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Parkinson Disease: HELP
Articles by Claudia Schulte
Based on 45 articles published since 2010
(Why 45 articles?)
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Between 2010 and 2020, C. Schulte wrote the following 45 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. 2011

van Es, Michael A / Schelhaas, Helenius J / van Vught, Paul W J / Ticozzi, Nicola / Andersen, Peter M / Groen, Ewout J N / Schulte, Claudia / Blauw, Hylke M / Koppers, Max / Diekstra, Frank P / Fumoto, Katsumi / LeClerc, Ashley Lyn / Keagle, Pamela / Bloem, Bastiaan R / Scheffer, Hans / van Nuenen, Bart F L / van Blitterswijk, Marka / van Rheenen, Wouter / Wills, Anne-Marie / Lowe, Patrick P / Hu, Guo-fu / Yu, Wenhao / Kishikawa, Hiroko / Wu, David / Folkerth, Rebecca D / Mariani, Claudio / Goldwurm, Stefano / Pezzoli, Gianni / Van Damme, Philip / Lemmens, Robin / Dahlberg, Caroline / Birve, Anna / Fernández-Santiago, Rubén / Waibel, Stefan / Klein, Christine / Weber, Markus / van der Kooi, Anneke J / de Visser, Marianne / Verbaan, Dagmar / van Hilten, Jacobus J / Heutink, Peter / Hennekam, Eric A M / Cuppen, Edwin / Berg, Daniela / Brown, Robert H / Silani, Vincenzo / Gasser, Thomas / Ludolph, Albert C / Robberecht, Wim / Ophoff, Roel A / Veldink, Jan H / Pasterkamp, R Jeroen / de Bakker, Paul I W / Landers, John E / van de Warrenburg, Bart P / van den Berg, Leonard H. ·Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands. ·Ann Neurol · Pubmed #22190368.

ABSTRACT: 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 × 10(-6) for ALS and p = 4.3 × 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.

2 Article Genetic modifiers of risk and age at onset in GBA associated Parkinson's disease and Lewy body dementia. 2020

Blauwendraat, Cornelis / Reed, Xylena / Krohn, Lynne / Heilbron, Karl / Bandres-Ciga, Sara / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Kumaran, Ravindran / Langston, Rebekah / Bonet-Ponce, Luis / Alcalay, Roy N / Hassin-Baer, Sharon / Greenbaum, Lior / Iwaki, Hirotaka / Leonard, Hampton L / Grenn, Francis P / Ruskey, Jennifer A / Sabir, Marya / Ahmed, Sarah / Makarious, Mary B / Pihlstrøm, Lasse / Toft, Mathias / van Hilten, Jacobus J / Marinus, Johan / Schulte, Claudia / Brockmann, Kathrin / Sharma, Manu / Siitonen, Ari / Majamaa, Kari / Eerola-Rautio, Johanna / Tienari, Pentti J / Anonymous21571124 / Pantelyat, Alexander / Hillis, Argye E / Dawson, Ted M / Rosenthal, Liana S / Albert, Marilyn S / Resnick, Susan M / Ferrucci, Luigi / Morris, Christopher M / Pletnikova, Olga / Troncoso, Juan / Grosset, Donald / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / Noyce, Alastair J / Masliah, Eliezer / Wood, Nick / Hardy, John / Shulman, Lisa M / Jankovic, Joseph / Shulman, Joshua M / Heutink, Peter / Gasser, Thomas / Cannon, Paul / Scholz, Sonja W / Morris, Huw / Cookson, Mark R / Nalls, Mike A / Gan-Or, Ziv / Singleton, Andrew B. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · 23andMe, Inc., Mountain View, CA, USA. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Sheba Medical Center, Tel Hashomer, Israel. · Movement Disorders Institute, Sheba Medical Center, Tel Hashomer, Israel. · The Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer, Israel. · The Danek Gertner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Neuroregeneration and Stem Cell Program, Institute for Cell Engineering, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA. · Longitudinal Studies Section, National Institute on Aging, Baltimore, MD, USA. · Newcastle Brain Tissue Resource, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. · Department of Pathology (Neuropathology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, UK. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, UK. · Department of Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. · Department of Neurology, Baylor College of Medicine, Houston, USA. · Departments of Molecular and Human Genetics and Neuroscience, Baylor College of Medicine, Houston, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, USA. · Data Tecnica International, Glen Echo, MD, USA. · Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. ·Brain · Pubmed #31755958.

ABSTRACT: Parkinson's disease is a genetically complex disorder. Multiple genes have been shown to contribute to the risk of Parkinson's disease, and currently 90 independent risk variants have been identified by genome-wide association studies. Thus far, a number of genes (including SNCA, LRRK2, and GBA) have been shown to contain variability across a spectrum of frequency and effect, from rare, highly penetrant variants to common risk alleles with small effect sizes. Variants in GBA, encoding the enzyme glucocerebrosidase, are associated with Lewy body diseases such as Parkinson's disease and Lewy body dementia. These variants, which reduce or abolish enzymatic activity, confer a spectrum of disease risk, from 1.4- to >10-fold. An outstanding question in the field is what other genetic factors that influence GBA-associated risk for disease, and whether these overlap with known Parkinson's disease risk variants. Using multiple, large case-control datasets, totalling 217 165 individuals (22 757 Parkinson's disease cases, 13 431 Parkinson's disease proxy cases, 622 Lewy body dementia cases and 180 355 controls), we identified 1691 Parkinson's disease cases, 81 Lewy body dementia cases, 711 proxy cases and 7624 controls with a GBA variant (p.E326K, p.T369M or p.N370S). We performed a genome-wide association study and analysed the most recent Parkinson's disease-associated genetic risk score to detect genetic influences on GBA risk and age at onset. We attempted to replicate our findings in two independent datasets, including the personal genetics company 23andMe, Inc. and whole-genome sequencing data. Our analysis showed that the overall Parkinson's disease genetic risk score modifies risk for disease and decreases age at onset in carriers of GBA variants. Notably, this effect was consistent across all tested GBA risk variants. Dissecting this signal demonstrated that variants in close proximity to SNCA and CTSB (encoding cathepsin B) are the most significant contributors. Risk variants in the CTSB locus were identified to decrease mRNA expression of CTSB. Additional analyses suggest a possible genetic interaction between GBA and CTSB and GBA p.N370S induced pluripotent cell-derived neurons were shown to have decreased cathepsin B expression compared to controls. These data provide a genetic basis for modification of GBA-associated Parkinson's disease risk and age at onset, although the total contribution of common genetics variants is not large. We further demonstrate that common variability at genes implicated in lysosomal function exerts the largest effect on GBA associated risk for disease. Further, these results have implications for selection of GBA carriers for therapeutic interventions.

3 Article Elemental fingerprint: Reassessment of a cerebrospinal fluid biomarker for Parkinson's disease. 2020

Maass, Fabian / Michalke, Bernhard / Willkommen, Desiree / Leha, Andreas / Schulte, Claudia / Tönges, Lars / Mollenhauer, Brit / Trenkwalder, Claudia / Rückamp, Daniel / Börger, Matthias / Zerr, Inga / Bähr, Mathias / Lingor, Paul. ·Department of Neurology, University Medical Center Goettingen, Germany. Electronic address: fabian.maass@med.uni-goettingen.de. · Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Zentrum Munich, Neuherberg, Germany. Electronic address: bernhard.michalke@helmholtz-muenchen.de. · Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Zentrum Munich, Neuherberg, Germany. Electronic address: desi.willkommen@gmx.de. · Department of Medical Statistics, University Medical Center, Goettingen, Germany. Electronic address: andreas.leha@med.uni-goettingen.de. · DZNE, German Center for Neurodegenerative Diseases, University of Tuebingen, Germany; Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Germany. Electronic address: claudia.schulte@uni-tuebingen.de. · Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Bochum, Germany. Electronic address: lars.toenges@rub.de. · Department of Neurology, University Medical Center Goettingen, Germany; Paracelsus-Elena-Klinik, Kassel, Germany. Electronic address: brit.mollenhauer@med.uni-goettingen.de. · Paracelsus-Elena-Klinik, Kassel, Germany; Dept. Neurosurgery, University Medical Center, Goettingen, Germany. · Federal Institute for Geosciences and Natural Resources, Hannover, Germany. Electronic address: daniel.rueckamp@bgr.de. · Department of Neurology, University Medical Center Goettingen, Germany. Electronic address: matthias.boerger@med.uni-goettingen.de. · Department of Neurology, University Medical Center Goettingen, Germany; DZNE, German Center for Neurodegenerative Diseases Goettingen, Germany. Electronic address: ingazerr@med.uni-goettingen.de. · Department of Neurology, University Medical Center Goettingen, Germany; Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Goettingen, Germany. Electronic address: mbaehr@gwdg.de. · Department of Neurology, University Medical Center Goettingen, Germany; DZNE, German Center for Neurodegenerative Diseases Goettingen, Germany; Cluster of Excellence Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB), Goettingen, Germany; Center for Biostructural Imaging of Neurodegeneration (BIN), University Medical Center Goettingen, Germany; Department of Neurology, Klinikum rechts der Isar, School of Medicine, Technical University Munich, 81675 Munich, Germany. Electronic address: paul.lingor@tum.de. ·Neurobiol Dis · Pubmed #31733347.

