74 results on '"Lewerenz, J"'
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2. Identification of symbol digit modality test score extremes in Huntington's disease
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Braisch, U, Muche, R, Rothenbacher, D, Landwehrmeyer, GB, Long, JD, Bentivoglio, AR, Biunno, I, Bonelli, RM, Dunnett, SB, Illmann, T, Levey, J, Ramos-Arroyo, M, Nielsen, JE, Paivarinta, M, Sebastian, AR, Tabrizi, SJ, Vandenberghe, W, Uhrova, T, Come, A, Garde, MB, Betz, S, Capodarca, S, Wildson, SC, da Silva, V, Di Renzo, M, Finisterra, M, Genoves, C, Gilling, M, Handley, OJ, Hvalstedt, C, Koppers, K, Lamanna, C, Laura, M, Descals, AM, Monza, D, Mutze, L, Oehmen, M, Padieu, H, Paterski, L, Koivisto, SP, Rindal, B, Roren, N, Sasinkova, P, Seliverstov, Y, Timewell, E, Cubillo, PT, van Walsem, MR, Witjes-Ane, MN, Yudina, E, Zielonka, E, Zinzi, P, Braunwarth, EM, Brugger, F, Buratti, L, Hametner, EM, Hepperger, C, Holas, C, Hotter, A, Hussl, A, Larcher, B, Mahlknecht, P, Muller, C, Pinter, B, Poewe, W, Seppi, K, Sprenger, F, Wenning, G, Dupuis, M, Minet, C, Ribai, P, Van Paemel, D, Verellen-Dumoulin, C, Klempir, J, Majerova, V, Roth, J, Babiloni, B, Debruxelles, S, Duche, C, Goizet, C, Jameau, L, Lafoucriere, D, Spampinato, U, Bachoud-Levi, AC, Boisse, MF, de Langavant, LC, Lemoine, L, Morgado, G, Youssov, K, Annic, A, Barthelemy, R, De Bruycker, C, Cabaret, M, Carette, AS, Carriere, N, Decorte, E, Defebvre, L, Delliaux, M, Delval, A, Depelchin, A, Destee, A, Dewulf-Pasz, N, Dondaine, T, Dugauquier, F, Dujardin, K, Lemaire, MH, Manouvrier, S, Peter, M, Plomhause, L, Sablonniere, B, Simonin, C, Tard, C, Thibault-Tanchou, S, Vuillaume, I, Bellonet, M, Benoit, A, Blin, S, Courtin, F, Duru, C, Fasquel, V, Godefroy, O, Krystkowiak, P, Mantaux, B, Roussel, M, Tir, M, Schuler, B, Wannepain, S, Azulay, JP, Chabot, C, Delfini, M, Eusebio, A, Fluchere, F, Grosjean, H, Mundler, L, Nowak, M, Bioux, S, Bliaux, E, Girard, C, Guyant-Marechal, L, Hannequin, D, Hannier, V, Jourdain, S, Maltete, D, Pouliquen, D, Blondeau, L, Calvas, F, Cheriet, S, Delabaere, H, Demonet, JF, Pariente, J, Pierre, M, Beuth, M, Gelderblom, H, Priller, J, Pruss, H, Spruth, E, Thiel, S, Ellrichmannberlin, G, Herrmann, L, Hoffmann, R, Kaminski, B, Saft, C, Bosredon, C, Hunger, U, Lohle, M, Maass, A, Ossig, C, Schmidt, S, Storch, A, Wolz, A, Wolz, M, Kohl, Z, Kozay, C, Ullah, J, Winkler, J, Bergmann, U, Boringer, R, Capetian, P, Kammel, G, Lambeck, J, Meier, S, Rijntjes, M, Zucker, B, Boelmans, K, Ganos, C, Goerendt, I, Heinicke, W, Hidding, U, Munchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Dressler, D, Francis, F, Gayde-Stephan, S, Gorzolla, H, Kramer, B, Minschke, R, Schrader, C, Tacik, P, Longinus, B, Lusebrink, A, Muhlau, M, Peinemann, A, Stadtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bechtel, N, Beckmann, H, Bohlen, S, Gopfert, N, Holzner, E, Lange, H, Reilmann, R, Rohm, S, Rumpf, S, Sass, C, Schepers, S, Weber, N, Barth, K, Buck, A, Connemann, J, Ecker, D, Geitner, C, Held, C, Kesse, A, Landwehrmeyer, B, Lezius, F, Lewerenz, J, Nepper, S, Niess, A, Orth, M, Schneider, A, Schwenk, D, Sussmuth, S, Trautmann, S, Weydt, P, Klebe, S, Musacchio, T, Leypold, C, Noth, K, Cormio, C, de Tommaso, M, Franco, G, Sciruicchio, V, Serpino, C, Calandra-Buonaura, G, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Sambati, L, Scaglione, C, Maserati, MS, Agosti, C, Barlati, S, Compostella, S, Marchina, E, Padovani, A, Bertini, E, Ghelli, E, Ginestroni, A, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, AM, Sorbi, S, Abbruzzese, G, di Poggio, MB, Ferrandes, G, Mandich, P, Marchese, R, Tamburini, T, Baake, V, van den Bogaard, SJA, Bos, R, Dumas, EM, t'Hart, EP, Kampstra, A, Roos, RAC, Schoonderbeek, A, Aaserud, O, Bjorgo, K, Borgeod, N, Dramstad, E, Fannemel, M, Frich, JC, Gorvell, PF, Heiberg, A, Lorentzen, E, Retterstol, L, Rosby, O, Sikiric, A, Stokke, B, van Walsem, M, Wehus, R, Bjornevoll, I, Sando, SB, Haug, MG, Storseth, HH, Arntsen, V, Dziadkiewicz, A, Konkel, A, Narozanska, E, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Arkuszewski, M, Blaszczyk, M, Boczarska-Jedynak, M, Ciach-Wysocka, E, Gorzkowska, A, Nska-Myga, BJ, Kaczmarczyk, A, Klodowska-Duda, G, Opala, G, Stompel, D, Banaszkiewicz, K, Bocwinska, D, Bojakowska-Jaremek, K, Dec, M, Grabska, N, Krawczyk, GM, Kubowicz, E, Malec-Litwinowicz, M, Rudzinska, M, Stenwak, A, Szczudlik, A, Szczygiel, E, Wojcik, M, Wasielewska, A, Bryl, JAA, Ciesielska, A, Klimberg, A, Marcinkowski, J, Samara, H, Sempolowicz, J, Sniewski, BW, Zielonka, D, Gogol, A, Janik, P, Jamrozik, Z, Kaminska, A, Kwiecinski, H, Antczak, J, Jachinska, K, Krysa, W, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz-Jarosz, H, Stepniak, I, Sulek, A, Witkowski, G, Zaremba, J, Zdzienicka, E, Ziora-Jakutowicz, K, Januario, C, Julio, F, Guedes, LC, Coelho, M, Finisterra, AM, Ferreira, JJ, Mestre, T, Mendes, T, Rosa, MM, Valadas, A, Kopishinskaya, S, Korotysh, M, Herrera, CD, Moreno, PG, Bas, J, Busquets, N, Calopa, M, Classen, SJ, Dedicha, NR, Buongiorno, MT, Maria, ADS, Munoz, E, Santacruz, P, Barbera, MA, Pardo, SA, Guia, DB, Calzado, N, Hernanz, LC, Diaz-Zorita, JPT, Catena, JL, Ferrer, PQ, Carruesco, GT, Robert, MF, Viladrich, CM, Roca, E, Idiago, JMR, Riballo, AV, Campolongo, A, de Bobadilla, RF, Bojarsky, JK, Martinez-Horta, S, Pagonabarraga, J, Perez, JP, Ribosa, R, Villa, C, Gil, MAA, Corrales, KB, Esteban, JCG, Gonzalez, A, Merino, BT, Cubo, E, Polo, CG, Mariscal, N, Romero, SG, Arbelo, JM, de Molina, RM, Martin, I, Perianez, JM, Udaeta, B, Alonso-Frech, F, Frades, B, Villanueva, MA, Sevilla, MAZ, Frech, FA, Fenollar, MD, Garcia, RGR, Villanueva, C, Bascunana, M, Ventura, MF, Ribas, GG, de Yebenes, JG, Moreno, JLLS, Barral, VM, Ruiz, PJG, Garcia, A, Lopez, RG, Barcenas, AH, Martinez-Descals, A, Martin, VP, Martinez, NR, Artiga, MJS, Sanchez, V, Pueyo, A, Gonzalez, S, Guisasola, LM, Ribacoba, MPPR, Salvador, C, Lozano, PS, Caldentey, JG, Ramirez, IL, Arques, PN, Lopera, MR, Pastor, BV, Gaston, I, Garcia-Amigot, F, Martinez-Jaurrieta, MD, Ramos-Arroyo, MA, Carrillo, F, Redondo, MTC, Mir, P, Gonzalez, LV, Moreno, JMG, Lucena, CM, Pena, JC, Redondo, L, Sanchez, VS, Fernandez, CM, Mata, MP, Lemos, MDR, Bosca, M, Burguera, JA, Vilaplana, FCBCP, Solis, P, Figuerola, BJ, Palanca, PM, Berglund, P, Constantinescu, R, Fredlund, G, Hosterey-Ugander, U, Linnsand, P, Neleborn-Lingefjard, L, Wahlstrom, J, Palhagen, S, Svenningsson, P, Paucar, M, Wallden, T, Ekwall, C, Goller, ML, Sundblom, J, Stebler, Y, Kaelin, A, Romero, I, Schupbach, M, Zaugg, SW, Jung, H, Petersen, J, Auer, M, Mihaylova, V, Vernon, N, Akhtar, S, Crooks, J, Curtis, A, de Souza, J, Piedad, J, Rickards, H, Wright, J, Pallett, A, Coulthard, E, Gethin, L, Hayward, B, Sieradzan, K, Wright, A, Busse, M, Butcher, C, Dunnett, S, Clenaghan, C, Hunt, S, Jones, L, Jones, U, Khalil, H, Minster, S, Owen, M, Price, K, Townhill, J, Rosser, A, Edwards, M, Ho, C, McGill, M, Porteous, M, Pearson, P, Harrower, T, Irvine, S, Brockie, P, Foster, J, Johns, N, McKenzie, S, Rothery, J, Thomas, G, Yates, S, Deith, C, Ireland, J, Ritchie, S, Andrew, A, Frost, J, Noad, R, Cosgrove, J, Gallantree, D, Hamer, S, Hobson, E, Jamieson, S, Kraus, A, Longthorpe, M, Markova, I, Musgrave, H, Peacy, C, Raman, A, Rowett, L, Toscano, J, Wild, S, Yardumian, P, Clayton, C, Dipple, H, Freire-Patino, D, Hallam, C, Middleton, J, Alusi, S, Davies, R, Foy, K, Gerrans, E, Leggett, H, Pate, L, Anjum, U, Coebergh, J, Eddy, C, McEntagart, M, Patton, M, Peterson, M, Rose, S, Andrews, T, Brown, S, Bruno, S, Doherty, K, Golding, C, Haider, S, Hensman, D, Lahiri, N, Lewis, M, Novak, M, Patel, A, Robertson, N, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Arran, N, Bek, J, Callaghan, J, Craufurd, D, Fullam, R, Howard, L, Huson, S, Johnson, L, Jones, M, Krishnamoorthy, A, Murphy, H, Oughton, E, Partington-Jones, L, Rogers, D, Sollom, A, Snowden, J, Stopford, C, Thompson, J, Tinkler, P, Trender-Gerhard, I, Verstraelen, N, Westmoreland, L, Cass, G, Davidson, L, Davison, J, Fullerton, N, Holmes, K, Komati, S, McDonnell, S, Mohammed, Z, Morgan, K, Savage, L, Singh, B, Wood, J, Chu, E, Knight, C, O'Neill, M, Das Purkayastha, D, Nemeth, AH, Siuda, G, Valentine, R, Dixon, K, Armstrong, R, Harrison, D, Hughes, M, Large, S, Donovan, JO, Palmer, A, Parkinson, A, Soltysiak, B, Timings, L, Williams, J, Burn, J, Weekes, R, Craven, J, Bailey, W, Coleman, C, Haig-Brown, D, Simpson, S, Hare, M, Majeed, T, Bandmann, O, Bradbury, A, Fairtlough, H, Fillingham, K, Foustanos, I, Gill, P, Kazoka, M, Nevitt, L, Peppa, N, Quarrell, O, Taylor, C, Tidswell, K, O'Donovan, K, Agarwal, V, Anderson, M, Gunner, K, Harris, K, Hayward, E, Heywood, M, Keys, L, Kipps, C, MacKinnon, L, Smalley, S, Gowers, L, Powell, K, Bethwaite, P, Edwards, R, Fuller, K, Phillips, M, Tan, L, Burgunder, JM, Lau, PN, Pica, E, Shoulson, I, Gusella, JG, Antonijevic, I, vankammen, D, Foroud, T, Warner, J, Giuliano, J, Vetter, L, Marshall, F, Marder, K, Frucht, S, Moskowitz, C, Clouse, R, Wasserman, P, Shannon, K, Jaglin, J, Jankovic, J, Palao, A, Harrison, M, Singer, C, Quesada, M, Hersch, S, Rosas, D, Tanev, K, Malarick, K, Colcher, A, Sanchez-Ramos, J, Kostyk, S, Paulsen, J, Perlmutter, J, Tabbal, S, Ross, C, Dorsey, R, Nucifora, F, Dubinsky, R, Dubinsky, H, Suchowersky, O, Klimek, ML, Jones, R, Morgan, J, Mohlo, E, Kang, U, Agarwal, P, Factor, S, Jennings, D, Higgins, D, Adams, J, Frank, S, Saint-Hilaire, M, Diggin, M, Furtado, S, Walker, F, O'Neill, C, Quaid, K, LeDoux, M, Raymond, L, Leavitt, B, Decolongon, J, Perlman, S, Peavy, G, Goldstein, J, Kumar, R, McCusker, E, Griffith, J, Loy, C, Wheelock, V, Tempkin, T, Martin, A, Nance, M, Mallonee, W, Suter, G, Revilla, F, Gartner, M, Drazinic, C, Fitzpatrick, MJ, Panisset, M, Duff, K, Scott, B, Weiner, W, Robottom, B, Chiu, E, Yastrubetskaya, O, Churchyard, A, Greenamyre, TJ, Oakes, D, Beck, C, Robertson, S, Eaton, K, Lindsay, P, Deuel, L, MacDonald, M, Hickey, C, Muratori, L, Leserman, A, Doucette, N, Uc, E, Rodnitzky, R, Vik, S, Davis, R, Dietrich, S, Segro, V, Erickson, D, Hunt, V, Lucarelli, N, Broyles, J, Delarosa, J, Louis, E, Panegyres, P, Schmidt, A, Barton, S, Sperin, E, Testa, C, Thiede, F, Zauber, SE, McInnis, R, Welsh, C, Wesson, M, Coleman, A, and European Commission
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Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,COHORT ,Cox hazard model ,quantile regression ,REGISTRY ,symbol digit modalities test ,Genotype ,Neuropsychological Tests ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cognition ,0302 clinical medicine ,Huntington's disease ,Rating scale ,mental disorders ,medicine ,Humans ,Verbal fluency test ,Longitudinal Studies ,Genetics (clinical) ,Proportional Hazards Models ,030304 developmental biology ,0303 health sciences ,Proportional hazards model ,business.industry ,Reproducibility of Results ,Middle Aged ,medicine.disease ,nervous system diseases ,Psychiatry and Mental health ,Huntington Disease ,Phenotype ,Test score ,Cohort ,Disease Progression ,Female ,Observational study ,business ,030217 neurology & neurosurgery ,Stroop effect ,Clinical psychology - Abstract
REGISTRY Investigators of the European Huntington's Disease Network and COHORT Investigators of the Huntington Study Group., Studying individuals with extreme phenotypes could facilitate the understanding of disease modification by genetic or environmental factors. Our aim was to identify Huntington's disease (HD) patients with extreme symbol digit modality test (SDMT) scores. We first examined in HD the contribution of cognitive measures of the Unified Huntington's Disease Rating Scale (UHDRS) in predicting clinical endpoints. The language-independent SDMT was used to identify patients performing very well or very poorly relative to their CAG and age cohort. We used data from REGISTRY and COHORT observational study participants (5,603 HD participants with CAG repeats above 39 with 13,868 visits) and of 1,006 healthy volunteers (with 2,241 visits), included to identify natural aging and education effects on cognitive measures. Separate Cox proportional hazards models with CAG, age at study entry, education, sex, UHDRS total motor score and cognitive (SDMT, verbal fluency, Stroop tests) scores as covariates were used to predict clinical endpoints. Quantile regression for longitudinal language-independent SDMT data was used for boundary (2.5% and 97.5% quantiles) estimation and extreme score analyses stratified by age, education, and CAG repeat length. Ten percent of HD participants had an extreme SDMT phenotype for at least one visit. In contrast, only about 3% of participants were consistent SDMT extremes at two or more visits. The thresholds for the one-visit and two-visit extremes can be used to classify existing and new individuals. The identification of these phenotype extremes can be useful in the search for disease modifiers., This work was in part funded by a grant from the EuropeanCommission under the 7th framework programme (RD-Connect, grantagreement number 305444).
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- 2019
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3. Successful immunosuppressive treatment and long-term follow-up of anti-Ri-associated paraneoplastic myelitis
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Leypoldt, F, Eichhorn, P, Saager, C, Münchau, A, and Lewerenz, J
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- 2006
4. Bevacizumab in temozolomide refractory high-grade gliomas: single-centre experience and review of the literature
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Jeck, J., Kassubek, R., Coburger, J., Edenhofer, S., Schönsteiner, S.S., Ludolph, A.C., Schmitz, B., Engelke, J., Mayer-Steinacker, R., Lewerenz, J., and Bullinger, L.
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Cancer Research - Abstract
BACKGROUND: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience. METHODS: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany. RESULTS: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients. CONCLUSIONS: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV.
