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1. Theme 11 Cognitive and Psychological Assessment and Support.

Author

Balz, L. T., Uttner, I., Ludolph, A. C., Landwehrmeyer, G. B., Lulé, D. E., Kinzl, D., Dorst, J., Balz, L., Lulé, D., Olesen, L. K., Hakala, C., Heintzelmann, M. B., Nikolova, N., Allen, M., Rossau, C. D., Blicher, J., Trucco, A. P., Khondoker, M., Kishita, N., and Backhouse, T.

Subjects
PSYCHOTHERAPY, PATIENTS' attitudes, MEDICAL personnel, PSYCHOLOGICAL tests, EMOTION recognition, APATHY
Abstract

The article discusses the psychosocial adjustment (PSA) in patients with Amyotrophic Lateral Sclerosis (ALS) and Huntington's disease (HD), comparing their quality of life and level of depressiveness. It also explores cognitive domains in C9orf72 mutation carriers and the impact of an online peer-support group intervention for adult children of ALS patients. Additionally, the study investigates cognitive alterations, apathy, and sexual behavior in ALS patients, highlighting sex differences in cognitive function and the importance of addressing sexual behavior and intimacy in ALS care. [Extracted from the article]

Published
2024
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3. Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease

Author

Mcallister, B., Gusella, J. F., Landwehrmeyer, G. B., Lee, J. -M., Macdonald, M. E., Orth, M., Rosser, A. E., Williams, N. M., Holmans, P., Jones, L., Massey, T. H., the REGISTRY Investigators of the European Huntington’s Disease Network, and Romano, S.

Subjects
neuropsychological tests, 0301 basic medicine, medicine.medical_specialty, Psychosis, adult, aged, cognition disorders, female, humans, huntington disease, male, mental disorders, middle aged, motor skills disorders, retrospective studies, time factors, internationality, Disease, Irritability, Logistic regression, 03 medical and health sciences, 0302 clinical medicine, medicine, Apathy, Psychiatry, Depression (differential diagnoses), business.industry, Cognition, medicine.disease, 030104 developmental biology, Neurology (clinical), medicine.symptom, Age of onset, business, 030217 neurology & neurosurgery
Abstract

ObjectiveTo assess the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers, we analyzed retrospective clinical data from individuals with manifest HD.MethodsClinical features of patients with HD were analyzed for 6,316 individuals in an observational study of the European Huntington's Disease Network (REGISTRY) from 161 sites across 17 countries. Data came from clinical history and the patient-completed Clinical Characteristics Questionnaire that assessed 8 symptoms: motor, cognitive, apathy, depression, perseverative/obsessive behavior, irritability, violent/aggressive behavior, and psychosis. Multiple logistic regression was used to analyze relationships between symptoms and functional outcomes.ResultsThe initial manifestation of HD is increasingly likely to be motor and less likely to be psychiatric as age at presentation increases and is independent of pathogenic CAG repeat length. The Clinical Characteristics Questionnaire captures data on nonmotor symptom prevalence that correlate specifically with validated clinical measures. Psychiatric and cognitive symptoms are common in HD gene carriers, with earlier onsets associated with longer CAG repeats. Of patients with HD, 42.4% reported at least 1 psychiatric or cognitive symptom before motor symptoms, with depression most common. Each nonmotor symptom was associated with significantly reduced total functional capacity scores.ConclusionsPsychiatric and cognitive symptoms are common and functionally debilitating in HD gene carriers. They require recognition and targeting with clinical outcome measures and treatments. However, because it is impossible to distinguish confidently between nonmotor symptoms arising from HD and primary psychiatric disorders, particularly in younger premanifest patients, nonmotor symptoms should not be used to make a clinical diagnosis of HD.Trial Registration InformationClinicalTrials.gov Identifier: NCT01590589

Published
2021

4. An MDS Evidence-Based Review on Treatments for Huntington's Disease

Author

Ferreira, J. J., Rodrigues, F. B., Duarte, G. S., Mestre, T. A., Bachoud-Levi, A. -C., Bentivoglio, Anna Rita, Burgunder, J. -M., Cardoso, F., Claassen, D. O., Landwehrmeyer, G. B., Kulisevsky, J., Nirenberg, M. J., Rosser, A., Roth, J., Seppi, K., Slawek, J., Furr-Stimming, E., Tabrizi, S. J., Walker, F. O., Vandenberghe, W., Costa, J., Sampaio, C., Bentivoglio A. R. (ORCID:0000-0002-9663-095X), Ferreira, J. J., Rodrigues, F. B., Duarte, G. S., Mestre, T. A., Bachoud-Levi, A. -C., Bentivoglio, Anna Rita, Burgunder, J. -M., Cardoso, F., Claassen, D. O., Landwehrmeyer, G. B., Kulisevsky, J., Nirenberg, M. J., Rosser, A., Roth, J., Seppi, K., Slawek, J., Furr-Stimming, E., Tabrizi, S. J., Walker, F. O., Vandenberghe, W., Costa, J., Sampaio, C., and Bentivoglio A. R. (ORCID:0000-0002-9663-095X)