ABSTRACT: The aim of the study was to validate a predictive biomarker machine learning model for the classification of Parkinson's disease (PD) and age-matched controls (AMC), based on bioelement abundance in the cerebrospinal fluid (CSF). For this multicentric trial, participants were enrolled from four different centers. CSF was collected according to standardized protocols. For bioelement determination, CSF samples were subjected to inductively coupled plasma mass spectrometry. A predefined Support Vector Machine (SVM) model, trained on a previous discovery cohort was applied for differentiation, based on the levels of six different bioelements. 82 PD patients, 68 age-matched controls and 7 additional Normal Pressure Hydrocephalus (NPH) patients were included to validate a predefined SVM model. Six differentiating elements (As, Fe, Mg, Ni, Se, Sr) were quantified. Based on their levels, SVM was successfully applied to a new local cohort (AUROC 0.76, Sensitivity 0.80, Specificity 0.83), without taking any additional features into account. The same model did not discriminate PD and AMCs / NPH from three external cohorts, likely due to center effects. However, discrimination was possible in cohorts with a full elemental data set, now using center-specific discovery cohorts and a cross validated approach (AUROC 0.78 and 0.88, respectively). Pooled PD CSF iron levels showed a clear correlation with disease duration (p = .0001). In summary, bioelemental CSF patterns, obtained by mass spectrometry and integrated into a predictive model yield the potential to facilitate the differentiation of PD and AMC. Center-specific biases interfere with application in external cohorts. This must be carefully addressed using center-defined, local reference values and models.

4 Article Selenium speciation analysis in the cerebrospinal fluid of patients with Parkinson's disease. 2020

Maass, Fabian / Michalke, Bernhard / Willkommen, Desiree / Schulte, Claudia / Tönges, Lars / Boerger, Matthias / Zerr, Inga / Bähr, Mathias / Lingor, Paul. ·Department of Neurology, University Medical Center, Göttingen, Germany. Electronic address: fabian.maass@med.uni-goettingen.de. · Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. Electronic address: bernhard.michalke@helmholtz-muenchen.de. · Research Unit Analytical BioGeoChemistry, German Research Center for Environmental Health, Helmholtz Zentrum München, Neuherberg, Germany. Electronic address: desi.willkommen@gmx.de. · German Center for Neurodegenerative Diseases, University of Tübingen, Germany; Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany. Electronic address: claudia.schulte@uni-tuebingen.de. · Department of Neurology, Ruhr-University Bochum, St. Josef-Hospital, Bochum, Germany. Electronic address: lars.toenges@rub.de. · Department of Neurology, University Medical Center, Göttingen, Germany. Electronic address: matthias.boerger@med.uni-goettingen.de. · Department of Neurology, University Medical Center, Göttingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Göttingen, Germany. Electronic address: inga.zerr@med.uni-goettingen.de. · Department of Neurology, University Medical Center, Göttingen, Germany. Electronic address: mbaehr@gwdg.de. · Department of Neurology, University Medical Center, Göttingen, Germany; DZNE, German Center for Neurodegenerative Diseases, Göttingen, Germany; Center for Biostructural Imaging of Neurodegeneration (BIN), University of Göttingen Medical Center, Göttingen, Germany; Technical University of Munich, School of Medicine, Klinikum rechts der Isar, Department of Neurology, München, Germany. Electronic address: paul.lingor@tum.de. ·J Trace Elem Med Biol · Pubmed #31582281.

ABSTRACT: BACKGROUND: The aim of the study was to investigate if speciation analysis by liquid chromatography coupled to mass spectrometry could be used to detect organic and inorganic binding forms of selenium in the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and age-matched control subjects (AMC). METHODS: PD patients and control subjects were enrolled from three different neurological departments. CSF samples were collected according to standardized biomarker protocols and subjected to inductively coupled plasma mass spectrometry (ICP-MS) for total selenium determination and ion exchange chromatography (IEC) hyphenated to ICP-MS for selenium speciation analysis. RESULTS: 75 PD patients and 68 age-matched controls were enrolled for speciation analysis. 8 different species could be detected, but only selenoprotein P (SELENOP), human serum albumin-bound Se (Se-HSA), selenomethionine (Se-Met) and an unidentified Se-compound (U2) presented with more than 50% values above the limit of quantification, without showing significant differences between both groups (p > 0.05). The Se-HSA / Se-Met ratio yielded a significant difference between PD and AMC (p = 0.045). The inorganic species Se-IV and Se-VI were only detectable in a minor part of PD and AMC samples. A highly significant correlation between total selenium levels and SELENOP (PD p < 0.0001; AMC p < 0.0001) and Se-HSA (PD p < 0.0001; AMC p < 0.0001) could be demonstrated, respectively. CONCLUSIONS: Speciation analysis yielded new insight into selenium homeostasis in PD but cannot be used to establish a diagnostic biomarker. The small number of detectable values for Se-IV and Se-VI suggests an inferior role of these potentially neurotoxic binding forms in PD pathology in contrast to other neurodegenerative disorders.

5 Article Alterations in Blood Monocyte Functions in Parkinson's Disease. 2019

Nissen, Sara Konstantin / Shrivastava, Kalpana / Schulte, Claudia / Otzen, Daniel Erik / Goldeck, David / Berg, Daniela / Møller, Holger Jon / Maetzler, Walter / Romero-Ramos, Marina. ·DANDRITE & Department of Biomedicine, Aarhus University, Aarhus, Denmark. · Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen & German Center for Neurodegenerative Diseases, Tuebingen, Germany. · Department of Molecular Biology and Genetics & iNANO, Aarhus University, Aarhus, Denmark. · Department of Internal Medicine II, Centre for Medical Research, University of Tuebingen, Tuebingen, Germany. · Department of Neurology, Christian-Albrechts University, Kiel, Germany. · Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus, Denmark. ·Mov Disord · Pubmed #31449711.

ABSTRACT: BACKGROUND: PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied. OBJECTIVES: The purpose of this study was to investigate the PD-related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression. METHODS: Using flow cytometry, we investigated the monocytic population in peripheral blood mononuclear cells from PD patients and healthy individuals. We also evaluated the in vitro response to inflammogen lipopolysaccharides and to fibrillar α-synuclein by measuring the expression of CD14, CD163, and HLA-DR and by analysis of soluble immune-related molecules in the supernatant. RESULTS: Peripheral blood immune cells from PD patients had lower survival in culture, but showed a higher monocytic proliferative ability than control cells, which was correlated with shorter disease duration and late disease onset. In addition, PD patients' cells were less responsive to stimulation, as shown by the lack of changes in CD163 and CD14 expression, and by the absence of significant upregulation of anti-inflammatory cytokines in culture. Moreover, PD peripheral immune cells shed lower in vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells. Interestingly, some of the results were sex associated, supporting a differential immune response in females versus males. CONCLUSIONS: Our data suggest that PD involves monocytic changes in blood. These cells show reduced viability and are unresponsive to specific stimuli, which might have a relevant consequence for disease progression. © 2019 International Parkinson and Movement Disorder Society.