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- 2018
5. Suicidal ideation in a European Huntington's disease population
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Hubers, Aa, van Duijn, E, Roos, Ra, Craufurd, D, Rickards, H, Bernhard Landwehrmeyer, G, van der Mast RC, Giltay, Ej, Bachoud Lévi AC, Bentivoglio, Ar, Biunno, I, Bonelli, Rm, Burgunder, Jm, Dunnett, Sb, Ferreira, Jj, Handley, Oj, Heiberg, A, Llmann, Ti, Landwehrmeyer, Gb, Levey, J, Ramos Arroyo MA, Nielsen, Je, Prokoivisto, S, Päivärinta, M, Rojo Sebastián, A, Tabrizi, Sj, Vandenberghe, W, Verellen Dumoulin, C, Zaremba, J, Uhrova, T, Wahlström, J, Barth, K, Correia Guedes, L, Finisterra, Am, Garde, Mb, Bos, R, Betz, S, Callaghan, J, Fullam, R, Ecker, D, Nielsen, Mg, Hvalstedt, C, Held, C, Koppers, K, Laurà, M, Horta, Sm, Descals, Am, Mestre, T, Minster, S, Monza, D, Mütze, L, Oehmen, M, Townhill, J, Orth, M, Padieu, H, Paterski, L, Peppa, N, Pro Koivisto, S, Roedig, V, Rialland, A, Røren, N, Šašinková, P, Seliverstov, Y, Cubillo, Pt, Walsem, Mr, Wright, A, da Silva WV, Witjes Ané MN, Yudina, E, Zielonka, D, Zielonka, E, Zinzi, P, Herranhof, B, Holl, A, Kapfhammer, Hp, Koppitz, M, Magnet, M, Otti, D, Painold, A, Reisinger, K, Scheibl, M, Hecht, K, Lilek, S, Müller, N, Schöggl, H, Ullah, J, Brugger, F, Hepperger, C, Hotter, A, Seppi, K, Wenning, G, Buratti, L, Hametner, Em, Holas, C, Hussl, A, Poewe, W, Braunwarth, Em, Sprenger, F, Müller, C, Sinadinosa, D, Walleczek, Am, Ladurner, G, Staffen, W, Flamez, A, Morez, V, de Raedt, S, Boogaerts, A, van Reijen, D, Klempíř, J, Majerová, V, Roth, J, Hartikainen, P, Hiivola, H, Martikainen, K, Tuuha, K, Ignatius, J, Kärppä, M, Åman, J, Mustonen, A, Kajula, O, Santala, M, Allain, P, Guérid, Ma, Gohier, B, Olivier, A, Prundean, A, Scherer Gagou, C, Verny, C, Bost, M, Babiloni, B, Debruxelles, S, Duché, C, Goizet, C, Lafoucrière, D, Jameau, L, Spampinato, U, De Bruycker, C, Cabaret, M, Carette, As, Defebvre, L, Decorte, E, Delval, A, Delliaux, M, Destee, A, Dujardin, K, Peter, M, Plomhouse, L, Sablonnière, B, Simonin, C, Lemaire, Mh, Manouvrier, S, Thibault Tanchou, S, Vuillaume, I, Krystkowiak, P, Duru, C, Roussel, M, Wannepain, S, Berrissoul, H, Bellonet, M, Courtin, F, Mantaux, B, Fasquel, V, Godefroy, O, Azulay, Jp, Fluchère, F, Delfini, M, Eusebio, A, Mundler, L, Longato, N, Rudolf, G, Steinmetz, G, Tranchant, C, Wagner, C, Zimmermann, M, Marcel, C, Calvas, F, Pariente, J, Démonet, Jf, Cheriet, S, Kosinski, Cm, Milkereit, E, Probst, D, Reetz, K, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Gelderblom, H, Priller, J, Prüß, H, Spruth, Ej, Andrich, J, Ellrichmann, G, Hoffmann, R, Kaminski, B, Saft, C, Stamm, C, Lange, H, Bosredon, C, Maass, A, Schmidt, S, Storch, A, Wolz, M, Kohl, Z, Winkler, J, Capetian, P, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Goerendt, I, Hidding, U, Lewerenz, J, Münchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Dressler, D, Gorzolla, H, Schrader, C, Tacik, P, Heinicke, W, Longinus, B, Bürk, K, Möller, Jc, Rissling, I, Mühlau, M, Peinemann, A, Städtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bohlen, S, Hölzner, E, Reilmann, R, Dose, M, Leythaeuser, G, Marquard, R, Raab, T, Schrenk, C, Schuierer, M, Buck, A, Connemann, J, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Schwenk, D, Süßmuth, S, Trautmann, S, Weydt, P, Cormio, C, Sciruicchio, V, Serpino, C, Tommaso, M, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Rizzo, G, Scaglione, C, Bertini, E, Ghelli, E, Ginestroni, A, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, di Poggio MB, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Albanese, A, Di Bella, D, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Paridi, D, Soliveri, P, Tomasello, C, De Michele, G, Di Maio, L, Salvatore, E, Rinaldi, C, Rossi, F, Massarelli, M, Roca, A, Ammendola, S, Russo, Cv, Squitieri, F, Elifani, F, Maglione, V, Di Pardo, A, Alberti, S, Griguoli, A, Amico, E, Martino, T, Petrollini, M, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Piano, C, Chiara, P, Quaranta, D, Romano, Silvia, Soleti, F, Spadaro, M, Romano, S, van Hout MS, van Vugt JP, Weert, A, Bolwijn, J, Dekker, M, Leenders, K, Kremer, Hp, Dumas, Em, van den Bogaard SJ, 't Hart EP, Økland, E, Hauge, E, Tyvoll, H, Frich, J, Aaserud, O, Wehus, R, Bjørgo, K, Fannemel, M, Gørvell, P, Lorentzen, E, Koivisto, Sp, Retterstøl, L, Overland, T, Stokke, B, Sando, B, Dziadkiewicz, A, Nowak, M, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Blaszcyk, M, Boczarska Jedynak, M, Ciach Wysocka, E, Gorzkowska, A, Jasinska Myga, B, Opala, G, Kłodowska Duda, G, Stompel, D, Banaszkiewicz, K, Boćwińska, D, Szczudlik, A, Rudzińska, M, Wójcik, M, Dec, M, Krawczyk, M, Jaremek, Kb, Szczygieł, E, Stenwak, A, Ielewska, Aw, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Sempołowicz, J, Samara, H, Wiśniewski, B, Janik, P, Gogol, A, Kwiecinski, H, Jamrozik, Z, Kaminska, A, Antczak, J, Jachinska, K, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz Jarosz, H, Stępniak, I, Witkowski, G, Zdzienicka, E, Sułek, A, Krysa, W, Zieora Jakutowicz, K, Júlio, F, Januário, C, Coelho, M, Mendes, T, Valadas, A, Timóteo, Â, Costa, C, Cavaco, S, Damásio, J, Loureiro, R, Magalhães, M, Andrade, C, Gago, M, Garrett, C, Guerra, Mr, Lima, J, Massano, J, Meireles, J, Herrera, Cd, Garcia, Pm, Barrero, F, Morales, B, Cubo, E, Mariscal, N, Sánchez, J, Alonso Frech, F, Perez, Mr, Fenollar, M, García, Rg, Quiroga, Pp, Rivera, Sv, Villanueva, C, Alegre, J, Bascuñana, M, Caldentey, Jg, Ventura, Mf, Ribas, Gg, Yébenes, Jg, López Sendón Moreno JL, García Ruíz PJ, Martínez Descals, A, Artiga, Mj, Sánchez, V, Guerrero, R, Bárcenas, Ah, Noguera Perea MF, Fortuna, L, Martirio, M, Torres, A, Reinante, G, Moreau, Lv, Barbera, Ma, Guia, Db, Hernanz, Lc, Catena, Jl, Sebastián, Ar, Ferrer, Pq, Carruesco, Gt, Bas, J, Busquets, N, Calopa, M, Elorza, Md, Díez AjaLópez, C, Terol, Sd, Robert, Mf, Ruíz, Bg, Casado, Ag, Martínez, Ih, Viladrich, Cm, Càrdenas, Rp, Roca, E, Llesoy, Jr, Idiago, Jm, Vergara, Mr, García, Ss, Riballo, Av, González, Sg, Guisasola, Lm, Salvador, C, San Martín ES, González, M, Gorospe, A, Legarda, I, Arques, Pn, Torres Rodríguez MJ, Vives, B, Gaston, I, Martinez Jaurrieta MD, Manuel, J, Moreno, G, Peña, Jc, Avarvarei, Ld, Bastida, Am, Recio, Mf, Vergé, Lr, Sánchez, Vs, Carrillo, F, Cáceres, Mt, Mir, P, Suarez, Mj, Bosca, M, Burguera, Ja, Garcia, Ac, Brugada, Fc, Martínez, Lm, Val, Jl, Loutfi, G, Olofsson, C, Stattin, El, Westman, L, Wikström, B, Lhagen, Se, Paucar, M, Svenningsson, P, Reza Soltani TW, Höglund, A, Sandström, B, Høsterey Ugander, U, Fredlund, G, Constantinescu, R, Neleborn Lingefjärd, L, Tedr off, J, Esmaeilzadeh, M, Winnberg, E, Pålhagen, S, Svennigsson, P, Riza Soltani TW, Sundblom, J, Johansson, A, Wiklund, L, Ekwall, C, Göller, Ml, Petersén, A, Reimer, J, Widner, H, Stebler, Y, Kaelin, A, Romero, I, Schüpbach, M, Weber, S, Miedzybrodzka, Z, Rae, D, Downie, L, Simpson, S, Summers, F, Ure, A, Jack, R, Matheson, K, Akhtar, S, Crooks, J, Curtis, A, Souza, J, Wright, J, Hayward, B, Sieradzan, K, Barker, Ra, O'Keefe, D, Di Pietro, A, Fisher, K, Hill, S, Mason, S, Swain, R, Valle, N, Guzman, Bisson, J, Busse, M, Butcher, C, Clenaghan, C, Dunnett, S, Handley, O, Hunt, S, Hughes, A, Johnstone, C, Jones, L, Jones, U, Khalil, H, Owen, M, Price, K, Rose, Le, Rosser, A, Porteous, M, Edwards, M, Ho, C, Mcgill, M, Pearson, P, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Miller, J, Ritchie, S, Burrows, L, Fletcher, A, Harding, A, Laver, F, Silva, M, Thomson, A, Rowett, L, Gallantrae, D, Longthorpe, M, Markova, I, Raman, A, Hamer, S, Wild, S, Yarduiman, P, Chu, C, Kraus, A, Yardumian, P, Musgrave, H, Toscano, J, Jamieson, S, Hobson, E, Clayton, C, Dipple, H, Middleton, J, Freire Patino, D, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Laing, H, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Santhouse, A, Patton, M, Peterson, M, Rose, S, Bruno, S, Chu, E, Doherty, K, Haider, S, Hensman, D, Lahiri, N, Lewis, M, Novak, M, Patel, A, Robertson, N, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Howard, L, Sollom, A, Snowden, J, Thompson, J, Jones, M, Murphy, H, Trender Gerhard, I, Rogers, D, Bek, J, Oughton, E, Johnson, L, Hare, M, Arran, N, Verstraelen, N, Partington Jones, L, Huson, S, Stopford, C, Westmoreland, L, Davidson, J, Morgan, K, Savage, L, Singh, B, Komati, S, Nemeth, Ah, Armstrong, R, Valentine, R, Siuda, G, Harrison, D, Hughes, M, Parkinson, A, Soltysiak, B, Burn, J, Coleman, C, Bandmann, O, Bradbury, A, Gill, P, Fairtlough, H, Fillingham, K, Foustanos, I, Kazoka, M, O'Donovan, K, Taylor, C, Tidswell, K, Quarrell, O., Laboratoire de Psychologie des Pays de la Loire (LPPL), Université d'Angers (UA)-Université de Nantes - UFR Lettres et Langages (UFRLL), Université de Nantes (UN)-Université de Nantes (UN), A. A., M, E. v., Duijn, R. A., C, D., Craufurd, H., Rickard, G. B., Landwehrmeyer, R. C., Van, E. J., Giltay, R. E., G., Rinaldi, Carlo, Anna A.M. Huber, Erik van Duijn, Raymund A.C. Roo, David Craufurd, Hugh Rickard, G. Bernhard Landwehrmeyer, Rose C. van der Mast, Erik J. Giltay REGISTRY investigators of the European Huntington's Disease Network. Collaborators: Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, llmann TI, Landwehrmeyer GB, Levey J, Ramos-Arroyo MA, Nielsen JE, ProKoivisto S, Päivärinta M, Roos RA, Rojo Sebastián A, Tabrizi SJ, Vandenberghe W, Verellen- Dumoulin C, Zaremba J, Uhrova T, Wahlström J, Barth K, Correia-Guedes L, Finisterra AM, Garde MB, Bos R, Betz S, Callaghan J, Fullam R, Ecker D, Nielsen MG, Hvalstedt C, Held C, Koppers K, Laurà M, Horta SM, Descals AM, Mestre T, Minster S, Monza D, Mütze L, Oehmen M, Townhill J, Orth M, Padieu H, Paterski L, Peppa N, Pro Koivisto S, Roedig V, Rialland A, Røren N, Šašinková P, Seliverstov Y, Cubillo PT, Walsem MR, Wright A, da Silva WV, Witjes-Ané MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinger K, Scheibl M, Hecht K, Lilek S, Müller N, Schöggl H, Ullah J, Brugger F, Hepperger C, Hotter A, Seppi K, Wenning G, Buratti L, Hametner EM, Holas C, Hussl A, Poewe W, Braunwarth EM, Sprenger F, Müller C, Sinadinosa D, Walleczek AM, Ladurner G, Staffen W, Flamez A, Morez V, de Raedt S, Boogaerts A, van Reijen D, Klempíř J, Majerová V, Roth J, Hartikainen P, Hiivola H, Martikainen K, Tuuha K, Ignatius J, Kärppä M, Åman J, Mustonen A, Kajula O, Santala M, Allain P, Guérid MA, Gohier B, Olivier A, Prundean A, Scherer- Gagou C, Verny C, Bost M, Babiloni B, Debruxelles S, Duché C, Goizet C, Lafoucrière D, Jameau L, Spampinato U, De Bruycker C, Cabaret M, Carette AS, Defebvre L, Decorte E, Delval A, Delliaux M, Destee A, Dujardin K, Peter M, Plomhouse L, Sablonnière B, Simonin C, Lemaire MH, Manouvrier S, Thibault-Tanchou S, Vuillaume I, Krystkowiak P, Duru C, Roussel M, Wannepain S, Berrissoul H, Bellonet M, Courtin F, Mantaux B, Fasquel V, Godefroy O, Azulay JP, Fluchère F, Delfini M, Eusebio A, Mundler L, Longato N, Rudolf G, Steinmetz G, Tranchant C, Wagner C, Zimmermann M, Marcel C, Calvas F, Pariente J, Démonet JF, Cheriet S, Kosinski CM, Milkereit E, Probst D, Reetz K, Sass C, Schiefer J, Schlangen C, Werner CJ, Gelderblom H, Priller J, Prüß H, Spruth EJ, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Lange H, Bosredon C, Maass A, Schmidt S, Storch A, Wolz M, Kohl Z, Winkler J, Capetian P, Lambeck J, Zucker B, Boelmans K, Ganos C, Goerendt I, Hidding U, Lewerenz J, Münchau A, Schmalfeld J, Stubbe L, Zittel S, Diercks G, Dressler D, Gorzolla H, Schrader C, Tacik P, Heinicke W, Longinus B, Bürk K, Möller JC, Rissling I, Mühlau M, Peinemann A, Städtler M, Weindl A, Winkelmann J, Ziegler C, Bohlen S, Hölzner E, Reilmann R, Dose M, Leythaeuser G, Marquard R, Raab T, Schrenk C, Schuierer M, Buck A, Connemann J, Eschenbach C, Landwehrmeyer B, Lezius F, Nepper S, Niess A, Schwenk D, Süßmuth S, Trautmann S, Weydt P, Cormio C, Sciruicchio V, Serpino C, Tommaso M, Capellari S, Cortelli P, Gallassi R, Poda R, Rizzo G, Scaglione C, Bertini E, Ghelli E, Ginestroni A, Massaro F, Mechi C, Paganini M, Piacentini S, Pradella S, Romoli AM, Sorbi S, Abbruzzese G, di Poggio MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Albanese A, Di Bella D, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Paridi D, Soliveri P, Tomasello C, De Michele G, Di Maio L, Salvatore E, Rinaldi C, Rossi F, Massarelli M, Roca A, Ammendola S, Russo CV, Squitieri F, Elifani F, Maglione V, Di Pardo A, Alberti S, Griguoli A, Amico E, Martino T, Petrollini M, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Chiara P, Quaranta D, Romano S, Soleti F, Spadaro M, van Hout MS, van Vugt JP, Weert A, Bolwijn J, Dekker M, Leenders K, Kremer HP, Dumas EM, van den Bogaard SJ, 't Hart EP, van Duijn E, Økland E, Hauge E, Tyvoll H, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E, Koivisto SP, Retterstøl L, Overland T, Stokke B, Sando B, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszcyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Opala G, Kłodowska-Duda G, Stompel D, Banaszkiewicz K, Boćwińska D, Szczudlik A, Rudzińska M, Wójcik M, Dec M, Krawczyk M, Jaremek KB, Szczygieł E, Stenwak A, ielewska AW, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Sempołowicz J, Samara H, Wiśniewski B, Janik P, Gogol A, Kwiecinski H, Jamrozik Z, Kaminska A, Antczak J, Jachinska K, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz-Jarosz H, Stępniak I, Witkowski G, Zdzienicka E, Sułek A, Krysa W, Zieora-Jakutowicz K, Júlio F, Januário C, Coelho M, Mendes T, Valadas A, Timóteo Â, Costa C, Cavaco S, Damásio J, Loureiro R, Magalhães M, Andrade C, Gago M, Garrett C, Guerra MR, Lima J, Massano J, Meireles J, Herrera CD, Garcia PM, Barrero F, Morales B, Cubo E, Mariscal N, Sánchez J, Alonso-Frech F, Perez MR, Fenollar M, García RG, Quiroga PP, Rivera SV, Villanueva C, Alegre J, Bascuñana M, Caldentey JG, Ventura MF, Ribas GG, Yébenes JG, López-Sendón Moreno JL, García Ruíz PJ, Martínez-Descals A, Artiga MJ, Sánchez V, Guerrero R, Bárcenas AH, Noguera Perea MF, Fortuna L, Martirio M, Torres A, Reinante G, Moreau LV, Barbera MA, Guia DB, Hernanz LC, Catena JL, Sebastián AR, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Elorza MD, Díez-AjaLópez C, Terol SD, Robert MF, Ruíz BG, Casado AG, Martínez IH, Viladrich CM, Càrdenas RP, Roca E, Llesoy JR, Idiago JM, Vergara MR, García SS, Riballo AV, González SG, Guisasola LM, Salvador C, San Martín ES, González M, Gorospe A, Legarda I, Arques PN, Torres Rodríguez MJ, Vives B, Gaston I, Martinez-Jaurrieta MD, Manuel J, Moreno G, Peña JC, Avarvarei LD, Bastida AM, Recio MF, Vergé LR, Sánchez VS, Carrillo F, Cáceres MT, Mir P, Suarez MJ, Bosca M, Burguera JA, Garcia AC, Brugada FC, Martínez LM, Val JL, Loutfi G, Olofsson C, Stattin EL, Westman L, Wikström B, lhagen SE, Paucar M, Svenningsson P, Reza- Soltani TW, Höglund A, Sandström B, Høsterey-Ugander U, Fredlund G, Constantinescu R, Neleborn-Lingefjärd L, Tedr- off J, Esmaeilzadeh M, Winnberg E, Pålhagen S, Svennigsson P, Riza-Soltani TW, Sundblom J, Johansson A, Wiklund L, Ekwall C, Göller ML, Petersén A, Reimer J, Widner H, Stebler Y, Kaelin A, Romero I, Schüpbach M, Weber S, Miedzybrodzka Z, Rae D, Downie L, Simpson S, Summers F, Ure A, Jack R, Matheson K, Akhtar S, Crooks J, Curtis A, Souza J, Rickards H, Wright J, Hayward B, Sieradzan K, Barker RA, O'Keefe D, Di Pietro A, Fisher K, Hill S, Mason S, Swain R, Valle N, Guzman, Bisson J, Busse M, Butcher C, Clenaghan C, Dunnett S, Handley O, Hunt S, Hughes A, Johnstone C, Jones L, Jones U, Khalil H, Owen M, Price K, Rose LE, Rosser A, Porteous M, Edwards M, Ho C, McGill M, Pearson P, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Miller J, Ritchie S, Burrows L, Fletcher A, Harding A, Laver F, Silva M, Thomson A, Rowett L, Gallantrae D, Longthorpe M, Markova I, Raman A, Hamer S, Wild S, Yarduiman P, Chu C, Kraus A, Yardumian P, Musgrave H, Toscano J, Jamieson S, Hobson E, Clayton C, Dipple H, Middleton J, Freire-Patino D, Andrews T, Dougherty A, Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A, Santhouse A, Patton M, Peterson M, Rose S, Bruno S, Chu E, Doherty K, Haider S, Hensman D, Lahiri N, Lewis M, Novak M, Patel A, Robertson N, Rosser E, Tabrizi S, Taylor R, Warner T, Wild E, Craufurd D, Howard L, Sollom A, Snowden J, Thompson J, Jones M, Murphy H, Trender-Gerhard I, Rogers D, Bek J, Oughton E, Johnson L, Hare M, Arran N, Verstraelen N, Partington-Jones L, Huson S, Stopford C, Westmoreland L, Davidson J, Morgan K, Savage L, Singh B, Komati S, Nemeth AH, Armstrong R, Valentine R, Siuda G, Harrison D, Hughes M, Parkinson A, Soltysiak B, Burn J, Coleman C, Bandmann O, Bradbury A, Gill P, Fairtlough H, Fillingham K, Foustanos I, Kazoka M, O'Donovan K, Taylor C, Tidswell K, Quarrell O., Molecular Neuroscience and Ageing Research (MOLAR), Hubers, Aa, van Duijn, E, Roos, Ra, Craufurd, D, Rickards, H, Bernhard Landwehrmeyer, G, van der Mast, Rc, Giltay, Ej, CollaboratorsBachoud Lévi AC, REGISTRY investigators of the European Huntington's Disease N. e. t. w. o. r. k., Bentivoglio, Ar, Biunno, I, Bonelli, Rm, Burgunder, Jm, Dunnett, Sb, Ferreira, Jj, Handley, Oj, Heiberg, A, Llmann, Ti, Landwehrmeyer, Gb, Levey, J, Ramos Arroyo, Ma, Nielsen, Je, Prokoivisto, S, Päivärinta, M, Rojo Sebastián, A, Tabrizi, Sj, Vandenberghe, W, Verellen Dumoulin, C, Zaremba, J, Uhrova, T, Wahlström, J, Barth, K, Correia Guedes, L, Finisterra, Am, Garde, Mb, Bos, R, Betz, S, Callaghan, J, Fullam, R, Ecker, D, Nielsen, Mg, Hvalstedt, C, Held, C, Koppers, K, Laurà, M, Horta, Sm, Descals, Am, Mestre, T, Minster, S, Monza, D, Mütze, L, Oehmen, M, Townhill, J, Orth, M, Padieu, H, Paterski, L, Peppa, N, Pro Koivisto, S, Roedig, V, Rialland, A, Røren, N, a??inková, P, Seliverstov, Y, Cubillo, Pt, Walsem, Mr, Wright, A, da Silva, Wv, Witjes Ané, Mn, Yudina, E, Zielonka, D, Zielonka, E, Zinzi, P, Herranhof, B, Holl, A, Kapfhammer, Hp, Koppitz, M, Magnet, M, Otti, D, Painold, A, Reisinger, K, Scheibl, M, Hecht, K, Lilek, S, Müller, N, Schöggl, H, Ullah, J, Brugger, F, Hepperger, C, Hotter, A, Seppi, K, Wenning, G, Buratti, L, Hametner, Em, Holas, C, Hussl, A, Poewe, W, Braunwarth, Em, Sprenger, F, Müller, C, Sinadinosa, D, Walleczek, Am, Ladurner, G, Staffen, W, Flamez, A, Morez, V, de Raedt, S, Boogaerts, A, van Reijen, D, Klempí??, J, Majerová, V, Roth, J, Hartikainen, P, Hiivola, H, Martikainen, K, Tuuha, K, Ignatius, J, Kärppä, M, Åman, J, Mustonen, A, Kajula, O, Santala, M, Allain, P, Guérid, Ma, Gohier, B, Olivier, A, Prundean, A, Scherer Gagou, C, Verny, C, Bost, M, Babiloni, B, Debruxelles, S, Duché, C, Goizet, C, Lafoucrière, D, Jameau, L, Spampinato, U, De Bruycker, C, Cabaret, M, Carette, A, Defebvre, L, Decorte, E, Delval, A, Delliaux, M, Destee, A, Dujardin, K, Peter, M, Plomhouse, L, Sablonnière, B, Simonin, C, Lemaire, Mh, Manouvrier, S, Thibault Tanchou, S, Vuillaume, I, Krystkowiak, P, Duru, C, Roussel, M, Wannepain, S, Berrissoul, H, Bellonet, M, Courtin, F, Mantaux, B, Fasquel, V, Godefroy, O, Azulay, Jp, Fluchère, F, Delfini, M, Eusebio, A, Mundler, L, Longato, N, Rudolf, G, Steinmetz, G, Tranchant, C, Wagner, C, Zimmermann, M, Marcel, C, Calvas, F, Pariente, J, Démonet, Jf, Cheriet, S, Kosinski, Cm, Milkereit, E, Probst, D, Reetz, K, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Gelderblom, H, Priller, J, Prüß, H, Spruth, Ej, Andrich, J, Ellrichmann, G, Hoffmann, R, Kaminski, B, Saft, C, Stamm, C, Lange, H, Bosredon, C, Maass, A, Schmidt, S, Storch, A, Wolz, M, Kohl, Z, Winkler, J, Capetian, P, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Goerendt, I, Hidding, U, Lewerenz, J, Münchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Dressler, D, Gorzolla, H, Schrader, C, Tacik, P, Heinicke, W, Longinus, B, Bürk, K, Möller, Jc, Rissling, I, Mühlau, M, Peinemann, A, Städtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bohlen, S, Hölzner, E, Reilmann, R, Dose, M, Leythaeuser, G, Marquard, R, Raab, T, Schrenk, C, Schuierer, M, Buck, A, Connemann, J, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Schwenk, D, Süßmuth, S, Trautmann, S, Weydt, P, Cormio, C, Sciruicchio, V, Serpino, C, Tommaso, M, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Rizzo, G, Scaglione, C, Bertini, E, Ghelli, E, Ginestroni, A, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, di Poggio, Mb, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Albanese, A, Di Bella, D, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Paridi, D, Soliveri, P, Tomasello, C, DE MICHELE, Giuseppe, Di Maio, L, Salvatore, Elena, Rossi, F, Massarelli, Marco, Roca, Alessandro, Ammendola, S, Russo, Cinzia, Squitieri, F, Elifani, F, Maglione, V, Di Pardo, A, Alberti, S, Griguoli, A, Amico, E, Martino, T, Petrollini, M, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Piano, C, Chiara, P, Quaranta, D, Romano, S, Soleti, F, Spadaro, M, Rinaldi, C, Massarelli, M, Roca, A, Russo, Cv, van Hout, M, van Vugt, Jp, Weert, A, Bolwijn, J, Dekker, M, Leenders, K, Kremer, Hp, Dumas, Em, van den Bogaard, Sj, 't Hart, Ep, Økland, E, Hauge, E, Tyvoll, H, Frich, J, Aaserud, O, Wehus, R, Bjørgo, K, Fannemel, M, Gørvell, P, Lorentzen, E, Koivisto, Sp, Retterstøl, L, Overland, T, Stokke, B, Sando, B, Dziadkiewicz, A, Nowak, M, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Blaszcyk, M, Boczarska Jedynak, M, Ciach Wysocka, E, Gorzkowska, A, Jasinska Myga, B, Opala, G, K??odowska Duda, G, Stompel, D, Banaszkiewicz, K, Bo??wi??ska, D, Szczudlik, A, Rudzi??ska, M, Wójcik, M, Dec, M, Krawczyk, M, Jaremek, Kb, Szczygie??, E, Stenwak, A, Ielewska, Aw, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Sempo??owicz, J, Samara, H, Wi??niewski, B, Janik, P, Gogol, A, Kwiecinski, H, Jamrozik, Z, Kaminska, A, Antczak, J, Jachinska, K, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz Jarosz, H, St??pniak, I, Witkowski, G, Zdzienicka, E, Su??ek, A, Krysa, W, Zieora Jakutowicz, K, Júlio, F, Januário, C, Coelho, M, Mendes, T, Valadas, A, Timóteo, Â, Costa, C, Cavaco, S, Damásio, J, Loureiro, R, Magalhães, M, Andrade, C, Gago, M, Garrett, C, Guerra, Mr, Lima, J, Massano, J, Meireles, J, Herrera, Cd, Garcia, Pm, Barrero, F, Morales, B, Cubo, E, Mariscal, N, Sánchez, J, Alonso Frech, F, Perez, Mr, Fenollar, M, García, Rg, Quiroga, Pp, Rivera, Sv, Villanueva, C, Alegre, J, Bascuñana, M, Caldentey, Jg, Ventura, Mf, Ribas, Gg, Yébenes, Jg, López Sendón Moreno, Jl, García Ruíz, Pj, Martínez Descals, A, Artiga, Mj, Sánchez, V, Guerrero, R, Bárcenas, Ah, Noguera Perea, Mf, Fortuna, L, Martirio, M, Torres, A, Reinante, G, Moreau, Lv, Barbera, Ma, Guia, Db, Hernanz, Lc, Catena, Jl, Sebastián, Ar, Ferrer, Pq, Carruesco, Gt, Bas, J, Busquets, N, Calopa, M, Elorza, Md, Díez AjaLópez, C, Terol, Sd, Robert, Mf, Ruíz, Bg, Casado, Ag, Martínez, Ih, Viladrich, Cm, Càrdenas, Rp, Roca, E, Llesoy, Jr, Idiago, Jm, Vergara, Mr, García, S, Riballo, Av, González, Sg, Guisasola, Lm, Salvador, C, San Martín, E, González, M, Gorospe, A, Legarda, I, Arques, Pn, Torres Rodríguez, Mj, Vives, B, Gaston, I, Martinez Jaurrieta, Md, Manuel, J, Moreno, G, Peña, Jc, Avarvarei, Ld, Bastida, Am, Recio, Mf, Vergé, Lr, Carrillo, F, Cáceres, Mt, Mir, P, Suarez, Mj, Bosca, M, Burguera, Ja, Garcia, Ac, Brugada, Fc, Martínez, Lm, Val, Jl, Loutfi, G, Olofsson, C, Stattin, El, Westman, L, Wikström, B, Lhagen, Se, Paucar, M, Svenningsson, P, Reza Soltani, Tw, Höglund, A, Sandström, B, Høsterey Ugander, U, Fredlund, G, Constantinescu, R, Neleborn Lingefjärd, L, Tedr off, J, Esmaeilzadeh, M, Winnberg, E, Pålhagen, S, Svennigsson, P, Riza Soltani, Tw, Sundblom, J, Johansson, A, Wiklund, L, Ekwall, C, Göller, Ml, Petersén, A, Reimer, J, Widner, H, Stebler, Y, Kaelin, A, Romero, I, Schüpbach, M, Weber, S, Miedzybrodzka, Z, Rae, D, Downie, L, Simpson, S, Summers, F, Ure, A, Jack, R, Matheson, K, Akhtar, S, Crooks, J, Curtis, A, Souza, J, Wright, J, Hayward, B, Sieradzan, K, Barker, Ra, O'Keefe, D, Di Pietro, A, Fisher, K, Hill, S, Mason, S, Swain, R, Valle, N, Bisson, J, Busse, M, Butcher, C, Clenaghan, C, Dunnett, S, Handley, O, Hunt, S, Hughes, A, Johnstone, C, Jones, L, Jones, U, Khalil, H, Owen, M, Price, K, Rose, Le, Rosser, A, Porteous, M, Edwards, M, Ho, C, Mcgill, M, Pearson, P, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Miller, J, Ritchie, S, Burrows, L, Fletcher, A, Harding, A, Laver, F, Silva, M, Thomson, A, Rowett, L, Gallantrae, D, Longthorpe, M, Markova, I, Raman, A, Hamer, S, Wild, S, Yarduiman, P, Chu, C, Kraus, A, Yardumian, P, Musgrave, H, Toscano, J, Jamieson, S, Hobson, E, Clayton, C, Dipple, H, Middleton, J, Freire Patino, D, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Laing, H, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Santhouse, A, Patton, M, Peterson, M, Rose, S, Bruno, S, Chu, E, Doherty, K, Haider, S, Hensman, D, Lahiri, N, Lewis, M, Novak, M, Patel, A, Robertson, N, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Howard, L, Sollom, A, Snowden, J, Thompson, J, Jones, M, Murphy, H, Trender Gerhard, I, Rogers, D, Bek, J, Oughton, E, Johnson, L, Hare, M, Arran, N, Verstraelen, N, Partington Jones, L, Huson, S, Stopford, C, Westmoreland, L, Davidson, J, Morgan, K, Savage, L, Singh, B, Komati, S, Nemeth, Ah, Armstrong, R, Valentine, R, Siuda, G, Harrison, D, Hughes, M, Parkinson, A, Soltysiak, B, Burn, J, Coleman, C, Bandmann, O, Bradbury, A, Gill, P, Fairtlough, H, Fillingham, K, Foustanos, I, Kazoka, M, O'Donovan, K, Taylor, C, Tidswell, K, and Quarrell, O.
