Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.124
R. Walker, M. Miranda, H. Jung, A. Danek
Background and aims Chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS), the two core neuroacanthocytosis syndromes, are progressive neurodegenerative conditions which underlie a wide spectrum of Huntington Disease-like neurological presentations. To date there are no data regarding life expectancy and causes of death in these rare disorders. Identifying causes of mortality is valuable for disease management and ultimately for clinical trials. Methods We reviewed our personal databases and the published literature to identify cases of ChAc and MLS for whom adequate information was available regarding age of disease onset, age at death, cause of death, and clinical information such as presence of seizures or cardiac disease. Results Adequate information was obtained on 55 patients with ChAc and 30 with McLeod syndrome. Causes of death included pneumonia, cardiac disease, seizure, suicide, and sepsis. Mean disease duration for ChAc was 11 years, while for McLeod syndrome it was 20 years. Conclusions Causes of death in ChAc and McLeod syndrome are similar to those in Huntington’s disease, with additional risks due to the presence of seizures and cardiac disease. Suicidality was seen in 10% of patients with ChAc. Sudden unexplained deaths were frequently seeen. In the absence of disease-modifying agents, disease management should focus upon treating symptoms which may contribute to morbidity and mortality.
{"title":"F20 Life expectancy and mortality in neuroacanthocytosis","authors":"R. Walker, M. Miranda, H. Jung, A. Danek","doi":"10.1136/jnnp-2018-EHDN.124","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.124","url":null,"abstract":"Background and aims Chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS), the two core neuroacanthocytosis syndromes, are progressive neurodegenerative conditions which underlie a wide spectrum of Huntington Disease-like neurological presentations. To date there are no data regarding life expectancy and causes of death in these rare disorders. Identifying causes of mortality is valuable for disease management and ultimately for clinical trials. Methods We reviewed our personal databases and the published literature to identify cases of ChAc and MLS for whom adequate information was available regarding age of disease onset, age at death, cause of death, and clinical information such as presence of seizures or cardiac disease. Results Adequate information was obtained on 55 patients with ChAc and 30 with McLeod syndrome. Causes of death included pneumonia, cardiac disease, seizure, suicide, and sepsis. Mean disease duration for ChAc was 11 years, while for McLeod syndrome it was 20 years. Conclusions Causes of death in ChAc and McLeod syndrome are similar to those in Huntington’s disease, with additional risks due to the presence of seizures and cardiac disease. Suicidality was seen in 10% of patients with ChAc. Sudden unexplained deaths were frequently seeen. In the absence of disease-modifying agents, disease management should focus upon treating symptoms which may contribute to morbidity and mortality.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"22 1","pages":"A46 - A47"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77793336","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.16
H. Kampinga
Huntington’s disease is driven by protein aggregation related to the polyglutamine expansion, although the precise entities that cause toxicity are still a matter of debate. It is likely that these aggregates have dominant toxic effects through multiple, likely parallel acting and self-perpetuating mechanisms, including multi-organellar damage and a progressive decline in protein quality control. A very early event seen in many Huntington models (and well as many other aggregation diseases) is a collapse of nuclear pore complexes, resulting in defects in nucleocytoplasmic trafficking (Grima et al., Neuron 94 (2017) 93). One possible way to counteract the downstream effects of mutant huntingtin aggregation is to increase selective components of the protein quality control system in cells that can prevent the amyloidogenesis process. In a screen done some years ago, we identified that up-regulation of the Hsp70 co-chaperone DNAJB6 can powerfully suppress mutant huntington aggregation (Hageman et al., Mol Cell. 37 (2010) 355) and delay disease onset in the R6/2 huntington mouse model (Kakkar et al., Mol Cell 62 (2016)272). Our recent data now link DNAJB6 expression not only to neuronal hypersensitivity to polyglutamine aggregation, but also show that DNAJB6 is crucial for physiological maintenance of nuclear pore integrity function.
