Pub Date : 2018-09-13DOI: 10.1136/jnnp-2018-ABN.125
Cleaver Jonathan, R. Shelley, T. Mario, Clatworthy Philip
A 50-year-old female was admitted following a subacute and increasing headache, numbness in both hands and feet, generalised weakness and confusion. An MRI brain revealed an acute left temporal infarct with multi-focal established infarcts. MR angiography demonstrated marked occlusive disease affecting terminal internal carotid artery and both middle cerebral and posterior cerebral arteries, in a potential Moyamoya pattern. Lumbar puncture, extensive blood tests and echocardiography were unremarkable. A skin biopsy showed intimal thickening of the deep dermal arteries compatible with a diagnosis of Sneddon Syndrome. Livedo reticularis was absent and antiphospholipid antibodies negative. Antiplatelet therapy only was commenced given her seronegativity and Moyamoya. Discussion Sneddon syndrome is an uncommon disorder, characterised as generalised livedo reticularis with stroke (Sneddon, 1965). It is an increasingly recognised cause of ischaemic stroke in young adults, however, its clinical course remains poorly defined in the literature (Boesch et al. 2003). It is increasingly associated with Moyamoya syndrome, posing a challenge in terms of anticoagulation in these patients (Fierini et al. 2015). To our knowledge, this is only the second reported case without livedo reticularis (Marianetti et al. 2011) - highlighting the importance of skin biopsy - and the first with this clinical and radiological combination.
一名50岁女性因亚急性和日益加重的头痛、手脚麻木、全身无力和意识不清而入院。脑MRI显示急性左颞梗死伴多灶性梗死。磁共振血管造影显示明显的闭塞性疾病，影响颈内动脉终末和大脑中动脉和大脑后动脉，呈潜在的烟雾型。腰椎穿刺、广泛的血液检查和超声心动图无明显异常。皮肤活检显示真皮深部动脉内膜增厚，符合Sneddon综合征的诊断。网状活线虫不存在，抗磷脂抗体阴性。由于血清阴性和烟雾病，仅开始抗血小板治疗。Sneddon综合征是一种不常见的疾病，其特征为全身性网状肌亢伴中风(Sneddon, 1965)。它越来越被认为是年轻人缺血性中风的原因，然而，其临床过程在文献中仍然定义不清(Boesch et al. 2003)。它越来越多地与烟雾综合征相关，对这些患者的抗凝治疗提出了挑战(Fierini et al. 2015)。据我们所知，这是报告的第二例没有网状活斑的病例(Marianetti et al. 2011)——这突出了皮肤活检的重要性——也是第一例临床和放射学结合的病例。
{"title":"WED 253 An atypical presentation of sneddon syndrome","authors":"Cleaver Jonathan, R. Shelley, T. Mario, Clatworthy Philip","doi":"10.1136/jnnp-2018-ABN.125","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ABN.125","url":null,"abstract":"A 50-year-old female was admitted following a subacute and increasing headache, numbness in both hands and feet, generalised weakness and confusion. An MRI brain revealed an acute left temporal infarct with multi-focal established infarcts. MR angiography demonstrated marked occlusive disease affecting terminal internal carotid artery and both middle cerebral and posterior cerebral arteries, in a potential Moyamoya pattern. Lumbar puncture, extensive blood tests and echocardiography were unremarkable. A skin biopsy showed intimal thickening of the deep dermal arteries compatible with a diagnosis of Sneddon Syndrome. Livedo reticularis was absent and antiphospholipid antibodies negative. Antiplatelet therapy only was commenced given her seronegativity and Moyamoya. Discussion Sneddon syndrome is an uncommon disorder, characterised as generalised livedo reticularis with stroke (Sneddon, 1965). It is an increasingly recognised cause of ischaemic stroke in young adults, however, its clinical course remains poorly defined in the literature (Boesch et al. 2003). It is increasingly associated with Moyamoya syndrome, posing a challenge in terms of anticoagulation in these patients (Fierini et al. 2015). To our knowledge, this is only the second reported case without livedo reticularis (Marianetti et al. 2011) - highlighting the importance of skin biopsy - and the first with this clinical and radiological combination.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"34 1","pages":"A36 - A36"},"PeriodicalIF":0.0,"publicationDate":"2018-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81344638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.55
Stephan Kurat, Á. Horváth, S. Flunkert, H. Nguyen, R. Wronski, B. Hutter-Paier
Background Behavioral changes in Huntington’s disease (HD) are directly associated with the dysfunction and degeneration of certain brain areas, most prominently striatum and cortex. The sole cause of developing HD is the expansion of an unstable repeat of CAG base triplets in the coding region of the Huntingtin gene, HTT. The BACHD rat overexpresses full length human mutant huntingtin with 97 alternating CAA/CAG repeats and is thus a well suited genetic animal model of HD. Aims To analyze homozygous BACHD rats for motor, learning as well as memory deficits and compare data with results of heterozygous BACHD rats who are already well characterized for their behavioral phenotype. Methods Two and five months old homozygous animals were analyzed for motor as well as learning, memory and relearning deficits. Results Our results show motor deficits analyzed with the grip strength test and RotaRod in homozygous BACHD rats at the age of two and five months. Additional analyses in the Barnes maze test showed initial learning, memory and relearning deficits at the age of two months, which were further increased at the age of 5 months. Further analysis in the passive avoidance test revealed emotional learning deficits of 2 months old homozygous BACHD rats. Conclusions Our results show that homozygous BACHD rats present a very early motor and cognitive phenotype. Cognitive deficits already start at the young age of two months and therefore appear much earlier compared to heterozygous BACHD rats. Although homozygous animals need to be further characterized, our data already suggest that homozygous BACHD rats will be of great importance for future HD research. Testing new compounds that influence HD disease progression could be facilitated, since treatment could be significantly shortened compared to heterozygous BACHD rats.