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Male ,medicine.medical_specialty ,Heterozygote ,Psychopharmacology ,Population ,Poison control ,psychology/statistics /&/ numerical data ,Suicide, Attempted ,Suicide prevention ,Suicidal Ideation ,[SHS]Humanities and Social Sciences ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Prevalence ,Humans ,epidemiology, Europe ,Psychiatry ,education ,Suicidal ideation ,ComputingMilieux_MISCELLANEOUS ,Proportional Hazards Models ,Attempted ,Psychiatric Status Rating Scales ,education.field_of_study ,Psychological Tests ,Suicide attempt ,Psychopathology ,Depression ,Hazard ratio ,Huntington's disease ,Odds ratio ,Middle Aged ,3. Good health ,030227 psychiatry ,Europe ,psychology, Male, Middle Aged, Prevalence, Proportional Hazards Models, Psychiatric Status Rating Scales, Psychological Tests, Suicidal Ideation, Suicide ,Clinical Psychology ,Psychiatry and Mental health ,Suicide ,Huntington Disease ,epidemiology, Female, Heterozygote, Humans, Huntington Disease ,Cohort studies ,Female ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery ,Clinical psychology - Abstract
BACKGROUND: Previous studies indicate increased prevalences of suicidal ideation, suicide attempts, and completed suicide in Huntington's disease (HD) compared with the general population. This study investigates correlates and predictors of suicidal ideation in HD.METHODS: The study cohort consisted of 2106 HD mutation carriers, all participating in the REGISTRY study of the European Huntington's Disease Network. Of the 1937 participants without suicidal ideation at baseline, 945 had one or more follow-up measurements. Participants were assessed for suicidal ideation by the behavioural subscale of the Unified Huntington's Disease Rating Scale (UHDRS). Correlates of suicidal ideation were analyzed using logistic regression analysis and predictors were analyzed using Cox regression analysis.RESULTS: At baseline, 169 (8.0%) mutation carriers endorsed suicidal ideation. Disease duration (odds ratio [OR]=0.96; 95% confidence interval [CI]: 0.9-1.0), anxiety (OR=2.14; 95%CI: 1.4-3.3), aggression (OR=2.41; 95%CI: 1.5-3.8), a previous suicide attempt (OR=3.95; 95%CI: 2.4-6.6), and a depressed mood (OR=13.71; 95%CI: 6.7-28.0) were independently correlated to suicidal ideation at baseline. The 4-year cumulative incidence of suicidal ideation was 9.9%. Longitudinally, the presence of a depressed mood (hazard ratio [HR]=2.05; 95%CI: 1.1-4.0) and use of benzodiazepines (HR=2.44; 95%CI: 1.2-5.0) at baseline were independent predictors of incident suicidal ideation, whereas a previous suicide attempt was not predictive.LIMITATIONS: As suicidal ideation was assessed by only one item, and participants were a selection of all HD mutation carriers, the prevalence of suicidal ideation was likely underestimated.CONCLUSIONS: Suicidal ideation in HD frequently occurs. Assessment of suicidal ideation is a priority in mutation carriers with a depressed mood and in those using benzodiazepines.
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- 2013
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6. The V471A polymorphism in autophagy-related gene ATG7 modifies age at onset specifically in Italian Huntington disease patients
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Metzger S, Walter C, Riess O, Roos RA, Nielsen JE, Craufurd D, Nguyen HP, REGISTRY Investigators of the European Huntington’s Disease Network:Bachoud Lévi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer G, Levey J, Ramos Arroyo MA, Nielsen J, Koivisto SP, Päivärinta M, Sebastián AR, Tabrizi S, Vandenberghe W, Verellen Dumoulin C, Zaremba J, Uhrová T, Wahlström J, Barth K, Correia Guedes L, Finisterra AM, Garde MB, Bos R, Betz S, Callaghan J, Fullam R, Ecker D, Nielsen MG, Hvalstedt C, Held C, Koppers K, Laurà M, Horta SM, Descals AM, Díaz MF, Mestre T, Minster S, Monza D, Mütze L, Oehmen M, Townhill J, Orth M, Padieu H, Paterski L, Peppa N, Roedig V, Rialland A, Røren N, Šašinková P, Seliverstov Y, Cubillo PT, van Walsem MR, Wright A, Silva WV, Witjes Anné MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinger K, Scheibl M, Hecht K, Lilek S, Müller N, Schöggl H, Ullah J, Ribaï P, Boogaerts A, van Reijen D, Klempíř J, Majerová V, Roth J, Hjermind L, Jacobsen O, Vinthev Jensen T, Larsen IU, Stockholm J, Hiivola H, Martikainen K, Tuuha K, Ignatius J, Kärppä M, Åman J, Mustonen A, Kajula O, Santala M, Allain P, Guérid MA, Gohier B, Olivier A, Prundean A, Scherer Gagou C, Verny C, Bost M, Babiloni B, Debruxelles S, Duché C, Goizet C, Lafoucrière D, Jameau L, Spampinato U, De Bruycker C, Cabaret M, Carette AS, Defebvre L, Decorte E, Delval A, Delliaux M, Destee A, Dujardin K, Peter M, Plomhouse L, Sablonnière B, Simonin C, Lemaire MH, Manouvrier S, Thibault Tanchou S, Vuillaume I, Krystkowiak P, Duru C, Roussel M, Wannepain S, Berrissoul H, Bellonet M, Courtin F, Mantaux B, Fasquel V, Godefroy O, Azulay JP, Fluchère F, Delfini M, Eusebio A, Mundler L, Longato N, Rudolf G, Steinmetz G, Tranchant C, Wagner C, Zimmermann MA, Marcel C, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Boelmans K, Ganos C, Goerendt I, Hidding U, Lewerenz J, Münchau A, Schmalfeld J, Stubbe L, Zittel S, Bürk K, Möller JC, Rissling I, Cormio C, Sciruicchio V, Serpino C, de Tommaso M, CAPELLARI, SABINA, CORTELLI, PIETRO, Gallassi R, PODA, ROBERTO, RIZZO, GIOVANNI, Scaglione C, Abbruzzese G, di Poggio MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Albanese A, Di Bella D, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Paridi D, Soliveri P, Tomasello C, Squitieri F, Elifani F, Maglione V, Di Pardo A, Alberti S, Griguoli A, Amico E, Martino T, Petrollini M, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Chiara P, Quaranta D, Romano S, Soleti F, Spadaro M, van Hout MS, van Vugt JP, de Weert A, Bolwijn JJ, Dekker M, Leenders KL, Dumas EM, van den Bogaard SJ, 't Hart EP, van Duijn E, Kremer B, Verstappen CC, Blinkenberg EØ, Hauge E, Tyvoll H, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E, Retterstøl L, Overland T, Stokke B, Bjørnevoll I, Sando SB, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszcyk M, Boczarska Jedynak M, Ciach Wysocka E, Gorzkowska A, Jasinska Myga B, Opala G, Kłodowska Duda G, Stompel D, Banaszkiewicz K, Boćwińska D, Szczudlik A, Rudzinska M, Wójcik M, Dec M, Krawczyk M, Bojakowska Jaremek K, Szczygieł E, Stenwak A, Wasielewska A, Bryl A, Ciesielska A, Klimberg A, Marcinkowski J, Sempołowicz J, Samara H, Wiśniewski B, Janik P, Gogol A, Kwiecinski H, Jamrozik Z, Kaminska A, Antczak J, Jachinska K, Rakowicz M, Richter P, Rola R, Ryglewicz D, Sienkiewicz Jarosz H, Stępniak I, Witkowski G, Zdzienicka E, Sułek A, Krysa W, Stepniak I, Zieora Jakutowicz K, Júlio F, Januário C, Coelho M, Mendes T, Valadas A, Andrade C, Gago M, Garrett C, Guerra MR, Lima J, Massano J, Meireles J, Herrera CD, Garcia PM, Barrero F, Morales B, Cubo E, Mariscal N, Sánchez J, Alonso Frech F, Perez MR, Fenollar M, García RG, Pin Quiroga P, Vázquez Rivera S, Villanueva C, Alegre J, Bascuñana M, Caldentey JG, Ventura MF, Ribas GG, de Yébenes JG, Moreno JL, Ruíz PJ, Martínez Descals A, Artiga MJ, Sánchez V, Guerrero R, Bárcenas AH, Perea MF, Fortuna L, Torres MM, Reinante G, Moreau LV, Barbera MA, Guia DB, Hernanz LC, Catena JL, Ferrer PQ, Carruesco GT, Bas J, Busquets N, Calopa M, Elorza MD, López CD, Durán Sindreu Terol S, Robert MF, Ruíz BG, Casado AG, Martínez IH, Viladrich CM, Cárdenas RP, Roca E, Llesoy JR, Idiago JM, Vergara MR, García SS, Riballo AV, González SG, Guisasola LM, Salvador C, Martín ES, González M, Gorospe A, Legarda I, Arques PN, Rodríguez MJ, Vives B, Gaston I, Martinez Jaurrieta MD, Moreno JM, Peña JC, Avarvarei LD, Bastida AM, Recio MF, Vergé LR, Sánchez VS, Carrillo F, Cáceres MT, Mir P, Suarez MJ, Loutfi G, Olofsson C, Stattin EL, Westman L, Wikström B, Pålhagen SE, Paucar M, Svenningsson P, Reza Soltani TW, Höglund A, Sandström B, Høsterey Ugander U, Fredlund G, Constantinescu R, Neleborn Lingefjärd L, Stebler Y, Kaelin A, Romero I, Schüpbach M, Zaugg SW, Miedzybrodzka Z, Rae D, Downie L, Simpson S, Summers F, Ure A, Jack R, Matheson K, Akhtar S, Crooks J, Curtis A, de Souza J, Rickards H, Wright J, Barker RA, O' Keefe D, Di Pietro A, Fisher K, Goodman A, Hill S, Mason S, Swain R, Guzman NV, Bisson J, Busse M, Butcher C, Clenaghan C, Dunnett S, Handley O, Hunt S, Hughes A, Johnstone C, Jones L, Jones U, Khalil H, Owen M, Price K, Rose LE, Rosser A, Porteous M, Edwards M, Ho C, McGill M, Pearson P, Brockie P, Foster J, Johns N, McKenzie S, Rothery J, Thomas G, Yates S, Burrows L, Fletcher A, Harding A, Laver F, Silva M, Thomson A, Rowett L, Gallantrae D, Longthorpe M, Markova I, Raman A, Hamer S, Yarduiman P, Chu C, Kraus A, Wild S, Musgrave H, Toscano J, Jamieson S, Hobson E, Clayton C, Dipple H, Middleton J, Freire Patino D, Andrews T, Dougherty A, Kavalier F, Golding C, Laing H, Lashwood A, Robertson D, Ruddy D, Whaite A, Santhouse A, Patton M, Peterson M, Rose S, Bruno S, Chu E, Doherty K, Haider S, Hensman D, Lahiri N, Lewis M, Novak M, Patel A, Robertson N, Rosser E, Taylor R, Warner T, Wild E, Howard L, Sollom A, Snowden J, Thompson J, Jones M, Murphy H, Trender Gerhard I, Rogers D, Bek J, Oughton E, Johnson L, Hare M, Arran N, Verstraelen N, Partington Jones L, Huson S, Stopford C, Westmoreland L, Davidson J, Morgan K, Savage L, Singh B, Komati S, Nemeth AH, Armstrong R, Valentine R, Siuda G, Harrison D, Hughes M, Parkinson A, Soltysiak B, Bandmann O, Bradbury A, Gill P, Fairtlough H, Fillingham K, Foustanos I, Kazoka M, O' Donovan K, Taylor C, Tidswell K, Quarrell O, Metzger S, Walter C, Riess O, Roos RA, Nielsen JE, Craufurd D, Nguyen HP, REGISTRY Investigators of the European Huntington’s Disease Network:Bachoud-Lévi AC, Bentivoglio AR, Biunno I, Bonelli RM, Burgunder JM, Dunnett SB, Ferreira JJ, Handley OJ, Heiberg A, Illmann T, Landwehrmeyer G, Levey J, Ramos-Arroyo MA, Nielsen J, Koivisto SP, Päivärinta M, Sebastián AR, Tabrizi S, Vandenberghe W, Verellen-Dumoulin C, Zaremba J, Uhrová T, Wahlström J, Barth K, Correia-Guedes L, Finisterra AM, Garde MB, Bos R, Betz S, Callaghan J, Fullam R, Ecker D, Nielsen MG, Hvalstedt C, Held C, Koppers K, Laurà M, Horta SM, Descals AM, Díaz MF, Mestre T, Minster S, Monza D, Mütze L, Oehmen M, Townhill J, Orth M, Padieu H, Paterski L, Peppa N, Roedig V, Rialland A, Røren N, Šašinková P, Seliverstov Y, Cubillo PT, van Walsem MR, Wright A, Silva WV, Witjes-Anné MN, Yudina E, Zielonka D, Zielonka E, Zinzi P, Herranhof B, Holl A, Kapfhammer HP, Koppitz M, Magnet M, Otti D, Painold A, Reisinger K, Scheibl M, Hecht K, Lilek S, Müller N, Schöggl H, Ullah J, Ribaï P, Boogaerts A, van Reijen D, Klempíř J, Majerová V, Roth J, Hjermind L, Jacobsen O, Vinthev-Jensen T, Larsen IU, Stockholm J, Hiivola H, Martikainen K, Tuuha K, Ignatius J, Kärppä M, Åman J, Mustonen A, Kajula O, Santala M, Allain P, Guérid MA, Gohier B, Olivier A, Prundean A, Scherer-Gagou C, Verny C, Bost M, Babiloni B, Debruxelles S, Duché C, Goizet C, Lafoucrière D, Jameau L, Spampinato U, De Bruycker C, Cabaret M, Carette AS, Defebvre L, Decorte E, Delval A, Delliaux M, Destee A, Dujardin K, Peter M, Plomhouse L, Sablonnière B, Simonin C, Lemaire MH, Manouvrier S, Thibault-Tanchou S, Vuillaume I, Krystkowiak P, Duru C, Roussel M, Wannepain S, Berrissoul H, Bellonet M, Courtin F, Mantaux B, Fasquel V, Godefroy O, Azulay JP, Fluchère F, Delfini M, Eusebio A, Mundler L, Longato N, Rudolf G, Steinmetz G, Tranchant C, Wagner C, Zimmermann MA, Marcel C, Andrich J, Ellrichmann G, Hoffmann R, Kaminski B, Saft C, Stamm C, Boelmans K, Ganos C, Goerendt I, Hidding U, Lewerenz J, Münchau A, Schmalfeld J, Stubbe L, Zittel S, Bürk K, Möller JC, Rissling I, Cormio C, Sciruicchio V, Serpino C, de Tommaso M, Capellari S, Cortelli P, Gallassi R, Poda R, Rizzo G, Scaglione C, Abbruzzese G, di Poggio MB, Di Maria E, Ferrandes G, Mandich P, Marchese R, Albanese A, Di Bella D, Di Donato S, Gellera C, Genitrini S, Mariotti C, Nanetti L, Paridi D, Soliveri P, Tomasello C, Squitieri F, Elifani F, Maglione V, Di Pardo A, Alberti S, Griguoli A, Amico E, Martino T, Petrollini M, Catalli C, Di Giacopo R, Fasano A, Frontali M, Guidubaldi A, Ialongo T, Jacopini G, Loria G, Piano C, Chiara P, Quaranta D, Romano S, Soleti F, Spadaro M, van Hout MS, van Vugt JP, de Weert A, Bolwijn JJ, Dekker M, Leenders KL, Dumas EM, van den Bogaard SJ, 't Hart EP, van Duijn E, Kremer B, Verstappen CC, Blinkenberg EØ, Hauge E, Tyvoll H, Frich J, Aaserud O, Wehus R, Bjørgo K, Fannemel M, Gørvell P, Lorentzen E, Retterstøl L, Overland T, Stokke B, Bjørnevoll I, Sando SB, Dziadkiewicz A, Nowak M, Robowski P, Sitek E, Slawek J, Soltan W, Szinwelski M, Blaszcyk M, Boczarska-Jedynak M, Ciach-Wysocka E, Gorzkowska A, Jasinska-Myga B, Opala G, Kłodowska-Duda G, Stompel D, Banaszkiewicz K, Boćwińska D, Szczudlik A, Rudzinska M, Wójcik M, Dec M, Krawczyk M, Bojakowska-Jaremek K, Szczygieł E, Stenwak A, Wasielewska A, Bryl A, Ciesielska A, Klimberg A, Marcinkowski 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M, Parkinson A, Soltysiak B, Bandmann O, Bradbury A, Gill P, Fairtlough H, Fillingham K, Foustanos I, Kazoka M, O' Donovan K, Taylor C, Tidswell K, and Quarrell O
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Adult ,Adolescent ,Genotype ,Huntington ,Ubiquitin-Activating Enzymes ,Autophagy-Related Protein 7 ,Polymorphism, Single Nucleotide ,Cohort Studies ,Young Adult ,Gene Frequency ,V471A polymorphism ,Genetics ,Autophagy ,Humans ,Age of Onset ,Child ,Biology ,Genetic Association Studies ,Aged ,Clinical Genetics ,Evolutionary Biology ,Computational Biology ,Human Genetics ,Middle Aged ,Huntington Disease ,Neurology ,Italy ,Autosomal Dominant ,Child, Preschool ,Genetic Polymorphism ,Medicine ,Population Genetics ,gene ATG7 ,Research Article - Abstract
The cause of Huntington disease (HD) is a polyglutamine repeat expansion of more than 36 units in the huntingtin protein, which is inversely correlated with the age at onset of the disease. However, additional genetic factors are believed to modify the course and the age at onset of HD. Recently, we identified the V471A polymorphism in the autophagy-related gene ATG7, a key component of the autophagy pathway that plays an important role in HD pathogenesis, to be associated with the age at onset in a large group of European Huntington disease patients. To confirm this association in a second independent patient cohort, we analysed the ATG7 V471A polymorphism in additional 1,464 European HD patients of the "REGISTRY" cohort from the European Huntington Disease Network (EHDN). In the entire REGISTRY cohort we could not confirm a modifying effect of the ATG7 V471A polymorphism. However, analysing a modifying effect of ATG7 in these REGISTRY patients and in patients of our previous HD cohort according to their ethnic origin, we identified a significant effect of the ATG7 V471A polymorphism on the HD age at onset only in the Italian population (327 patients). In these Italian patients, the polymorphism is associated with a 6-years earlier disease onset and thus seems to have an aggravating effect. We could specify the role of ATG7 as a genetic modifier for HD particularly in the Italian population. This result affirms the modifying influence of the autophagic pathway on the course of HD, but also suggests population-specific modifying mechanisms in HD pathogenesis.