Abstract

Background: Huntington's disease (HD) is a rare neurodegenerative disorder with protean clinical manifestations. Its management is challenging, consisting mainly of off-label treatments. Objectives: The International Parkinson and Movement Disorder Society commissioned a task force to review and evaluate the evidence of available therapies for HD gene expansion carriers. Methods: We followed the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Eligible randomized controlled trials were identified via an electronic search of the CENTRAL, MEDLINE, and EMBASE databases. All eligible trials that evaluated one or more of 33 predetermined clinical questions were included. Risk of bias was evaluated using the Cochrane Risk of Bias tool. A framework was adapted to allow for efficacy and safety conclusions to be drawn from the balance between the GRADE level of evidence and the importance of the benefit/harm of the intervention. Results: Twenty-two eligible studies involving 17 interventions were included, providing data to address 8 clinical questions. These data supported a likely effect of deutetrabenazine on motor impairment, chorea, and dystonia and of tetrabenazine on chorea. The data did not support a disease-modifying effect for premanifest and manifest HD. There was no eligible evidence to support the use of specific treatments for depression, psychosis, irritability, apathy, or suicidality. Similarly, no evidence was eligible to support the use of physiotherapy, occupational therapy, exercise, dietary, or surgical treatments. Conclusions: Data for therapeutic interventions in HD are limited and support only the use of VMAT2 inhibitors for specific motor symptoms. © 2021 International Parkinson and Movement Disorder Society.

Published
2022

14. Meaningful and measurable health domains in Huntington’s: large-scale validation of the Huntington’s disease health-related quality of life questionnaire (HDQoL) across severity stages

Author

Ho, Aileen K., Horton, M. C., Landwehrmeyer, G. B., Burgunder, J-M., and Tennant, A.

Abstract

Objectives: While health-related quality of life is key for patients with long-term neurodegenerative conditions, measuring this is less straightforward and complex in Huntington’s disease. This study aimed to refine and validate a fully patient-derived instrument, the Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), and to elucidate health domains that are meaningful to patients’ lived experience. \ud Methods: Five-hundred and forty-one participants, from pre-manifest to end-stage disease completed the HDQoL, together with generic quality of life measures, and in-person motor, cognitive and behavioural assessments. The psychometric properties of the HDQoL were examined using factor analysis and Rasch analysis. \ud Results: Four HDQoL domains emerged reflecting the classical triad of HD features - they were Physical-Functional, Cognitive, and two different behavioural aspects i.e. Mood-Self domain, as well as a distinct Worries domain. These domains clarify the behavioural sequelae as experienced by patients, and all showed good to excellent internal consistency. Known groups analyses illustrated significant and graded changes in clinical assesments and corresponding HDQoL domains across severity levels. Convergent and discriminant validity was demonstrated by the expected pattern of correlations between specific HDQoL domains and corresponding domain-relevant clinical assesments as well as patient-reported measures. The data demonstrate robust support for the refined HDQoL across disease stages.\ud Conclusions: The HDQoL with its two distinct behavioural domains of Mood-Self and of Worries, as well as a Physical-Functional and a Cognitive domain, is a relevant, reliable and valid patient-derived instrument to measure the impact of Huntington’s disease across all severity stages.