6 Article No association between Parkinson disease and autoantibodies against NMDA-type glutamate receptors. 2019

Hopfner, Franziska / Müller, Stefanie H / Steppat, Dagmar / Miller, Joanna / Schmidt, Nele / Wandinger, Klaus-Peter / Leypoldt, Frank / Berg, Daniela / Franke, Andre / Lieb, Wolfgang / Tittmann, Lukas / Balzer-Geldsetzer, Monika / Baudrexel, Simon / Dodel, Richard / Hilker-Roggendorf, Ruediger / Kalbe, Elke / Kassubek, Jan / Klockgether, Thomas / Liepelt-Scarfone, Inga / Mollenhauer, Brit / Neuser, Petra / Reetz, Kathrin / Riedel, Oliver / Schulte, Claudia / Schulz, Jörg B / Spottke, Annika / Storch, Alexander / Trenkwalder, Claudia / Wittchen, Hans-Ulrich / Witt, Karsten / Wüllner, Ullrich / Deuschl, Günther / Kuhlenbäumer, Gregor. ·1Department of Neurology, University Hospital Schleswig Holstein, Arnold-Heller Str. 3, 24105 Kiel, Germany. · 0000 0004 0646 2097 · grid.412468.d · 27Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Nußbaumstraße 7, 80336 München, Germany. · 0000 0004 1936 973X · grid.5252.0 · 2Center of Blood Transfusion, University Hospital Schleswig Holstein, Kiel & Lübeck, Germany. · 3Department of Clinical Chemistry, University Hospital Schleswig-Holstein, Kiel, Germany. · 14Center for Neurology, Hertie Institute for Clinical Brain Research, Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. · 0000 0001 2190 1447 · grid.10392.39 · 15DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. · 0000 0004 0438 0426 · grid.424247.3 · 4Institute of Clinical Molecular Biology, University Hospital Schleswig-Holstein, Kiel, Germany. · 5Institute of Epidemiology, University Hospital Schleswig-Holstein, Kiel, Germany. · 6Chair of Geriatric Medicine, University Hospital Essen, Essen, Germany. · 0000 0001 0262 7331 · grid.410718.b · 7Department of Neurology, Philipps-University Marburg, Marburg, Germany. · 0000 0004 1936 9756 · grid.10253.35 · 8Department of Neurology, Goethe University, Frankfurt/Main, Germany. · 0000 0004 1936 9721 · grid.7839.5 · 9Brain Imaging Center, Goethe University, Frankfurt/Main, Germany. · 10Department of Medical Psychology | Neuropsychology and Gender Studies & Center for Neuropsychological Diagnostics and Intervention (CeNDI), University Hospital Cologne, Cologne, Germany. · 0000 0000 8852 305X · grid.411097.a · 11Psychological Gerontology, Institute of Gerontology, University of Vechta, Vechta, Germany. · 0000 0001 0742 8825 · grid.449789.f · 12Department of Neurology, University of Ulm, Ulm, Germany. · 0000 0004 1936 9748 · grid.6582.9 · 13Department of Neurology, University of Bonn, and German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. · 0000 0001 2240 3300 · grid.10388.32 · 16Paracelsus-Elena-Klinik, Kassel, Germany. · grid.440220.0 · 17Institute of Neuropathology and Department of Neurosurgery, University Medical Center Göttingen, Göttingen, Germany. · 0000 0001 0482 5331 · grid.411984.1 · 18Coordinating Centre for Clinical Trials, Philipps-University, Marburg, Germany. · 19Department of Neurology, RWTH Aachen University, Aachen, Germany. · 0000 0001 0728 696X · grid.1957.a · 20JARA-BRAIN Institute of Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany. · 21Leibniz Institute for Prevention Research and Epidemiology - BIPS, Achterstrasse 30, 28359 Bremen, Germany. · 0000 0000 9750 3253 · grid.418465.a · 22Department of Neurology, Technische Universität Dresden, 01307 Dresden, Germany. · 0000 0001 2111 7257 · grid.4488.0 · 23German Center for Neurodegenerative Diseases (DZNE), Research Site Rostock, 18147 Rostock, Germany. · 24Department of Neurology, University of Rostock, 18147 Rostock, Germany. · 0000000121858338 · grid.10493.3f · 25Technische Universtität Dresden, Institute of Clinical Psychology and Psychotherapy, Chemnitzer Str. 46, 01187 Dresden, Germany. · 26Technische Universtität Dresden, Center for Epidemiological and Longitudinal Studies (CELOS), Chemnitzer Str. 46, 01187 Dresden, Germany. · 28Department of Neurology, European Medical School, University Oldenburg, Oldenburg, Germany. · 0000 0001 1009 3608 · grid.5560.6 · 29Research Center Neurosensory Science, Carl von Ossietzky University Oldenburg, Oldenburg, Germany. ·Transl Neurodegener · Pubmed #30984390.

ABSTRACT: Background: IgG-class autoantibodies to N-Methyl-D-Aspartate (NMDA)-type glutamate receptors define a novel entity of autoimmune encephalitis. Studies examining the prevalence of NMDA IgA/IgM antibodies in patients with Parkinson disease with/without dementia produced conflicting results. We measured NMDA antibodies in a large, well phenotyped sample of Parkinson patients without and with cognitive impairment ( Methods: NMDA antibodies were analysed in the serum of patients and controls using well established validated assays. We used anti-NMDA antibody positivity as the main independent variable and correlated it with disease status and phenotypic characteristics. Results: The frequency of NMDA IgA/IgM antibodies was lower in Parkinson patients (13%) than in controls (22%) and higher than in previous studies in both groups. NMDA IgA/IgM antibodies were neither significantly associated with diagnostic subclasses of Parkinson disease according to cognitive impairment, nor with quantitative indicators of disease severity and cognitive impairment. A positive NMDA antibody status was positively correlated with age in controls but not in Parkinson patients. Conclusion: It is unlikely albeit not impossible that NMDA antibodies play a significant role in the pathogenesis or progression of Parkinson disease e.g. to Parkinson disease with dementia, while NMDA IgG antibodies define a separate disease of its own.

7 Article Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and α-synuclein mechanisms. 2019

Blauwendraat, Cornelis / Heilbron, Karl / Vallerga, Costanza L / Bandres-Ciga, Sara / von Coelln, Rainer / Pihlstrøm, Lasse / Simón-Sánchez, Javier / Schulte, Claudia / Sharma, Manu / Krohn, Lynne / Siitonen, Ari / Iwaki, Hirotaka / Leonard, Hampton / Noyce, Alastair J / Tan, Manuela / Gibbs, J Raphael / Hernandez, Dena G / Scholz, Sonja W / Jankovic, Joseph / Shulman, Lisa M / Lesage, Suzanne / Corvol, Jean-Christophe / Brice, Alexis / van Hilten, Jacobus J / Marinus, Johan / Anonymous861129 / Eerola-Rautio, Johanna / Tienari, Pentti / Majamaa, Kari / Toft, Mathias / Grosset, Donald G / Gasser, Thomas / Heutink, Peter / Shulman, Joshua M / Wood, Nicolas / Hardy, John / Morris, Huw R / Hinds, David A / Gratten, Jacob / Visscher, Peter M / Gan-Or, Ziv / Nalls, Mike A / Singleton, Andrew B / Anonymous871129. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · 23andMe, Inc., Mountain View, California, USA. · Institute for Molecular Bioscience, The University of Queensland, Brisbane, Australia. · Department of Neurology, University of Maryland School of Medicine, Baltimore, Maryland, USA. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tubingen, Germany. · Department of Human Genetics, McGill University, Montreal, Quebec, Canada. · Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada. · Institute of Clinical Medicine, Department of Neurology, University of Oulu, Oulu, Finland. · Department of Neurology and Medical Research Center, Oulu University Hospital, Oulu, Finland. · The Michael J Fox Foundation for Parkinson's Research, New York, New York, USA. · Preventive Neurology Unit, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, United Kingdom. · Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA. · Inserm U1127, Sorbonne Universités, UPMC Univ Paris 06 UMR S1127, Institut du Cerveau et de la Moelle épinière, ICM, Paris, France. · Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. · Department of Neurology, Helsinki University Hospital, and Molecular Neurology, Research Programs Unit, Biomedicum, University of Helsinki, Helsinki, Finland. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom. · Departments of Molecular & Human Genetics and Neuroscience, Baylor College of Medicine, Houston, Texas, USA. · Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, USA. · Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom. · Mater Research, Translational Research Institute, Brisbane, Queensland, Australia. · Queensland Brain Institute, The University of Queensland, Brisbane, Australia. · Department of Neurology & Neurosurgery, McGill University, Montreal, Quebec, Canada. · Data Tecnica International, Glen Echo, Maryland, USA. ·Mov Disord · Pubmed #30957308.

