, rs2736990: P = 1.63 x 10(-5), OR = 1.325 and BST1, rs12502586: P = 1.63 x 10(-3), OR = 1.337). Within SNCA, two independent signals in two different linkage disequilibrium (LD) blocks in the 3' and 5' ends of the gene were detected. Besides, post-hoc analysis confirmed GAK/DGKQ, HLA and MAPT as PD risk loci among the Dutch (GAK/DGKQ, rs2242235: P = 1.22 x 10(-4), OR = 1.51; HLA, rs4248166: P = 4.39 x 10(-5), OR = 1.36; and MAPT, rs3785880: P = 1.9 x 10(-3), OR = 1.19).

Published
2011

47. DYT6 dystonia: mutation screening, phenotype, and response to deep brain stimulation.

Author

Groen, J.L., Ritz, K., Contarino, M.F., Warrenburg, B.P.C. van de, Aramideh, M., Foncke, E.M., Hilten, J.J. van, Schuurman, P.R., Speelman, J.D., Koelman, J.H., Bie, R.M. de, Baas, F., Tijssen, M.A., Groen, J.L., Ritz, K., Contarino, M.F., Warrenburg, B.P.C. van de, Aramideh, M., Foncke, E.M., Hilten, J.J. van, Schuurman, P.R., Speelman, J.D., Koelman, J.H., Bie, R.M. de, Baas, F., and Tijssen, M.A.

Abstract

Contains fulltext : 88049.pdf (publisher's version ) (Closed access), Mutations in THAP1, a gene encoding a nuclear pro-apoptotic protein, have been associated with DYT6 dystonia. First reports on the phenotype of DYT6 dystonia show an early onset dystonia with predominant cranio-cervical and laryngeal involvement. Here we assessed the frequency and phenotype of THAP1 mutation carriers in a large Dutch cohort of adult-onset (>/=26 years) dystonia (n = 388) and early-onset dystonia (n = 67) patients. We describe the phenotype of DYT6 dystonia patients and their response on GPi DBS. Overall, 3 nonsynonymous heterozygous mutations were detected in the early-onset group (4.5%). Two DYT6 families were identified, showing a heterozygous phenotype. All patients had segmental or generalized dystonia, often associated with profound oromandibular and laryngeal involvement. No nonsynonymous mutations were found in patients with adult-onset focal dystonia. Rare synonymous variants were identified in conserved regions of THAP1, two in the adult-onset cervical dystonia group and one in the control group. Four DYT6 dystonia patients were treated with GPi DBS with moderate to good response on motor function but marginal benefit on speech.

Published
2010

48. International study on the psychometric attributes of the non-motor symptoms scale in Parkinson disease.

Author

Martinez-Martin, P., Rodriguez-Blazquez, C., Abe, K., Bhattacharyya, K.B., Bloem, B.R., Carod-Artal, F.J., Prakash, R., Esselink, R.A.J., Falup-Pecurariu, C., Gallardo, M., Mir, P., Naidu, Y., Nicoletti, A., Sethi, K., Tsuboi, Y, Hilten, J.J. van, Visser, M. de, Zappia, M., Chaudhuri, K.R., Martinez-Martin, P., Rodriguez-Blazquez, C., Abe, K., Bhattacharyya, K.B., Bloem, B.R., Carod-Artal, F.J., Prakash, R., Esselink, R.A.J., Falup-Pecurariu, C., Gallardo, M., Mir, P., Naidu, Y., Nicoletti, A., Sethi, K., Tsuboi, Y, Hilten, J.J. van, Visser, M. de, Zappia, M., and Chaudhuri, K.R.