Published
2019

15. Abstracts Second Congress of the European Society for Clinical Neuropharmacology: Würzburg, November 9–11, 1995

Author

Agid, Y., Arendt, T., Gärtner, U., Holzer, M., Fruth, P., Brückner, M. K., Arzberger, T., Weindl, A., Baas, H., Demisch, L., Harder, S., Bürklin, F., Fischer, P. A., Bagli, M., Rao, M. L., Sobanski, T., Laux, G., Barbier, P., Fumagalli, F., Donati, E., Maggio, R., Racagni, G., Corsini, G. U., Riva, M., Berger, J., Löschl, B., Bernheimer, H., Lugowska, A., Tylki-Szymanska, A., Gieselmann, V., Molzer, B., Faé, I., Bernocchi, G., Scherini, E., Necchi, D., Bigl, M., Bleyl, D., Bigl, V., Eschrich, K., Block, F., Schwarz, M., Blum-Degen, D., Müller, Th., Kuhn, W., Gerlach, M., Przuntek, H., Riederer, R., Bonuccelli, U., Ceravolo, R., Nuti, A., D'Avino, C., Placidi, G., Perugi, G., Cassano, G. B., Del Dotto, P., Piccini, P., Colzi, A., Muratorio, A., Braak, H., Braak, E., Yilmazer, D. M., de Vos, R. A. I., Jansen, E. N. H., Bringmann, G., Clement, H. W., Grote, C., Rausch, F., Reichmann, H., Riederer, P., Sontag, K. -H., Wesemann, W., God, R., Feineis, D., Brückner, R., Protzen, J. -A., Fähr, S., Rausch, W. -D., Brunt, E. R. P., Pruim, J., Willemsen, A. J., van Weerden, T. W., Bryan-Lluka, L. J., Bönisch, H., Büttner, Th., Kühn, W., McMonagle, U., Calza, L., Pozza, M., Coraddu, F., Farci, G., Carlsson, A., Napolitano, A., Salvetti, S., Dell'Agnello, G., Renna, M., Conquet, F., Bashir, Z., Daniel, H., Ferraguti, F., Collingridge, G., Crépel, F., Coos Verhoef, J., Merkus, F. W. H. M., Junginger, H. E., Cruz-Sánchez, F. F., Kutschka, T., Beeg, M., Deuschle, M., Weber, B., Körner, A., Standhardt, H., Lammers, C. -H., Motzek-Noé, T., Heuser, I., Earl, C. D., Reum, T., Sautter, J., Xie, J. -X, Kupsch, A., Oertel, W. H., Morgenstern, R., Emilien, G. M., Maloteaux, J. M., Seghers, A., Charles, G., Erdmann, R., Högemann, D., Fichter, N., Lücking, C. H., Landwehrmeyer, G. B., Winter, T., Feuerstein, T. J., Fitzgeral, D., Anderson, M. C., Lawlor, B., Tipton, K. F., Frackowiak, R. S. J., Freo, U., Dam, M., Pizzolato, G., Merico, A., Ori, C., Sale, E., Battistin, L., Fritze, J., Froelich, L., Goetz, M., Gsell, W., Jellinger, K., Beckmann, H., Fünfgeld, E. W., Glinka, Y., Youdim, M. B. H., Götz, M. E., Breithaupt, W., Burger, R., Streifler, M., Simanyi, M., Müller, F., Danielczyk, W., Hirning, T., Sohlbach, M., Nafc, R., Sternadl, H., Winter, M., Nöth, U., Heim, C., Hartmann, J., Künig, G., Niedermeyer, B., Berger, W., Deckert, J., Abel, F., Heinsen, H., Senitz, D., Mayr, J., Ransmayr, G., Hartung, H. -P., Heils, A., Teufel, A., Petri, S., Seemann, M., Bengel, D., Degen, H. J., Lesch, K. P., Sontag, T., Heinen, F., Korinthenberg, R., Heiss, W. -D., Rüb, U., Gangus, B., Jungkunz, G., Bauer, M., Ulmar, G., Böcker, F., Schüler, M., Bethke, B., Lockemann, U., Hermans, E., Vanhoorde, P., Hesse, S., Hüll, M., Fiebich, B., Lieb, K., Strauss, S., Berger, M., Volk, B., Bauer, J., Iversen, L. L., Janetzky, B., Hauck, S., Jeanjean, A. P., Laterre, E. C., Bancher, C., Jost, W. H., Kalus, P., Kanner, B., Khrapova, E. V., Brusov, O. S., Knauber, J., Müller, W. E., Korczyn, A. D., Kornhuber, J., Parsons, C. G., Hartmann, S., Retz, W., Kamolz, S., Thome, J., Koutsilieri, E., Chen, T. -S., Kreutzberg, G. W., Krieglstein, J., Winkel, R., Danielcyk, S., Gerstner, A., Mattern, C., Häcker, R., Labunsky, D., Zhirnova, I., Komelkova, L., Popova, L., Avdiunina, I., Lakke, J. P. W. F., Lange, K. W., Steup, A., Tucha, O., Naumann, M., Lassmann, H., Leszek, J., Gasiorowski, K., Inglot, D., Lohse, M. J., Löschmann, P. -A., Eblen, F., Wüllner, U., Klockgether, T., Dichgans, J., Macrae, I. M., Mimmack, M. L., Emson, P., Norta, M., Borchert, H. -H., Medori, R., Chan, W. W., Heinemann, T., Melzacka, M., Kolasiewicz, W., Sieklucka, M., Jaros, T., Mesec, A., Šega, S., Kiauta, T., Moser, A., Vieregge, P., Siebecker, F., Münch, G., Schinzel, R., Michaelis, J., Cunningham, A., Da Prada, M., Borroni, E., Zürcher, G., Reiners, K., Neveu, P. J., Nitsch, R. M., Pavese, N., Lucetti, C., Rossi, G., Offen, D., Ziv, I., Stein, R., Barzilai, A., Hochman, A., Melamed, E., Ozawa, H., Hashimoto, E., Saito, T., Ymamoto, M., Takahata, N., Frölich, L., Paulus, W., Hermsteiner, E., Haug, B., Bandelow, B., Peckys, D., Gleichauf, O., Jackisch, R., Landwehrmeyer, B., Bloß, H. G., Plaschke, K., Müller, D., Hoyer, S., Avdyuna, L. A., Putzke, J., Spanagel, R., Tolle, T. R., Zieglgänsberger, W., Rabey, J. -M., Orlov, E., von Raison, F., Lehmann, K., Havemann-Reinecke, U., Butà, M., Federspiel, S., Maier, H., Abdel-mohsen, M., Abdel-moneim, M., Reynolds, G. P., Sardar, A. M., Eggett, C. J., Rosario, P., de la Morena, E., José Barro, M., Rossini, P. M., Roth, J., Růžička, E., Svobodová, I., Mečíř, P., Jech, R., Remeš, F., Kleinschroth, A., Schliebs, R., Roßner, S., Heider, M., Schubert, H., König, P., Schuttes, H., HaveIec, L., Schwartz, J. -C., Sendtner, M., Smith, A., Li, M., Griesbeck, O., Parsadanian, A., Holtmann, B., Carroll, P., Toyka, K. V., Thoenen, H., Sharkawy, A. A., Ibrahim, T. A., Pulkowski, U., Siesjö, B. K., Klessaschek, M., Sopper, S., Demuth, M., Dörries, R., Hemm, S., Stahl-Hennig, C., Brinkmann, R., ter Meulen, V., Sperk, G., Schwarzer, C., Stern, G., Storm, G., Strein, I., Struck, M., Stürenburg, H. J., Kunze, K., Svadovsky, A. I., Morgunov, K. V., Peresedov, V. V., Moshkin, A. V., Teherani, D. K., Baumer, A., Rösier, M., Rösler, M., Wiesbeck, G. A., Wodarz, N., Boning, J., Timerbaeva, S. L., Alekseeva, N. S., Toso, A., Barletta, D., Tuulik, V., Lossmann, E., Raja, A., Meister, A., Uitti, R. J., Rajput, A. H., Ahlskog, J. E., Offord, K. P., Schroeder, D. R., O'Brien, P. C., Vaglini, F., Fascetti, F., Pardini, C., Mancino, L., Velbinger, K., Hartmann, H., Eckert, A., Grüter, S., Behrens, S., Niemann, J., Guschelbauer, B., Lauk, M., Wissel, J., Poewe, W., Wurthman, C., Janzen, E. N. H., Goping, G., Adegemo, O. M., Gemma, A., Kuijpers, J., Pollard, H. B., Zielke, B., Ziemann, U., and Bruns, D.