{"title":"B03 Behavioral characterization of homozygous BACHD rats","authors":"Stephan Kurat, Á. Horváth, S. Flunkert, H. Nguyen, R. Wronski, B. Hutter-Paier","doi":"10.1136/jnnp-2018-EHDN.55","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.55","url":null,"abstract":"Background Behavioral changes in Huntington’s disease (HD) are directly associated with the dysfunction and degeneration of certain brain areas, most prominently striatum and cortex. The sole cause of developing HD is the expansion of an unstable repeat of CAG base triplets in the coding region of the Huntingtin gene, HTT. The BACHD rat overexpresses full length human mutant huntingtin with 97 alternating CAA/CAG repeats and is thus a well suited genetic animal model of HD. Aims To analyze homozygous BACHD rats for motor, learning as well as memory deficits and compare data with results of heterozygous BACHD rats who are already well characterized for their behavioral phenotype. Methods Two and five months old homozygous animals were analyzed for motor as well as learning, memory and relearning deficits. Results Our results show motor deficits analyzed with the grip strength test and RotaRod in homozygous BACHD rats at the age of two and five months. Additional analyses in the Barnes maze test showed initial learning, memory and relearning deficits at the age of two months, which were further increased at the age of 5 months. Further analysis in the passive avoidance test revealed emotional learning deficits of 2 months old homozygous BACHD rats. Conclusions Our results show that homozygous BACHD rats present a very early motor and cognitive phenotype. Cognitive deficits already start at the young age of two months and therefore appear much earlier compared to heterozygous BACHD rats. Although homozygous animals need to be further characterized, our data already suggest that homozygous BACHD rats will be of great importance for future HD research. Testing new compounds that influence HD disease progression could be facilitated, since treatment could be significantly shortened compared to heterozygous BACHD rats.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"52 1","pages":"A20 - A21"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73786019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.30
K. Lindenberg, U. Schumann, F. Hummes, G. Landwehrmeyer, J. Steinacker, P. Weydt, E. Calzia, M. Zügel
Metabolic abnormalities and alterations in mitochondrial respiration are described in Huntington’s disease (HD). Since there is great variability concerning disease onset and progression, it is of interest to elucidate the genetic and environmental factors, such as exercise, contributing to this variability. In addition, it is unclear, if mitochondrial dysfunction become evident before onset of neurological manifestation. The aim of this study was to evaluate circulatory, cardiopulmonary and skeletal muscle metabolic responses of HD patients and age-matched controls to acute aerobic exercise. Skeletal muscle biopsies were taken from the M. vastus lateralis at rest and 3 hour after an acute bout of endurance exercise on a cycling ergometer (65% Pmax). The integrated respiratory chain function of the human quadriceps muscle vastus lateralis was measured in freshly taken fine needle biopsies by high-resolution respirometry (HRR). Preliminary results showed that the acute circulatory and skeletal muscle metabolic response to aerobic exercise appears to be blunted in HD patients vs. healthy controls. However, HRR-analysis did not show any changes in mitochondrial respiration before and after exercise comparing healthy controls and HD mutation carriers. Our data show that mitochondrial respiration can be quantified in minimal volume needle biopsies from the M. vastus lateralis of human subjects. This minimal invasive technique can be used to repeat the analysis in short time intervals. In early premanifest HD mutation carriers, mitochondrial respiration and its response to exercise is still unaffected.