{"title":"A17 Chaperone biology and huntington aggregation","authors":"H. Kampinga","doi":"10.1136/jnnp-2018-EHDN.16","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.16","url":null,"abstract":"Huntington’s disease is driven by protein aggregation related to the polyglutamine expansion, although the precise entities that cause toxicity are still a matter of debate. It is likely that these aggregates have dominant toxic effects through multiple, likely parallel acting and self-perpetuating mechanisms, including multi-organellar damage and a progressive decline in protein quality control. A very early event seen in many Huntington models (and well as many other aggregation diseases) is a collapse of nuclear pore complexes, resulting in defects in nucleocytoplasmic trafficking (Grima et al., Neuron 94 (2017) 93). One possible way to counteract the downstream effects of mutant huntingtin aggregation is to increase selective components of the protein quality control system in cells that can prevent the amyloidogenesis process. In a screen done some years ago, we identified that up-regulation of the Hsp70 co-chaperone DNAJB6 can powerfully suppress mutant huntington aggregation (Hageman et al., Mol Cell. 37 (2010) 355) and delay disease onset in the R6/2 huntington mouse model (Kakkar et al., Mol Cell 62 (2016)272). Our recent data now link DNAJB6 expression not only to neuronal hypersensitivity to polyglutamine aggregation, but also show that DNAJB6 is crucial for physiological maintenance of nuclear pore integrity function.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"47 1","pages":"A6 - A6"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78414945","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.198
A. Mühlbäck, N. Hofstetter, K. Mühlbäck, A. Arnesen, E. Meijer, J. Klempr
Background Huntington disease (HD) is an incurable and devastating neurogenerative disease. Patients, family members and caregivers are often in need of information on HD. Although nowadays, the access to various information about HD via literature and virtual media, mostly internet, seems to be unlimited, it is important to consider that single information without basic content may be misunderstood or interpreted in an improper way. Persons in geographically isolated or less developed areas – away from centers of expertise or due to personal limitations to visit the center of expertise (no ability to drive, limited infrastructure, isolation, no social integration) may experience problems to reach professionals to obtain proper information. Methods Therefore, the European Huntington Association (EHA) launched in December 2016 a pilot project on the patient online service ‘Ask The Doctor’ that provides accurate information about HD to individual persons at the level and in the language of the user in a very confidential way. Within the project, so far 65 requests were received via an online form. Most users provide information on the country of origin, stating 15 different countries. The service communicates mostly in English, upon request of the user communication is as well done in different languages. Results The service provides needs based solutions under consideration of the individual’s resources and tries to obtain long term solutions for individuals by providing contacts in the country of origin, if required. It works with local patient’s associations, being fully an advisory service without providing any online therapy. The service ‘Ask The Doctor’ presents the results annually at the board meeting of the EHA. The EHA plans to introduce a survey obtaining information on the satisfaction level of users. Conclusion There is a significant need for such kind of service, in particular in even more languages than now.
{"title":"H19 ‘ask the doctor’ of the european huntington association (EHA) – a pilot project on online patients advisory service","authors":"A. Mühlbäck, N. Hofstetter, K. Mühlbäck, A. Arnesen, E. Meijer, J. Klempr","doi":"10.1136/JNNP-2018-EHDN.198","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.198","url":null,"abstract":"Background Huntington disease (HD) is an incurable and devastating neurogenerative disease. Patients, family members and caregivers are often in need of information on HD. Although nowadays, the access to various information about HD via literature and virtual media, mostly internet, seems to be unlimited, it is important to consider that single information without basic content may be misunderstood or interpreted in an improper way. Persons in geographically isolated or less developed areas – away from centers of expertise or due to personal limitations to visit the center of expertise (no ability to drive, limited infrastructure, isolation, no social integration) may experience problems to reach professionals to obtain proper information. Methods Therefore, the European Huntington Association (EHA) launched in December 2016 a pilot project on the patient online service ‘Ask The Doctor’ that provides accurate information about HD to individual persons at the level and in the language of the user in a very confidential way. Within the project, so far 65 requests were received via an online form. Most users provide information on the country of origin, stating 15 different countries. The service communicates mostly in English, upon request of the user communication is as well done in different languages. Results The service provides needs based solutions under consideration of the individual’s resources and tries to obtain long term solutions for individuals by providing contacts in the country of origin, if required. It works with local patient’s associations, being fully an advisory service without providing any online therapy. The service ‘Ask The Doctor’ presents the results annually at the board meeting of the EHA. The EHA plans to introduce a survey obtaining information on the satisfaction level of users. Conclusion There is a significant need for such kind of service, in particular in even more languages than now.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"15 1","pages":"A74 - A74"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83446925","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.72