ABSTRACT: BACKGROUND: Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. OBJECTIVES: To identify the genetic determinants of PD age at onset. METHODS: Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. RESULTS: We estimated that the heritability of PD age at onset attributed to common genetic variation was ∼0.11, lower than the overall heritability of risk for PD (∼0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in α-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. CONCLUSIONS: Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. © 2019 International Parkinson and Movement Disorder Society.

8 Article Parkinson's disease: evolution of cognitive impairment and CSF Aβ 2019

Lerche, Stefanie / Wurster, Isabel / Röben, Benjamin / Machetanz, Gerrit / Zimmermann, Milan / Bernhard, Felix / Stransky, Elke / Deuschle, Christian / Schulte, Claudia / Hansson, Oskar / Zetterberg, Henrik / Gasser, Thomas / Berg, Daniela / Maetzler, Walter / Brockmann, Kathrin. ·Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany stefanie.lerche@uni-tuebingen.de. · German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany. · Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden. · Department of Neurology, Skåne University Hospital, Lund, Sweden. · Memory Clinic, Skåne University Hospital, Malmö, Sweden. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, UK. · Department of Neurology, Christian-Albrechts University, Kiel, Germany. ·J Neurol Neurosurg Psychiatry · Pubmed #30254084.

ABSTRACT: OBJECTIVE: To evaluate the evolution of cognitive impairment in relation to cerebrospinal fluid (CSF) profiles of amyloid-β (Aβ), total-Tau and phosphorylated-Tau in Parkinson's disease (PD). METHODS: Prospective, longitudinal, observational study up to 10 years with follow-up every 2  years. We assessed CSF profiles in 415 patients with sporadic PD (median age 66; 63% men) and 142 healthy controls (median age 62; 43% men). RESULTS: Patients with PD with low CSF Aβ CONCLUSION: We conclude that in patients with sporadic PD, low levels of Aβ

9 Article Patient's perception: shorter and more severe prodromal phase in GBA-associated PD. 2019

Zimmermann, M / Gaenslen, A / Prahl, K / Srulijes, K / Hauser, A-K / Schulte, C / Csoti, I / Berg, D / Brockmann, K. ·Department of Neurodegeneration, Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tuebingen, Germany. · Gertrudis Klinik, Leun-Biskirchen, Germany. · Department of Neurology, Christian-Albrechts-University of Kiel, Kiel, Germany. ·Eur J Neurol · Pubmed #30107068.

ABSTRACT: BACKGROUND: Prevalence and time of occurrence of prodromal symptoms of Parkinson's disease (PD) in relation to the onset of classical motor manifestation varies between patients. Possible modifying factors might be different genetic architectures predisposing to varying burden of manifestations. OBJECTIVES: To characterize the prodromal phase in PD patients with heterozygous mutations in the GBA gene compared to PD patients without GBA mutation. METHODS: In a retrospective design, 151 participants [47 PD patients carrying a GBA mutation (PD RESULTS: PD CONCLUSION: The short and severe prodromal phase in PD

10 Article Evaluation of cerebrospinal fluid proteins as potential biomarkers for early stage Parkinson's disease diagnosis. 2018

Dos Santos, Marcia Cristina T / Scheller, Dieter / Schulte, Claudia / Mesa, Irene R / Colman, Peter / Bujac, Sarah R / Bell, Rosie / Berteau, Caroline / Perez, Luis Tosar / Lachmann, Ingolf / Berg, Daniela / Maetzler, Walter / Nogueira da Costa, Andre. ·Translational Medicine, UCB Biopharma SPRL, Braine L'Alleud, Belgium. · Consultancy Neuropharm, Neuss, Germany. · Hertie Institute for Clinical Brain Research, Department of Neurodegeneration, University of Tuebingen and German Center for Neurodegenerative Diseases, Tuebingen, Germany. · Exploratory Statistics, Global Exploratory Development, UCB Pharma SA, Slough, United Kingdom. · Bioanalytical Sciences, Non Clinical Development, UCB Biopharma SPRL, Braine L'Alleud, Belgium. · Research and Development, Analytik Jena, Jena, Germany. · Department of Neurology, Christian-Albrechts-University Kiel, Kiel, Germany. ·PLoS One · Pubmed #30383831.

ABSTRACT: Cerebrospinal fluid (CSF) has often been used as the source of choice for biomarker discovery with the goal to support the diagnosis of neurodegenerative diseases. For this study, we selected 15 CSF protein markers which were identified in previously published clinical investigations and proposed as potential biomarkers for PD diagnosis. We aimed at investigating and confirming their suitability for early stage diagnosis of the disease. The current study was performed in a two-fold confirmatory approach. Firstly, the CSF protein markers were analysed in confirmatory cohort I comprising 80 controls and 80 early clinical PD patients. Through univariate analysis we found significant changes of six potential biomarkers (α-syn, DJ-1, Aβ42, S100β, p-Tau and t-Tau). In order to increase robustness of the observations for potential patient differentiation, we developed-based on a machine learning approach-an algorithm which enabled identifying a panel of markers which would improve clinical diagnosis. Based on that model, a panel comprised of α-syn, S100β and UCHL1 were suggested as promising candidates. Secondly, we aimed at replicating our observations in an independent cohort (confirmatory cohort II) comprising 30 controls and 30 PD patients. The univariate analysis demonstrated Aβ42 as the only reproducible potential biomarker. Taking into account both technical and clinical aspects, these observations suggest that the large majority of the investigated CSF proteins currently proposed as potential biomarkers lack robustness and reproducibility in supporting diagnosis in the early clinical stages of PD.

11 Article Polygenic load: Earlier disease onset but similar longitudinal progression in Parkinson's disease. 2018

Lerche, Stefanie / Liepelt-Scarfone, Inga / Wurster, Isabel / Schulte, Claudia / Schäffer, Eva / Röben, Benjamin / Machetanz, Gerrit / Zimmermann, Milan / Akbas, Selda / Hauser, Ann-Kathrin / Gasser, Thomas / Maetzler, Walter / Berg, Daniela / Brockmann, Kathrin. ·Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany. · Department of Neurology, Christian-Albrechts-University, Kiel, Germany. ·Mov Disord · Pubmed #30132985.

ABSTRACT: OBJECTIVES: In order to evaluate the influence of the genetic load of 49 genetic variants known to be associated with PD on the age at onset as well as on clinical outcome parameters. BACKGROUND: PD patients show a large variability in phenotype and progression reflecting interindividual heterogeneity. This might be influenced by a diverse genetic architecture. METHODS: Six hundred seventeen PD patients were included in this study and stratified by their "genetic load," which is based on the weighted odds ratios of 49 genetic variants known to be associated with PD from genome-wide association studies. Clinical parameters (H & Y, UPDRS-III, MMSE, and Beck's Depression Inventory) were evaluated cross-sectionally and in a subgroup longitudinally over 8 years. RESULTS: PD patients with the highest genetic load were younger at disease onset, whereas severity of clinical parameters were similar compared to patients with the lowest genetic load. These findings could be confirmed regarding progression to clinical endpoints in the longitudinal analysis. CONCLUSION: A high genetic load is associated with a younger age at onset, which, in turn, might possibly promote more effective compensatory mechanisms resulting in a similar rate of disease progression. © 2018 International Parkinson and Movement Disorder Society.

12 Article Frequency of Loss of Function Variants in LRRK2 in Parkinson Disease. 2018

Blauwendraat, Cornelis / Reed, Xylena / Kia, Demis A / Gan-Or, Ziv / Lesage, Suzanne / Pihlstrøm, Lasse / Guerreiro, Rita / Gibbs, J Raphael / Sabir, Marya / Ahmed, Sarah / Ding, Jinhui / Alcalay, Roy N / Hassin-Baer, Sharon / Pittman, Alan M / Brooks, Janet / Edsall, Connor / Hernandez, Dena G / Chung, Sun Ju / Goldwurm, Stefano / Toft, Mathias / Schulte, Claudia / Bras, Jose / Wood, Nicholas W / Brice, Alexis / Morris, Huw R / Scholz, Sonja W / Nalls, Mike A / Singleton, Andrew B / Cookson, Mark R / Anonymous7931112. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland. · Department of Molecular Neurosciences, Institute of Neurology, University College London (UCL), London, United Kingdom. · Department of Human Genetics, McGill University, Montréal, Quebec, Canada. · Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. · Institut National de la Santé et de la Recherche Medicale U1127, Centre National de la Recherche Scientifique-Unité Mixte de Recherché (UMR) 7225, Sorbonne Universités, Université Pierre-et-Marie-Curie, University of Paris 06, UMR S1127, Institut du Cerveau et de la Moelle Épinière, Paris, France. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Dementia Research Institute, UCL, London, United Kingdom. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom. · Department of Medical Sciences and Institute for Research in Biomedicine, University of Aveiro, Aveiro, Portugal. · Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York. · Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York. · Movement Disorders Institute, Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, Tel-Hashomer, Ramat Gan, Israel. · Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. · Parkinson Institute of Milan, Azienda Socio Sanitaria Territoriale Gaetano Pini/CTO, Milano, Italy. · Department of Neuroscience, Rita Levi Montalcini, University of Turin, Turin, Italy. · Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, United Kingdom. · Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland. · Data Tecnica International, Glen Echo, Maryland. ·JAMA Neurol · Pubmed #30039155.