{"title":"A32 Metabolic capacity and mitochondrial respiration at rest and after physical exercise in huntington’s disease mutation carriers and healthy controls","authors":"K. Lindenberg, U. Schumann, F. Hummes, G. Landwehrmeyer, J. Steinacker, P. Weydt, E. Calzia, M. Zügel","doi":"10.1136/jnnp-2018-EHDN.30","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.30","url":null,"abstract":"Metabolic abnormalities and alterations in mitochondrial respiration are described in Huntington’s disease (HD). Since there is great variability concerning disease onset and progression, it is of interest to elucidate the genetic and environmental factors, such as exercise, contributing to this variability. In addition, it is unclear, if mitochondrial dysfunction become evident before onset of neurological manifestation. The aim of this study was to evaluate circulatory, cardiopulmonary and skeletal muscle metabolic responses of HD patients and age-matched controls to acute aerobic exercise. Skeletal muscle biopsies were taken from the M. vastus lateralis at rest and 3 hour after an acute bout of endurance exercise on a cycling ergometer (65% Pmax). The integrated respiratory chain function of the human quadriceps muscle vastus lateralis was measured in freshly taken fine needle biopsies by high-resolution respirometry (HRR). Preliminary results showed that the acute circulatory and skeletal muscle metabolic response to aerobic exercise appears to be blunted in HD patients vs. healthy controls. However, HRR-analysis did not show any changes in mitochondrial respiration before and after exercise comparing healthy controls and HD mutation carriers. Our data show that mitochondrial respiration can be quantified in minimal volume needle biopsies from the M. vastus lateralis of human subjects. This minimal invasive technique can be used to repeat the analysis in short time intervals. In early premanifest HD mutation carriers, mitochondrial respiration and its response to exercise is still unaffected.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"6 1","pages":"A11 - A12"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73071417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.49
M. Sjögren, R. Soylu-Kucharz, T. Stan, Unali Dandunna, M. Björkqvist
Background Accumulating evidence suggests altered energy metabolism, with a hyper-catabolic state, as a key feature of Huntington´s disease pathology. Interestingly, it has been suggested that a higher BMI can postpone onset and slow down the progression rate in human HD. The R6/2 mouse model of HD mirrors human HD and in addition to central pathological changes, the mice exhibit progressive weight loss, skeletal muscle atrophy, altered glucose metabolism and body composition, as well as increased oxygen consumption. Ob/Ob mice are leptin deficient; they eat more and have a slower energy metabolism leading to increased body weight and fat mass. An amyotrophic lateral sclerosis (ALS) mouse model on a leptin deficient background has been shown to have normalized energy expenditure, improved motor function, decreased motor neuronal loss as well as enhanced survival, suggesting a slower rate of the disease progression. Aim In this study, we therefore aim to investigate whether a higher BMI and a slower energy metabolism, can affect HD disease progression in the R6/2 mouse model. Methods We generated a novel mouse model, R6/2;Ob/Ob, and evaluated body weight and composition, as well as the effects in central and peripheral target tissues using real-time PCR, histological and stereological analysis. Results Crossing the R6/2 mouse with Ob/Ob mice (R6/2;Ob/Ob mice) results in a dramatic body weight increase compared to R6/2 mice (of both male and female mice). Energy metabolism features, as well as central and peripheral pathology, is currently evaluated. Conclusion Our findings suggest that it is possible to affect energy metabolism features and body weight in R6/2 mice.
{"title":"A51 Genetically altering metabolism by leptin-deficiency affects peripheral disease features in the R6/2 mouse model of huntington´s disease","authors":"M. Sjögren, R. Soylu-Kucharz, T. Stan, Unali Dandunna, M. Björkqvist","doi":"10.1136/jnnp-2018-EHDN.49","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.49","url":null,"abstract":"Background Accumulating evidence suggests altered energy metabolism, with a hyper-catabolic state, as a key feature of Huntington´s disease pathology. Interestingly, it has been suggested that a higher BMI can postpone onset and slow down the progression rate in human HD. The R6/2 mouse model of HD mirrors human HD and in addition to central pathological changes, the mice exhibit progressive weight loss, skeletal muscle atrophy, altered glucose metabolism and body composition, as well as increased oxygen consumption. Ob/Ob mice are leptin deficient; they eat more and have a slower energy metabolism leading to increased body weight and fat mass. An amyotrophic lateral sclerosis (ALS) mouse model on a leptin deficient background has been shown to have normalized energy expenditure, improved motor function, decreased motor neuronal loss as well as enhanced survival, suggesting a slower rate of the disease progression. Aim In this study, we therefore aim to investigate whether a higher BMI and a slower energy metabolism, can affect HD disease progression in the R6/2 mouse model. Methods We generated a novel mouse model, R6/2;Ob/Ob, and evaluated body weight and composition, as well as the effects in central and peripheral target tissues using real-time PCR, histological and stereological analysis. Results Crossing the R6/2 mouse with Ob/Ob mice (R6/2;Ob/Ob mice) results in a dramatic body weight increase compared to R6/2 mice (of both male and female mice). Energy metabolism features, as well as central and peripheral pathology, is currently evaluated. Conclusion Our findings suggest that it is possible to affect energy metabolism features and body weight in R6/2 mice.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"2010 1","pages":"A18 - A18"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73346931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.253
F. Elifani, S. Castaldo, L. Capocci, P. Rosa, Elena Montano, A. Calogero, S. Filosa, S. Crispi, V. Maglione, A. D. Pardo