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- 2013
7. Observing Huntington's disease: the European Huntington's Disease Network's REGISTRY
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Wolf, E, Zangerl, A, Braunwarth, Em, Sinadinosa, D, Walleczek, Am, Ladurner, G, Staffen, W, Ribaï, P, Flamez, A, Morez, V, de Raedt, S, Boogaerts, A, van Reijen, D, Klempíř, J, Kucharík, M, Roth, J, Šenkárová, Z, Hasholt, L, Hjermind, Le, Jakobsen, O, Nørremølle, A, Sørensen, Sa, Stokholm, J, Nielsen, J, Hiivola, H, Martikainen, K, Tuuha, K, Peippo, M, Sipponen, M, Ignatius, J, Kärppä, M, Åman, J, Santala, M, Allain, P, Guérid, Ma, Gohier, B, Olivier, A, Prundean, A, Scherer Gagou, C, Verny, C, Babiloni, B, Debruxelles, S, Goizet, C, Lafoucrière, D, De Bruycker, C, Carette, A, Decorte, E, Delval, A, Delliaux, M, Dujardin, K, Peter, M, Plomhouse, L, Simonin, C, Thibault Tanchou, S, Bellonet, M, Duru, C, Krystkowiak, P, Roussel, M, Wannepain, S, Azulay, Jp, Chabot, C, Delphini, M, Eusebio, A, Grosjean, H, Mundler, L, Nowak, M, Rudolf, G, Steinmetz, G, Tranchant, C, Wagner, C, Zimmermann, Ma, Calvas, F, Cheriet, S, Démonet, Jf, Galitzky, M, Kosinski, Cm, Milkereit, E, Probst, D, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Gelderblom, H, Priller, J, Prüss, H, Spruth, Ej, Andrich, J, Hoffmann, R, Kraus, Ph, Muth, S, Prehn, C, Saft, C, Salmen, S, Stamm, C, Steiner, T, Strassburger, K, Lange, H, Friedrich, A, Hunger, U, Löhle, M, Schmidt, S, Storch, A, Wolz, A, Wolz, M, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Hidding, U, Lewerenz, J, Münchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Diercks, G, Gorzolla, H, Schrader, C, Heinicke, W, Ribbat, M, Longinus, B, Bürk, K, Möller, Jc, Rissling, I, Peinemann, A, Städtler, M, Weindl, A, Bechtel, N, Beckmann, H, Bohlen, S, Hölzner, E, Reilmann, R, Rohm, S, Rumpf, S, Schepers, S, Beister, A, Dose, M, Hammer, K, Kieni, J, Leythaeuser, G, Marquard, R, Raab, T, Richter, S, Selimbegovic Turkovic, A, Schrenk, C, Schuierer, M, Wiedemann, A, Buck, A, Connemann, J, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Süssmuth, S, Trautmann, S, Weydt, P, Cormio, C, Difruscolo, O, Sciruicchio, V, Serpino, C, de Tommaso, M, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Rizzo, G, Scaglione, C, Bertini, E, Ghelli, E, Ginestroni, A, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, di Poggio, Mb, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Albanese, A, Di Bella, D, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Paridi, D, Soliveri, P, Tomasello, C, DE MICHELE, Giuseppe, Di Maio, L, Rinaldi, Carlo, Russo, Cv, Salvatore, Elena, Tucci, T, Cannella, M, Codella, V, De Gregorio, F, De Nicola, N, Martino, T, Simonelli, M, Squitieri, F, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Modoni, A, Piano, C, Chiara, P, Quaranta, D, Romano, S, Soleti, F, Spadaro, M, van Hout, M, van Vugt, Jp, de Weert, Am, Bolwijn, Jj, Dekker, M, Leenders, Kl, van Oostrom, Jc, Dumas, Em, Jurgens, Ck, van den Bogaard, Sj, 't Hart, Ep, Kremer, B, Verstappen, Cc, Frich, J, Wehus, R, Aaserud, O, Borgerød, N, Bjørgo, K, Fannemel, M, Gørvell, P, Pro Koivisto, S, Retterstøl, L, Overland, T, Stokke, B, Bjørnevoll, I, Sando, Sb, Blinkenberg, Eø, Hauge, E, Tyvoll, H, Sitek, E, Slawek, J, Soltan, W, Boczarska Jedynak, M, Jasinska Myga, B, Opala, G, Kłodowska Duda, G, Banaszkiewicz, K, Szczudlik, A, Rudzińska, M, Wójcik, M, Dec, M, Krawczyk, M, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Sempołowicz, J, Samara, H, Janik, P, Kalbarczyk, A, Kwiecinski, H, Jamrozik, Z, Antczak, J, Jachinska, K, Rakowicz, M, Richter, P, Ryglewicz, D, Witkowski, G, Zdzienicka, E, Sułek, A, Krysa, W, Júlio, F, Januário, C, Guedes, L, Coelho, M, Mendes, T, Valadas, A, Timóteo, Â, Costa, C, Vale, J, Cavaco, S, Damásio, J, Magalhães, M, Gago, M, Garrett, C, Guerra, Mr, Solis, P, Herrera, Cd, Garcia, Pm, Barrero, F, Morales, B, Cubo, E, Mariscal, N, Alonso Frech, F, Perez, Mr, Fenollar, M, García, Rg, Quiroga, Pp, Rivera, Sv, Villanueva, C, Bascuñana, M, Ventura, Mf, Ribas, Gg, de Yébenes, Jg, Moreno, Jl, Ruíz, Pj, Martínez Descals, A, Artiga, Mj, Sánchez, V, Perea, Mf, Lorenza, F, Torres, Mm, Reinante, G, Moreau, Lv, Barbera, Ma, Guia, Db, Hernanz, Lc, Catena, Jl, Ferrer, Pq, Carruesco, Gt, Bas, J, Busquets, N, Calopa, M, Buongiorno, Mt, Muñoz, E, Elorza, Md, López, Cd, Terol, Sd, Robert, Mf, Ruíz, Bg, Casado, Ag, Martínez, Ih, Viladrich, Cm, Pons i., Càrdenas R, Roca, E, Llesoy, Jr, Idiago, Jm, Vergara, Mr, García, S, Villa Riballo, A, González, Sg, Guisasola, Lm, Salvador, C, San Martín, E, Gorospe, A, Legarda, I, Arques, Pn, Rodríguez, Mj, Vives, B, Gaston, I, Ramos Arroyo, Ma, Moreno, Jm, Peña, Jc, Avarvarei, Ld, Bastida, Am, Recio, Mf, Vergé, Lr, Carrillo, F, Cáceres, Mt, Mir, P, Suarez, Mj, Bosca, M, Burguera, Ja, Garcia, Ac, Martínez, Lm, del Val, Jl, Loutfi, G, Olofsson, C, Stattin, El, Westman, L, Wikström, B, Höglund, A, Pålhagen, Se, Paucar, M, Sandström, B, Soltani, R, Svenningsson, P, Reza Soltani, Tw, Constantinescu, R, Fredlund, G, Høsterey Ugander, U, Neleborn Lingefjärd, L, Esmaeilzadeh, M, Tedroff, J, Winnberg, E, Björn, Y, Ekwall, C, Gøller, Ml, Johansson, A, Wiklund, L, Petersen, Å, Reimer, J, Widner, H, Burgunder, Y, Stebler, Y, Kaelin, A, Romero, I, Schüpbach, M, Zaugg, Sw, Jack, R, Matheson, K, Miedzybrodzka, Z, Rae, D, Simpson, S, Summers, F, Ure, A, Crooks, J, Curtis, A, de Souza Keylock, J, Rickards, H, Wright, J, Hayward, B, Sieradzan, K, Wright, A, Barker, Ra, Di Pietro, A, Fisher, K, Goodman, A, Hill, S, Kershaw, A, Mason, S, Paterson, N, Raymond, L, Bisson, J, Busse, M, Clenaghan, C, Ellison Rose, L, Handley, O, Hunt, S, Price, K, Rosser, A, Edwards, M, Hughes, T, Mcgill, M, Pearson, P, Porteous, M, Smith, P, Zeman, A, Causley, A, Harrower, T, Howcroft, D, Lambord, N, Rankin, J, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Miller, J, Ritchie, S, Burrows, L, Fletcher, A, Harding, A, Laver, F, Silva, M, Thomson, A, Burns, P, Chu, C, Evans, C, Hamer, S, Markova, I, Raman, A, Barnes, K, Hobson, E, Jamieson, S, Thomson, J, Toscano, J, Wild, S, Yardumian, P, Bourne, C, Clayton, C, Dipple, H, Clapton, J, Grant, D, Hallam, C, Middleton, J, Murch, A, Patino, D, Bate, L, Pate, L, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Patton, M, Peterson, M, Rose, S, Bruno, S, Chu, E, Doherty, K, Henley, S, Lahiri, N, Novak, M, Patel, A, Read, J, Rosser, E, Say, M, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Arran, N, Callaghan, J, Craufurd, D, Fullam, R, Howard, L, Huson, S, Oughton, E, Partington Jones, L, Snowden, J, Sollom, A, Stopford, C, Thompson, J, Trender Gerhad, I, Verstraelen, N, Westmoreland, L, Nemeth, Ah, Siuda, G, Harrison, D, Hughes, M, Parkinson, A, Soltysiak, B, Burn, J, Coleman, C, Majeed, T, Verstraelen Ritchie, N, Bandmann, O, Bradbury, A, Gill, P, Fairtlough, H, Fillingham, K, Foustanos, I, O'Donovan, K, Tidswell, K, Quarrell, O., Faculty of Economic and Social Sciences and Solvay Business School, Neurology, Clinical sciences, Neuroprotection & Neuromodulation, Orth M., European Huntington's Disease Network, Handley O.J., Schwenke C., Dunnet S., Wild E.J., Tabrizi S.J., Landwehrmeyer G.B., Capellari S., Cortelli P., Gallassi R., Poda R., Rizzo G., and Scaglione C.
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Gerontology ,medicine.medical_specialty ,Neurology ,International Cooperation ,Disease ,Irritability ,Data Collection/methods ,Huntington's disease ,medicine ,Humans ,Registries ,Psychiatry ,Suicidal ideation ,Disease burden ,business.industry ,Data Collection ,medicine.disease ,Europe ,Huntington Disease ,Psychiatry and Mental health ,European Huntington's Disease Network ,Surgery ,Observational study ,Neurology (clinical) ,medicine.symptom ,business - Abstract
BACKGROUND: Huntington's disease (HD) is a rare triplet repeat (CAG) disorder. Advanced, multi-centre, multi-national research frameworks are needed to study simultaneously multiple complementary aspects of HD. This includes the natural history of HD, its management and the collection of clinical information and biosamples for research. METHODS: We report on cross-sectional data of the first 1766 participants in REGISTRY, the European Huntington's Disease Network's (EHDN), multi-lingual, multi-national prospective observational study of HD in Europe. Data collection (demographics, phenotype, genotype, medication, co-morbidities, biosamples) followed a standard protocol. RESULTS: Phenotype, and the HD genotype, of manifest HD participants across different European regions was similar. Motor onset was most common (48%) with a non-motor onset in more than a third of participants. Motor signs increased, and cognitive abilities and functional capacity declined as the disease burden (CAGn-35.5) X age) increased. A life-time history of behavioural symptoms was common, but the behavioural score was not related to disease burden. One fifth of participants had severe psychiatric problems, e.g. suicidal ideation and attempts, and/or irritability/aggression, with psychosis being less common. Participants on anti-dyskinetic medication had a higher motor and lower cognitive score, were older, and more prone to physical trauma. A higher motor and a lower cognitive score predicted more advanced disease. CONCLUSIONS: The unparalleled collection of clinical data and biomaterials within the EHDN's REGISTRY can expedite the search for disease modifiers (genetic and environmental) of age at onset and disease progression that could be harnessed for the development of novel treatments.
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- 2011
8. β-Defensin Genomic Copy Number Does Not Influence the Age of Onset in Huntington's Disease
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Vittori, A, Orth, M, Roos, Ra, Outeiro, Tf, Giorgini, F, Hollox, Ej, Bachoud-Levi, Ac, Bentivoglio, Ar, Biunno, I, Bonelli, Rm, Burgunder, Jm, Dunnett, Sb, Ferreira, Jj, Handley, Oj, Heiberg, A, Illmann, T, Landwehrmeyer, Gb, Levey, J, Martinez-Jaurrieta, Md, Nielsen, Je, Pro Koivisto, S, Piiiviirinta, M, Sebastian, Ar, Tabrizi, Sj, Vandenberghe, W, Verellen-Dumoulin, C, Zaremba, J, Uhrova, T, Wahlstrom, J, Barth, K, Correia-Guedes, L, Finisterra, Am, Bascuiiana Garde, M, Betz, S, Bos, R, Ecker, D, Held, C, Koppers, K, Laura, M, Descals, Am, Mestre, T, Monza, D, Townhill, J, Padieu, H, Paterski, L, Peppa, N, Rialland, A, Røren, N, Sasinkova, P, Trigo Cubillo, P, van Walsem, M, Witjes-Ane, Mn, Yudina, E, Zielonka, D, Zielonka, E, Zinzi, P, Herranhof, B, Hod, A, Kapfhammer, Hp, Koppitz, M, Magnet, M, Otti, D, Painold, A, Reisinge, K, Scheib, M, Hecht, K, Lilek, S, Muller, N, Schoggl, H, Ullah, J, Ribal, P, Klempff, J, Majerova, V, Roth, J, Hjermind, Le, Jakobsen, O, Vinthev-Jensen, T, Larsen, Iu, Stokholm, J, Hiivola, H, Martikainen, K, Tuuha, K, Santala, M, Milkereit, E, Kosinski, Cm, Probst, D, Reetz, K, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Andrich, J, Ellrichmann, G, Hoffmann, R, Kaminski, B, Saft, C, Stamm, C, Lange, H, Lohle, M, Schmidt, S, Storch, A, Wolz, A, Wolz, M, Capetian, P, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Hidding, U, Lewerenz, J, Miinchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Heinicke, W, Ribbat, M, Longinus, B, Miihlau, M, Peinemann, A, Stiidtler, M, Weindl, A, Winkelmann, J, Ziegler, C, Bechtel, N, Beckmann, H, Bohlen, S, Holzner, E, Reilmann, R, Rohm, S, Rumpf, S, Schepers, S, Dose, M, Leythaeuser, G, Marquard, R, Raab, T, Schrenk, C, Schuierer, M, Buck, A, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Schwenk, D, Siissmuth, S, Trautmann, S, Weydt, P, Cormio, C, de Tommaso, M, Sciruicchio, V, Serpino, C, Ghelli, E, Ginestroni, A, Bertini, E, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, Ferrandes, Mb, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Soliveri, P, Tomasello, C, De Michele, G, Dimaio, L, Massarelli, M, Rinaldi, C, Roca, A, Rossi, F, Russo, Cv, Salvatore, E, Sorrentino, P, Tucci, T, De Nicola, A, Elifani, F, Petrollini, M, Martino, T, Lovo, F, Squitieri, F, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Piano, C, Piccininni, C, Quaranta, D, Romano, S, Soleti, F, Spadaro, M, van Hout MS, van Vugt JP, de Weert, A, Bolwijn, Jj, Neurologie, P, Dekker, M, Leenders, Kl, van Oostrom JC, Dumas, Em, Jurgens, Ck, van den Bogaard SJ, 't Hart EP, Kremer, B, Verstappen, Cc, van Walsem MR, Frich, J, Aaserud, O, Wehus, R, Bjørgo, K, Fannemel, M, Gørvell, P, Lorentzen, E, Koivisto, Sp, Retterstøl, L, Stokke, B, Bjørnevoll, I, Sando, Sb, Dziadkiewicz, A, Nowak, M, Robowski, P, Sitek, E, Slawek, J, Soltan, W, Szinwelski, M, Blaszczyk, M, Boczarska-Jedynak, M, Ciach-Wysocka, E, Gorzkowska, A, Jasinska-Myga, B, Opala, G, Klodowska, G, Stompel, D, Banaszkiewicz, K, Boewiriska, D, Bojakowska-Jaremek, K, Neurologii, A, Dec, M, Krawczyk, M, Rudziriska, M, Szczudlik, A, Szczygiel, E, Wasielewska, A, Wojcik, M, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Samara, H, Sempolowicz, J, Janik, P, Kalbarczyk, A, Kwiecinski, H, Jamrozik, Z, Antczak, J, Jachinska, K, Krysa, W, Rakowicz, M, Richter, P, Rola, R, Ryglewicz, D, Sienkiewicz-Jarosz, H, Sulek, A, Witkowski, G, Zdzienicka, E, Zieora-Jakutowicz, K, Coelho, M, Mendes, T, Valadas, A, Andrade, C, Joao, Ps, Gago, M, Garrett, C, Guerra, Mr, Solis, P, Herrera, Cd, Garcia, Pm, Cubo, E, Mariscal, N, Sanchez, J, Barrero, Fj, Alonso-Frech, F, Perez, Mr, Fenollar, M, Garda, R, Rivera, Sv, Villanueva, C, Alegre, J, Bascuiiana, M, Ventura, Mf, Ribas, Gg, Moreno, Jl, Cubillo, Pt, Rufz, Pj, Frech, Fa, Dfaz, J, Guerrero, R, Artiga, Mj, Sanchez, V, Alcaraz, Lf, de Ia Arrixaca, V, Manzanares, S, Perea, Mf, Reinante, G, Arrixaca, Ia, Torres, Mm, Moreau, Lv, Barbera, Ma, Guia, Db, Hernanz, Lc, Catena, Jl, Sebastian, R, Ferrer, Pq, Carruesco, Gt, Bas, J, Busquets, N, Calopa, M, Buongiorno, Mt, Munoz, E, Elorza, Md, Lopez, Cd, Terol, Ds, Robert, Mf, Rufz, Bg, Casado, Ag, Martinez, Ih, Viladrich, Cm, Pons, R, Roca, E, Llesoy, Jr, Idiago, Jm, Vergara, Mr, Garcia, Ss, Riballo, Av, Hoglund, A, Palhagen, Se, Paucar, M, Sandstrom, B, Svenningsson, P, Reza-Soltani, Tw, Kaelin, A, Romero, I, Schupbach, M, Stebler, Y, Zaugg, Sw, Akhtar, S, Crooks, J, Curtis, A, de Souza, J, Rickards, H, Wright, J, Barker, Ra, Di Pietro, A, Fisher, K, Goodman, Ao, Hill, S, Kershaw, A, Mason, S, O'Keefe, D, Swain, R, Guzman, Nv, Busse, M, Butcher, C, Clenaghan, C, Dunnett, S, Fullam, R, Jones, L, Jones, U, Khalil, H, Minster, S, Owen, M, Hunt, S, Price, K, Rosser, A, Edwards, M, Ho, C, Mcgill, M, Pearson, P, Porteous, M, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Burrows, L, Chu, C, Fletcher, A, Gallantrae, D, Harding, A, Hamer, S, Kraus, A, Laver, F, Longthorpe, M, Markova, I, Raman, A, Silva, M, Thomson, A, Wild, S, Yardumian, P, Hobson, E, Jamieson, S, Musgrave, H, Rowett, L, Toscano, J, Clayton, C, Dipple, H, Middleton, J, Patino, D, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Laing, H, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Santhouse, A, Bruno, S, Doherty, K, Lahiri, N, Novak, M, Patel, A, Rosser, E, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Arran, N, Bek, J, Callaghan, J, Craufurd, D, Howard, L, Hare, M, Huson, S, Johnson, L, Jones, M, Murphy, H, Oughton, E, Partington-Janes, L, Rogers, D, Snowden, J, Sollom, A, Stopford, C, Thompson, J, Trender-Gerhard, I., Vittori, Angelica, Orth, Michael, Roos, Raymund A C, Outeiro, Tiago F, Giorgini, F, Russo, Cinzia Valeria, Flaviano, and Hollox, Edward J
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Adult ,Male ,Age of Onset ,DNA Copy Number Variations ,Female ,Genotype ,Humans ,Huntington Disease ,Middle Aged ,beta-Defensins ,Disease ,Biology ,Genetic modifier ,Article ,Pathogenesis ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Huntington's disease ,medicine ,Copy-number variation ,Defensin ,030304 developmental biology ,Genetics ,0303 health sciences ,copy number variation ,inflammation ,Acquired immune system ,medicine.disease ,3. Good health ,Beta defensin ,Neurology (clinical) ,Age of onset ,030217 neurology & neurosurgery - Abstract
Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammations is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2)- encoded by DEFB4- is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD. Objective: In this study we tested the hypothesis that copy number variation (CNV) of the β-defensin region, including DEFB4, modifies the AO in HD. Methods and results: We genotyped β-defensin CNV in 490 HD individuals using the paralogue ratio test and found no association between β-defensin CNV and onset of HD. Conclusions: We conclude that it is unlikely that DEFB4 plays a role in HD pathogenesis.