ABSTRACT: Importance: Pathogenic variants in LRRK2 are a relatively common genetic cause of Parkinson disease (PD). Currently, the molecular mechanism underlying disease is unknown, and gain and loss of function (LOF) models of pathogenesis have been postulated. LRRK2 variants are reported to result in enhanced phosphorylation of substrates and increased cell death. However, the double knockout of Lrrk2 and its homologue Lrrk1 results in neurodegeneration in a mouse model, suggesting that disease may occur by LOF. Because LRRK2 inhibitors are currently in development as potential disease-modifying treatments in PD, it is critical to determine whether LOF variants in LRRK2 increase or decrease the risk of PD. Objective: To determine whether LRRK1 and LRRK2 LOF variants contribute to the risk of developing PD. Design, Setting, and Participants: To determine the prevailing mechanism of LRRK2-mediated disease in human populations, next-generation sequencing data from a large case-control cohort (>23 000 individuals) was analyzed for LOF variants in LRRK1 and LRRK2. Data were generated at 5 different sites and 5 different data sets, including cases with clinically diagnosed PD and neurologically normal control individuals. Data were collected from 2012 through 2017. Main Outcomes and Measures: Frequencies of LRRK1 and LRRK2 LOF variants present in the general population and compared between cases and controls. Results: Among 11 095 cases with PD and 12 615 controls, LRRK1 LOF variants were identified in 0.205% of cases and 0.139% of controls (odds ratio, 1.48; SE, 0.571; 95% CI, 0.45-4.44; P = .49) and LRRK2 LOF variants were found in 0.117% of cases and 0.087% of controls (odds ratio, 1.48; SE, 0.431; 95% CI, 0.63-3.50; P = .36). All association tests suggested lack of association between LRRK1 or LRRK2 variants and PD. Further analysis of lymphoblastoid cell lines from several heterozygous LOF variant carriers found that, as expected, LRRK2 protein levels are reduced by approximately half compared with wild-type alleles. Conclusions and Relevance: Together these findings indicate that haploinsufficiency of LRRK1 or LRRK2 is neither a cause of nor protective against PD. Furthermore, these results suggest that kinase inhibition or allele-specific targeting of mutant LRRK2 remain viable therapeutic strategies in PD.

13 Article Insufficient evidence for pathogenicity of SNCA His50Gln (H50Q) in Parkinson's disease. 2018

Blauwendraat, Cornelis / Kia, Demis A / Pihlstrøm, Lasse / Gan-Or, Ziv / Lesage, Suzanne / Gibbs, J Raphael / Ding, Jinhui / Alcalay, Roy N / Hassin-Baer, Sharon / Pittman, Alan M / Brooks, Janet / Edsall, Connor / Chung, Sun Ju / Goldwurm, Stefano / Toft, Mathias / Schulte, Claudia / Anonymous2670935 / Hernandez, Dena / Singleton, Andrew B / Nalls, Mike A / Brice, Alexis / Scholz, Sonja W / Wood, Nicholas W. ·Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA. · Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK. · Department of Neurology, Oslo University Hospital, Oslo, Norway. · Department of Human Genetics, McGill University, Montréal, Quebec, Canada; Department of Neurology & Neurosurgery, Montreal Neurological Institute, McGill University, Montréal, Quebec, Canada. · Inserm U1127, CNRS UMR7225, Sorbonne Universités, UPMC Univ Paris 06, UMR_S1127, Institut du Cerveau et de la Moelle épinière, Paris, France. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Neurology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA. · Department of Neurology and Sagol Neuroscience Center, Chaim Sheba Medical Center, The Movement Disorders Institute, Tel-Hashomer, Ramat Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. · Parkinson Institute of Milan, ASST "Gaetano Pini/CTO", Milano, Italy; Department of Neuroscience, "Rita Levi Montalcini", University of Turin, Italy. · Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; Founder/Consultant with Data Tecnica International, Glen Echo, MD, USA. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurology, Johns Hopkins University Medical Center, Baltimore, MD, USA. · Department of Molecular Neurosciences, Institute of Neurology, University College London, London, UK. Electronic address: n.wood@ucl.ac.uk. ·Neurobiol Aging · Pubmed #29398121.

ABSTRACT: SNCA missense mutations are a rare cause of autosomal dominant Parkinson's disease (PD). To date, 6 missense mutations in SNCA have been nominated as causal. Here, we assess the frequency of these 6 mutations in public population databases and PD case-control data sets to determine their true pathogenicity. We found that 1 of the 6 reported SNCA mutations, His50Gln, was consistently identified in large population databases, and no enrichment was evident in PD cases compared to controls. These results suggest that His50Gln is probably not a pathogenic variant. This information is important to provide counseling for His50Gln carriers and has implications for the interpretation of His50Gln α-synuclein functional investigations.

14 Article SNPs in Aβ clearance proteins: Lower CSF Aβ 2017

Brockmann, Kathrin / Lerche, Stefanie / Dilger, Sarah Selina / Stirnkorb, Johannes Georg / Apel, Anja / Hauser, Ann-Kathrin / Liepelt-Scarfone, Inga / Berg, Daniela / Gasser, Thomas / Schulte, Claudia / Maetzler, Walter. ·From the Center of Neurology, Department of Neurodegenerative Diseases, and Hertie Institute for Clinical Brain Research (K.B., S.L., S.S.D., J.G.S., A.A., A.-K.H., I.L.-S., D.B., T.G., C.S., W.M.), and German Center for Neurodegenerative Diseases (DZNE) (K.B., S.L., A.A., A.-K.H., I.L.-S., T.G., C.S.), University of Tübingen · and Department of Neurology (D.B., W.M.), Christian-Albrechts University, Kiel, Germany. ·Neurology · Pubmed #29117956.

ABSTRACT: OBJECTIVE: To evaluate whether genetic variants in β-amyloid (Aβ) clearance proteins are associated with CSF levels of Aβ METHODS: We analyzed genetic variants known to be involved in Aβ clearance in a PD group comprising 456 patients, 103 of them with dementia. Single nucleotide polymorphisms in the genes RESULTS: Risk variants in the genes CONCLUSIONS: This study suggests that genetic variants associated with Aβ clearance are involved in the pathogenesis of dementia in PD and possibly influence the onset of dementia.

15 Article Cognitive impairment in Glucocerebrosidase (GBA)-associated PD: Not primarily associated with cerebrospinal fluid Abeta and Tau profiles. 2017

Lerche, Stefanie / Schulte, Claudia / Srulijes, Karin / Pilotto, Andrea / Rattay, Tim W / Hauser, Ann-Kathrin / Stransky, Elke / Deuschle, Christian / Csoti, Ilona / Lachmann, Ingolf / Zetterberg, Henrik / Liepelt-Scarfone, Inga / Gasser, Thomas / Maetzler, Walter / Berg, Daniela / Brockmann, Kathrin. ·Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. · German Center for Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Germany. · Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. · Gertrudis Klinik, Parkinson-Center, Leun-Biskirchen, Germany. · AJ Roboscreen GmbH, Leipzig, Germany. · Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden. · Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Department of Neurology, Christian-Albrechts University, Kiel, Germany. ·Mov Disord · Pubmed #29094781.