Background Huntington Disease (HD) has traditionally been described as a disorder purely of the brain, however emerging evidence indicates that peripheral abnormalities are also commonly seen. Among others, unintended body weight loss represents a hallmark of peripheral HD pathology. It correlates with disease progression and significantly affects the quality of life of HD patients. Although the underlying molecular mechanism is still unknown, evidence suggests that body weight loss seems not to be secondary to inadequate nutrition or to chorea, but rather attributable to changes in the metabolism and defective nutrients absorption along the intestinal tract. Curcumin, a naturally occurring polyphenol, has been validated to exert important beneficial effects in a multitude of gastrointestinal dysfunction and neurodegenerative processes similar to those occurring in HD. Although its therapeutic effect in HD is still questionable, recent evidence indicates that curcumin significantly improves neuropathology as well neurochemical and neurobehavioral defects in a mouse model of the disease, however whether it may be suited to be developed to treat gastrointestinal dysfunction in the disease is not clear yet. Aim In this study, we aimed to investigate the potential beneficial effects that the chronic administration of curcumin may have on gastrointestinal dysfunction commonly occurring in R6/2 mice as the disease progresses. Method Curcumin along with bioperine (bioavailability enhancing-agent) was orally administered to females 10 days before pregnancy and during the entire gestation period up to the end of lactation. Starting from the third week of age, pups were daily treated with 40 mg/kg curcumin for 7 weeks. KCl-induced contraction was evaluated in isolated intestinal tract from both curcumin and vehicle-treated mice. Results Our preliminary data demonstrate that chronic administration of curcumin is safe and well tolerated in R6/2 mice. It prevents the gradual weight loss despite no changes in food intake were observed. From the functional point of view, curcumin considerably ameliorates the intestinal phenotype and restores the normal intestinal reactivity compared to untreated R6/2 mice.
{"title":"I17 Curcumin-supplemented diet preserves body weight and ameliorates intestinal functionality in R6/2 mice","authors":"F. Elifani, S. Castaldo, L. Capocci, P. Rosa, Elena Montano, A. Calogero, S. Filosa, S. Crispi, V. Maglione, A. D. Pardo","doi":"10.1136/jnnp-2018-EHDN.253","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.253","url":null,"abstract":"Background Huntington Disease (HD) has traditionally been described as a disorder purely of the brain, however emerging evidence indicates that peripheral abnormalities are also commonly seen. Among others, unintended body weight loss represents a hallmark of peripheral HD pathology. It correlates with disease progression and significantly affects the quality of life of HD patients. Although the underlying molecular mechanism is still unknown, evidence suggests that body weight loss seems not to be secondary to inadequate nutrition or to chorea, but rather attributable to changes in the metabolism and defective nutrients absorption along the intestinal tract. Curcumin, a naturally occurring polyphenol, has been validated to exert important beneficial effects in a multitude of gastrointestinal dysfunction and neurodegenerative processes similar to those occurring in HD. Although its therapeutic effect in HD is still questionable, recent evidence indicates that curcumin significantly improves neuropathology as well neurochemical and neurobehavioral defects in a mouse model of the disease, however whether it may be suited to be developed to treat gastrointestinal dysfunction in the disease is not clear yet. Aim In this study, we aimed to investigate the potential beneficial effects that the chronic administration of curcumin may have on gastrointestinal dysfunction commonly occurring in R6/2 mice as the disease progresses. Method Curcumin along with bioperine (bioavailability enhancing-agent) was orally administered to females 10 days before pregnancy and during the entire gestation period up to the end of lactation. Starting from the third week of age, pups were daily treated with 40 mg/kg curcumin for 7 weeks. KCl-induced contraction was evaluated in isolated intestinal tract from both curcumin and vehicle-treated mice. Results Our preliminary data demonstrate that chronic administration of curcumin is safe and well tolerated in R6/2 mice. It prevents the gradual weight loss despite no changes in food intake were observed. From the functional point of view, curcumin considerably ameliorates the intestinal phenotype and restores the normal intestinal reactivity compared to untreated R6/2 mice.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"38 1","pages":"A94 - A95"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73864770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.267
S. Bohlen, I. Paty, M. Volteau, I. Meyer, W. Rein, C. Kosinski, R. Reilmann
Background Preclinical research indicates that BN82451B has potential to interfere with excitotoxicity, and possesses antioxidant, anti-inflammatory, and mitochondrial protection properties. In-vivo studies in tgHD mice suggested neuroprotective and antidyskinetic effects. Aims The safety and tolerability of BN82451B was tested in Huntington’s Disease (HD) alongside exploratory efficacy with a focus on motor symptoms. Methods This 4-week, randomized, placebo-controlled, double-blind, in-patient, proof-of-concept study explored escalating doses (40 – 80 mg BID) of BN82451B in symptomatic HD subjects. Primary objective was safety and tolerability, secondary objectives were motor symptoms assessed by Q-Motor and the UHDRS-TMS. Results A total of 30 subjects were planned to be included, but the study was terminated after inclusion of 17 subjects (14 BN82451B/3 placebo). Recruitment in this study was complicated by an obligatory in-patient setting at a phase-1 research-unit for four weeks. There were no severe safety issues, but 6 of the 14 treated subjects (43%) developed cutaneous adverse events (rash) which led to discontinuation of treatment in 3 cases and resolved after discontinuation of treatment in all 6 cases. Another 2 subjects were withdrawn due to nausea and vomiting. BN82451B treatment did not differentiate from placebo in the exploratory outcome variables. While placebo subjects showed a mean improvement in the UHDRS-TMS, Q-Motor measures indicated no change in the placebo group. However, mean Q-Motor changes of BN82451B treated patients suggested a none-significant deterioration of motor performance while on drug, which reverted after drug discontinuation. Conclusions BN82451B induced skin rash in 43% of exposed patients and increased nausea/vomiting. Exploratory analysis did suggest a potential for deterioration of motor symptoms in HD subjects under treatment. Q-Motor measures showed much less variance and no placebo response in repeated assessments compared to the UHDRS-TMS. It was decided to discontinue the study.