Published
1995
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21. Cognitive decline in Huntington's disease expansion gene carriers

Author

Baake, V, Reijntjes, Rham, Dumas, Em, Thompson, Jc, Roos, Rac, Bentivoglio, Anna Rita, Biunno, I., Bronzova, J., Dunnett, S. B., Frich, J., Giuliano, J., Illarioshkin, S., Illmann, T., Klempír, J. j., Landwehrmeyer, G. B., Levey, J., Mclean, T., Nielsen, J. E., Päivärinta, M., Pålhagen, S., Ramos-Arroyo, M., Tabrizi, S. J., Vandenberghe, W., Uhrova, T., Bernard, T., Betz, S., Bentivoglio, AR (ORCID:0000-0002-9663-095X), Baake, V, Reijntjes, Rham, Dumas, Em, Thompson, Jc, Roos, Rac, Bentivoglio, Anna Rita, Biunno, I., Bronzova, J., Dunnett, S. B., Frich, J., Giuliano, J., Illarioshkin, S., Illmann, T., Klempír, J. j., Landwehrmeyer, G. B., Levey, J., Mclean, T., Nielsen, J. E., Päivärinta, M., Pålhagen, S., Ramos-Arroyo, M., Tabrizi, S. J., Vandenberghe, W., Uhrova, T., Bernard, T., Betz, S., and Bentivoglio, AR (ORCID:0000-0002-9663-095X)

Abstract

Background: In Huntington's Disease (HD) cognitive decline can occur before unequivocal motor signs become apparent. As cognitive decline often starts early in the course of the disease and has a progressive nature over time, cognition can be regarded as a key target for symptomatic treatment. The specific progressive profile of cognitive decline over time is unknown.Objective: The aim of this study is to quantify the progression of cognitive decline across all HD stages, from pre-motormanifest to advanced HD, and to investigate if CAG length mediates cognitive decline.Methods: In the European REGISTRY study 2669 HD expansion gene carriers underwent annual cognitive assessment. General linear mixed models were used to model the cognitive decline for each cognitive task across all disease stages. Additionally, a model was developed to evaluate the cognitive decline based on CAG length and age rather than disease stage.Results: There was significant cognitive decline on all administered tasks throughout pre-motormanifest (close to estimated disease onset) participants and the subsequent motormanifest participants from stage 1 to stage 4. Performance on the Stroop Word and Stroop Color tests additionally declined significantly across the two pre-motormanifest groups: far and close to estimated disease onset.The evaluation of cognition performance in relation to CAG length and age revealed a more rapid cognitive decline in participants with longer CAG length than participants with shorter CAG length over time.Conclusion: Cognitive performance already shows decline in pre-motormanifest HD gene expansion carriers and gradually worsens to late stage HD. HD gene expansion carriers with certain CAG length have their own cognitive profile, i.e., longer CAG length is associated with more rapid decline. (C) 2017 Elsevier Ltd. All rights reserved.