M. Ciosi, Alastair Maxwell, S. Cumming, D. H. Moss, A. Alshammari, M. Flower, A. Durr, B. Leavitt, R. Roos, P. Holmans, L. Jones, D. Langbehn, S. Kwak, S. Tabrizi, D. Monckton
Background Huntington disease (HD) is caused by the expansion of a polyglutamine encoding CAG repeat in exon 1 of the HTT gene. Affected individuals inherit ≥40 repeats and longer alleles are associated with earlier onset and higher HD severity. The HTT CAG repeat is genetically unstable in both the germline and soma. Somatic mosaicism is dependent on the number of CAG repeats and age, and is expansion biased and cell-type specific. Recent genome-wide association studies (GWAS) have identified components of the DNA repair system as trans¬-acting modifiers of HD severity, some of which are known to modify somatic instability of the HTT CAG repeat in HD mouse models. We thus hypothesise that the trans¬-acting modifiers identified by GWAS affect HD severity by their direct effect on HTT CAG somatic instability. Aims Determine the exact trinucleotide structure of the HTT exon 1 repeat and quantify its somatic mosaicism to investigate their association with HD severity. Methods/techniques Using genotyping-by-sequencing, we determined the exact genotype of the polyglutamine and polyproline encoding repeats in HTT exon 1 and quantified the somatic mosaicism associated with the CAG repeat in blood DNA from 807 HD expansion carriers. Results/outcome The sequence encoding the HTT polyglutamine and polyproline tract has an atypical structure in ˜8% of the non-HD-causing alleles and ˜3% of the HD-causing alleles, differing from the typical structure by the number of glutamine encoding CAA codons and/or the number of proline encoding CCA and CCT codons. Multiple linear regression analysis revealed that the number of CAA codons is negatively correlated with HD severity and that the number of CAG repeats is a better predictor of HD severity (r2=0.559) than the number of glutamines (r2=0.537). Moreover, somatic mosaicism in blood correlates with HD severity (r2 ≥0.014, p≤2.5 × 10–3) and some of the polymorphisms associated with HD severity (p=1.5 × 10–5 for FAN1 rs3512, p=1.8 × 10–4 for MLH3 rs175080, p=3.6 × 10–3 for MLH1 rs1799977 and p=0.016 for MSH3 rs1382539). Conclusion Our data show that atypical HD-causing alleles have major implications for genetic diagnosis and counselling and confirm the correlation of somatic expansion with HD severity. The latter further supports the therapeutic potential of targeting expansion causing components of the DNA repair system.
{"title":"C01 Glutamine codon usage and somatic mosaicism of the HTT cag repeat are modifiers of huntington disease severity","authors":"M. Ciosi, Alastair Maxwell, S. Cumming, D. H. Moss, A. Alshammari, M. Flower, A. Durr, B. Leavitt, R. Roos, P. Holmans, L. Jones, D. Langbehn, S. Kwak, S. Tabrizi, D. Monckton","doi":"10.1136/jnnp-2018-EHDN.72","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.72","url":null,"abstract":"Background Huntington disease (HD) is caused by the expansion of a polyglutamine encoding CAG repeat in exon 1 of the HTT gene. Affected individuals inherit ≥40 repeats and longer alleles are associated with earlier onset and higher HD severity. The HTT CAG repeat is genetically unstable in both the germline and soma. Somatic mosaicism is dependent on the number of CAG repeats and age, and is expansion biased and cell-type specific. Recent genome-wide association studies (GWAS) have identified components of the DNA repair system as trans¬-acting modifiers of HD severity, some of which are known to modify somatic instability of the HTT CAG repeat in HD mouse models. We thus hypothesise that the trans¬-acting modifiers identified by GWAS affect HD severity by their direct effect on HTT CAG somatic instability. Aims Determine the exact trinucleotide structure of the HTT exon 1 repeat and quantify its somatic mosaicism to investigate their association with HD severity. Methods/techniques Using genotyping-by-sequencing, we determined the exact genotype of the polyglutamine and polyproline encoding repeats in HTT exon 1 and quantified the somatic mosaicism associated with the CAG repeat in blood DNA from 807 HD expansion carriers. Results/outcome The sequence encoding the HTT polyglutamine and polyproline tract has an atypical structure in ˜8% of the non-HD-causing alleles and ˜3% of the HD-causing alleles, differing from the typical structure by the number of glutamine encoding CAA codons and/or the number of proline encoding CCA and CCT codons. Multiple linear regression analysis revealed that the number of CAA codons is negatively correlated with HD severity and that the number of CAG repeats is a better predictor of HD severity (r2=0.559) than the number of glutamines (r2=0.537). Moreover, somatic mosaicism in blood correlates with HD severity (r2 ≥0.014, p≤2.5 × 10–3) and some of the polymorphisms associated with HD severity (p=1.5 × 10–5 for FAN1 rs3512, p=1.8 × 10–4 for MLH3 rs175080, p=3.6 × 10–3 for MLH1 rs1799977 and p=0.016 for MSH3 rs1382539). Conclusion Our data show that atypical HD-causing alleles have major implications for genetic diagnosis and counselling and confirm the correlation of somatic expansion with HD severity. The latter further supports the therapeutic potential of targeting expansion causing components of the DNA repair system.