ABSTRACT: BACKGROUND: A proportion of idiopathic Parkinson's disease patients (PD OBJECTIVE: The objective of this study was to evaluate whether CSF profiles of Aβ and tau are associated with the prominent cognitive impairment in PD METHODS: CSF levels of Aβ RESULTS: Older age was associated with cognitive impairment in PD CONCLUSIONS: The prominent cognitive impairment in PD

16 Article Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson's disease. 2017

Fitzgerald, Julia C / Zimprich, Alexander / Carvajal Berrio, Daniel A / Schindler, Kevin M / Maurer, Brigitte / Schulte, Claudia / Bus, Christine / Hauser, Anne-Kathrin / Kübler, Manuela / Lewin, Rahel / Bobbili, Dheeraj Reddy / Schwarz, Lisa M / Vartholomaiou, Evangelia / Brockmann, Kathrin / Wüst, Richard / Madlung, Johannes / Nordheim, Alfred / Riess, Olaf / Martins, L Miguel / Glaab, Enrico / May, Patrick / Schenke-Layland, Katja / Picard, Didier / Sharma, Manu / Gasser, Thomas / Krüger, Rejko. ·Department of Neurodegenerative Diseases, Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen and German Centre for Neurodegenerative Diseases, Tübingen, Germany. · Medical University Vienna, Department of Neurology, Vienna, Austria. · Department of Women's Health, Research Institute for Women's Health, University of Tübingen, Tübingen, Germany. · University of Tübingen, Interfaculty Institute of Biochemistry, Tübingen, Germany. · Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg. · Graduate Training Centre of Neuroscience, International Max Planck Research School, Tübingen, Germany. · University of Geneva, Department of Cell Biology, Geneva, Switzerland. · Department of Psychiatry and Psychotherapie, University Hospital Tübingen, Germany. · University of Tübingen, Interfaculty Institute for Cell Biology, Proteome Center Tübingen, Tübingen, Germany. · University of Tübingen, Interfaculty Institute of Cell Biology, Unit of Molecular Biology, Tübingen, Germany. · University of Tübingen, Institute of Medical Genetics and Applied Genomics, Tübingen, Germany. · MRC Toxicology Unit, University of Leicester, Leicester, UK. · Department of Cell and Tissue Engineering, Fraunhofer Institute for Interfacial Engineering and Biotechnology IGB Stuttgart, Germany. · Department of Medicine/ Cardiology, CVRL, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. · Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Germany. · Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg. ·Brain · Pubmed #29050400.

ABSTRACT: The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson's disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson's disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson's disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson's disease and provide new prospects for targeted therapies.

17 Article No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease in nine ADHD candidate SNPs. 2017

Geissler, Julia M / Anonymous941133 / Romanos, Marcel / Gerlach, Manfred / Berg, Daniela / Schulte, Claudia. ·Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany. Geissler_J@ukw.de. · Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany. · Department of Neurodegeneration, Hertie-Institute of Clinical Brain Research, University of Tübingen, Tübingen, Germany. · DZNE-German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. · Department of Neurology, Christian-Albrechts-University, Kiel, Germany. ·Atten Defic Hyperact Disord · Pubmed #28176268.

ABSTRACT: Attention-deficit/hyperactivity disorder (ADHD) and Parkinson's disease (PD) involve pathological changes in brain structures such as the basal ganglia, which are essential for the control of motor and cognitive behavior and impulsivity. The cause of ADHD and PD remains unknown, but there is increasing evidence that both seem to result from a complicated interplay of genetic and environmental factors affecting numerous cellular processes and brain regions. To explore the possibility of common genetic pathways within the respective pathophysiologies, nine ADHD candidate single nucleotide polymorphisms (SNPs) in seven genes were tested for association with PD in 5333 cases and 12,019 healthy controls: one variant, respectively, in the genes coding for synaptosomal-associated protein 25 k (SNAP25), the dopamine (DA) transporter (SLC6A3; DAT1), DA receptor D4 (DRD4), serotonin receptor 1B (HTR1B), tryptophan hydroxylase 2 (TPH2), the norepinephrine transporter SLC6A2 and three SNPs in cadherin 13 (CDH13). Information was extracted from a recent meta-analysis of five genome-wide association studies, in which 7,689,524 SNPs in European samples were successfully imputed. No significant association was observed after correction for multiple testing. Therefore, it is reasonable to conclude that candidate variants implicated in the pathogenesis of ADHD do not play a substantial role in PD.

18 Article Inflammatory profile discriminates clinical subtypes in LRRK2-associated Parkinson's disease. 2017

Brockmann, K / Schulte, C / Schneiderhan-Marra, N / Apel, A / Pont-Sunyer, C / Vilas, D / Ruiz-Martinez, J / Langkamp, M / Corvol, J-C / Cormier, F / Knorpp, T / Joos, T O / Bernard, A / Gasser, T / Marras, C / Schüle, B / Aasly, J O / Foroud, T / Marti-Masso, J F / Brice, A / Tolosa, E / Berg, D / Maetzler, W. ·Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa, Spain. · Mediagnost GmbH, Reutlingen, Germany. · Département de Génétique et Cytogénétique, Hôpital de la Pitié Salpêtrière, Sorbonne Universités, INSERM, Paris, France. · Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's Disease, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada. · Parkinson Institute and Clinical Center, Sunnyvale, CA, USA. · Department of Neurology, St Olavs Hospital, Trondheim, Norway. · Department of Medical and Molecular Genetics, Indiana University, Bloomington, IN, USA. ·Eur J Neurol · Pubmed #28102045.

ABSTRACT: BACKGROUND AND PURPOSE: The presentation of Parkinson's disease patients with mutations in the LRRK2 gene (PD METHODS: An extensive battery of peripheral inflammatory markers was measured in human serum in a multicentre cohort of 142 PD RESULTS: Patients classified as diffuse/malignant presented with the highest levels of the pro-inflammatory proteins interleukin 8 (IL-8), monocyte chemotactic protein 1 (MCP-1) and macrophage inflammatory protein 1-β (MIP-1-β) paralleled by high levels of the neurotrophic protein brain-derived neurotrophic factor (BDNF). It was also possible to distinguish the clinical subtypes based on their inflammatory profile by using discriminant and area under the receiver operating characteristic curve analysis. CONCLUSIONS: Inflammation seems to be associated with the presence of a specific clinical subtype in PD

19 Article Apolipoprotein E ε4 does not affect cognitive performance in patients with Parkinson's disease. 2016

Mengel, David / Dams, Judith / Ziemek, Jannis / Becker, Julian / Balzer-Geldsetzer, Monika / Hilker, Rüdiger / Baudrexel, Simon / Kalbe, Elke / Schmidt, Nele / Witt, Karsten / Liepelt-Scarfone, Inga / Gräber, Susanne / Petrelli, Annette / Neuser, Petra / Schulte, Claudia / Linse, Katharina / Storch, Alexander / Wittchen, Hans-Ulrich / Riedel, Oliver / Mollenhauer, Brit / Ebentheuer, Jens / Trenkwalder, Claudia / Klockgether, Thomas / Spottke, Annika / Wüllner, Ullrich / Schulz, Jörg B / Reetz, Kathrin / Heber, Ines Ann / Ramirez, Alfredo / Dodel, Richard. ·Department of Neurology, Philipps-University, Marburg, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany. · Department of Neurology, Goethe-University, Frankfurt/Main, Germany. · Department of Medical Psychology & Center for Neuropsychological Diagnostics and Intervention (CeNDI), University Hospital Cologne, Cologne, Germany; Psychological Gerontology Institute of Gerontology, University of Vechta, Vechta, Germany. · Department of Neurology, Kiel University, Kiel, Germany. · Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tuebingen, and German Center for Neurodegenerative Diseases, Tuebingen, Germany. · Psychological Gerontology Institute of Gerontology, University of Vechta, Vechta, Germany. · Coordinating Centre for Clinical Trials, Philipps-University, Marburg, Germany. · Department of Neurology, Technical University Dresden, Germany. · Department of Neurology, University Medical Center Rostock, Germany. · Institute of Clinical Psychology and Psychotherapy, Technische Universitaet Dresden, Dresden, Germany. · Institute of Clinical Psychology and Psychotherapy, Technische Universitaet Dresden, Dresden, Germany; Leibniz Institute for Prevention Research and Epidemiology-BIPS GmbH, Bremen, Germany. · Paracelsus-Elena-Klinik, Kassel, Germany; Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany. · Paracelsus-Elena-Klinik, Kassel, Germany. · Department of Neurology, University of Bonn, and German Center for Neurodegenerative Diseases, Bonn, Germany. · Institute of Neuropathology, University Medical Center Goettingen, Goettingen, Germany; Department of Neurology, University of Bonn, and German Center for Neurodegenerative Diseases, Bonn, Germany. · Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA - Translational Brain Medicine, Jülich and Aachen, Germany. · Department of Neurology, RWTH Aachen University, Aachen, Germany. · Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany. · Department of Neurology, Philipps-University, Marburg, Germany. Electronic address: dodel@med.uni-marburg.de. ·Parkinsonism Relat Disord · Pubmed #27321987.