Published
2017

23. Observing Huntington's Disease: the European Huntington's Disease Network's REGISTRY

Author

Orth, M., Handley, O. J., Schwenke, C., Dunnett, S. B., Craufurd, D., Ho, A. K., Wild, E., Tabrizi, S. J., Landwehrmeyer, G. B., and Investigators of the European Huntington s Disease Network, The

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.

Published
2010

24. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion

Author

Lee, J-M, Ramos, E M, Lee, J-H, Gillis, T, Mysore, J S, Hayden, M R, Warby, S C, Morrison, P, Nance, M, Ross, C A, Margolis, R L, Squitieri, F, Orobello, S, Di Donato, S, Gomez-Tortosa, E, Ayuso, C, Suchowersky, O, Trent, R J A, McCusker, E, Novelletto, A, Frontali, M, Jones, R, Ashizawa, T, Frank, S, Saint-Hilaire, M H, Hersch, S M, Rosas, H D, Lucente, D, Harrison, M B, Zanko, A, Abramson, R K, Marder, K, Sequeiros, J, Paulsen, J S, Landwehrmeyer, G B, Myers, R H, MacDonald, M E, Gusella, J F, Hasholt, Lis Frydenreich, Nørremølle, Anne, Nielsen, Jørgen Erik, Lee, J-M, Ramos, E M, Lee, J-H, Gillis, T, Mysore, J S, Hayden, M R, Warby, S C, Morrison, P, Nance, M, Ross, C A, Margolis, R L, Squitieri, F, Orobello, S, Di Donato, S, Gomez-Tortosa, E, Ayuso, C, Suchowersky, O, Trent, R J A, McCusker, E, Novelletto, A, Frontali, M, Jones, R, Ashizawa, T, Frank, S, Saint-Hilaire, M H, Hersch, S M, Rosas, H D, Lucente, D, Harrison, M B, Zanko, A, Abramson, R K, Marder, K, Sequeiros, J, Paulsen, J S, Landwehrmeyer, G B, Myers, R H, MacDonald, M E, Gusella, J F, Hasholt, Lis Frydenreich, Nørremølle, Anne, and Nielsen, Jørgen Erik

Abstract

Age at onset of diagnostic motor manifestations in Huntington disease (HD) is strongly correlated with an expanded CAG trinucleotide repeat. The length of the normal CAG repeat allele has been reported also to influence age at onset, in interaction with the expanded allele. Due to profound implications for disease mechanism and modification, we tested whether the normal allele, interaction between the expanded and normal alleles, or presence of a second expanded allele affects age at onset of HD motor signs.

Published
2012

25. Observing Huntington's disease:the European Huntington's Disease Network's REGISTRY

Author

Orth, Michael, Handley, O J, Schwenke, C, Dunnett, S, Wild, E J, Tabrizi, S J, Landwehrmeyer, G B, Hasholt, Lis Frydenreich, Hjermind, Lena Elisabeth, Nørremølle, Anne, Nielsen, Jørgen Erik, Orth, Michael, Handley, O J, Schwenke, C, Dunnett, S, Wild, E J, Tabrizi, S J, Landwehrmeyer, G B, Hasholt, Lis Frydenreich, Hjermind, Lena Elisabeth, Nørremølle, Anne, and Nielsen, Jørgen Erik

Published
2011

27. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease

Author

Aziz, N A, Jurgens, C K, Landwehrmeyer, G B, van Roon-Mom, W M C, van Ommen, G J B, Stijnen, T, Roos, R A C, Hasholt, Lis Frydenreich, Aziz, N A, Jurgens, C K, Landwehrmeyer, G B, van Roon-Mom, W M C, van Ommen, G J B, Stijnen, T, Roos, R A C, and Hasholt, Lis Frydenreich

Abstract

Udgivelsesdato: 2009-Oct-20, OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using linear regression and mixed-effects models, the influence of mutant and normal CAG repeat sizes interaction was assessed on 1) age at onset in 921 patients with HD, 2) clinical severity and progression in 512 of these patients with follow-up data available, and 3) basal ganglia volume on magnetic resonance images in 16 premanifest HD mutation carriers. RESULTS: Normal and mutant CAG repeat sizes interacted to influence 1) age at onset (p = 0.001), 2) severity or progression of motor, cognitive, and functional, but not behavioral, symptoms in patients with HD (all p < 0.05), and 3) in premanifest subjects, basal ganglia volumes (p < 0.05). In subjects with mutant CAG expansions in the low range, increasing size of the normal repeat correlated with more severe symptoms and pathology, whereas for those subjects with expansions in the high range, increasing size of the normal repeat correlated with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal and mutant huntingtin (fragments) and needs further elucidation. These findings may have predictive value and are essential for the design and interpretation of future therapeutic trials.