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- 2013
9. Discrepancies in reporting the CAG repeat lengths for Huntington's disease
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Quarrell, Ow, Handley, O, O'Donovan, K, Dumoulin, C, Ramos Arroyo, M, Biunno, I, Bauer, P, Kline, M, Landwehrmeyer, Gb, Barth, K, Correia Guedes, L, Maria Finisterra, A, Bascuñana Garde, M, Bos, R, Ecker, D, Held, C, Koppers, K, Laurà, M, Martínez Descals, A, Mclean, T, Mestre, T, Minster, S, Monza, D, Townhill, J, Orth, M, Padieu, H, Paterski, L, Peppa, N, Koivisto, Sp, Rialland, A, Røren, N, Šašinková, P, Cubillo, Pt, van Walsem MR, Witjes Ané MN, Yudina, E, Zielonka, D, Zielonka, E, Zinzi, P, Bachoud Lévi AC, Bentivoglio, Ar, Bonelli, R, Burgunder, Jm, Dunnett, Sb, Ferreira, Jj, Handley, Oj, Heiberg, A, Illmann, T, Levey, J, Nielsen, Je, Päivärinta, M, Roos, Ra, Rojo Sebastián, A, Tabrizi, Sj, Vandenberghe, W, Verellen Dumoulin, C, Zaremba, J, Uhrova, T, Wahlström, J, Bonelli, Rm, Herranhof, B, Holl, A, Kapfhammer, Hp, Koppitz, M, Magnet, M, Otti, D, Painold, A, Reisinger, K, Scheibl, M, Hecht, K, Lilek, S, Müller, N, Schöggl, H, Ullah, J, Brugger, F, Hepperger, C, Hotter, A, Mahlknecht, P, Nocker, M, Seppi, K, Wenning, G, Buratti, L, Hametner, Em, Holas, C, Hussl, A, Mair, K, Poewe, W, Wolf, E, Zangerl, A, Braunwarth, Em, Ribaï, P, Flamez, A, Morez, V, de Raedt, S, Boogaerts, A, van Reijen, D, Klempíř, J, Kucharík, M, Roth, J, Hjermind, Le, Jakobsen, O, Stokholm, J, Hasholt, L, Nørremølle, A, Sørensen, Sa, Hiivola, H, Martikainen, K, Tuuha, K, Peippo, M, Sipponen, M, Kosinski, Cm, Milkereit, E, Probst, D, Sass, C, Schiefer, J, Schlangen, C, Werner, Cj, Gelderblom, H, Priller, J, Prüss, H, Spruth, Ej, Andrich, J, Hoffmann, R, Kraus, Ph, Muth, S, Prehn, C, Saft, C, Salmen, S, Stamm, C, Steiner, T, Strassburger, K, Lange, H, Friedrich, A, Hunger, U, Löhle, M, Schmidt, S, Storch, A, Wolz, A, Wolz, M, Lambeck, J, Zucker, B, Boelmans, K, Ganos, C, Hidding, U, Lewerenz, J, Münchau, A, Schmalfeld, J, Stubbe, L, Zittel, S, Heinicke, W, Longinus, B, Uni, M, Bürk, K, Möller, Jc, Rissling, I, Peinemann, A, Städtler, M, Weindl, A, Bechtel, N, Beckmann, H, Bohlen, S, Hölzner, E, Reilmann, R, Rohm, S, Rumpf, S, Schepers, S, Beister, A, Dose, M, Hammer, K, Kieni, J, Leythaeuser, G, Marquard, R, Raab, T, Richter, S, Selimbegovic Turkovic, A, Schrenk, C, Schuierer, M, Wiedemann, A, Buck, A, Connemann, J, Eschenbach, C, Landwehrmeyer, B, Lezius, F, Nepper, S, Niess, A, Süssmuth, S, Trautmann, S, Weydt, P, Cormio, C, Difruscolo, O, Sciruicchio, V, Serpino, C, de Tommaso, M, Capellari, S, Cortelli, P, Gallassi, R, Poda, R, Rizzo, G, Scaglione, C, Bertini, E, Ghelli, E, Ginestroni, A, Massaro, F, Mechi, C, Paganini, M, Piacentini, S, Pradella, S, Romoli, Am, Sorbi, S, Abbruzzese, G, Bandettini di Poggio, M, Di Maria, E, Ferrandes, G, Mandich, P, Marchese, R, Albanese, A, Di Bella, D, Di Donato, S, Gellera, C, Genitrini, S, Mariotti, C, Nanetti, L, Paridi, D, Soliveri, P, Tomasello, C, De Michele, G, Di Maio, L, Rinaldi, C, Valeria Russo, C, Salvatore, E, Tucci, T, Cannella, M, Codella, V, De Gregorio, F, De Nicola, N, Martino, T, Simonelli, M, Squitieri, F, Catalli, C, Di Giacopo, R, Fasano, A, Frontali, M, Guidubaldi, A, Ialongo, T, Jacopini, G, Loria, G, Modoni, A, Piano, C, Piccininni, C, Quaranta, D, Romano, Silvia, Soleti, F, Spadaro, M, van Hout MS, van Vugt JP, Marit de Weert, A, Bolwijn, Jj, Dekker, M, Leenders, Kl, van Oostrom JC, Dumas, Em, Jurgens, Ck, van den Bogaard SJ, 't Hart EP, Kremer, B, Verstappen, Cc, Aaserud, O, Wehus, R, Bjørgo, K, Fannemel, M, Gørvell, P, Retterstøl, L, Overland, T, Stokke, B, Bjørnevoll, I, Sando, Sb, Sitek, E, Slawek, J, Soltan, W, Boczarska Jedynak, M, Jasinska Myga, B, Opala, G, Kodowska Duda, G, Banaszkiewicz, K, Szczudlik, A, Rudziñska, M, Wójcik, M, Dec, M, Krawczyk, M, Bryl, A, Ciesielska, A, Klimberg, A, Marcinkowski, J, Sempoowicz, J, Samara, H, Janik, P, Kalbarczyk, A, Kwiecinski, H, Jamrozik, Z, Antczak, J, Jachinska, K, Rakowicz, M, Richter, P, Ryglewicz, D, Witkowski, G, Zdzienicka, E, Suek, A, Krysa, W, Guedes, L, Coelho, M, Mendes, T, Valadas, A, Cavaco, S, Damásio, J, Magalhães, M, Gago, M, Garrett, C, Guerra, Mr, Barrero, F, Morales, B, Cubo, E, Mariscal, N, Sánchez, J, Alonso Frech, F, Rabasa Perez, M, Fenollar, M, García, R, Quiroga, Pp, Vázquez Rivera, S, Villanueva, C, Bascuñana, M, Fatás Ventura, M, García Ribas, G, García de Yébenes, J, López Sendón Moreno JL, García Ruíz PJ, José Saiz Artiga, M, Sánchez, V, Noguera Perea, F, Lorenza, F, Torres, Mm, Reinante, G, Vivancos Moreau, L, Barbera, Ma, Badenes Guia, D, Hernanz, Lc, Catena, Jl, Ferrer, Pq, Tome Carruesco, G, Bas, J, Busquets, N, Calopa, M, Dalmau Elorza, M, Díez, C, López, A, Durán, S, Terol, S, Floriach Robert, M, Garzón Ruíz, B, González Casado, A, Haro Martínez, I, Viladrich, Cm, Càrdenas R, Pons i., Roca, E, Llesoy, Jr, Ruiz Idiago JM, Ruíz Vergara, M, Soriano García, S, Villa Riballo, A, Gorospe, A, Legarda, I, Arques, Pn, Torres Rodríguez MJ, Vives, B, Gaston, I, Bosca, M, Burguera, Ja, Garcia, Ac, Pålhagen, Se, Paucar, M, Svenningsson, P, Walldén Reza Soltani, T, Höglund, A, Sandström, B, Høsterey Ugander, U, Fredlund, G, Constantinescu, R, Neleborn Lingefjärd, L, Tedroff, J, Esmaeilzadeh, M, Winnberg, E, Burgunder, Y, Stebler, Y, Kaelin, A, Romero, I, Schüpbach, M, Zaugg, Sw, Jack, R, Matheson, K, Miedzybrodzka, Z, Rae, D, Simpson, S, Summers, F, Ure, A, Crooks, J, Curtis, A, de Souza, J, Rickards, H, Wright, J, Barker, Ra, Di Pietro, A, Fisher, K, Goodman, A, Hill, S, Kershaw, A, Mason, S, Paterson, N, Raymond, L, Bisson, J, Busse, M, Clenaghan, C, Ellison Rose, L, Hunt, S, Price, K, Rosser, A, Edwards, M, Hughes, T, Mcgill, M, Pearson, P, Porteous, M, Smith, P, Zeman, A, Causley, A, Harrower, T, Howcroft, D, Lambord, N, Rankin, J, Brockie, P, Foster, J, Johns, N, Mckenzie, S, Rothery, J, Thomas, G, Yates, S, Miller, J, Ritchie, S, Burrows, L, Fletcher, A, Harding, A, Laver, F, Silva, M, Thomson, A, Barnes, K, Chu, C, Hobson, E, Jamieson, S, Markova, I, Thomson, J, Toscano, J, Wild, S, Yardumian, P, Bourne, C, Clayton, C, Dipple, H, Clapton, J, Grant, J, Gross, D, Hallam, C, Middleton, J, Murch, A, Patino, D, Andrews, T, Dougherty, A, Kavalier, F, Golding, C, Lashwood, A, Robertson, D, Ruddy, D, Whaite, A, Patton, M, Peterson, M, Rose, S, Bruno, S, Chu, E, Doherty, K, Henley, S, Lahiri, N, Novak, M, Patel, A, Read, J, Rosser, E, Say, M, Tabrizi, S, Taylor, R, Warner, T, Wild, E, Arran, N, Callaghan, J, Craufurd, D, Fullam, R, Howard, L, Huson, S, Oughton, E, Partington Jones, L, Snowden, J, Sollom, A, Stopford, C, Thompson, J, Trender Gerhad, I, Verstraelen, N, Westmoreland, L, Nemeth, Ah, Suida, G, Harrison, D, Hughes, M, Parkinson, A, Soltysiak, B, Bandmann, O, Bradbury, A, Gill, P, Fairtlough, H, Fillingham, K, Foustanos, I, Tidswell, K., Kaelin, André, Quarrel O.W., Handley O., O'Donovan K., Dumoulin C., Ramos-Arroyo M., Biunno I., Bauer P., Kline M., Capellari S., Cortelli P., Gallassi R., Landwehrmeyer G.B., European Huntington's Disease Network., Neurology, Clinical sciences, Neuroprotection & Neuromodulation, Quarrell, Ow, Handley, O, O'Donovan, K, Dumoulin, C, Ramos Arroyo, M, Biunno, I, Bauer, P, Kline, M, Landwehrmeyer, Gb, European Huntington's Disease, Network, European Huntington's Disease, N. e. t. w. o. r. k., Rinaldi, Carlo, Salvatore, Elena, and DE MICHELE, Giuseppe
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medicine.medical_specialty ,Concordance ,International Cooperation ,Diagnostic Errors/statistics & numerical data ,Nerve Tissue Proteins ,Guidelines as Topic ,Bioinformatics ,Sensitivity and Specificity ,Article ,Huntingtin Gene ,Huntington's disease ,Trinucleotide Repeats ,Internal medicine ,External quality assessment ,Genetics ,medicine ,Humans ,Nerve Tissue Proteins/genetics ,Diagnostic laboratory ,Genetic Testing ,Genetic Testing/methods/standards ,Allele ,Diagnostic Errors ,standard reference material ,Genetics (clinical) ,Alleles ,Huntingtin Protein ,ddc:618 ,business.industry ,international cooperation ,Nuclear Proteins ,Reproducibility of Results ,Reference Standards ,medicine.disease ,CAG repeat length ,Nuclear Proteins/genetics ,Huntington Disease ,Huntington Disease/diagnosis ,Mutation ,Medical genetics ,reproducibility of results ,mutation ,business ,Trinucleotide repeat expansion ,Huntington Disease/diagnosis/genetics ,Genetic Testing/methods - Abstract
Huntington's disease results from a CAG repeat expansion within the Huntingtin gene; this is measured routinely in diagnostic laboratories. The European Huntington's Disease Network REGISTRY project centrally measures CAG repeat lengths on fresh samples; these were compared with the original results from 121 laboratories across 15 countries. We report on 1326 duplicate results; a discrepancy in reporting the upper allele occurred in 51% of cases, this reduced to 13.3% and 9.7% when we applied acceptable measurement errors proposed by the American College of Medical Genetics and the Draft European Best Practice Guidelines, respectively. Duplicate results were available for 1250 lower alleles; discrepancies occurred in 40% of cases. Clinically significant discrepancies occurred in 4.0% of cases with a potential unexplained misdiagnosis rate of 0.3%. There was considerable variation in the discrepancy rate among 10 of the countries participating in this study. Out of 1326 samples, 348 were re-analysed by an accredited diagnostic laboratory, based in Germany, with concordance rates of 93% and 94% for the upper and lower alleles, respectively. This became 100% if the acceptable measurement errors were applied. The central laboratory correctly reported allele sizes for six standard reference samples, blind to the known result. Our study differs from external quality assessment (EQA) schemes in that these are duplicate results obtained from a large sample of patients across the whole diagnostic range. We strongly recommend that laboratories state an error rate for their measurement on the report, participate in EQA schemes and use reference materials regularly to adjust their own internal standards.
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- 2012
10. Supratentorial white matter blurring associated with voltage-gated potassium channel-complex limbic encephalitis
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Urbach, H., Rauer, S., Mader, I., Paus, S., Wagner, J., Malter, M. P., Pruess, H., Lewerenz, J., Kassubek, J., Hegen, H., Auer, M., Deisenhammer, F., Ufer, F., Bien, C. G., Baumgartner, A., Urbach, H., Rauer, S., Mader, I., Paus, S., Wagner, J., Malter, M. P., Pruess, H., Lewerenz, J., Kassubek, J., Hegen, H., Auer, M., Deisenhammer, F., Ufer, F., Bien, C. G., and Baumgartner, A.
- Abstract
Limbic encephalitis (LE) associated with voltage-gated potassium channel-complex antibodies (VGKC-LE) is frequently non-paraneoplastic and associated with marked improvement following corticosteroid therapy. Mesial temporal lobe abnormalities are present in around 80 % of patients. If associated or preceded by faciobrachial dystonic seizures, basal ganglia signal changes may occur. In some patients, blurring of the supratentorial white matter on T2-weighted images (SWMB) may be seen. The purpose of this study was to evaluate the incidence of SWMB and whether it is specific for VGKC-LE. Two experienced neuroradiologists independently evaluated signal abnormalities on FLAIR MRI in 79 patients with LE while unaware on the antibody type. SWMB was independently assessed as present in 10 of 36 (28 %) compared to 2 (5 %) of 43 non-VGKC patients (p = 0.009). It was not related to the presence of LGI1 or CASPR2 proteins of VGKC antibodies. MRI showed increased temporomesial FLAIR signal in 22 (61 %) VGKC compared to 14 (33 %) non-VGKC patients (p = 0.013), and extratemporomesial structures were affected in one VGKC (3 %) compared to 11 (26 %) non-VGKC patients (p = 0.005). SWMB is a newly described MRI sign rather specific for VGKC-LE.
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- 2015
11. Periventricular white matter lesion and incomplete MRZ reaction in a male patient with anti-N-methyl-D-aspartate receptor encephalitis presenting with dysphoric mania
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Gahr, M., primary, Lauda, F., additional, Wigand, M. E., additional, Connemann, B. J., additional, Rosenbohm, A., additional, Tumani, H., additional, Reindl, M., additional, Uzelac, Z., additional, and Lewerenz, J., additional
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- 2015
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12. Successful immunosuppressive treatment and long-term follow-up and anti-Ri-associated paraneoplastic myelitis
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Leypoldt, F., Eichhorn, P., Saager, C., Munchau, A., and Lewerenz, J.
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Myelitis -- Care and treatment ,Paraneoplastic syndromes -- Care and treatment ,Immunosuppressive agents -- Dosage and administration ,Immunosuppression -- Patient outcomes ,Anti-antibodies -- Analysis ,Health ,Psychology and mental health - Published
- 2006
13. The plasma membrane channel ORAI1 mediates detrimental calcium influx caused by endogenous oxidative stress
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Henke, N, primary, Albrecht, P, additional, Bouchachia, I, additional, Ryazantseva, M, additional, Knoll, K, additional, Lewerenz, J, additional, Kaznacheyeva, E, additional, Maher, P, additional, and Methner, A, additional
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- 2013
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14. Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression
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Lewerenz, J, primary, Sato, H, additional, Albrecht, P, additional, Henke, N, additional, Noack, R, additional, Methner, A, additional, and Maher, P, additional
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- 2011
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15. Dementia and leukoencephalopathy due to lymphomatosis cerebri
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Lewerenz, J., primary, Ding, X.-Q., additional, Matschke, J, additional, Schnabel, C, additional, Emami, P, additional, von Borczyskowski, D, additional, Buchert, R, additional, Krieger, T, additional, de Wit, M, additional, and Munchau, A, additional
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- 2009
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16. Dementia and leukoencephalopathy due to lymphomatosis cerebri
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Lewerenz, J., primary, Ding, X., additional, Matschke, J., additional, Schnabel, C., additional, Emami, P., additional, von Borczyskowski, D., additional, Buchert, R., additional, Krieger, T., additional, de Wit, M., additional, and Munchau, A., additional
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- 2006
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17. Mutation of ATF4 mediates resistance of neuronal cell lines against oxidative stress by inducing xCT expression.
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Lewerenz, J, Sato, H, Albrecht, P, Henke, N, Noack, R, Methner, A, and Maher, P
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NEURAL stem cells , *OXIDATIVE stress , *NEURODEGENERATION , *PARKINSON'S disease , *GLUTAMIC acid - Abstract
Selecting neuronal cell lines for resistance against oxidative stress might recapitulate some adaptive processes in neurodegenerative diseases where oxidative stress is involved like Parkinson's disease. We recently reported that in hippocampal HT22 cells selected for resistance against oxidative glutamate toxicity, the cystine/glutamate antiporter system xc−, which imports cystine for synthesis of the antioxidant glutathione, and its specific subunit, xCT, are upregulated. (Lewerenz et al., J Neurochem 98(3):916-25). Here, we show that in these glutamate-resistant HT22 cells upregulation of xCT mediates glutamate resistance, and xCT expression is induced by upregulation of the transcription factor ATF4. The mechanism of ATF4 upregulation consists of a 13 bp deletion in the upstream open reading frame (uORF2) overlapping the ATF4 open reading frame. The resulting uORF2-ATF4 fusion protein is efficiently translated even at a low phosphorylation levels of the translation initiation factor eIF2α, a condition under which ATF4 translation is normally suppressed. A similar ATF4 mutation associated with prominent upregulation of xCT expression was identified in PC12 cells selected for resistance against amyloid β-peptide. Our data indicate that ATF4 has a central role in regulating xCT expression and resistance against oxidative stress. ATF4 mutations might have broader significance as upregulation of xCT is found in tumor cells and associated with anticancer drug resistance. [ABSTRACT FROM AUTHOR]
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- 2012
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18. Dementia and leukoencephalopathy due to lymphomatosis cerebri.
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Lewerenz J, Ding X, Matschke J, Schnabel C, Emami P, von Borczyskowski D, Buchert R, Krieger T, de Wit M, Münchau A, Lewerenz, Jan, Ding, Xiaoqi, Matschke, Jakob, Schnabel, Claudia, Emami, Pedram, von Borczyskowski, Daniel, Buchert, Ralph, Krieger, Thorsten, de Wit, Maike, and Münchau, Alexander
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- 2007
19. A novel non-rapid-eye movement and rapid-eye-movement parasomnia with sleep breathing disorder associated with antibodies to IgLON5: a case series, characterisation of the antigen, and post-mortem study
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Ellen Gelpi, Isabel Vilaseca, Carles Gaig, Lidia Sabater, Yaroslau Compta, Francesc Graus, Alex Iranzo, Bruno Giometto, Estefanía Torres-Vega, Angeles Contreras, Josep Dalmau, Jan Lewerenz, Luis Bataller, Joan Santamaria, Cristina Embid, Sabater, L, Gaig, C, Gelpi, E, Bataller, L, Lewerenz, J, Torres-Vega, E, Contreras, A, Giometto, B, Compta, Y, Embid, C, Vilaseca, I, Iranzo, A, Santamaría, J, Dalmau, J, and Graus, F
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Sleep disorder ,Pediatrics ,medicine.medical_specialty ,Pathology ,medicine.diagnostic_test ,business.industry ,Sleep apnea ,Chorea ,Polysomnography ,Parasomnia ,REM Sleep Parasomnias ,medicine.disease ,Non-rapid eye movement sleep ,Sleep in non-human animals ,medicine ,Neurology (clinical) ,medicine.symptom ,business - Abstract
Background Autoimmunity might be associated with or implicated in sleep and neurodegenerative disorders. We aimed to describe the features of a novel neurological syndrome associated with prominent sleep dysfunction and antibodies to a neuronal antigen. Methods In this observational study, we used clinical and video polysomnography to identify a novel sleep disorder in three patients referred to the Sleep Unit of Hospital Clinic, University of Barcelona, Spain, for abnormal sleep behaviours and obstructive sleep apnoea. These patients had antibodies against a neuronal surface antigen, which were also present in five additional patients referred to our laboratory for antibody studies. These five patients had been assessed with polysomnography, which was done in our sleep unit in one patient and the recording reviewed in a second patient. Two patients underwent post-mortem brain examination. Immunoprecipitation and mass spectrometry were used to characterise the antigen and develop an assay for antibody testing. Serum or CSF from 298 patients with neurodegenerative, sleep, or autoimmune disorders served as control samples. Findings All eight patients (five women; median age at disease onset 59 years [range 52-76]) had abnormal sleep movements and behaviours and obstructive sleep apnoea, as confirmed by polysomnography. Six patients had chronic progression with a median duration from symptom onset to death or last visit of 5 years (range 2-12); in four the sleep disorder was the initial and most prominent feature, and in two it was preceded by gait instability followed by dysarthria, dysphagia, ataxia, or chorea. Two patients had a rapid progression with disequilibrium, dysarthria, dysphagia, and central hypoventilation, and died 2 months and 6 months, respectively, after symptom onset. In five of five patients, video polysomnography showed features of obstructive sleep apnoea, stridor, and abnormal sleep architecture (undifferentiated non-rapid-eye-movement [non-REM] sleep or poorly structured stage N2, simple movements and fmalistic behaviours, normalisation of non-REM sleep by the end of the night, and, in the four patients with REM sleep recorded, REM sleep behaviour disorder). Four of four patients had HLA-DRB1*1001 and HLA-DQB1*0501 alleles. All patients had antibodies (mainly IgG4) against IgLON5, a neuronal cell adhesion molecule. Only one of the 298 controls, who had progressive supranudear palsy, had IgLON5 antibodies. Neuropathology showed neuronal loss and extensive deposits of hyperphosphorylated tau mainly involving the tegmentum of the brainstem and hypothalamus in the two patients studied. Interpretation IgLON5 antibodies identify a unique non-REM and REM parasomnia with sleep breathing dysfunction and pathological features suggesting a tauopathy. Funding Fondo de Investigaciones Sanitarias, Centros de Investigacion Biomedica en Red de enfermedades neurodegenerativas (CIBERNED) and Respiratorias (CIBERES), Ministerio de Economia y Competitividad, Fundacin la Marato TV3, and the National Institutes of Health.
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- 2014
20. Frequency, characteristics, and immunological accompaniments of ataxia in anti-NMDAR antibody-associated encephalitis.
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Jesse S, Riemann M, Schneider H, Ringelstein M, Melzer N, Vogel N, Pfeffer LK, Friese MA, Sühs KW, Hudasch D, Schwenkenbecher P, Günther A, Geis C, Wickel J, Lesser M, Kather A, Leypoldt F, Dargvainiene J, Markewitz R, Wandinger KP, Thaler FS, Kuchling J, Wurdack K, Sabater L, Finke C, and Lewerenz J
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- Humans, Male, Female, Adult, Child, Adolescent, Young Adult, Cerebellar Ataxia immunology, Middle Aged, Child, Preschool, Ataxia immunology, Myelin-Oligodendrocyte Glycoprotein immunology, Anti-N-Methyl-D-Aspartate Receptor Encephalitis immunology, Anti-N-Methyl-D-Aspartate Receptor Encephalitis complications, Anti-N-Methyl-D-Aspartate Receptor Encephalitis diagnosis, Autoantibodies immunology, Autoantibodies blood
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Introduction: Very rarely, adult NMDAR antibody-associated encephalitis (NMDAR-E) leads to persistent cerebellar atrophy and ataxia. Transient cerebellar ataxia is common in pediatric NMDAR-E. Immune-mediated cerebellar ataxia may be associated with myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP-4), kelch-like family member 11 (KLHL11), and glutamate kainate receptor subunit 2 (GluK2) antibodies, all of which may co-occur in NMDAR-E. Here, we aimed to investigate the frequency, long-term outcome, and immunological concomitants of ataxia in NMDAR-E., Methods: In this observational study, patients with definite NMDAR-E with a follow-up of >12 months were recruited from the GENERATE registry. Cases with documented ataxia were analyzed in detail., Results: In 12 of 62 patients (19%), ataxia was documented. Bilateral cerebellar ataxia without additional focal CNS findings was found in four (one child and three adults); one of these was previously reported as a case with persistent cerebellar atrophy and ataxia. Two patients with bilateral cerebellar ataxia had additional focal neurological symptoms, optic neuritis and facial palsy. Two patients developed hemiataxia: one with diplopia suggesting brainstem dysfunction and the other probably resulting from cerebellar diaschisis due to contralateral status epilepticus. In all but the one developing cerebellar atrophy, cerebellar ataxia was transient and not associated with a worse long-term outcome. In all five patients with cerebellar ataxia tested, MOG, AQP-4, GluK2, and KLHL11 antibodies were negative. In two additional patients negative for both MOG and AQP-4 antibodies, ataxia was sensory and explained by cervical myelitis as part of multiple sclerosis (MS) manifesting temporal relation to NMDAR-E. One of the patients with bilateral ataxia with focal neurological deficits was also diagnosed with MS upon follow-up. Finally, in two patients, ataxia was explained by cerebral hypoxic damage following circulatory failure during an ICU stay with severe NMDAR-E., Discussion: Ataxia of different types is quite common in NMDAR-E. Cerebellar ataxia in NMDAR-E is mostly transient. NMDAR-E followed by persistent ataxia and cerebellar atrophy is very rare. Cerebellar ataxia in NMDAR-E may not be explained by concomitant KLHL11, MOG, AQP-4, or GluK2 autoimmunity. Of note, ataxia in NMDAR-E may result from treatment complications and, most interestingly, from MS manifesting in temporal association with NMDAR-E., Competing Interests: MF received honoraria as speaker and for consultation from Alexion, Biogen, Kyverna, Lundbeck, Merck KGaA, Novartis, Roche and Sudo Biosciences, as well as from the Gemeinnützige Hertie-Stiftung and Wings for Life. His research is funded by the German Federal Ministry of Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Landesforschungsförderung Hamburg, Gemeinnützige Hertie-Stiftung, Else Kröner-Fresenius-Stiftung, Deutsche Multiple Sklerose Gesellschaft, Fritz-Thyssen-Stiftung, Werner-Otto-Stiftung, Walter und Ilse Rose-Stiftung, Stiftung zur Bekämpfung neuroviraler Erkrankungen and Research Fund of the University Medical Center Hamburg-Eppendorf; AG received speaker’s honoraria from Boehringer Ingelheim, Daichii Sankyo, Pfizer, Merz, Shionogi, Occlutech and Ipsen Pharma as well as research grants from MERZ and Ipsen Pharma; FL discloses speaker honoraria from Grifols, Teva, Biogen, Bayer, Roche, Novartis, Fresenius, travel funding from Merck, Grifols and Bayer and serving on advisory boards for Roche, Biogen and Alexion. His research FL is supported by German Ministry of Education and Research (BMBF), 01GM1908A und 01GM2208A, CONNECT-GENERATE, by E-Rare Joint Transnational research support ERA-Net, LE3064/2-1, Stiftung Pathobiochemie of the German Society for Laboratory Medicine and HORIZON MSCA 2022 Doctoral Network 101119457 — IgG4-TREAT; JL reports travel honoraria and speaker’s fees from the Cure Huntington’s Disease Initiative (CHDI), the Movement Disorders Society as the German Society for Cerebrospinal Fluid Diagnostic and Clinical Neurochemistry (DGLN), Alexion, Biogen, Sanofi, Teva, Merck, Novartis, Janssen, Fujirebio, Roche, and Neuraxpharm. His institution received financial compensation for clinical trials with JL as principal investigator from CHDI and SOM Biotech. He is member of the executive board of the DGLN. He received research funding from the German Federal Ministry of Education and Research (BMBF), CONNECT-GENERATE, 01GM1908B und 01GM2208B; and the Boehringer Ingelheim University Biocenter; NM has received honoraria for lecturing and travel expenses for attending meetings from Biogen Idec, GlaxoSmith Kline, Teva, Novartis Pharma, Bayer Healthcare, Genzyme, Alexion Pharmaceuticals, Fresenius Medical Care, Diamed, UCB Pharma, AngeliniPharma, BIAL and Sanofi-Aventis, has received royalties for consulting from UCB Pharma, Alexion Pharmaceuticals; and Sanofi-Aventis and has received financial research support from Euroimmun, Fresenius Medical Care, Diamed, Alexion Pharmaceuticals, and Novartis Pharma; MR received speaker honoraria from Novartis, Bayer Vital GmbH, Roche, Alexion, Horizon/Amgen; and Ipsen and travel reimbursement from Bayer Schering, Biogen Idec, Merz, Genzyme, Teva, Roche, Horizon, Alexion; and Merck, none related to this study; K-WS reports honoraria for lectures or travel reimbursements for attending meetings from Biogen, Merck, Mylan, Roche, Bavarian Nordic, Viatris and Bristol-Myers Squibb as well as research support from Bristol-Myers Squibb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Jesse, Riemann, Schneider, Ringelstein, Melzer, Vogel, Pfeffer, Friese, Sühs, Hudasch, Schwenkenbecher, Günther, Geis, Wickel, Lesser, Kather, Leypoldt, Dargvainiene, Markewitz, Wandinger, Thaler, Kuchling, Wurdack, Sabater, Finke and Lewerenz.)