{"title":"J07 What can we learn from a phase ii study with BN82451B in hd beyond safety and tolerability – clinical versus objective motor measures","authors":"S. Bohlen, I. Paty, M. Volteau, I. Meyer, W. Rein, C. Kosinski, R. Reilmann","doi":"10.1136/jnnp-2018-EHDN.267","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.267","url":null,"abstract":"Background Preclinical research indicates that BN82451B has potential to interfere with excitotoxicity, and possesses antioxidant, anti-inflammatory, and mitochondrial protection properties. In-vivo studies in tgHD mice suggested neuroprotective and antidyskinetic effects. Aims The safety and tolerability of BN82451B was tested in Huntington’s Disease (HD) alongside exploratory efficacy with a focus on motor symptoms. Methods This 4-week, randomized, placebo-controlled, double-blind, in-patient, proof-of-concept study explored escalating doses (40 – 80 mg BID) of BN82451B in symptomatic HD subjects. Primary objective was safety and tolerability, secondary objectives were motor symptoms assessed by Q-Motor and the UHDRS-TMS. Results A total of 30 subjects were planned to be included, but the study was terminated after inclusion of 17 subjects (14 BN82451B/3 placebo). Recruitment in this study was complicated by an obligatory in-patient setting at a phase-1 research-unit for four weeks. There were no severe safety issues, but 6 of the 14 treated subjects (43%) developed cutaneous adverse events (rash) which led to discontinuation of treatment in 3 cases and resolved after discontinuation of treatment in all 6 cases. Another 2 subjects were withdrawn due to nausea and vomiting. BN82451B treatment did not differentiate from placebo in the exploratory outcome variables. While placebo subjects showed a mean improvement in the UHDRS-TMS, Q-Motor measures indicated no change in the placebo group. However, mean Q-Motor changes of BN82451B treated patients suggested a none-significant deterioration of motor performance while on drug, which reverted after drug discontinuation. Conclusions BN82451B induced skin rash in 43% of exposed patients and increased nausea/vomiting. Exploratory analysis did suggest a potential for deterioration of motor symptoms in HD subjects under treatment. Q-Motor measures showed much less variance and no placebo response in repeated assessments compared to the UHDRS-TMS. It was decided to discontinue the study.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"46 1","pages":"A100 - A100"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74333103","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/JNNP-2018-EHDN.173
M. Dema, C. Borrelli, S. Migliore, C. Fusilli, Sabrina Maffi, I. Santimone, M. Gabriele, Loris Belcastro, B. D’Alessio, F. Squitieri
Background LIRH Foundation started to collect data from HD subjects and families since 2001. The collection includes data from LIRH archives, REGISTRY (since 2004) and ENROLL-HD (since 2014) data. Aims To develop a large HD database starting from ENROLL-HD data. Methods The database was constructed through shiny, plyr and DT R packages (R 3.4.4 version) for automatically merging different clinical items. Results Since July 2014, we recruited 626 people into ENROLL-HD, until May 2018. Follow-ups are available for 432 subjects (one-year), 268 (two-years) and 152 (three years). Our cohort includes 404 gene positive (346 patients and 58 pre-manifest) individuals, 153 genetically ‘unknown’ (50% at risk), 36 gene negative and 43 family member subjects. Mean age at onset is 47,6±14,7 (range 7–86), thus including adolescent (<20 years, N=15 subjects), children (<10 years; N=5 subjects) and late onset (>60 years; N=35 subjects) cohorts. Onset symptoms includes motors signs in 47,9%, mixed in 34,9%, psychiatric in 15.6% and cognitive in 1.5% cases. Suicide ideation occurred in 17,4%, calculated according to the C-SSRS scale activation. Mean, fully penetrant expanded repeat number is 44,4±5,06 (range 40–84); two 2 subjects have intermediate alleles (29,5±0,7; range 29–30), and 23 reduced penetrance (38,2±0,8; range 36–39). Disease stage, according to the TFC scale score (9,7±3,9; range 1–13), ranges between 1 to 5. Conclusions A proper database and stratification of HD subjects according to genetic condition, symptom presentation, mutation length and development of further symptoms is crucial for both improving the disease knowledge and to driving people to research plans.