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"38 1","pages":"A26 - A27"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83588765","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.47
Erwan Bigan, S. Nair, F. Lejeune, H. Fragnaud, F. Parmentier, M. Verny, J. Aaronson, J. Rosinski, C. Néri
Gene deregulation has been associated with several neurodegenerative diseases (NDs) and modeling genome-wide data such as transcriptomic data has provided holistic models of ND progression on a gene expression level. However, the consequences of gene deregulation on the temporal dynamics of gene-gene interaction systems (genetic cooperativity) is poorly understood in NDs. Using a multi-layer network approach, we cross-integrated three families of networks describing RNA-seq time series data in Huntington’s disease (HD) knock-in mice for reconstructing the dynamics of genetic cooperativity in the brain of these mice based on the consistency and complementarity of edge information in source networks. The resulting model suggests that the HD process may develop as two critical phases of genetic cooperativity, pre-symptomatically in the cortex, involving a neurotransmission response, and symptomatically in the striatum, involving cell survival responses intertwined with cellular senescence and DNA damage responses. These data highlight a 2-step logic for injury/adaptation of the HD mouse brain in which a cortical response for modulating neurotransmission may precede a striatal response for regulating cellular homeostasis synchronous to symptoms.
{"title":"A49 Modeling the dynamics of genetic cooperativity in the brain of huntington’s disease mice","authors":"Erwan Bigan, S. Nair, F. Lejeune, H. Fragnaud, F. Parmentier, M. Verny, J. Aaronson, J. Rosinski, C. Néri","doi":"10.1136/jnnp-2018-EHDN.47","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.47","url":null,"abstract":"Gene deregulation has been associated with several neurodegenerative diseases (NDs) and modeling genome-wide data such as transcriptomic data has provided holistic models of ND progression on a gene expression level. However, the consequences of gene deregulation on the temporal dynamics of gene-gene interaction systems (genetic cooperativity) is poorly understood in NDs. Using a multi-layer network approach, we cross-integrated three families of networks describing RNA-seq time series data in Huntington’s disease (HD) knock-in mice for reconstructing the dynamics of genetic cooperativity in the brain of these mice based on the consistency and complementarity of edge information in source networks. The resulting model suggests that the HD process may develop as two critical phases of genetic cooperativity, pre-symptomatically in the cortex, involving a neurotransmission response, and symptomatically in the striatum, involving cell survival responses intertwined with cellular senescence and DNA damage responses. These data highlight a 2-step logic for injury/adaptation of the HD mouse brain in which a cortical response for modulating neurotransmission may precede a striatal response for regulating cellular homeostasis synchronous to symptoms.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"58 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":"82308700","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.207
Brigit Burer- van der Zeeuw, Ondine de Hullu, Sylvia Alders, Tamara Ouwersloot, Caroline Kuijt
Background Topaz Huntington Centre Overduin is a long term care facility that provides care to both ambulant (100) and long term care patients (70). In the last stages of disease many clients require assistance with transfers and care because of the physical limitations, in combination with involuntary movements, reduced cognitive abilities and behavioral disorders. Standard procedures for transfers or the use of equipment are not designed for these patients and are a potential threat to the health of patients and a tremendous physical strain for nurses. Aims To develop an advanced HD friendly transfer handbook and training guide. Methods/techniques First, a selection of the top 5 most strenuous transfers was selected by way of a survey in HD-experienced care staff. A study team consisting of physiotherapists, an occupation therapist and care staff used a predefined ‘trial and error’ protocol to compare traditional and experimental methods. Results After experimenting with new methods, a new handbook is developed with procedures and materials for advanced HD adjusted transfers and practical tools. Conclusions Standard procedures are not always efficient when providing care to clients with HD. Adaption of these procedures and tools and knowledge transfer is necessary in order to give employees the ability to care in a precise, proper way for clients with advanced HD.