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- 2024
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21. HLA dependency and possible clinical relevance of intrathecally synthesized anti-IgLON5 IgG4 in anti-IgLON5 disease.
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Koneczny I, Macher S, Hutterer M, Seifert-Held T, Berger-Sieczkowski E, Blaabjerg M, Breu M, Dreyhaupt J, Dutra LA, Erdler M, Fae I, Fischer G, Frommlet F, Heidbreder A, Högl B, Klose V, Klotz S, Liendl H, Nissen MS, Rahimi J, Reinecke R, Ricken G, Stefani A, Süße M, Teive HAG, Weis S, Berger T, Sabater L, Gaig C, Lewerenz J, and Höftberger R
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- Humans, Female, Male, Middle Aged, Aged, Cell Adhesion Molecules, Neuronal immunology, HLA Antigens immunology, Clinical Relevance, Immunoglobulin G cerebrospinal fluid, Immunoglobulin G blood, Immunoglobulin G immunology, Autoantibodies blood, Autoantibodies immunology, Autoantibodies cerebrospinal fluid
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Background: Anti-IgLON5 disease is a rare chronic autoimmune disorder characterized by IgLON5 autoantibodies predominantly of the IgG4 subclass. Distinct pathogenic effects were described for anti-IgLON5 IgG1 and IgG4, however, with uncertain clinical relevance., Methods: IgLON5-specific IgG1-4 levels were measured in 46 sera and 20 cerebrospinal fluid (CSF) samples from 13 HLA-subtyped anti-IgLON5 disease patients (six females, seven males) using flow cytometry. Intervals between two consecutive serum or CSF samplings (31 and 10 intervals, respectively) were categorized with regard to the immunomodulatory treatment active at the end of the interval, changes of anti-IgLON5 IgG1 and IgG4 levels, and disease severity. Intrathecal anti-IgLON5 IgG4 synthesis (IS) was assessed using a quantitative method., Results: The median age at onset was 66 years (range: 54-75), disease duration 10 years (range: 15-156 months), and follow-up 25 months (range: 0-83). IgLON5-specific IgG4 predominance was observed in 38 of 46 (83%) serum and 11 of 20 (55%) CSF samples. Anti-IgLON5 IgG4 levels prior clinical improvement in CSF but not serum were significantly lower than in those prior stable/progressive disease. Compared to IgLON5 IgG4 levels in serum, CSF levels in HLA-DRB1*10:01 carriers were significantly higher than in non-carriers. Indeed, IgLON5-specific IgG4 IS was demonstrated not only in four of five HLA-DRB1*10:01 carriers but also in one non-carrier. Immunotherapy was associated with decreased anti-IgGLON5 IgG serum levels. In CSF, lower anti-IgLON5 IgG was associated with immunosuppressive treatments used in combination, that is, corticosteroids and/or azathioprine plus intravenous immunoglobulins or rituximab., Conclusion: Our findings might indicate that CSF IgLON5-specific IgG4 is frequently produced intrathecally, especially in HLA-DRB1*10:01 carriers. Intrathecally produced IgG4 may be clinically relevant. While many immunotherapies reduce serum IgLON5 IgG levels, more intense immunotherapies induce clinical improvement and may be able to target intrathecally produced anti-IgLON5 IgG. Further studies need to confirm whether anti-IgLON5 IgG4 IS is a suitable prognostic and predictive biomarker in anti-IgLON5 disease., Competing Interests: TS-H reports travel grants and speaker honoraria from Roche. MBr has received honoraria for speaking from Sanofi. No conflict of interest with respect to the present study. AH reports speaker honoraria for UCB, Bioprojet, Servier, Medice, Jazz Pharmaceuticals BH reports speaker honoraria Jazz and Abbvie and advisor feed from Lundbeck. MS reports personal fees and grants from Merck Healthcare Deutschland and Bayer Vital GmbH and grant support from the University of Greifswald Gerhard-Domagk fellowship. HT reports speaker honoraria from Jansen, UCB and Zambon. TB has participated in meetings sponsored by and received honoraria lectures, advisory boards, consultations from pharmaceutical companies marketing treatments for MS: Allergan, Biogen, Biologix, Bionorica, BMS/Celgene, Eisei, Janssen-Cilag, MedDay, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme, Teva, UCB. His institution has received financial support in the past 12 months by unrestricted research grants Bayer, Biogen, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, Teva and for participation in clinical trials in multiple sclerosis sponsored by Alexion, Bayer, Biogen, BMS/Celgene, Merck, Novartis, Roche, Sanofi-Aventis, Teva. JL reports travel honoraria and speakers fees from the Cure Huntington’s Disease Initiative CHDI, the Movement Disorders Society as the German Society for Cerebrospinal Fluid Diagnostic and Clinical Neurochemistry DGLN. His institution received financial compensation for clinical trials with JL as principal investigator from CHDI. He is member of the executive board of the DGLN. He received research funding from the German Federal Ministry of Education and Research BMBF. RH reports speaker honoraria from UCB and Biogen. The Medical University of Vienna Austria; employer of RH receives payment for antibody assays and for antibody validation experiments organized by Euroimmun Lübeck, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Koneczny, Macher, Hutterer, Seifert-Held, Berger-Sieczkowski, Blaabjerg, Breu, Dreyhaupt, Dutra, Erdler, Fae, Fischer, Frommlet, Heidbreder, Högl, Klose, Klotz, Liendl, Nissen, Rahimi, Reinecke, Ricken, Stefani, Süße, Teive, Weis, Berger, Sabater, Gaig, Lewerenz and Höftberger.)
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- 2024
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22. Development of an algorithm for identifying paraneoplastic ischemic stroke in association with lung, pancreatic, and colorectal cancer.
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Kassubek R, Winter MGR, Dreyhaupt J, Laible M, Kassubek J, Ludolph AC, and Lewerenz J
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Background: Paraneoplastic ischemic stroke has a poor prognosis. We have recently reported an algorithm based on the number of ischemic territories, C-reactive protein (CRP), lactate dehydrogenase (LDH), and granulocytosis to predict the underlying active cancer in a case-control setting. However, co-occurrence of cancer and stroke might also be merely incidental., Objective: To detect cancer-associated ischemic stroke in a large, unselected cohort of consecutive stroke patients by detailed analysis of ischemic stroke associated with specific cancer subtypes and comparison to patients with bacterial endocarditis., Methods: Retrospective single-center cohort study of consecutive 1612 ischemic strokes with magnetic resonance imaging, CRP, LDH, and relative granulocytosis data was performed, including identification of active cancers, history of now inactive cancers, and the diagnosis of endocarditis. The previously developed algorithm to detect paraneoplastic cancer was applied. Tumor types associated with paraneoplastic stroke were used to optimize the diagnostic algorithm., Results: Ischemic strokes associated with active cancer, but also endocarditis, were associated with more ischemic territories as well as higher CRP and LDH levels. Our previous algorithm identified active cancer-associated strokes with a specificity of 83% and sensitivity of 52%. Ischemic strokes associated with lung, pancreatic, and colorectal (LPC) cancers but not with breast and prostate cancers showed more frequent and prominent characteristics of paraneoplastic stroke. A multiple logistic regression model optimized to identify LPC cancers detected active cancer with a sensitivity of 77.8% and specificity of 81.4%. The positive predictive value (PPV) for all active cancers was 13.1%., Conclusion: Standard clinical examinations can be employed to identify suspect paraneoplastic stroke with an adequate sensitivity, specificity, and PPV when it is considered that the association of ischemic stroke with breast and prostate cancers in the stroke-prone elderly population might be largely incidental., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)
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- 2024
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23. Early Neuroaxonal Damage in Neurologic Disorders Associated With GAD65 Antibodies.
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Eisenhut K, Faber J, Engels D, Gerhards R, Lewerenz J, Doppler K, Sommer C, Markewitz R, Falk KK, Rössling R, Pruess H, Finke C, Wickel J, Geis C, Ratuszny D, Pfeffer LK, Bittner S, Piepgras J, Kraft A, Klausewitz J, Nuscher B, Kümpfel T, and Thaler FS
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- Humans, Atrophy, Autoantibodies, Cerebellar Ataxia, Nervous System Diseases, Stiff-Person Syndrome
- Abstract
Objectives: Neurodegeneration is considered a relevant pathophysiologic feature in neurologic disorders associated with antibodies against glutamic acid decarboxylase 65 (GAD65). In this study, we investigate surrogates of neuroaxonal damage in relation to disease duration and clinical presentation., Methods: In a multicentric cohort of 50 patients, we measured serum neurofilament light chain (sNfL) in relation to disease duration and disease phenotypes, applied automated MRI volumetry, and analyzed clinical characteristics., Results: In patients with neurologic disorders associated with GAD65 antibodies, we detected elevated sNfL levels early in the disease course. By contrast, this elevation of sNfL levels was less pronounced in patients with long-standing disease. Increased sNfL levels were observed in patients presenting with cerebellar ataxia and limbic encephalitis, but not in those with stiff person syndrome. Using MRI volumetry, we identified atrophy predominantly of the cerebellar cortex, cerebellar superior posterior lobe, and cerebral cortex with similar atrophy patterns throughout all clinical phenotypes., Discussion: Together, our data provide evidence for early neuroaxonal damage and support the need for timely therapeutic interventions in GAD65 antibody-associated neurologic disorders., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2023
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24. Clinical associations and characteristics of the polyspecific intrathecal immune response in elderly patients with non-multiple sclerosis chronic autoimmune-inflammatory neurological diseases - a retrospective cross-sectional study.
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Brauchle F, Rapp D, Senel M, Huss A, Dreyhaupt J, Klose V, Süße M, Stürner KH, Leypoldt F, Tumani H, and Lewerenz J
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Introduction: The polyspecific intrathecal immune response (PSIIR), aka MRZ reaction ( M = measles, R = rubella, Z = zoster, optionally Herpes simplex virus, HSV) is defined as intrathecal immunoglobulin synthesis (IIS) for two or more unrelated viruses. Although an established cerebrospinal fluid (CSF) biomarker for multiple sclerosis (MS), a chronic autoimmune-inflammatory neurological disease (CAIND) of the central nervous system (CNS) usually starting in young adulthood, the full spectrum of CAINDs with a positive PSIIR remains ill defined., Methods: In this retrospective, cross-sectional study, patients with CSF-positive oligoclonal bands (OCB) and - to enrich for non-MS diagnoses - aged ≥50 years were enrolled., Results: Of 415 with PSIIR testing results (MRZ, HSV optional), 76 were PSIIR-positive. Of these, 25 (33%) did not meet the diagnostic criteria for MS spectrum diseases (MS-S) comprising clinically or radiologically isolated syndrome (CIS/RIS) or MS. PSIIR-positive non-MS-S phenotypes were heterogenous with CNS, peripheral nerve and motor neuron involvement and often defied unequivocal diagnostic classification. A rating by neuroimmunology experts suggested non-MS CAINDs in 16/25 (64%). Long-term follow-up available in 13 always showed a chronically progressive course. Four of five responded to immunotherapy. Compared to MS-S patients, non-MS CAIND patients showed less frequent CNS regions with demyelination (25% vs. 75%) and quantitative IgG IIS (31% vs. 81%). MRZ-specific IIS did not differ between both groups, while additional HSV-specific IIS was characteristic for non-MS CAIND patients., Discussion: In conclusion, PSIIR positivity occurs frequently in non-MS-S patients ≥50 years. Although sometimes apparently coincidental, the PSIIR seems to represent a suitable biomarker for previously unnoticed chronic neurologic autoimmunities, which require further characterization., Competing Interests: FB, DR, AH, JD, and VK report no conflict of interest. MSe has received consulting and/or speaker honoraria from Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Roche, and Sanofi Genzyme. She has received travel support from Celgene, and TEVA. She has received research funding from the Hertha-Nathorff-Program. MSue reports personal fees and grants from Merck Healthcare Deutschland and Bayer Vital GmbH and grant support from the University of Greifswald (Gerhard-Domagk fellowship). KHS has received personal fees and travel grants from Bayer, Biogen, MerckSerono and Genzyme. FL received speaker fees, travel compensation and serves on advisory boards for/from Alexion, Bayer, Biogen, Fresenius, Merck-Serono, Novartis, Roche, Teva. His research is funded by German Federal Ministry of Education and Research (BMBF) and Deutsche Forschungsgesellschaft (DFG) and European Union (EU), outside the submitted work. HT reports funding for research projects, lectures and travel from Alexion, Bayer, Biogen, Celgene, Sanofi-Genzyme, Fresenius, Merck, Mylan, Novartis, Roche, Siemens Health Diagnostics, and Teva, and received research support from DMSG, DMS Stiftung, AMSEL-Stiftung Ursula Späth, Bayerische DMSG-Stiftung, Ministry of Science and Art of the State Baden-Württemberg (MWK-BW), and German Federal Ministry of Education and Research (BMBF). JL received speaker fees or travel compensation from UCB, Bayer, Roche, Teva and the Cure Huntington’s Disease Initiative (CHDI). His institution has been reimbursed for his role as a principal investigator in trials for UCB and CHDI. His research is funded by the European Huntington’s Disease Initiative and Ministry for Education and Research Baden-Württemberg outside the submitted work, as well as the German Federal Ministry of Education and Research (BMBF)., (Copyright © 2023 Brauchle, Rapp, Senel, Huss, Dreyhaupt, Klose, Süße, Stürner, Leypoldt, Tumani and Lewerenz.)
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- 2023
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25. Translational imaging of TSPO reveals pronounced innate inflammation in human and murine CD8 T cell-mediated limbic encephalitis.
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Gallus M, Roll W, Dik A, Barca C, Zinnhardt B, Hicking G, Mueller C, Naik VN, Anstötz M, Krämer J, Rolfes L, Wachsmuth L, Pitsch J, van Loo KMJ, Räuber S, Okada H, Wimberley C, Strippel C, Golombeck KS, Johnen A, Kovac S, Groß CC, Backhaus P, Seifert R, Lewerenz J, Surges R, Elger CE, Wiendl H, Ruck T, Becker AJ, Faber C, Jacobs AH, Bauer J, Meuth SG, Schäfers M, and Melzer N
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- Carrier Proteins metabolism, Receptors, GABA metabolism, Inflammation metabolism, Humans, Mice, Autoimmune Diseases, Animals, Positron-Emission Tomography methods, Limbic Encephalitis diagnostic imaging
- Abstract
Autoimmune limbic encephalitis (ALE) presents with new-onset mesial temporal lobe seizures, progressive memory disturbance, and other behavioral and cognitive changes. CD8 T cells are considered to play a key role in those cases where autoantibodies (ABs) target intracellular antigens or no ABs were found. Assessment of such patients presents a clinical challenge, and novel noninvasive imaging biomarkers are urgently needed. Here, we demonstrate that visualization of the translocator protein (TSPO) with [
18 F]DPA-714-PET-MRI reveals pronounced microglia activation and reactive gliosis in the hippocampus and amygdala of patients suspected with CD8 T cell ALE, which correlates with FLAIR-MRI and EEG alterations. Back-translation into a preclinical mouse model of neuronal antigen-specific CD8 T cell-mediated ALE allowed us to corroborate our preliminary clinical findings. These translational data underline the potential of [18 F]DPA-714-PET-MRI as a clinical molecular imaging method for the direct assessment of innate immunity in CD8 T cell-mediated ALE.- Published
- 2023
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26. CSF oligoclonal IgG bands are not associated with ALS progression and prognosis.
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Klose V, Jesse S, Lewerenz J, Kassubek J, Dorst J, Tumani H, Ludolph AC, and Roselli F
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Introduction: Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive motoneuron degeneration through cell autonomous and non-cell autonomous mechanisms; and the involvement of the innate and adaptive immune system has been hypothesized based on human and murine model data. We have explored if B-cell activation and IgG responses, as detected by IgG Oligoclonal bands (OCB) in serum and cerebrospinal fluid, were associated with ALS or with a subgroup of patients with distinct clinical features., Methods: IgG OCB were determined in patients affected by ALS (n=457), Alzheimer Disease (n=516), Mild Cognitive Impairment (n=91), Tension-type Headache (n=152) and idiopathic Facial Palsy (n=94). For ALS patients, clinico-demographic and survival data were prospectively collected in the Register Schabia., Results: The prevalence of IgG OCB is comparable in ALS and the four neurological cohorts. When the OCB pattern was considered (highlighting either intrathecal or systemic B-cells activation), no effect of OCB pattern on clinic-demographic parameters and overall. ALS patients with intrathecal IgG synthesis (type 2 and 3) were more likely to display infectious, inflammatory or systemic autoimmune conditions., Discussion: These data suggest that OCB are not related to ALS pathophysiology but rather are a finding possibly indicative a coincidental infectious or inflammatory comorbidity that merits further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Klose, Jesse, Lewerenz, Kassubek, Dorst, Tumani, Ludolph and Roselli.)
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- 2023
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27. A genome-wide association study in autoimmune neurological syndromes with anti-GAD65 autoantibodies.
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Strippel C, Herrera-Rivero M, Wendorff M, Tietz AK, Degenhardt F, Witten A, Schroeter C, Nelke C, Golombeck KS, Madlener M, Rüber T, Ernst L, Racz A, Baumgartner T, Widman G, Doppler K, Thaler F, Siebenbrodt K, Dik A, Kerin C, Räuber S, Gallus M, Kovac S, Grauer OM, Grimm A, Prüss H, Wickel J, Geis C, Lewerenz J, Goebels N, Ringelstein M, Menge T, Tackenberg B, Kellinghaus C, Bien CG, Kraft A, Zettl U, Ismail FS, Ayzenberg I, Urbanek C, Sühs KW, Tauber SC, Mues S, Körtvélyessy P, Markewitz R, Paliantonis A, Elger CE, Surges R, Sommer C, Kümpfel T, Gross CC, Lerche H, Wellmer J, Quesada CM, Then Bergh F, Wandinger KP, Becker AJ, Kunz WS, Meyer Zu Hörste G, Malter MP, Rosenow F, Wiendl H, Kuhlenbäumer G, Leypoldt F, Lieb W, Franke A, Meuth SG, Stoll M, and Melzer N
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- Humans, Proteome genetics, Histocompatibility Antigens Class II, HLA Antigens, Haplotypes, Alleles, Autoantibodies, HLA-DRB1 Chains genetics, Genome-Wide Association Study, Genetic Predisposition to Disease genetics
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Autoimmune neurological syndromes (AINS) with autoantibodies against the 65 kDa isoform of the glutamic acid decarboxylase (GAD65) present with limbic encephalitis, including temporal lobe seizures or epilepsy, cerebellitis with ataxia, and stiff-person-syndrome or overlap forms. Anti-GAD65 autoantibodies are also detected in autoimmune diabetes mellitus, which has a strong genetic susceptibility conferred by human leukocyte antigen (HLA) and non-HLA genomic regions. We investigated the genetic predisposition in patients with anti-GAD65 AINS. We performed a genome-wide association study (GWAS) and an association analysis of the HLA region in a large German cohort of 1214 individuals. These included 167 patients with anti-GAD65 AINS, recruited by the German Network for Research on Autoimmune Encephalitis (GENERATE), and 1047 individuals without neurological or endocrine disease as population-based controls. Predictions of protein expression changes based on GWAS findings were further explored and validated in the CSF proteome of a virtually independent cohort of 10 patients with GAD65-AINS and 10 controls. Our GWAS identified 16 genome-wide significant (P < 5 × 10-8) loci for the susceptibility to anti-GAD65 AINS. The top variant, rs2535288 [P = 4.42 × 10-16, odds ratio (OR) = 0.26, 95% confidence interval (CI) = 0.187-0.358], localized to an intergenic segment in the middle of the HLA class I region. The great majority of variants in these loci (>90%) mapped to non-coding regions of the genome. Over 40% of the variants have known regulatory functions on the expression of 48 genes in disease relevant cells and tissues, mainly CD4+ T cells and the cerebral cortex. The annotation of epigenomic marks suggested specificity for neural and immune cells. A network analysis of the implicated protein-coding genes highlighted the role of protein kinase C beta (PRKCB) and identified an enrichment of numerous biological pathways participating in immunity and neural function. Analysis of the classical HLA alleles and haplotypes showed no genome-wide significant associations. The strongest associations were found for the DQA1*03:01-DQB1*03:02-DRB1*04:01HLA haplotype (P = 4.39 × 10-4, OR = 2.5, 95%CI = 1.499-4.157) and DRB1*04:01 allele (P = 8.3 × 10-5, OR = 2.4, 95%CI = 1.548-3.682) identified in our cohort. As predicted, the CSF proteome showed differential levels of five proteins (HLA-A/B, C4A, ATG4D and NEO1) of expression quantitative trait loci genes from our GWAS in the CSF proteome of anti-GAD65 AINS. These findings suggest a strong genetic predisposition with direct functional implications for immunity and neural function in anti-GAD65 AINS, mainly conferred by genomic regions outside the classical HLA alleles., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
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- 2023
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28. Antibodies Against Glutamic Acid Decarboxylase 65 Are Locally Produced in the CSF and Arise During Affinity Maturation.
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Biljecki M, Eisenhut K, Beltrán E, Winklmeier S, Mader S, Thaller A, Eichhorn P, Steininger P, Flierl-Hecht A, Lewerenz J, Kümpfel T, Kerschensteiner M, Meinl E, and Thaler FS
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- Humans, Antibodies, Monoclonal, Syndrome, Immunoglobulin G, Autoantibodies, Glutamate Decarboxylase
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Background and Objectives: Antibodies (Abs) against the cytoplasmic protein glutamic acid decarboxylase 65 (GAD65) are detected in patients with neurologic syndromes together referred to as GAD65-Ab spectrum disorders. The response of some of these patients to plasma exchange or immunoglobulins indicates that GAD65-Abs could contribute to disease pathogenesis at least at some stages of disease. However, the involvement of GAD65-reactive B cells in the CNS is incompletely understood., Methods: We studied 7 patients with high levels of GAD65-Abs and generated monoclonal Abs (mAbs) derived from single cells in the CSF. Sequence characteristics, reactivity to GAD65, and the role of somatic hypermutations of the mAbs were analyzed., Results: Twelve CSF-derived mAbs were generated originating from 3 patients with short disease duration, and 7/12 of these mAbs (58%) were GAD65 reactive in at least 1 detection assay. Four of 12 (33%) were definitely positive in all 3 detection assays. The intrathecal anti-GAD65 response was polyclonal. GAD65-Abs were mostly of the IgG1 subtype and had undergone affinity maturation. Reversion of 2 GAD65-reactive mAbs to their corresponding germline-encoded unmutated common ancestors abolished GAD65 reactivity., Discussion: GAD65-specific B cells are present in the CNS and represent a sizable fraction of CSF B cells early in the disease course. The anti-GAD65 response in the CSF is polyclonal and shows evidence of antigen-driven affinity maturation required for GAD65 recognition. Our data support the hypothesis that the accumulation of GAD65-specific B cells and plasma cells in the CSF is an important feature of early disease stages., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2023
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29. Distinct movement disorders in contactin-associated-protein-like-2 antibody-associated autoimmune encephalitis.