Published
2009

28. The neuroanatomy of subthreshold depressive symptoms in Huntington's disease: a combined diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) study

Author

Sprengelmeyer, R., primary, Orth, M., additional, Müller, H.-P., additional, Wolf, R. C., additional, Grön, G., additional, Depping, M. S., additional, Kassubek, J., additional, Justo, D., additional, Rees, E. M., additional, Haider, S., additional, Cole, J. H., additional, Hobbs, N. Z., additional, Roos, R. A. C., additional, Dürr, A., additional, Tabrizi, S. J., additional, Süssmuth, S. D., additional, and Landwehrmeyer, G. B., additional

Published
2013
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29. N-Methyl-D-Aspartat-Antagonisten induzierten apoptotische Zelluntergänge im Gehirn junger Ratten

Author

Landwehrmeyer, G. B., Hoffmann, G. F., Ikonomidou, H., Miksa, Michael, Landwehrmeyer, G. B., Hoffmann, G. F., Ikonomidou, H., and Miksa, Michael

Abstract

Der wichtigste exzitatorische Neurotransmitter Glutamat spielt eine grosse Rolle in der Gehirnentwicklung, wie neuronale Migration und Synaptogenese. Ob glutamaterge Stimulation für das Überleben entwickelnder Neuronen notwendig ist, war bislang jedoch unbekannt. Um zu untersuchen, ob eine Hemmung von Glutamatrezeptoren im unreifen Gehirn zu Neurodegeneration führt, wurden Ratten im Alter von 1 bis 31 Tagen für 24 Stunden mit dem N-Methyl-D-Aspartat-(NMDA) Glutamatrezeptorantagonisten Dizocilpin (MK801) behandelt. Die Dichte neuronaler Degeneration wurde mikroskopisch in Kupfer-Silber- und TUNEL- gefärbten Hirnschnittpräparaten ermittelt und Unterschiede mittels ANOVA analysiert (Signifikanzniveau p, The predominant excitatory neurotransmitter glutamate plays a major role in certain aspects of neural development. However, whether developing neurons depend on glutamate for survival remains unknown. To investigate if deprivation of glutamate stimulation in the immature mammalian brain causes neuronal cell death (apoptosis), rat pups aged 0 to 30 days were treated for 24 hours with dizocilpine maleate (MK801), an N-methyl-D-aspartate-(NMDA) glutamate receptor antagonist. Density of neural degeneration was evaluated by a stereological dissector method in cupric-silver and TUNEL-stained brain slices. Groups were compared by ANOVA and significance considered at p

Published
2004

30. Tapping linked to function and structure in premanifest and symptomatic Huntington disease

Author

Bechtel, N., primary, Scahill, R. I., additional, Rosas, H. D., additional, Acharya, T., additional, van den Bogaard, S. J. A., additional, Jauffret, C., additional, Say, M. J., additional, Sturrock, A., additional, Johnson, H., additional, Onorato, C. E., additional, Salat, D. H., additional, Durr, A., additional, Leavitt, B. R., additional, Roos, R. A. C., additional, Landwehrmeyer, G. B., additional, Langbehn, D. R., additional, Stout, J. C., additional, Tabrizi, S. J., additional, and Reilmann, R., additional

Published
2010
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32. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

Author

Maier, C., primary, Baron, R., additional, Tölle, T. R., additional, Binder, A., additional, Birbaumer, N., additional, Birklein, F., additional, Gierthmühlen, J., additional, Flor, H., additional, Geber, C., additional, Huge, V., additional, Krumova, E. K., additional, Landwehrmeyer, G. B., additional, Magerl, W., additional, Maihöfner, C., additional, Richter, H., additional, Rolke, R., additional, Scherens, A., additional, Schwarz, A., additional, Sommer, C., additional, Tronnier, V., additional, Üçeyler, N., additional, Valet, M., additional, Wasner, G., additional, and Treede, D.-R., additional

Published
2010
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36. A20 Interaction of huntingtin and the ryanodine receptor

Author

Lindenberg, K S, primary, Davranche, A, additional, Klein, F, additional, Thomas, A V, additional, Lill, C, additional, Lenk, T, additional, Orlando, L R, additional, Kama, J, additional, Young, A B, additional, Landwehrmeyer, G B, additional, and Trottier, Y, additional

Published
2010
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39. Corrigendum to “Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values” [Pain 123 (2006) 231–243]