{"title":"F75 A huntington’s disease (HD) database at lirh foundation (LIRH-rome site): enroll-hd study as a starting point","authors":"M. Dema, C. Borrelli, S. Migliore, C. Fusilli, Sabrina Maffi, I. Santimone, M. Gabriele, Loris Belcastro, B. D’Alessio, F. Squitieri","doi":"10.1136/JNNP-2018-EHDN.173","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.173","url":null,"abstract":"Background LIRH Foundation started to collect data from HD subjects and families since 2001. The collection includes data from LIRH archives, REGISTRY (since 2004) and ENROLL-HD (since 2014) data. Aims To develop a large HD database starting from ENROLL-HD data. Methods The database was constructed through shiny, plyr and DT R packages (R 3.4.4 version) for automatically merging different clinical items. Results Since July 2014, we recruited 626 people into ENROLL-HD, until May 2018. Follow-ups are available for 432 subjects (one-year), 268 (two-years) and 152 (three years). Our cohort includes 404 gene positive (346 patients and 58 pre-manifest) individuals, 153 genetically ‘unknown’ (50% at risk), 36 gene negative and 43 family member subjects. Mean age at onset is 47,6±14,7 (range 7–86), thus including adolescent (<20 years, N=15 subjects), children (<10 years; N=5 subjects) and late onset (>60 years; N=35 subjects) cohorts. Onset symptoms includes motors signs in 47,9%, mixed in 34,9%, psychiatric in 15.6% and cognitive in 1.5% cases. Suicide ideation occurred in 17,4%, calculated according to the C-SSRS scale activation. Mean, fully penetrant expanded repeat number is 44,4±5,06 (range 40–84); two 2 subjects have intermediate alleles (29,5±0,7; range 29–30), and 23 reduced penetrance (38,2±0,8; range 36–39). Disease stage, according to the TFC scale score (9,7±3,9; range 1–13), ranges between 1 to 5. Conclusions A proper database and stratification of HD subjects according to genetic condition, symptom presentation, mutation length and development of further symptoms is crucial for both improving the disease knowledge and to driving people to research plans.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"9 1","pages":"A65 - A65"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78923588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.272
M. Papoutsi, Joerg Magerkurth, O. Josephs, Sophia E. Pépés, Temi Ibitoye, R. Reilmann, N. Weiskopf, D. Langbehn, G. Rees, S. Tabrizi
Background and aims Methods that can normalize neuronal function, such as neurofeedback (NF) training, could support symptom management in HD as primary or adjunct treatments to other disease-modifying therapies. During NF training, participants receive feedback on the activity of a target brain region and learn by trial and error to regulate it. The aim of the present study was to test whether HD patients can learn to regulate their brain activity using NF training and to compare two different NF training protocols to establish which one is more effective. Methods Thirty-two HD patients completed a real-time fMRI NF training paradigm consisting of 4 training visits (4–14 days apart). Half of the participants received feedback derived from their own brain activity measured using BOLD contrast fMRI (treatment group), while the other half received sham feedback derived from unrelated participants in the treatment group (control group). Participants were further divided in two subgroups, one receiving neurofeedback derived from the Supplementary Motor Area (SMA), and another receiving neurofeedback based on the cross-correlation of SMA and left striatum activity (a measure of connectivity). Participants were blinded to group allocation. Results To evaluate successful learning, we tested for a linear increase in participants’ ability to enhance fMRI activity/connectivity voluntarily across visits. Participants in the SMA-activity NF group were the only group that showed a linear increase across visits. We also evaluated participants’ capacity to upregulate their brain activity after the end of training in the absence of explicit feedback (transfer effects). The SMA-activity NF group was again the only group that showed successful upregulation. Conclusions Our results suggest that SMA-activity NF training is a more promising approach than connectivity-based NF training. Future larger trials focusing only on activity-based NF training, are now needed to enable us to gather more evidence on the efficacy of the method in symptom-management in HD.