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Gövert F, Abrante L, Becktepe J, Balint B, Ganos C, Hofstadt-van Oy U, Krogias C, Varley J, Irani SR, Paneva S, Titulaer MJ, de Vries JM, Boon AJW, Schreurs MWJ, Joubert B, Honnorat J, Vogrig A, Ariño H, Sabater L, Dalmau J, Scotton S, Jacob S, Melzer N, Bien CG, Geis C, Lewerenz J, Prüss H, Wandinger KP, Deuschl G, and Leypoldt F
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- Humans, Aged, Retrospective Studies, Tremor, Intracellular Signaling Peptides and Proteins metabolism, Ataxia, Autoantibodies, Contactins metabolism, Limbic Encephalitis, Myoclonus, Potassium Channels, Voltage-Gated, Encephalitis, Movement Disorders etiology, Autoimmune Diseases of the Nervous System
- Abstract
Autoimmune encephalitis can be classified into antibody-defined subtypes, which can manifest with immunotherapy-responsive movement disorders sometimes mimicking non-inflammatory aetiologies. In the elderly, anti-LGI1 and contactin associated protein like 2 (CASPR2) antibody-associated diseases compose a relevant fraction of autoimmune encephalitis. Patients with LGI1 autoantibodies are known to present with limbic encephalitis and additionally faciobrachial dystonic seizures may occur. However, the clinical spectrum of CASPR2 autoantibody-associated disorders is more diverse including limbic encephalitis, Morvan's syndrome, peripheral nerve hyperexcitability syndrome, ataxia, pain and sleep disorders. Reports on unusual, sometimes isolated and immunotherapy-responsive movement disorders in CASPR2 autoantibody-associated syndromes have caused substantial concern regarding necessity of autoantibody testing in patients with movement disorders. Therefore, we aimed to systematically assess their prevalence and manifestation in patients with CASPR2 autoimmunity. This international, retrospective cohort study included patients with CASPR2 autoimmunity from participating expert centres in Europe. Patients with ataxia and/or movement disorders were analysed in detail using questionnaires and video recordings. We recruited a comparator group with anti-LGI1 encephalitis from the GENERATE network. Characteristics were compared according to serostatus. We identified 164 patients with CASPR2 autoantibodies. Of these, 149 (90.8%) had only CASPR2 and 15 (9.1%) both CASPR2 and LGI1 autoantibodies. Compared to 105 patients with LGI1 encephalitis, patients with CASPR2 autoantibodies more often had movement disorders and/or ataxia (35.6 versus 3.8%; P < 0.001). This was evident in all subgroups: ataxia 22.6 versus 0.0%, myoclonus 14.6 versus 0.0%, tremor 11.0 versus 1.9%, or combinations thereof 9.8 versus 0.0% (all P < 0.001). The small group of patients double-positive for LGI1/CASPR2 autoantibodies (15/164) significantly more frequently had myoclonus, tremor, 'mixed movement disorders', Morvan's syndrome and underlying tumours. We observed distinct movement disorders in CASPR2 autoimmunity (14.6%): episodic ataxia (6.7%), paroxysmal orthostatic segmental myoclonus of the legs (3.7%) and continuous segmental spinal myoclonus (4.3%). These occurred together with further associated symptoms or signs suggestive of CASPR2 autoimmunity. However, 2/164 patients (1.2%) had isolated segmental spinal myoclonus. Movement disorders and ataxia are highly prevalent in CASPR2 autoimmunity. Paroxysmal orthostatic segmental myoclonus of the legs is a novel albeit rare manifestation. Further distinct movement disorders include isolated and combined segmental spinal myoclonus and autoimmune episodic ataxia., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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30. Clinical, serological and genetic predictors of response to immunotherapy in anti-IgLON5 disease.
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Grüter T, Möllers FE, Tietz A, Dargvainiene J, Melzer N, Heidbreder A, Strippel C, Kraft A, Höftberger R, Schöberl F, Thaler FS, Wickel J, Chung HY, Seifert F, Tschernatsch M, Nagel M, Lewerenz J, Jarius S, Wildemann BC, de Azevedo L, Heidenreich F, Heusgen R, Hofstadt-van Oy U, Linsa A, Maaß JJ, Menge T, Ringelstein M, Pedrosa DJ, Schill J, Seifert-Held T, Seitz C, Tonner S, Urbanek C, Zittel S, Markewitz R, Korporal-Kuhnke M, Schmitter T, Finke C, Brüggemann N, Bien CI, Kleiter I, Gold R, Wandinger KP, Kuhlenbäumer G, Leypoldt F, and Ayzenberg I
- Subjects
- Humans, Male, Female, Glial Fibrillary Acidic Protein, Retrospective Studies, Immunoglobulin G metabolism, Disease Progression, Immunotherapy, Sleep Wake Disorders
- Abstract
Anti-IgLON5 disease is a newly defined clinical entity characterized by a progressive course with high disability and mortality rate. While precise pathogenetic mechanisms remain unclear, features characteristic of both autoimmune and neurodegenerative diseases were reported. Data on immunotherapy are limited, and its efficacy remains controversial. In this study, we retrospectively investigated an anti-IgLON5 disease cohort with special focus on clinical, serological and genetic predictors of the immunotherapy response and long-term outcome. Patients were recruited from the GENERATE (German Network for Research on Autoimmune Encephalitis) registry. Along with clinical parameters, anti-IgLON5 immunoglobulin (Ig)G in serum and CSF, anti-IgLON5 IgG1-4, IgA and IgM in serum, neurofilament light chain and glial fibrillary acidic protein in serum as well as human leukocyte antigen-genotypes were determined. We identified 53 patients (symptom onset 63.8 ± 10.3 years, female:male 1:1.5). The most frequent initial clinical presentations were bulbar syndrome, hyperkinetic syndrome or isolated sleep disorder [at least one symptom present in 38% (20/53)]. At the time of diagnosis, the majority of patients had a generalized multi-systemic phenotype; nevertheless, 21% (11/53) still had an isolated brainstem syndrome and/or a characteristic sleep disorder only. About one third of patients [28% (15/53)] reported subacute disease onset and 51% (27/53) relapse-like exacerbations during the disease course. Inflammatory CSF changes were evident in 37% (19/51) and increased blood-CSF-barrier permeability in 46% (21/46). CSF cell count significantly decreased, while serum anti-IgLON5 IgG titre increased with disease duration. The presence of human leukocyte antigen-DRB1*10:01 [55% (24/44)] was associated with higher serum anti-IgLON5 IgG titres. Neurofilament light chain and glial fibrillary acidic protein in serum were substantially increased (71.1 ± 103.9 pg/ml and 126.7 ± 73.3 pg/ml, respectively). First-line immunotherapy of relapse-like acute-to-subacute exacerbation episodes resulted in improvement in 41% (11/27) of patients and early initiation within the first 6 weeks was a predictor for therapy response. Sixty-eight per cent (36/53) of patients were treated with long-term immunotherapy and 75% (27/36) of these experienced no further disease progression (observation period of 20.2 ± 15.4 months). Long-term immunotherapy initiation during the first year after onset and low pre-treatment neurofilament light chain were significant predictors for a better outcome. In conclusion, subacute disease onset and early inflammatory CSF changes support the primary role of autoimmune mechanisms at least at initial stages of anti-IgLON5 disease. Early immunotherapy, prior to advanced neurodegeneration, is associated with a better long-term clinical outcome. Low serum neurofilament light chain at treatment initiation may serve as a potential biomarker of the immunotherapy response., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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31. Study protocol of IMAGINE-HD: Imaging iron accumulation and neuroinflammation with 7T-MRI + CSF in Huntington's disease.
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van de Zande NA, Bulk M, Najac C, van der Weerd L, de Bresser J, Lewerenz J, Ronen I, and de Bot ST
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- Humans, Biomarkers cerebrospinal fluid, Cross-Sectional Studies, Iron metabolism, Magnetic Resonance Imaging methods, Neuroinflammatory Diseases, Huntington Disease diagnostic imaging, Huntington Disease genetics, Neurodegenerative Diseases
- Abstract
Introduction: Strong evidence suggests a significant role for iron accumulation in the brain in addition to the well-documented neurodegenerative aspects of Huntington's disease (HD). The putative mechanisms by which iron is linked to the HD pathogenesis are multiple, including oxidative stress, ferroptosis and neuroinflammation. However, no previous study in a neurodegenerative disease has linked the observed increase of brain iron accumulation as measured by MRI with well-established cerebrospinal fluid (CSF) and blood biomarkers for iron accumulation, or with associated processes such as neuroinflammation. This study is designed to link quantitative data from iron levels and neuroinflammation metabolites obtained from 7T MRI of HD patients, with specific and well-known clinical biofluid markers for iron accumulation, neurodegeneration and neuroinflammation. Biofluid markers will provide quantitative measures of overall iron accumulation, neurodegeneration and neuroinflammation, while MRI measurements on the other hand will provide quantitative spatial information on brain pathology, neuroinflammation and brain iron accumulation, which will be linked to clinical outcome measures., Methods: This is an observational cross-sectional study, IMAGINE-HD, in HD gene expansion carriers and healthy controls. We include premanifest HD gene expansion carriers and patients with manifest HD in an early or moderate stage. The study includes a 7T MRI scan of the brain, clinical evaluation, motor, functional, and neuropsychological assessments, and sampling of CSF and blood for the detection of iron, neurodegenerative and inflammatory markers. Quantitative Susceptibility Maps will be reconstructed using T2* weighted images to quantify brain iron levels and Magnetic Resonance Spectroscopy will be used to obtain information about neuroinflammation by measuring cell-specific intracellular metabolites' level and diffusion. Age and sex matched healthy subjects are included as a control group., Discussion: Results from this study will provide an important basis for the evaluation of brain iron levels and neuroinflammation metabolites as an imaging biomarker for disease stage in HD and their relationship with the salient pathomechanisms of the disease on the one hand, and with clinical outcome on the other., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2023
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32. Seizure Semiology in Antibody-Associated Autoimmune Encephalitis.
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Kaaden T, Madlener M, Angstwurm K, Bien CG, Bogarin Y, Doppler K, Finke A, Gerner ST, Reimann G, Häusler M, Handreka R, Hellwig K, Kaufmann M, Kellinghaus C, Koertvelyessy P, Kraft A, Lewerenz J, Menge T, Paliantonis A, von Podewils F, Prüss H, Rauer S, Ringelstein M, Rostásy K, Schirotzek I, Schwabe J, Sokolowski P, Suesse M, Sühs KW, Surges R, Tauber SC, Thaler F, Bergh FT, Urbanek C, Wandinger KP, Wildemann B, Mues S, Zettl U, Leypoldt F, Melzer N, Geis C, Malter M, and Kunze A
- Subjects
- Humans, Glutamate Decarboxylase, Receptors, N-Methyl-D-Aspartate, Prospective Studies, Leucine, Intracellular Signaling Peptides and Proteins, Seizures etiology, Autoantibodies, Encephalitis, Status Epilepticus
- Abstract
Background and Objectives: To assess seizure characteristics in antibody (ab)-associated autoimmune encephalitis (ab + AE) with the 3 most prevalent abs against N-methyl-d-aspartate receptor (NMDAR), leucine-rich glioma-inactivated protein 1 (LGI1), and glutamic acid decarboxylase (GAD)., Methods: Multicenter nationwide prospective cohort study of the German Network for Research in Autoimmune Encephalitis., Results: Three hundred twenty patients with ab + AE were eligible for analysis: 190 NMDAR+, 89 LGI1+, and 41 GAD+. Seizures were present in 113 (60%) NMDAR+, 69 (78%) LGI1+, and 26 (65%) GAD+ patients and as leading symptoms for diagnosis in 53 (28%) NMDAR+, 47 (53%) LGI+, and 20 (49%) GAD+ patients. Bilateral tonic-clonic seizures occurred with almost equal frequency in NMDAR+ (38/51, 75%) and GAD+ (14/20, 70%) patients, while being less common in LGI1+ patients (27/59, 46%). Focal seizures occurred less frequently in NMDAR+ (67/113; 59%) than in LGI1+ (54/69, 78%) or in GAD+ patients (23/26; 88%). An aura with déjà-vu phenomenon was nearly specific in GAD+ patients (16/20, 80%). Faciobrachial dystonic seizures (FBDS) were uniquely observed in LGI1+ patients (17/59, 29%). Status epilepticus was reported in one-third of NMDAR+ patients, but only rarely in the 2 other groups. The occurrence of seizures was associated with higher disease severity only in NMDAR+ patients., Discussion: Seizures are a frequent and diagnostically relevant symptom of ab + AE. Whereas NMDAR+ patients had few localizing semiological features, semiology in LGI1+ and GAD+ patients pointed toward a predominant temporal seizure onset. FBDS are pathognomonic for LGI1 + AE. Status epilepticus seems to be more frequent in NMDAR + AE., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2022
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33. Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients.
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Jarius S, Pache F, Körtvelyessy P, Jelčić I, Stettner M, Franciotta D, Keller E, Neumann B, Ringelstein M, Senel M, Regeniter A, Kalantzis R, Willms JF, Berthele A, Busch M, Capobianco M, Eisele A, Reichen I, Dersch R, Rauer S, Sandner K, Ayzenberg I, Gross CC, Hegen H, Khalil M, Kleiter I, Lenhard T, Haas J, Aktas O, Angstwurm K, Kleinschnitz C, Lewerenz J, Tumani H, Paul F, Stangel M, Ruprecht K, and Wildemann B
- Subjects
- Adult, Blood-Brain Barrier, COVID-19 complications, Cerebrospinal Fluid Proteins cerebrospinal fluid, Cytokines cerebrospinal fluid, Europe, Female, Humans, Immunity, Cellular, Immunoglobulin G cerebrospinal fluid, Lactic Acid cerebrospinal fluid, Leukocyte Count, Male, Middle Aged, Nervous System Diseases cerebrospinal fluid, Nervous System Diseases etiology, Oligoclonal Bands cerebrospinal fluid, Retrospective Studies, Spinal Puncture, Post-Acute COVID-19 Syndrome, COVID-19 cerebrospinal fluid
- Abstract
Background: Comprehensive data on the cerebrospinal fluid (CSF) profile in patients with COVID-19 and neurological involvement from large-scale multicenter studies are missing so far., Objective: To analyze systematically the CSF profile in COVID-19., Methods: Retrospective analysis of 150 lumbar punctures in 127 patients with PCR-proven COVID-19 and neurological symptoms seen at 17 European university centers RESULTS: The most frequent pathological finding was blood-CSF barrier (BCB) dysfunction (median QAlb 11.4 [6.72-50.8]), which was present in 58/116 (50%) samples from patients without pre-/coexisting CNS diseases (group I). QAlb remained elevated > 14d (47.6%) and even > 30d (55.6%) after neurological onset. CSF total protein was elevated in 54/118 (45.8%) samples (median 65.35 mg/dl [45.3-240.4]) and strongly correlated with QAlb. The CSF white cell count (WCC) was increased in 14/128 (11%) samples (mostly lympho-monocytic; median 10 cells/µl, > 100 in only 4). An albuminocytological dissociation (ACD) was found in 43/115 (37.4%) samples. CSF L-lactate was increased in 26/109 (24%; median 3.04 mmol/l [2.2-4]). CSF-IgG was elevated in 50/100 (50%), but was of peripheral origin, since QIgG was normal in almost all cases, as were QIgA and QIgM. In 58/103 samples (56%) pattern 4 oligoclonal bands (OCB) compatible with systemic inflammation were present, while CSF-restricted OCB were found in only 2/103 (1.9%). SARS-CoV-2-CSF-PCR was negative in 76/76 samples. Routine CSF findings were normal in 35%. Cytokine levels were frequently elevated in the CSF (often associated with BCB dysfunction) and serum, partly remaining positive at high levels for weeks/months (939 tests). Of note, a positive SARS-CoV-2-IgG-antibody index (AI) was found in 2/19 (10.5%) patients which was associated with unusually high WCC in both of them and a strongly increased interleukin-6 (IL-6) index in one (not tested in the other). Anti-neuronal/anti-glial autoantibodies were mostly absent in the CSF and serum (1509 tests). In samples from patients with pre-/coexisting CNS disorders (group II [N = 19]; including multiple sclerosis, JC-virus-associated immune reconstitution inflammatory syndrome, HSV/VZV encephalitis/meningitis, CNS lymphoma, anti-Yo syndrome, subarachnoid hemorrhage), CSF findings were mostly representative of the respective disease., Conclusions: The CSF profile in COVID-19 with neurological symptoms is mainly characterized by BCB disruption in the absence of intrathecal inflammation, compatible with cerebrospinal endotheliopathy. Persistent BCB dysfunction and elevated cytokine levels may contribute to both acute symptoms and 'long COVID'. Direct infection of the CNS with SARS-CoV-2, if occurring at all, seems to be rare. Broad differential diagnostic considerations are recommended to avoid misinterpretation of treatable coexisting neurological disorders as complications of COVID-19., (© 2022. The Author(s).)
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- 2022
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34. CSF Findings in Acute NMDAR and LGI1 Antibody-Associated Autoimmune Encephalitis.
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Dürr M, Nissen G, Sühs KW, Schwenkenbecher P, Geis C, Ringelstein M, Hartung HP, Friese MA, Kaufmann M, Malter MP, Madlener M, Thaler FS, Kümpfel T, Senel M, Häusler MG, Schneider H, Bergh FT, Kellinghaus C, Zettl UK, Wandinger KP, Melzer N, Gross CC, Lange P, Dreyhaupt J, Tumani H, Leypoldt F, and Lewerenz J
- Subjects
- Acute Disease, Adolescent, Adult, Aged, Female, Humans, Male, Middle Aged, Prospective Studies, Retrospective Studies, Young Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis cerebrospinal fluid, Autoantibodies cerebrospinal fluid, Autoimmune Diseases of the Nervous System cerebrospinal fluid, Encephalitis cerebrospinal fluid, Intracellular Signaling Peptides and Proteins immunology, Registries
- Abstract
Background and Objectives: CSF in antibody-defined autoimmune encephalitis (AE) subtypes shows subtype-dependent degrees of inflammation ranging from rare and often mild to frequent and often robust. AEs with NMDA receptor antibodies (NMDAR-E) and leucine-rich glioma-inactivated protein 1 antibodies (LGI1-E) represent opposite ends of this spectrum: NMDAR-E with typically frequent/robust and LGI1-E with rare/mild CSF inflammation. For a more in-depth analysis, we characterized CSF findings in acute, therapy-naive NMDAR-E and LGI1-E in a multicentric, retrospective, cross-sectional setting., Methods: Eighty-two patients with NMDAR-E and 36 patients with LGI1-E from the GErman NEtwork for Research of AuToimmune Encephalitis (GENERATE) with lumbar puncture within 90 days of onset and before immunotherapy were included. CSF parameters comprised leukocytes, oligoclonal bands (OCBs), and CSF/serum ratios for albumin, immunoglobulin G (IgG), A (IgA), and M (IgM), the latter 3 converted to Z scores according to Reiber formulas. The MRZ reaction was tested in 14 patients with NMDAR-E and 6 patients with LGI1-E, respectively., Results: CSF was abnormal in 94% of NMDAR-E but only in 36% of LGI1-E patients. Robust quantitative intrathecal immunoglobulin synthesis (IIS, IgG > IgM >> IgA) was characteristic for NMDAR-E, but absent in LGI-E. In NMDAR-E, CSF leukocytes were higher when IIS was present or more pronounced. In addition, in NMDAR-E, CSF leukocytes were lower and IIS occurred less often and if so to a lesser degree at older age. Patients with NMDAR-E with severe functional impairment more often had positive OCBs. In CSF obtained later than 3 weeks of onset, leukocytes were lower. In parallel, the correlation of leukocytes with IIS disappeared as IIS was partially independent of disease duration. The MRZ reaction was positive in 5 (36%) patients with NMDAR-E. All these associations were completely absent in LGI1-E. Here, younger patients showed more blood-CSF barrier dysfunction. In LGI1-E, but not in NMDAR-E, the blood-CSF barrier was more dysfunctional when CSF leukocytes were higher., Discussion: NMDAR-E and LGI-E differ in their typical extent of CSF inflammation. In addition, the patterns formed by the different inflammatory CSF parameters and their relationship with disease severity, age, and disease duration are subtype-characteristic. Moreover, signs for multiple sclerosis-like chronic inflammation are present in a subgroup of patients with NMDAR-E. These CSF patterns might be markers for the different immunopathogeneses of LGI1-E and NMDAR-E., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2021
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35. Rituximab Treatment and Long-term Outcome of Patients With Autoimmune Encephalitis: Real-world Evidence From the GENERATE Registry.
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Thaler FS, Zimmermann L, Kammermeier S, Strippel C, Ringelstein M, Kraft A, Sühs KW, Wickel J, Geis C, Markewitz R, Urbanek C, Sommer C, Doppler K, Penner L, Lewerenz J, Rößling R, Finke C, Prüss H, Melzer N, Wandinger KP, Leypoldt F, and Kümpfel T
- Subjects
- Adult, Aged, Anti-N-Methyl-D-Aspartate Receptor Encephalitis drug therapy, Anti-N-Methyl-D-Aspartate Receptor Encephalitis immunology, Autoantibodies immunology, Autoimmune Diseases of the Nervous System drug therapy, Female, Follow-Up Studies, Humans, Immunosuppressive Agents administration & dosage, Male, Middle Aged, Rituximab administration & dosage, Autoimmune Diseases of the Nervous System immunology, Encephalitis drug therapy, Encephalitis immunology, Immunosuppressive Agents pharmacology, Outcome Assessment, Health Care, Registries, Rituximab pharmacology
- Abstract
Background and Objectives: To determine the real-world use of rituximab in autoimmune encephalitis (AE) and to correlate rituximab treatment with the long-term outcome., Methods: Patients with NMDA receptor (NMDAR)-AE, leucine-rich glioma-inactivated-1 (LGI1)- AE, contactin-associated protein-like-2 (CASPR2)-AE, or glutamic acid decarboxylase 65 (GAD65) disease from the GErman Network for Research on AuToimmune Encephalitis who had received at least 1 rituximab dose and a control cohort of non-rituximab-treated patients were analyzed retrospectively., Results: Of the 358 patients, 163 (46%) received rituximab (NMDAR-AE: 57%, CASPR2-AE: 44%, LGI1-AE: 43%, and GAD65 disease: 37%). Rituximab treatment was initiated significantly earlier in NMDAR- and LGI1-AE (median: 54 and 155 days from disease onset) compared with CASPR2-AE or GAD65 disease (median: 632 and 1,209 days). Modified Rankin Scale (mRS) scores improved significantly in patients with NMDAR-AE, both with and without rituximab treatment. Although being more severely affected at baseline, rituximab-treated patients with NMDAR-AE more frequently reached independent living (mRS score ≤2) (94% vs 88%). In LGI1-AE, rituximab-treated and nontreated patients improved, whereas in CASPR2-AE, only rituximab-treated patients improved significantly. No improvement was observed in patients with GAD65 disease. A significant reduction of the relapse rate was observed in rituximab-treated patients (5% vs 13%). Detection of NMDAR antibodies was significantly associated with mRS score improvement. A favorable outcome was also observed with early treatment initiation., Discussion: We provide real-world data on immunosuppressive treatments with a focus on rituximab treatment for patients with AE in Germany. We suggest that early and short-term rituximab therapy might be an effective and safe treatment option in most patients with NMDAR-, LGI1-, and CASPR2-AE., Class of Evidence: This study provides Class IV evidence that rituximab is an effective treatment for some types of AE., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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36. Genome-wide Association Study Identifies 2 New Loci Associated With Anti-NMDAR Encephalitis.