ABSTRACT: INTRODUCTION: Cognitive impairment is a common and disabling non-motor symptom in Parkinson's disease (PD). The apolipoprotein E (APOE) allele ε4 is a known risk factor for Alzheimer's disease and has also been suggested to be a risk factor for dementia in PD and even a predictor of impairment in certain cognitive domains. METHODS: A total of 447 PD patients (PD patients without cognitive impairment: n = 187; PD patients with mild cognitive impairment: n = 188; PD patients with dementia: n = 72) were included from an ongoing observational German multicenter cohort study (LANDSCAPE study). All patients underwent an extensive neuropsychological test battery, including assessments of memory, visuospatial functioning, attention, language, and executive function. APOE genotype was determined by an allelic discrimination assay. Linear regression analysis was used to explore the associations between APOE-ε4 and cognitive performance. RESULTS: The APOE-ε4 allele was not associated with a diagnosis of cognitive impairment in PD (PD with mild cognitive impairment and PD with dementia) or with deficits in specific neuropsychological domains in our study cohort. CONCLUSION: Our data question the relevance of the APOE-ε4 allele as a predictor of cognitive impairment in PD.

20 Article Inflammatory profile in LRRK2-associated prodromal and clinical PD. 2016

Brockmann, Kathrin / Apel, Anja / Schulte, Claudia / Schneiderhan-Marra, Nicole / Pont-Sunyer, Claustre / Vilas, Dolores / Ruiz-Martinez, Javier / Langkamp, Markus / Corvol, Jean-Christophe / Cormier, Florence / Knorpp, Thomas / Joos, Thomas O / Gasser, Thomas / Schüle, Birgitt / Aasly, Jan O / Foroud, Tatiana / Marti-Masso, Jose Felix / Brice, Alexis / Tolosa, Eduardo / Marras, Connie / Berg, Daniela / Maetzler, Walter. ·Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. Kathrin.Brockmann@uni-tuebingen.de. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. Kathrin.Brockmann@uni-tuebingen.de. · Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. · German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. · Natural and Medical Sciences Institute at the University of Tübingen (NMI), Reutlingen, Germany. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Hospital Universitario Donostia, Biodonostia Institut, San Sebastián, Guipuzcoa, Spain. · Mediagnost GmbH, Reutlingen, Germany. · Département de Génétique et Cytogénétique, INSERM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Paris, France. · Parkinson Institute and Clinical Center, 675 Almanor Ave, Sunnyvale, CA, USA. · Department of Neurology, St. Olavs Hospital, Trondheim, Norway. · Department of Medical and Molecular Genetics, Indiana University, Bloomington, IN, USA. · Morton and Gloria Shulman Movement Disorders Centre and the Edmond J Safra Program in Parkinson's disease, Toronto Western Hospital, University of Toronto, Toronto, Canada. ·J Neuroinflammation · Pubmed #27220776.

ABSTRACT: BACKGROUND: There is evidence for a relevant role of inflammation in the pathogenesis of Parkinson's disease (PD). Mutations in the LRRK2 gene represent the most frequent genetic cause for autosomal dominant PD. LRRK2 is highly expressed in macrophages and microglia suggesting an involvement in inflammatory pathways. The objectives are to test (1) whether idiopathic PD and LRRK2-associated PD share common inflammatory pathways or present distinct profiles and (2) whether non-manifesting LRRK2 mutation carriers present with similar aspects of inflammatory profiles as seen in PD-affected patients. METHODS: We assessed serum profiles of 23 immune-associated markers and the brain-derived neurotrophic factor in 534 individuals from the MJFF LRRK2 consortium. RESULTS: A large proportion of inflammatory markers were gender-dependent. Both PD-affected cohorts showed increased levels of the pro-inflammatory marker fatty-acid-binding protein. Additionally, idiopathic PD but not LRRK2-associated PD patients showed increased levels of the pro-inflammatory marker interleukin-12-p40 as well as the anti-inflammatory species interleukin-10, brain-derived neurotrophic factor, and stem cell factor. Non-manifesting LRRK2 mutation carriers including those with prodromal characteristics of PD presented with control-like inflammatory profiles. CONCLUSIONS: Concomitant inflammation seems to be associated with idiopathic and LRRK2-associated PD. Identifying PD patients in whom inflammatory processes play a major role in their pathophysiology might offer a new therapeutic window at least for a subgroup of patients. Since non-manifesting LRRK2 mutation carriers with symptoms of the prodromal phase of PD did not show inflammatory profiles, activation of the immune system seems not an early event in the disease cascade.

21 Article Deletions at 22q11.2 in idiopathic Parkinson's disease: a combined analysis of genome-wide association data. 2016

Mok, Kin Y / Sheerin, Una / Simón-Sánchez, Javier / Salaka, Afnan / Chester, Lucy / Escott-Price, Valentina / Mantripragada, Kiran / Doherty, Karen M / Noyce, Alastair J / Mencacci, Niccolo E / Lubbe, Steven J / Anonymous8211124 / Williams-Gray, Caroline H / Barker, Roger A / van Dijk, Karin D / Berendse, Henk W / Heutink, Peter / Corvol, Jean-Christophe / Cormier, Florence / Lesage, Suzanne / Brice, Alexis / Brockmann, Kathrin / Schulte, Claudia / Gasser, Thomas / Foltynie, Thomas / Limousin, Patricia / Morrison, Karen E / Clarke, Carl E / Sawcer, Stephen / Warner, Tom T / Lees, Andrew J / Morris, Huw R / Nalls, Mike A / Singleton, Andrew B / Hardy, John / Abramov, Andrey Y / Plagnol, Vincent / Williams, Nigel M / Wood, Nicholas W. ·Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Division of Life Science, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, China. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. · Genetics and Epigenetics of Neurodegeneration, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; Genetics and Epigenetics of Neurodegeneration, Tübingen, Germany. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK; Medical Genetics and Laboratory Medicine Department, Faculty of Applied Medical Sciences, Umm Al-Qura University, Makkah, Saudi Arabia. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. · Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK; Department of Regional Neurosciences, Royal Victoria Hospital, Belfast, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK; Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK. · Department of Clinical Neuroscience, UCL Institute of Neurology, London, UK. · John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, Forvie Site, University of Cambridge, Cambridge, UK. · Department of Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, Netherlands. · Genome Biology of Neurodegenerative Diseases, Tübingen, Germany. · Research Unit U1127 at INSERM, Research Unit UMR 7225 at the French National Center for Scientific Research (CNRS), and Research Unit UMR_S 1127 at Pierre and Marie Curie University University of Paris VI at Sorbonne Universités, Institut du Cerveau et de la Moelle épinière Brain and Spine Institute (ICM), Paris, France; Clinical Investigation Center Unit 1422 at INSERM and AP-HP Hôpital de la Pitié Salpêtrière, Centre d'Investigation Clinique Pitié Neurosciences, Paris, France. · Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany. · Sobell Department of Motor Neuroscience, UCL Institute of Neurology, London, UK. · Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK. · School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK. · Department of Clinical Neurosciences, Cambridge Biomedical Campus, University of Cambridge, Cambridge, UK. · Reta Lila Weston Institute for Neurological Studies, UCL Institute of Neurology, London, UK. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. · UCL Genetics Institute, London, UK. · Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff University, Cardiff, UK. Electronic address: williamsnm@cf.ac.uk. · Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address: n.wood@ucl.ac.uk. ·Lancet Neurol · Pubmed #27017469.