Author

Rolke, R., primary, Baron, R., additional, Maier, C., additional, Tölle, T. R., additional, Treede, D.-R., additional, Beyer, A., additional, Binder, A., additional, Birbaumer, N., additional, Birklein, F., additional, Bötefür, I. C., additional, Braune, S., additional, Flor, H., additional, Huge, V., additional, Klug, R., additional, Landwehrmeyer, G. B., additional, Magerl, W., additional, Maihöfner, C., additional, Rolko, C., additional, Schaub, C., additional, Scherens, A., additional, Sprenger, T., additional, Valet, M., additional, and Wasserka, B., additional

Published
2006
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40. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values

Author

Rolke, R., primary, Baron, R., additional, Maier, C., additional, Tölle, T. R., additional, Treede, - D. R., additional, Beyer, A., additional, Binder, A., additional, Birbaumer, N., additional, Birklein, F., additional, Bötefür, I. C., additional, Braune, S., additional, Flor, H., additional, Huge, V., additional, Klug, R., additional, Landwehrmeyer, G. B., additional, Magerl, W., additional, Maihöfner, C., additional, Rolko, C., additional, Schaub, C., additional, Scherens, A., additional, Sprenger, T., additional, Valet, M., additional, and Wasserka, B., additional

Published
2006
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42. The Human N-Methyl-d-Aspartate Receptor 2C Subunit: Genomic Analysis, Distribution in Human Brain, and Functional Expression

Author

Daggett, L. P., primary, Johnson, E. C., additional, Varney, M. A., additional, Lin, F.-F., additional, Hess, S. D., additional, Deal, C. R., additional, Jachec, C., additional, Lu, C.-C., additional, Kerner, J. A., additional, Landwehrmeyer, G. B., additional, Standaert, D. G., additional, Young, A. B., additional, Harpold, M. M., additional, and Veliçelebi, G., additional

Published
2002
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43. The neuroanatomy of subthreshold depressive symptoms in Huntington's disease: a combined diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) study.

Author

Sprengelmeyer, R., Orth, M., Müller, H.-P., Wolf, R. C., Grön, G., Depping, M. S., Kassubek, J., Justo, D., Rees, E. M., Haider, S., Cole, J. H., Hobbs, N. Z., Roos, R. A. C., Dürr, A., Tabrizi, S. J., Süssmuth, S. D., and Landwehrmeyer, G. B.

Subjects
MENTAL depression, HUNTINGTON disease, PSYCHOLOGICAL tests, RESEARCH funding, SUICIDE, T-test (Statistics), U-statistics, DATA analysis software
Abstract

BackgroundDepressive symptoms are prominent psychopathological features of Huntington's disease (HD), making a negative impact on social functioning and well-being.MethodWe compared the frequencies of a history of depression, previous suicide attempts and current subthreshold depression between 61 early-stage HD participants and 40 matched controls. The HD group was then split based on the overall HD group's median Hospital Anxiety and Depression Scale-depression score into a group of 30 non-depressed participants (mean 0.8, s.d. = 0.7) and a group of 31 participants with subthreshold depressive symptoms (mean 7.3, s.d. = 3.5) to explore the neuroanatomy underlying subthreshold depressive symptoms in HD using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI).ResultsFrequencies of history of depression, previous suicide attempts or current subthreshold depressive symptoms were higher in HD than in controls. The severity of current depressive symptoms was also higher in HD, but not associated with the severity of HD motor signs or disease burden. Compared with the non-depressed HD group DTI revealed lower fractional anisotropy (FA) values in the frontal cortex, anterior cingulate cortex, insula and cerebellum of the HD group with subthreshold depressive symptoms. In contrast, VBM measures were similar in both HD groups. A history of depression, the severity of HD motor signs or disease burden did not correlate with FA values of these regions.ConclusionsCurrent subthreshold depressive symptoms in early HD are associated with microstructural changes – without concomitant brain volume loss – in brain regions known to be involved in major depressive disorder, but not those typically associated with HD pathology. [ABSTRACT FROM AUTHOR]

Published
2014
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47. [3H]Acetycholine release in rat striatal slices is not subject to dopamine heteroreceptor supersensitivity 30 months after 6-hydroxydopamine lesion of the substantia nigra.

Author

Löschmann, P.-A., De Groote, C., Albrecht, C., Darstein, M., Deransart, C., Landwehrmeyer, G. B., L¨cking, C. H., and Feuerstein, T. J.