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Tietz AK, Angstwurm K, Baumgartner T, Doppler K, Eisenhut K, Elisak M, Franke A, Golombeck KS, Handreka R, Kaufmann M, Kraemer M, Kraft A, Lewerenz J, Lieb W, Madlener M, Melzer N, Mojzisova H, Möller P, Pfefferkorn T, Prüss H, Rostásy K, Schnegelsberg M, Schröder I, Siebenbrodt K, Sühs KW, Wickel J, Wandinger KP, Leypoldt F, and Kuhlenbäumer G
- Subjects
- Adult, Case-Control Studies, Female, Genetic Loci, Humans, Male, Anti-N-Methyl-D-Aspartate Receptor Encephalitis genetics, Genome-Wide Association Study
- Abstract
Background and Objectives: To investigate the genetic determinants of the most common type of antibody-mediated autoimmune encephalitis, anti-NMDA receptor (anti-NMDAR) encephalitis., Methods: We performed a genome-wide association study in 178 patients with anti-NMDAR encephalitis and 590 healthy controls, followed by a colocalization analysis to identify putatively causal genes., Results: We identified 2 independent risk loci harboring genome-wide significant variants ( p < 5 × 10
-8 , OR ≥ 2.2), 1 on chromosome 15, harboring only the LRRK1 gene, and 1 on chromosome 11 centered on the ACP2 and NR1H3 genes in a larger region of high linkage disequilibrium. Colocalization signals with expression quantitative trait loci for different brain regions and immune cell types suggested ACP2 , NR1H3 , MADD , DDB2 , and C11orf49 as putatively causal genes. The best candidate genes in each region are LRRK1 , encoding leucine-rich repeat kinase 1, a protein involved in B-cell development, and NR1H3 liver X receptor alpha, a transcription factor whose activation inhibits inflammatory processes., Discussion: This study provides evidence for relevant genetic determinants of antibody-mediated autoimmune encephalitides outside the human leukocyte antigen (HLA) region. The results suggest that future studies with larger sample sizes will successfully identify additional genetic determinants and contribute to the elucidation of the pathomechanism., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2021
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37. Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis.
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Schwenkenbecher P, Skripuletz T, Lange P, Dürr M, Konen FF, Möhn N, Ringelstein M, Menge T, Friese MA, Melzer N, Malter MP, Häusler M, Thaler FS, Stangel M, Lewerenz J, and Sühs KW
- Subjects
- Adolescent, Adult, Aged, Antibodies, Viral blood, Autoimmune Diseases of the Nervous System blood, Encephalitis, Viral blood, Female, Humans, Male, Middle Aged, Young Adult, Antibodies, Viral cerebrospinal fluid, Autoimmune Diseases of the Nervous System cerebrospinal fluid, Encephalitis, Viral cerebrospinal fluid, Herpesvirus 4, Human immunology, Simplexvirus immunology
- Abstract
Background and Objectives: Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti-NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE., Methods: Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched., Results: An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected., Discussion: Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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38. Tick-Borne Encephalitis: A Differential Pattern of Intrathecal Humoral Immune Response and Inflammatory Cell Composition Compared with Other Viral CNS Infections.
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Senel M, Rapp D, Mayer B, Jesse S, Süssmuth SD, Otto M, Lewerenz J, and Tumani H
- Subjects
- Adult, Aged, Central Nervous System Infections blood, Central Nervous System Infections cerebrospinal fluid, Central Nervous System Infections virology, Encephalitis, Tick-Borne blood, Encephalitis, Tick-Borne cerebrospinal fluid, Encephalitis, Tick-Borne virology, Female, Herpesvirus 3, Human pathogenicity, Humans, Immunity, Humoral genetics, Immunity, Humoral immunology, Immunoglobulin M blood, Leukocytosis blood, Leukocytosis cerebrospinal fluid, Leukocytosis diagnosis, Leukocytosis virology, Magnetic Resonance Imaging, Male, Meningitis blood, Meningitis cerebrospinal fluid, Meningitis virology, Middle Aged, Simplexvirus immunology, Simplexvirus pathogenicity, Central Nervous System Infections diagnosis, Diagnosis, Differential, Encephalitis, Tick-Borne diagnosis, Meningitis diagnosis
- Abstract
To investigate whether and how cerebrospinal fluid (CSF) findings can contribute to distinguish tick-borne encephalitis (TBE) from herpes simplex virus (HSV) and varicella zoster virus (VZV) induced central nervous system (CNS) infections (HSV-I, VZV-I). Chart review and identification of TBE, HSV- I, and VZV-I was carried out, fulfilling the following criteria: (1) clinical signs of encephalitis and/or meningitis, (2) complete CSF analysis and confirmed viral etiology by either PCR or antibody testing in CSF, (3) hospitalized patients, and (4) available brain magnetic resonance imaging (MRI). Fifty-nine patients with 118 CSF/serum pairs were included. These comprised 21 with TBE (35 CSF/serum pairs), 20 (40 CSF/serum pairs) with HSV-I, and 18 (43 CSF/serum pairs) with VZV-I. In contrast to HSV-I and VZV-I, CSF cell differentiation in TBE showed more often an increased (>20%) proportion of granulocytes ( p < 0.01) and a more frequent quantitative intrathecal IgM synthesis ( p = 0.001 and p < 0.01, respectively), while the second was even more pronounced when follow-up CSF analyses were included ( p < 0.001). CSF findings help to distinguish TBE from other viral infections. In cases with CSF pleocytosis and a positive history for a stay in or near an endemic area, TBE antibodies in CSF and serum should be determined, especially if granulocytes in CSF cell differentiation and/or an intrathecal IgM synthesis is present.
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- 2020
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39. A 64-Year-Old Patient With a Mesiotemporal Mass and Symptomatic Epilepsy.
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Kuehn JC, Scheuerle A, Bauer J, Becker AJ, Wirtz R, and Lewerenz J
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- Autoantibodies immunology, Autoantigens immunology, Autoimmune Diseases pathology, Humans, Male, Middle Aged, Autoimmune Diseases immunology, Epilepsy immunology, Intracellular Signaling Peptides and Proteins immunology, Limbic Encephalitis immunology, Limbic Encephalitis pathology
- Published
- 2020
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40. Pathological characterization of T2*-weighted MRI contrast in the striatum of Huntington's disease patients.
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Bulk M, Hegeman-Kleinn I, Kenkhuis B, Suidgeest E, van Roon-Mom W, Lewerenz J, van Duinen S, Ronen I, and van der Weerd L
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- Corpus Striatum diagnostic imaging, Gray Matter, Humans, Magnetic Resonance Imaging, Myelin Sheath, Huntington Disease diagnostic imaging
- Abstract
Previous MRI studies consistently reported iron accumulation within the striatum of patients with Huntington's disease (HD). However, the pattern and origin of iron accumulation is poorly understood. This study aimed to characterize the histopathological correlates of iron-sensitive ex vivo MRI contrast change in HD brains. To this end, T2*-weighted 7T MRI was performed on postmortem tissue of the striatum of three control subjects and 10 HD patients followed by histological examination. In addition, formalin-fixed paraffin-embedded material of three control subjects and 14 HD patients was selected for only histology to identify the cellular localization of iron using stainings for iron, myelin, microglia and astrocytes. As expected HD striata showed prominent atrophy. Compared to controls, the striatum of HD patients was in general more hypointense on T2*-weighted high-field MRI and showed a more intense histopathological staining for iron. In addition, T2*-weighted MRI identified large focal hypointensities within the striatum of HD patients. Upon histological examination, these large focal hypointensities frequently colocalized with enlarged perivascular spaces and iron was found within the vessel wall and reactive astrocytes. In conclusion, we show that the striatum of HD patients has a distinctive phenotype on T2*-weighted MRI compared to control subjects. On ex vivo MRI, these contrast changes are heavily biased by enlarged perivascular spaces from which it is currently unknown whether this is a fixation artefact or a disease specific observation. Clinically, the observation of iron within reactive astrocytes is of importance for the interpretation and understanding of the potential underlying mechanisms of T2*-weighted MRI results in HD patients., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2020
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41. Cerebrospinal Fluid Findings in Patients With Autoimmune Encephalitis-A Systematic Analysis.
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Blinder T and Lewerenz J
- Abstract
Autoimmune encephalitides (AIE) comprise a group of inflammatory diseases of the central nervous system (CNS), which can be further characterized by the presence of different antineuronal antibodies. Recently, a clinical approach for diagnostic criteria for the suspected diagnosis of AIE as well as definitive AIE were proposed. These are intended to guide physicians when to order the antineuronal antibody testing and/or facilitate early diagnosis even prior to the availability of the specific disease-confirming test results to facilitate prompt treatment. These diagnostic criteria also include the results of basic cerebrospinal fluid (CSF) analysis. However, the different antibody-defined AIE subtypes might be highly distinct with regard to their immune pathophysiology, e.g., the pre-dominance of specific IgG subclasses, IgG1, or IgG4, or frequency of paraneoplastic compared to idiopathic origin. Thus, it is conceivable that the results of basic CSF analysis might also be very different. However, this has not been explored systematically. Here, we systematically reviewed the literature about the 10 most important AIE subtypes, AIE with antibodies against NMDA, AMPA, glycine, GABA
A , and GABAB receptors as well as DPPX, CASPR2, LGI1, IgLON5, or glutamate decarboxylase (GAD), with respect to the reported basic CSF findings comprising CSF leukocyte count, total protein, and the presence of oligoclonal bands (OCB) restricted to the CSF as a sensitive measure for intrathecal IgG synthesis. Our results indicate that these basic CSF findings are profoundly different among the 10 different AIE subtypes. Whereas, AIEs with antibodies against NMDA, GABAB , and AMPA receptors as well as DPPX show rather frequent inflammatory CSF changes, in AIEs with either CASPR2, LGI1, GABAA , or glycine receptor antibodies CSF findings were mostly normal. Two subtypes, AIEs defined by either GAD, or IgLON5 antibodies, did not fit into this general pattern. In AIE with GAD antibodies, positive OCBs in the absence of other changes were typical, while the CSF in IgLON5 antibody-positive AIE was characterized by elevated protein.- Published
- 2019
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42. CSF Free Light Chains as a Marker of Intrathecal Immunoglobulin Synthesis in Multiple Sclerosis: A Blood-CSF Barrier Related Evaluation in a Large Cohort.
- Author
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Senel M, Mojib-Yezdani F, Braisch U, Bachhuber F, Lewerenz J, Ludolph AC, Otto M, and Tumani H
- Subjects
- Adult, Aged, Biomarkers cerebrospinal fluid, Cross-Sectional Studies, Female, Humans, Immunoglobulin G cerebrospinal fluid, Immunoglobulin G immunology, Male, Middle Aged, Immunoglobulin kappa-Chains cerebrospinal fluid, Immunoglobulin kappa-Chains immunology, Immunoglobulin lambda-Chains cerebrospinal fluid, Immunoglobulin lambda-Chains immunology, Multiple Sclerosis cerebrospinal fluid, Multiple Sclerosis diagnosis, Multiple Sclerosis immunology
- Abstract
Objectives: The importance of immunoglobulin G (IgG) oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS) was reaffirmed again in the recently revised MS diagnostic criteria. Since OCB testing is based on non-quantitative techniques and demands considerable methodological experience, measurement of CSF immunoglobulin free light chains (FLC) has been suggested as quantitative alternative to OCB. We aimed to establish reference values for FLC measures and evaluate their diagnostic accuracy with regard to the diagnosis of MS. Methods: Immunoglobulin kappa (KFLC) and lambda (LFLC) free light chains were prospectively measured by nephelometry in CSF and serum sample pairs in 1,224 patients. The analyzed cohort included patients with MS, other autoimmune or infectious inflammatory diseases of the nervous system as well as 989 patients without signs for nervous system inflammation. Results: Regarding diagnosis of MS, the diagnostic sensitivity and specificity of intrathecal KFLC ratio were 93.3 and 93.7% using the CSF-serum albumin ratio-dependent reference values, 92.0 and 95.9% for intrathecal KFLC ratio applying the ROC-curve determined cut-off levels, 62.7 and 98.3% for IgG index, 64.0 and 98.8% for intrathecal IgG synthesis according to Reiber diagrams, and 94.7 and 93.3% for OCB. Diagnostic sensitivity and specificity of intrathecal LFLC were clearly lower than KFLC. Conclusions: Intrathecal KFLC and OCB showed the highest diagnostic sensitivities for MS. However, specificity was slightly lower compared to other quantitative IgG parameters. Consequently, CSF FLC may not replace OCB, but it may support diagnosis in MS as a quantitative parameter.
- Published
- 2019
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43. Genotypes and phenotypes of patients with Lafora disease living in Germany.
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Brenner D, Baumgartner T, von Spiczak S, Lewerenz J, Weis R, Grimmer A, Gaspirova P, Wurster CD, Kunz WS, Wagner J, Minassian BA, Elger CE, Ludolph AC, Biskup S, and Döcker D
- Abstract
Background: Lafora progressive myoclonus epilepsy (Lafora disease) is a rare, usually childhood-onset, fatal neurodegenerative disease caused by biallelic mutations in EPM2A (Laforin) or EPM2B ( NHLRC1 , Malin). The epidemiology of Lafora disease in Germany is largely unknown. The objective of this retrospective case series is to characterize the genotypes and phenotypes of patients with Lafora disease living in Germany., Methods: The patients described in this case series initially had the suspected clinical diagnosis of Lafora disease, or unclassified progressive myoclonus epilepsy. Molecular genetic diagnostics including next generation sequencing-based diagnostic panel analysis or whole exome sequencing was performed., Results: The parents of four out of the 11 patients are nonconsanguineous and of German origin while the other patients had consanguineous parents. Various variants were found in EPM2A (six patients) and in EPM2B (five patients). Eight variants have not been reported in the literature so far. The patients bearing novel variants had typical disease onset during adolescence and show classical disease courses., Conclusions: This is the first larger case series of Lafora patients in Germany. Our data enable an approximation of the prevalence of manifest Lafora disease in Germany to 1,69 per 10 million people. Broader application of gene panel or whole-exome diagnostics helps clarifying unclassified progressive myoclonus epilepsy and establish an early diagnosis, which will be even more important as causal therapy approaches have been developed and are soon to be tested in a phase I study.
- Published
- 2019
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44. On Razor's edge: Managing analgosedation during severe anti-NMDA receptor encephalitis.
- Author
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Jesse S, Wagner J, Gastl R, Steinacker P, Otto M, Kassubek J, and Lewerenz J
- Subjects
- Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis complications, Brain diagnostic imaging, Brain drug effects, Dyskinesias drug therapy, Dyskinesias etiology, Female, Humans, Hypnotics and Sedatives adverse effects, Primary Dysautonomias drug therapy, Primary Dysautonomias etiology, Treatment Outcome, Young Adult, Anti-N-Methyl-D-Aspartate Receptor Encephalitis diagnosis, Anti-N-Methyl-D-Aspartate Receptor Encephalitis drug therapy, Hypnotics and Sedatives therapeutic use
- Published
- 2018
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45. Management and prognostic markers in patients with autoimmune encephalitis requiring ICU treatment.
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Schubert J, Brämer D, Huttner HB, Gerner ST, Fuhrer H, Melzer N, Dik A, Prüss H, Ly LT, Fuchs K, Leypoldt F, Nissen G, Schirotzek I, Dohmen C, Bösel J, Lewerenz J, Thaler F, Kraft A, Juranek A, Ringelstein M, Sühs KW, Urbanek C, Scherag A, Geis C, Witte OW, and Günther A
- Subjects
- Adult, Female, Humans, Intensive Care Units statistics & numerical data, Male, Middle Aged, Outcome Assessment, Health Care, Prognosis, Registries, Risk Factors, Young Adult, Critical Care statistics & numerical data, Encephalitis diagnosis, Encephalitis therapy, Hashimoto Disease diagnosis, Hashimoto Disease therapy
- Abstract
Objective: To assess intensive care unit (ICU) complications, their management, and prognostic factors associated with outcomes in a cohort of patients with autoimmune encephalitis (AE)., Methods: This study was an observational multicenter registry of consecutively included patients diagnosed with AE requiring Neuro-ICU treatment between 2004 and 2016 from 18 tertiary hospitals. Logistic regression models explored the influence of complications, their management, and diagnostic findings on the dichotomized (0-3 vs 4-6) modified Rankin Scale score at hospital discharge., Results: Of 120 patients with AE (median age 43 years [interquartile range 24-62]; 70 females), 101 developed disorders of consciousness, 54 autonomic disturbances, 42 status epilepticus, and 39 severe sepsis. Sixty-eight patients were mechanically ventilated, 85 patients had detectable neuronal autoantibodies, and 35 patients were seronegative. Worse neurologic outcome at hospital discharge was associated with necessity of mechanical ventilation (sex- and age-adjusted OR 6.28; 95% CI, 2.71-15.61) tracheostomy (adjusted OR 6.26; 95% CI, 2.68-15.73), tumor (adjusted OR 3.73; 95% CI, 1.35-11.57), sepsis (adjusted OR 4.54; 95% CI, 1.99-10.43), or autonomic dysfunction (adjusted OR 2.91; 95% CI, 1.24-7.3). No significant association was observed with autoantibody type, inflammatory changes in CSF, or pathologic MRI., Conclusion: In patients with AE, mechanical ventilation, sepsis, and autonomic dysregulation appear to indicate longer or incomplete convalescence. Classic ICU complications better serve as prognostic markers than the individual subtype of AE. Increased awareness and effective management of these AE-related complications are warranted, and further prospective studies are needed to confirm our findings and to develop specific strategies for outcome improvement.
- Published
- 2018
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46. Oxytosis/Ferroptosis-(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System.
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Lewerenz J, Ates G, Methner A, Conrad M, and Maher P
- Abstract
Although nerve cell death is the hallmark of many neurological diseases, the processes underlying this death are still poorly defined. However, there is a general consensus that neuronal cell death predominantly proceeds by regulated processes. Almost 30 years ago, a cell death pathway eventually named oxytosis was described in neuronal cells that involved glutathione depletion, reactive oxygen species production, lipoxygenase activation, and calcium influx. More recently, a cell death pathway that involved many of the same steps was described in tumor cells and termed ferroptosis due to a dependence on iron. Since then there has been a great deal of discussion in the literature about whether these are two distinct pathways or cell type- and insult-dependent variations on the same pathway. In this review, we compare and contrast in detail the commonalities and distinctions between the two pathways concluding that the molecular pathways involved in the regulation of ferroptosis and oxytosis are highly similar if not identical. Thus, we suggest that oxytosis and ferroptosis should be regarded as two names for the same cell death pathway. In addition, we describe the potential physiological relevance of oxytosis/ferroptosis in multiple neurological diseases.
- Published
- 2018
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47. Bevacizumab in temozolomide refractory high-grade gliomas: single-centre experience and review of the literature.
- Author
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Jeck J, Kassubek R, Coburger J, Edenhofer S, Schönsteiner SS, Ludolph AC, Schmitz B, Engelke J, Mayer-Steinacker R, Lewerenz J, and Bullinger L
- Abstract
Background: Despite multidisciplinary treatment approaches, the prognosis for patients with high-grade glioma (HGG) is poor, with a median overall survival (OS) of 14.6 months for glioblastoma multiforme (GB). As high levels of vascular endothelial growth factor A (VEGF) are found in HGG, targeted anti-antiangiogenic therapy using the humanized monoclonal antibody bevacizumab (BEV) was studied in a series of clinical trials. Still, the discrepancy of BEV's efficacy with regard to initial clinical and radiological response and its reported failure to prolong survival remains to be explained. Here, we illustrate the effectiveness of BEV in recurrent HGG by summarizing our single-centre experience., Methods: We have retrospectively investigated the effect of BEV in temozolomide refractory HGG in 39 patients treated at the University Hospital of Ulm, Germany., Results: Median duration of BEV treatment was 12.5 weeks; 23% of patients received BEV for more than 6 months and 15% for more than 1 year, until clinical or radiological tumour progression led to discontinuation. Furthermore, Karnofsky performance status increased in 30.6% and steroid dose decreased in 39% of all patients., Conclusions: The review of literature reveals that phase II and III studies support BEV as an effective therapy in recurrent HGG, at least with regard to progression-free survival (PFS), but landmark phase III trials failed to prove benefit concerning OS. Here, we discuss reasons that may account for this observation. We conclude that prolonging PFS with maintenance of neurological function and personal and economic independency justifies the off-label use of BEV., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest.
- Published
- 2018
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48. Absence of system x c - on immune cells invading the central nervous system alleviates experimental autoimmune encephalitis.
- Author
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Merckx E, Albertini G, Paterka M, Jensen C, Albrecht P, Dietrich M, Van Liefferinge J, Bentea E, Verbruggen L, Demuyser T, Deneyer L, Lewerenz J, van Loo G, De Keyser J, Sato H, Maher P, Methner A, and Massie A
- Subjects
- Aged, Aged, 80 and over, Amino Acid Transport System y+ genetics, Amino Acid Transport System y+ immunology, Animals, Central Nervous System immunology, Central Nervous System pathology, Encephalomyelitis, Autoimmune, Experimental immunology, Encephalomyelitis, Autoimmune, Experimental pathology, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Microglia pathology, Microglia physiology, Middle Aged, Multiple Sclerosis immunology, Multiple Sclerosis pathology, Amino Acid Transport System y+ deficiency, Central Nervous System metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism, Immunity, Cellular physiology, Multiple Sclerosis metabolism
- Abstract
Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease that affects the central nervous system (CNS), leading to neurodegeneration and chronic disability. Accumulating evidence points to a key role for neuroinflammation, oxidative stress, and excitotoxicity in this degenerative process. System x
c - or the cystine/glutamate antiporter could tie these pathological mechanisms together: its activity is enhanced by reactive oxygen species and inflammatory stimuli, and its enhancement might lead to the release of toxic amounts of glutamate, thereby triggering excitotoxicity and neurodegeneration., Methods: Semi-quantitative Western blotting served to study protein expression of xCT, the specific subunit of system xc - , as well as of regulators of xCT transcription, in the normal appearing white matter (NAWM) of MS patients and in the CNS and spleen of mice exposed to experimental autoimmune encephalomyelitis (EAE), an accepted mouse model of MS. We next compared the clinical course of the EAE disease, the extent of demyelination, the infiltration of immune cells and microglial activation in xCT-knockout (xCT-/- ) mice and irradiated mice reconstituted in xCT-/- bone marrow (BM), to their proper wild type (xCT+/+ ) controls., Results: xCT protein expression levels were upregulated in the NAWM of MS patients and in the brain, spinal cord, and spleen of EAE mice. The pathways involved in this upregulation in NAWM of MS patients remain unresolved. Compared to xCT+/+ mice, xCT-/- mice were equally susceptible to EAE, whereas mice transplanted with xCT-/- BM, and as such only exhibiting loss of xCT in their immune cells, were less susceptible to EAE. In none of the above-described conditions, demyelination, microglial activation, or infiltration of immune cells were affected., Conclusions: Our findings demonstrate enhancement of xCT protein expression in MS pathology and suggest that system xc - on immune cells invading the CNS participates to EAE. Since a total loss of system xc - had no net beneficial effects, these results have important implications for targeting system xc - for treatment of MS.- Published
- 2017
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49. Decreased IL-8 levels in CSF and serum of AD patients and negative correlation of MMSE and IL-1β.
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Hesse R, Wahler A, Gummert P, Kirschmer S, Otto M, Tumani H, Lewerenz J, Schnack C, and von Arnim CA
- Abstract
Background: It is widely accepted that neuroinflammatory processes play an important role in the pathogenesis of Alzheimer's disease (AD) and high levels of cytokines and chemokines are detected around Aβ plaques., Methods: As neuroinflammation is involved in the development and progression of AD, we measured the pro-inflammatory cytokines interleukin 1β (IL-1β), IL-8 and tumor necrosis factor α (TNF-α) in serum and cerebrospinal fluid (CSF) samples from 45 AD patients and 53 age-matched control subjects using a highly sensitive multiplex electrochemiluminescence assay. To address the association with disease progression we correlated cognitive status with cytokine levels., Results: CSF as well as serum IL-8 levels were found to be significantly lower in AD patients than in controls (p = 0.02). A statistically significant inverse correlation was observed between the CSF level of IL-1β and the MMSE score (r
s = -0.03, p = 0.02). We therefore stratified the AD patients by their MMSE scores into three equal groups and found that in the AD group with the most severe cognitive impairment CSF-IL-1β was significantly increased compared to age-matched controls (p < 0.05), whereas in the other investigated groups the increase was not statistically significant., Conclusion: Our results confirm data suggesting that cytokine alterations are involved in AD pathogenesis and may be helpful as a biomarker for monitoring disease progression.- Published
- 2016
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50. Chronic Glutamate Toxicity in Neurodegenerative Diseases-What is the Evidence?
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Lewerenz J and Maher P
- Abstract
Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.
- Published
- 2015
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