Abstract

Contains fulltext : 80119.pdf (publisher's version ) (Open Access), BACKGROUND: Nonmotor symptoms (NMS) have a great impact on patients with Parkinson disease (PD). The Non-Motor Symptoms Scale (NMSS) is an instrument specifically designed for the comprehensive assessment of NMS in patients with PD. NMSS psychometric properties have been tested in this study. METHODS: Data were collected in 12 centers across 10 countries in America, Asia, and Europe. In addition to the NMSS, the following measures were applied: Scales for Outcomes in Parkinson's Disease (SCOPA)-Motor, SCOPA-Psychiatric Complications (SCOPA-PC), SCOPA-Cognition, Hoehn and Yahr Staging (HY), Clinical Impression of Severity Index for Parkinson's Disease (CISI-PD), SCOPA-Autonomic, Parkinson's Disease Sleep Scale (PDSS), Parkinson's Disease Questionnaire-39 items (PDQ-39), and EuroQol-5 dimensions (EQ-5D). NMSS acceptability, reliability, validity, and precision were analyzed. RESULTS: Four hundred eleven patients with PD, 61.3% men, were recruited. The mean age was 64.5 +/- 9.9 years, and mean disease duration was 8.1 +/- 5.7 years. The NMSS score was 57.1 +/- 44.0 points. The scale was free of floor or ceiling effects. For domains, the Cronbach alpha coefficient ranged from 0.44 to 0.85. The intraclass correlation coefficient (0.90 for the total score, 0.67-0.91 for domains) and Lin concordance coefficient (0.88) suggested satisfactory reproducibility. The NMSS total score correlated significantly with SCOPA-Autonomic, PDQ-39, and EQ-5D (r(S) = 0.57-0.70). Association was close between NMSS domains and the corresponding SCOPA-Autonomic domains (r(S) = 0.51-0.65) and also with scales measuring related constructs (PDSS, SCOPA-PC) (all p < 0.0001). The NMSS total score was higher for women (p < 0.02) and for increasing disease duration, HY, and CISI-PD severity level (p < 0.001). The SEM was 13.91 for total score and 1.71 to 4.73 for domains. CONCLUSION: The Non-Motor Symptoms Scale is an acceptable, reproducible, valid, and precise assessment instrument for nonmotor sym

Published
2009

49. Psychological features of patients with complex regional pain syndrome type I related dystonia

Author

Reedijk, W.B., Rijn, M.A. van, Roelofs, K., Tuijl, J.P., Marinus, J., Hilten, J.J. van, Reedijk, W.B., Rijn, M.A. van, Roelofs, K., Tuijl, J.P., Marinus, J., and Hilten, J.J. van

Abstract

Item does not contain fulltext, The objective of this study Was to evaluate psychological features in severely affected patients with complex regional pain syndrome type I- (CRPS-I) related dystonia. Personality traits. psychopathology. dissociative experiences. the number of traumatic experiences, and quality of life Were studied in 46 patients. Findings were compared with two historical psychiatric control groups [54 patients with conversion disorder (CD) and 50 patients smith affective disorders (AD)] and normative population data. The CRPS-I patients showed elevated scores on the measures for somatoform dissociation. traumatic experiences. general psychopathology. and lower scores on quality of life compared with general Population data. but had significantly lower total scores on the measures for personality trails, recent life events. and general psychopathology compared with the CD and AD patients. Rates of early traumatic experiences were comparable with the CD and AD patients, and the level of somatoform dissociation was comparable to the CD patients, but was elevated in comparison to the AD patients. Early traumatic experiences were reported in 87% of the CRPS-I patients and were found to be moderately related to somatoform dissociative experiences, indicating that early traumatic experiences might be a predisposing, although not a necessary factor for the development of CRPS-I-related dystonia. Although the psychological profile of the patients with CRPS-I-related dystonia shows some elevations, there dose not scent to be a unique disturbed psychological profile on a group level.

Published
2008

50. Effectiveness of physiotherapy in Parkinson's disease: the feasibility of a randomised controlled trial.

Author

Keus, S.H.J., Bloem, B.R., Hilten, J.J. van, Ashburn, A., Munneke, M., Keus, S.H.J., Bloem, B.R., Hilten, J.J. van, Ashburn, A., and Munneke, M.

Abstract

Contains fulltext : 52591.pdf (publisher's version ) (Closed access), To study the feasibility of a large randomised controlled trial (RCT) evaluating the effectiveness of physiotherapy in Parkinson's disease (PD), 173 patients were asked to participate in a study with random allocation to best practice physiotherapy, or to no physiotherapy. The primary outcome measures were the Parkinson's disease questionnaire-39, the Parkinson activity scale, and a patient preference outcome scale (PPOS). Only 14% of the patients could be included in the study. The PPOS showed the largest effect size (0.74) with a significant group effect (p<0.05). Specific alterations to the study design to ensure successful RCTs in this field are recommended.

Published
2007

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