Subjects
PARKINSON'S disease, NEUROTRANSMITTERS, NEUROSURGERY, DOPAMINE antagonists, MESSENGER RNA, ACETYLTRANSFERASES
Abstract

Using the rat model of Parkinson's disease described by Ungerstedt the release of [3H]acetylcholine ([3H]ACh) in the caudatoputamen was investigated to assess possible long-term effects of unilateral dopaminergic denervation on the modulation of cholinergic interneurons. This seemed of interest since rats with 6-hydroxydopamine (6-OHDA) lesions of the left substantia nigra showed an increase in the behavioural susceptibility to small doses of dopamine (DA) D2 receptor agonists 30 months after the lesion. Electrical field stimulation with 3 Hz elicited release of [3H]ACh in slices of both the lesioned and the intact striatum. The DA reuptake blocker nomifensine was ineffective on the lesioned side but diminished the release of [3H]ACh in the intact striatum. This inhibition was reversed by the D2 receptor antagonist domperidone and hence probably due to the effect of endogenously released DA. Single electrical pulses at 0.05 Hz, which neither induced autoinhibition of [3H]ACh release nor heteroinhibition by endogenous DA, elicited a higher release of [3H]ACh on the intact side. Under this stimulation paradigm activation of the D2 heteroreceptor with quinpirole depressed the release of [3H]ACh to a similar extent on both sides, irrespective of the absence or presence of the competitive NMDA receptor antagonist D-CPPene. Also blockade of the NMDA receptor channel by dizocilpine, or of AMPA receptors by NBQX, was ineffective on either side. The NMDA-evoked release of [3H]ACh was higher on the lesioned side. It was equally depressed by quinpirole and by ethanol on both sides. Thus, single electrical pulses and NMDA stimulation per se had opposite effects on the lesioned and the intact side, whereas the modulation of release was similar. Since the lesioned striata were considerably smaller, measurements of mRNA levels of choline acetyltransferase (ChAT) were used to assess the density of cholinergic interneurons and their content of ChAT mRNA. This analysis did not reveal any side difference. In conclusion, the function of D2 heteroreceptors on, and the density and ChAT mRNA content of, cholinergic interneurons are not or no longer altered after long-term DA denervation. Most probably, cholinergic interneurons are not involved in the increased behavioural susceptibility of 6-OHDA-lesioned rats to DA agonists. [ABSTRACT FROM AUTHOR]

Published
2001
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48. Changes in NMDA receptor subunit gene expression in the rat brain following withdrawal from forced long-term ethanol intake.

Author

Darstein, M. B., Landwehrmeyer, G. B., and Feuerstein, T. J.

Subjects
GENE expression, GENETIC regulation, MESSENGER RNA, ALCOHOL, ALCOHOLISM, SPASMS
Abstract

Changes in mRNA levels of N-methyl-d-aspartate receptor (NR) subunits were studied in a rat model of withdrawal from forced ethanol ingestion over a period of 8 days. In part, this model may reflect the epsilon-type of human alcoholism according to Jellinek (College University Press, New Haven; 1972). The epsilon-type is characterized by dipsomania over a period of several days, recurring every few months and often followed by ethanol-induced seizures. Seizures may be modulated by an increased glutamatergic neurotransmission to excitatory or inhibitory neurons on the basis of a changed gene expression of NR subunits. This hypothesis promoted the present study. Film autoradiograms and emulsion-coated brain sections following labeling of cholinergic and GABAergic neuron populations were evaluated. NR subunit 1 (NR1) expression, studied with a probe recognizing all NR1 transcripts, was unchanged after withdrawal from chronic ethanol treatment compared to control animals. Using probes specific for different splice segments of NR1, however, we found that, in ethanol-treated rats, the expression of NR1-2 was decreased in all, and that of NR1-4 in all but one, areas investigated (only single label experiments were performed with NR1 splice variants). Withdrawing rats revealed a higher expression of NR subunit 2A (NR2A) mRNA in GABAergic neurons. No changes could be observed at the regional level. Conversely, NR2B mRNA was not substantially altered in cholinergic and GABAergic neurons, but showed a decrease over brain areas. For both, NR2C and NR2D, no ethanol-related changes of mRNA expression were observed. A link between such differential alterations in NR mRNA subunit expression and ethanol-induced seizures in withdrawing alcoholics of the epsilon-type seems possible. [ABSTRACT FROM AUTHOR]

Published
2000
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49. Huntington's disease gene: regional and cellular expression in brain of normal and affected individuals.

Author

Landwehrmeyer, G. Bernhard, McNeil, Sandra M., Dure, Leon S., Ge, Pei, Aizawa, Hitoshi, Huang, Qin, Ambrose, Christine M., Duyao, Mabel P., Bird, Edward D., Bonilla, Ernesto, de Young, Margot, Avila-Gonzales, Alejandro J., Wexler, Nancy S., DiFiglia, Marian, Gusella, James F., MacDonald, Marcy E., Penney, John B., Young, Anne B., Vonsattel, Jean-Paul, and Landwehrmeyer, G B

Published
1995
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50. Normal and mutant HTTinteract to affect clinical severity and progression in Huntington diseaseSYMBOL

Author

Aziz, N A., Jurgens, C K., Landwehrmeyer, G B., Roon-Mom, W M.C. van, Ommen, G J.B. van, Stijnen, T, and Roos, R A.C.

Abstract

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression.

Published
2009
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