{"title":"J12 HD brain-train: enhancing neural plasticity using real-time FMRI neurofeedback training","authors":"M. Papoutsi, Joerg Magerkurth, O. Josephs, Sophia E. Pépés, Temi Ibitoye, R. Reilmann, N. Weiskopf, D. Langbehn, G. Rees, S. Tabrizi","doi":"10.1136/jnnp-2018-EHDN.272","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.272","url":null,"abstract":"Background and aims Methods that can normalize neuronal function, such as neurofeedback (NF) training, could support symptom management in HD as primary or adjunct treatments to other disease-modifying therapies. During NF training, participants receive feedback on the activity of a target brain region and learn by trial and error to regulate it. The aim of the present study was to test whether HD patients can learn to regulate their brain activity using NF training and to compare two different NF training protocols to establish which one is more effective. Methods Thirty-two HD patients completed a real-time fMRI NF training paradigm consisting of 4 training visits (4–14 days apart). Half of the participants received feedback derived from their own brain activity measured using BOLD contrast fMRI (treatment group), while the other half received sham feedback derived from unrelated participants in the treatment group (control group). Participants were further divided in two subgroups, one receiving neurofeedback derived from the Supplementary Motor Area (SMA), and another receiving neurofeedback based on the cross-correlation of SMA and left striatum activity (a measure of connectivity). Participants were blinded to group allocation. Results To evaluate successful learning, we tested for a linear increase in participants’ ability to enhance fMRI activity/connectivity voluntarily across visits. Participants in the SMA-activity NF group were the only group that showed a linear increase across visits. We also evaluated participants’ capacity to upregulate their brain activity after the end of training in the absence of explicit feedback (transfer effects). The SMA-activity NF group was again the only group that showed successful upregulation. Conclusions Our results suggest that SMA-activity NF training is a more promising approach than connectivity-based NF training. Future larger trials focusing only on activity-based NF training, are now needed to enable us to gather more evidence on the efficacy of the method in symptom-management in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"17 1","pages":"A102 - A102"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78410950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/JNNP-2018-EHDN.175
C. Goldsmith, K. Boycott
Background The protocol for HD predictive testing at our Centre includes a psychosocial assessment as step 2 of a 3-step process. In future, this resource may not be available. Aims To review our experience with our HD predictive testing protocol. Methods We performed a 5-year review of patients referred for pre-symptomatic testing for HD and solicited feedback from 10 recent patients. Results/outcome A total of 104 individuals at 50% risk requested predictive testing for HD. The majority (87; 84%) completed the protocol and received results. Almost all agreed to meet a neuropsychiatrist and none were flagged as poor candidates for predictive testing. Of the 17 that did not complete the protocol, 13 (76.5%) discontinued after the first session with the genetic counsellor, 2 never returned for results, 1 stopped after blood test, and 1 saw neuropsychiatrist but never had blood drawn. Conversations with the 10 most recent patients revealed that most felt the process worked well. Wait-time for results was the only complaint. Opinions differed regarding the helpfulness of neuropsychiatric consultation and few patients opted to access neuropsychiatry after the protocol was complete. Conclusions Assessing readiness is essential to HD predictive testing, as is psychological support after testing. Feedback from our patients was mixed with regard to usefulness of meeting with neuropsychiatrist. The significant number of patients (12.5%) who did not continue with the protocol after first session with the genetic counsellor vs the small number (3%) who did so after the neuropsychiatric evaluation, suggests the majority of patients are making decisions very early on in the protocol.
{"title":"G01 Huntington disease predictive testing protocol: a 5 year review of practice","authors":"C. Goldsmith, K. Boycott","doi":"10.1136/JNNP-2018-EHDN.175","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.175","url":null,"abstract":"Background The protocol for HD predictive testing at our Centre includes a psychosocial assessment as step 2 of a 3-step process. In future, this resource may not be available. Aims To review our experience with our HD predictive testing protocol. Methods We performed a 5-year review of patients referred for pre-symptomatic testing for HD and solicited feedback from 10 recent patients. Results/outcome A total of 104 individuals at 50% risk requested predictive testing for HD. The majority (87; 84%) completed the protocol and received results. Almost all agreed to meet a neuropsychiatrist and none were flagged as poor candidates for predictive testing. Of the 17 that did not complete the protocol, 13 (76.5%) discontinued after the first session with the genetic counsellor, 2 never returned for results, 1 stopped after blood test, and 1 saw neuropsychiatrist but never had blood drawn. Conversations with the 10 most recent patients revealed that most felt the process worked well. Wait-time for results was the only complaint. Opinions differed regarding the helpfulness of neuropsychiatric consultation and few patients opted to access neuropsychiatry after the protocol was complete. Conclusions Assessing readiness is essential to HD predictive testing, as is psychological support after testing. Feedback from our patients was mixed with regard to usefulness of meeting with neuropsychiatrist. The significant number of patients (12.5%) who did not continue with the protocol after first session with the genetic counsellor vs the small number (3%) who did so after the neuropsychiatric evaluation, suggests the majority of patients are making decisions very early on in the protocol.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"32 1","pages":"A66 - A66"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78037672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.146
Shani C. Missner, K. Anderson
Background Psychiatric morbidity is part of HD and patients experience a range of disorders and symptoms. Family members, both those at risk and not at risk, also experience psychiatric distress. The treatment of psychiatric disturbances is an essential part of HD care. Aim The overall prevalence of psychiatric morbidity in the HD community was assessed to inform clinicians about the need for support and treatment. Methods Data were analyzed from 140 participants of the Medstar Georgetown University Hospital Enroll-HD registry. Participants were categorized as family controls, genotype unknown, premanifest HD, and manifest HD. The overall prevalence of psychiatric morbidity was the summation of the presence of moderate symptoms on Problem Behaviours Assessment – Short (PBA–S), defined as a score of 4 or greater (severity × frequency), plus comorbid psychiatric history. Results Demographic data showed gender and years of education were distributed equally between groups. Family controls were the oldest in age, whereas employment rate was lowest in manifest HD. PBA-S revealed the presence of psychiatric symptoms in family control 48%, genotype unknown 74%, premanifest HD 42% and manifest HD 80%. For participants that did not meet criteria of moderate symptoms on PBA-S, there was a history of comorbid psychiatric diagnoses in the family control 19%, genotype unknown 21%, premanifest HD 25% and manifest HD 16%. The most common comorbid psychiatric diagnoses were depressive disorders and anxiety disorders. The total prevalence of active psychiatric symptoms and comorbid psychiatric history was 66% for the family controls, 95% for genotype unknown, 67% for premanifest HD, and 96% for manifest HD; these were statistically significant (p <0.05). Many of the participants were receiving psychotherapeutic interventions consisting of psychopharmacology and psychotherapy. Conclusions HD families experience psychiatric symptoms and diagnosed psychiatric disorders. Though psychiatric morbidity is recognized, diagnosed, and treated in many HD families, the high prevalence of mental health disturbances speaks to the need for support and treatment.