Topaz Huntington Centre Overduin是一家长期护理机构，为100名流动病人和70名长期护理病人提供护理。在疾病的最后阶段，由于身体上的限制，加上不自主的运动、认知能力下降和行为障碍，许多病人需要转移和护理方面的帮助。转移或设备使用的标准程序不是为这些病人设计的，对病人的健康构成潜在威胁，并给护士带来巨大的身体压力。目的开发一个先进的HD友好的转会手册和培训指南。方法/技术首先，通过对hd经验丰富的护理人员进行调查，选择了前5名最费力的转移。一个由物理治疗师、职业治疗师和护理人员组成的研究小组使用预先定义的“试错”协议来比较传统方法和实验方法。结果经过新方法的试验，编写了一份新的手册，其中包括高级HD调整转移和实用工具的程序和材料。结论:标准程序在为HD患者提供护理时并不总是有效的。为了让员工能够以精确、适当的方式照顾患有高级HD的客户，对这些程序、工具和知识转移进行调整是必要的。
{"title":"H29 Practical tools and transfer aids in daily care for clients with advanced hd","authors":"Brigit Burer- van der Zeeuw, Ondine de Hullu, Sylvia Alders, Tamara Ouwersloot, Caroline Kuijt","doi":"10.1136/jnnp-2018-EHDN.207","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.207","url":null,"abstract":"Background Topaz Huntington Centre Overduin is a long term care facility that provides care to both ambulant (100) and long term care patients (70). In the last stages of disease many clients require assistance with transfers and care because of the physical limitations, in combination with involuntary movements, reduced cognitive abilities and behavioral disorders. Standard procedures for transfers or the use of equipment are not designed for these patients and are a potential threat to the health of patients and a tremendous physical strain for nurses. Aims To develop an advanced HD friendly transfer handbook and training guide. Methods/techniques First, a selection of the top 5 most strenuous transfers was selected by way of a survey in HD-experienced care staff. A study team consisting of physiotherapists, an occupation therapist and care staff used a predefined ‘trial and error’ protocol to compare traditional and experimental methods. Results After experimenting with new methods, a new handbook is developed with procedures and materials for advanced HD adjusted transfers and practical tools. Conclusions Standard procedures are not always efficient when providing care to clients with HD. Adaption of these procedures and tools and knowledge transfer is necessary in order to give employees the ability to care in a precise, proper way for clients with advanced HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"66 1","pages":"A77 - A77"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72590712","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.255
Anne-Christine Plank, S. Schilling, T. Hoffmann, I. Lues, S. Hörsten
Background Huntington disease (HD) may be aggravated by enzymatic activity of glutaminyl cyclase (QC/QPCT) and its isoenzyme (isoQC/QPCTL) via the following mechanisms: Neurotoxic pyroglutamated (pGlu) mutant huntingtin (mHTT) fragments may be formed via N-terminal glutamine cyclization of truncated mHTT species by enzymatic activity of QC and/or isoQC. Subclinical neuroinflammation and gliosis in HD may be triggered via isoQC-dependent maturation of pGlu-CCL2. QC-associated interference in heat shock protein and chaperone levels may promote mHTT cellular toxicity. Aims The present study sought to investigate the role of QC/isoQC in HD via genetic and pharmacological proof-of-concept (POC) experiments targeting the (iso)enzyme in the BACHD mouse model of HD. Methods Genetic POC was achieved by crossbreeding of BACHD with QC-KO/isoQC-KO mice, pharmacological POC by early interventional studies in 6-weeks-old BACHD mice for 18 weeks using increasing dosages of the QC/isoQC inhibitor PQ912 (Probiodrug AG). Several behavioral and physiological end-points including cellular and morphological markers were examined. Results PQ912 treatment resulted in lowered mHTT and GFAP levels, associated with normalization of the abnormal body weight gain and energy metabolism of BACHD mice at 24 weeks of age. PQ912 treatment was well tolerated in a wide range of dosages with no obvious adverse effects. Crossbreeding of iso/QC-KO mice ameliorated the body weight increase and certain behavioral abnormalities in BACHD mice. Conclusion Experiments provide evidence for glutaminyl cyclases to represent a druggable target in HD. Early QC/isoQC-inhibitor-based pharmacological intervention in BACHD mice resulted in clear beneficial effects, including but not limited to a lowering of mHTT. Since the QC/isoQC inhibitor PQ912 is in clinical development for the indication AD, further preclinical and translational studies in HD are tempted.