ABSTRACT: BACKGROUND: Parkinson's disease has been reported in a small number of patients with chromosome 22q11.2 deletion syndrome. In this study, we screened a series of large, independent Parkinson's disease case-control studies for deletions at 22q11.2. METHODS: We used data on deletions spanning the 22q11.2 locus from four independent case-control Parkinson's disease studies (UK Wellcome Trust Case Control Consortium 2, Dutch Parkinson's Disease Genetics Consortium, US National Institute on Aging, and International Parkinson's Disease Genomics Consortium studies), which were independent of the original reports of chromosome 22q11.2 deletion syndrome. We did case-control association analysis to compare the proportion of 22q11.2 deletions found, using the Fisher's exact test for the independent case-control studies and the Mantel-Haenszel test for the meta-analyses. We retrieved clinical details of patients with Parkinson's disease who had 22q11.2 deletions from the medical records of these patients. FINDINGS: We included array-based copy number variation data from 9387 patients with Parkinson's disease and 13 863 controls. Eight patients with Parkinson's disease and none of the controls had 22q11.2 deletions (p=0·00082). In the 8451 patients for whom age at onset data were available, deletions at 22q11.2 were associated with Parkinson's disease age at onset (Mann-Whitney U test p=0·001). Age at onset of Parkinson's disease was lower in patients carrying a 22q11.2 deletion (median 37 years, 95% CI 32·0-55·5; mean 42·1 years [SD 11·9]) than in those who did not carry a deletion (median 61 years, 95% CI 60·5-61·0; mean 60·3 years [SD 12·8]). A 22q11.2 deletion was present in more patients with early-onset (p<0·0001) and late-onset Parkinson's disease (p=0·016) than in controls, and in more patients with early-onset than late-onset Parkinson's disease (p=0·005). INTERPRETATION: Clinicians should be alert to the possibility of 22q11.2 deletions in patients with Parkinson's disease who have early presentation or features associated with the chromosome 22q11.2 deletion syndrome, or both. FUNDING: UK Medical Research Council, UK Wellcome Trust, Parkinson's UK, Patrick Berthoud Trust, National Institutes of Health, "Investissements d'Avenir" ANR-10-IAIHU-06, Dutch Parkinson Foundation (Parkinson Vereniging), Neuroscience Campus Amsterdam, National Institute for Health Research, National Institute on Aging, National Institutes of Health.

22 Article Neurodegenerative CSF markers in genetic and sporadic PD: Classification and prediction in a longitudinal study. 2015

Brockmann, Kathrin / Schulte, Claudia / Deuschle, Christian / Hauser, Ann-Kathrin / Heger, Tanja / Gasser, Thomas / Maetzler, Walter / Berg, Daniela. ·Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. ·Parkinsonism Relat Disord · Pubmed #26475624.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) patients show a large phenotypic variability probably reflecting inter-individual pathologic heterogeneity. Next to typical Lewy-body pathology, β-amyloid (Aβ) and tau pathology have been found at autopsy and several studies have reported altered CSF levels of Aβ1-42, total-Tau (t-Tau) and phosphorylated-Tau (p-Tau). OBJECTIVES: To evaluate whether CSF levels of neurodegenerative markers are influenced by genetics and whether specific subgroups of PD are more prone to a concomitant pathology possibly reflecting aspects of disease progression. METHODS: In an explorative study we assessed CSF profiles of Aβ1-42, t-Tau, and p-Tau longitudinally in PD patients carrying LRRK2 (n = 5) or GBA mutations (n = 12), sporadic PD patients (n = 30) and healthy controls (n = 16). RESULTS: Compared to healthy controls, all three PD cohorts showed lower levels of Aβ1-42. Moreover, sporadic PD and GBA-PD patients presented with lower levels of t-Tau and p-Tau whereas this phenomenon was not seen in LRRK2-PD patients. Regression analyses revealed an association between higher levels of Baseline p-Tau with more accelerated cognitive deterioration over time in LRRK2-PD and GBA-PD patients, but not in sporadic PD. CONCLUSION: PD patients present with disease-specific CSF profiles of Aβ1-42, t-Tau and p-Tau arguing in favor of an involvement of these proteins in PD pathogenesis in both sporadic and genetic forms. Moreover, we found first hints for differences in these CSF profiles between genetically determined PD cohorts but that CSF constellations which tend to predict aspects of disease progression such as cognitive decline seem similar across subgroups of PD.

23 Article A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease. 2015

Kun-Rodrigues, Celia / Ganos, Christos / Guerreiro, Rita / Schneider, Susanne A / Schulte, Claudia / Lesage, Suzanne / Darwent, Lee / Holmans, Peter / Singleton, Andrew / Anonymous2970842 / Bhatia, Kailash / Bras, Jose. ·Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK. · Department of Neurology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg 20246, Germany, Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK. · Department of Neurology, University Hospital Schleswig Holstein, Campus Kiel 24105, Germany. · German Center for Neurodegenerative Diseases, Tübingen, Germany, Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen 72076, Germany. · INSERM U M27, Pitié-Salpêtrière Hospital, Brain and Spinal Cord Institute (ICM), Paris 75013, France. · Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF24 4HQ, UK and. · Laboratory of Neurogenetics, National Institutes on Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, London WC1N 3AR, UK, j.bras@ucl.ac.uk. ·Hum Mol Genet · Pubmed #26362251.

ABSTRACT: Despite the many advances in our understanding of the genetic basis of Mendelian forms of Parkinson's disease (PD), a large number of early-onset cases still remain to be explained. Many of these cases, present with a form of disease that is identical to that underlined by genetic causes, but do not have mutations in any of the currently known disease-causing genes. Here, we hypothesized that de novo mutations may account for a proportion of these early-onset, sporadic cases. We performed exome sequencing in full parent-child trios where the proband presents with typical PD to unequivocally identify de novo mutations. This approach allows us to test all genes in the genome in an unbiased manner. We have identified and confirmed 20 coding de novo mutations in 21 trios. We have used publicly available population genetic data to compare variant frequencies and our independent in-house dataset of exome sequencing in PD (with over 1200 cases) to identify additional variants in the same genes. Of the genes identified to carry de novo mutations, PTEN, VAPB and ASNA1 are supported by various sources of data to be involved in PD. We show that these genes are reported to be within a protein-protein interaction network with PD genes and that they contain additional rare, case-specific, mutations in our independent cohort of PD cases. Our results support the involvement of these three genes in PD and suggest that testing for de novo mutations in sporadic disease may aid in the identification of novel disease-causing genes.

24 Article GBA-associated Parkinson's disease: reduced survival and more rapid progression in a prospective longitudinal study. 2015

Brockmann, Kathrin / Srulijes, Karin / Pflederer, Sylvia / Hauser, Ann-Kathrin / Schulte, Claudia / Maetzler, Walter / Gasser, Thomas / Berg, Daniela. ·Department of Neurodegenerative Diseases and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Graduate School of Cellular & Molecular Neuroscience, Tübingen, Germany. ·Mov Disord · Pubmed #25448271.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) patients with GBA mutations show an earlier age at onset and more severe non-motor symptoms compared with PD patients without GBA mutations. OBJECTIVE: This study was undertaken to evaluate progression of motor and non-motor symptoms in sporadic PD patients depending on the mutational GBA status. METHODS: We used regression analysis to evaluate independent effects of the mutational GBA status, age at onset, age at examination, and disease duration on motor (Unified Parkinson's Disease Rating Scale [UPDRS]-III, Hoehn and Yahr [H&Y] stage, Levodopa [L-dopa]-equivalent-dosage) and non-motor characteristics (cognition and mood). Disease progression was assessed prospectively over 3 years. RESULTS: The GBA-associated PD patients compared with non-mutation PD patients, although younger and with an earlier age at onset, show (1) a more rapid disease progression of motor impairment and cognitive decline and (2) reduced survival rates. CONCLUSIONS: The mutational GBA status, rather than older age and age at onset, presents an important predictor for disease progression in this specific subgroup of PD patients.

25 Article In vivo markers of Parkinson's disease and dementia with Lewy bodies: current value of the 5G4 α-synuclein antibody. 2014

Maetzler, Walter / Pilotto, Andrea / Apel, Anja / Deuschle, Christian / Kuebart, Gabriele / Heinzel, Sebastian / Liepelt-Scarfone, Inga / Schulte, Claudia / Reusch, Dorothee / Schleicher, Erwin / Rothfuss, Oliver / Schneider, Anja / Dodel, Richard / Gasser, Thomas / Berg, Daniela. ·Department of Neurodegeneration and Hertie Institute for Clinical Brain Research, Center of Neurology, University of Tuebingen, Hoppe Seyler-Strasse 3, 72076, Tuebingen, Germany, Walter.maetzler@uni-tuebingen.de. ·Acta Neuropathol · Pubmed #25376537.

ABSTRACT: -- No abstract --

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