精神疾病是HD的一部分，患者会经历一系列的疾病和症状。家庭成员，无论是有风险的还是没有风险的，也会经历精神上的痛苦。精神障碍的治疗是HD护理的重要组成部分。目的评估HD社区精神疾病的总体患病率，告知临床医生需要支持和治疗。方法对Medstar Georgetown University Hospital enrollment - hd注册的140名参与者的数据进行分析。参与者分为家族对照、基因型未知、先兆HD和显性HD。精神疾病的总体患病率是在问题行为评估-短(PBA-S)中出现的中度症状的总和，定义为4分或更高(严重程度×频率)，加上共病精神病史。结果人口统计数据显示各组间性别和受教育年限分布均匀。家庭控制组年龄最大，就业率最低。PBA-S显示，家族对照组中有精神症状者占48%，基因型未知者占74%，先兆HD者占42%，显性HD者占80%。对于不符合PBA-S中度症状标准的参与者，在家族对照组中有19%的共病精神诊断史，基因型未知的21%，表现前HD的25%和表现HD的16%。最常见的精神疾病共病诊断为抑郁症和焦虑症。活跃精神症状和共病精神病史的总患病率在家族对照组中为66%，基因型未知组为95%，表现前HD组为67%，表现HD组为96%;差异均有统计学意义(p <0.05)。许多参与者正在接受包括精神药理学和心理治疗在内的心理治疗干预。结论HD家庭有精神症状，诊断为精神障碍。虽然在许多HD家庭中，精神疾病的发病率得到了承认、诊断和治疗，但精神健康障碍的高患病率表明需要支持和治疗。
{"title":"F42 Prevalence of psychiatric morbidity in the huntington’s disease community","authors":"Shani C. Missner, K. Anderson","doi":"10.1136/jnnp-2018-EHDN.146","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.146","url":null,"abstract":"Background Psychiatric morbidity is part of HD and patients experience a range of disorders and symptoms. Family members, both those at risk and not at risk, also experience psychiatric distress. The treatment of psychiatric disturbances is an essential part of HD care. Aim The overall prevalence of psychiatric morbidity in the HD community was assessed to inform clinicians about the need for support and treatment. Methods Data were analyzed from 140 participants of the Medstar Georgetown University Hospital Enroll-HD registry. Participants were categorized as family controls, genotype unknown, premanifest HD, and manifest HD. The overall prevalence of psychiatric morbidity was the summation of the presence of moderate symptoms on Problem Behaviours Assessment – Short (PBA–S), defined as a score of 4 or greater (severity × frequency), plus comorbid psychiatric history. Results Demographic data showed gender and years of education were distributed equally between groups. Family controls were the oldest in age, whereas employment rate was lowest in manifest HD. PBA-S revealed the presence of psychiatric symptoms in family control 48%, genotype unknown 74%, premanifest HD 42% and manifest HD 80%. For participants that did not meet criteria of moderate symptoms on PBA-S, there was a history of comorbid psychiatric diagnoses in the family control 19%, genotype unknown 21%, premanifest HD 25% and manifest HD 16%. The most common comorbid psychiatric diagnoses were depressive disorders and anxiety disorders. The total prevalence of active psychiatric symptoms and comorbid psychiatric history was 66% for the family controls, 95% for genotype unknown, 67% for premanifest HD, and 96% for manifest HD; these were statistically significant (p <0.05). Many of the participants were receiving psychotherapeutic interventions consisting of psychopharmacology and psychotherapy. Conclusions HD families experience psychiatric symptoms and diagnosed psychiatric disorders. Though psychiatric morbidity is recognized, diagnosed, and treated in many HD families, the high prevalence of mental health disturbances speaks to the need for support and treatment.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"46 1","pages":"A55 - A55"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85863554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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