谷氨酰环化酶(QC/QPCT)及其同工酶(isoQC/QPCTL)的酶活性可能通过以下机制使亨廷顿病(HD)恶化:神经毒性热谷氨酸(pGlu)突变体亨廷顿蛋白(mHTT)片段可能通过QC和/或isoQC的酶活性通过截断mHTT种的n端谷氨酰胺环化而形成。HD患者的亚临床神经炎症和神经胶质瘤可能通过依赖于isoqc的pGlu-CCL2成熟触发。qc相关的热休克蛋白和伴侣蛋白水平的干扰可能促进mHTT细胞毒性。本研究旨在通过针对(iso)酶在HD小鼠BACHD模型中的遗传和药理学概念验证(POC)实验，探讨QC/isoQC在HD中的作用。方法通过与QC- ko /isoQC- ko小鼠杂交获得遗传POC，通过增加QC/isoQC抑制剂PQ912 (Probiodrug AG)剂量对6周龄BACHD小鼠进行18周的早期干预研究获得药理学POC。几个行为和生理终点，包括细胞和形态标记进行了检查。结果PQ912治疗导致mHTT和GFAP水平降低，与24周龄BACHD小鼠异常体重增加和能量代谢正常化有关。PQ912在大剂量范围内耐受性良好，无明显不良反应。iso/QC-KO小鼠杂交可改善BACHD小鼠的体重增加和某些行为异常。结论实验证明谷氨酰胺环化酶是HD的一个可药物靶点。早期以QC/ isoqc抑制剂为基础的药物干预对BACHD小鼠产生了明显的有益效果，包括但不限于mHTT的降低。由于QC/isoQC抑制剂PQ912正处于针对AD的临床开发阶段，因此对HD的进一步临床前和转化研究受到了吸引。
{"title":"I19 Normalization of phenotype and reduction of gliosis levels via glutaminyl cyclases inhibition in a huntington disease mouse model","authors":"Anne-Christine Plank, S. Schilling, T. Hoffmann, I. Lues, S. Hörsten","doi":"10.1136/jnnp-2018-EHDN.255","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.255","url":null,"abstract":"Background Huntington disease (HD) may be aggravated by enzymatic activity of glutaminyl cyclase (QC/QPCT) and its isoenzyme (isoQC/QPCTL) via the following mechanisms: Neurotoxic pyroglutamated (pGlu) mutant huntingtin (mHTT) fragments may be formed via N-terminal glutamine cyclization of truncated mHTT species by enzymatic activity of QC and/or isoQC. Subclinical neuroinflammation and gliosis in HD may be triggered via isoQC-dependent maturation of pGlu-CCL2. QC-associated interference in heat shock protein and chaperone levels may promote mHTT cellular toxicity. Aims The present study sought to investigate the role of QC/isoQC in HD via genetic and pharmacological proof-of-concept (POC) experiments targeting the (iso)enzyme in the BACHD mouse model of HD. Methods Genetic POC was achieved by crossbreeding of BACHD with QC-KO/isoQC-KO mice, pharmacological POC by early interventional studies in 6-weeks-old BACHD mice for 18 weeks using increasing dosages of the QC/isoQC inhibitor PQ912 (Probiodrug AG). Several behavioral and physiological end-points including cellular and morphological markers were examined. Results PQ912 treatment resulted in lowered mHTT and GFAP levels, associated with normalization of the abnormal body weight gain and energy metabolism of BACHD mice at 24 weeks of age. PQ912 treatment was well tolerated in a wide range of dosages with no obvious adverse effects. Crossbreeding of iso/QC-KO mice ameliorated the body weight increase and certain behavioral abnormalities in BACHD mice. Conclusion Experiments provide evidence for glutaminyl cyclases to represent a druggable target in HD. Early QC/isoQC-inhibitor-based pharmacological intervention in BACHD mice resulted in clear beneficial effects, including but not limited to a lowering of mHTT. Since the QC/isoQC inhibitor PQ912 is in clinical development for the indication AD, further preclinical and translational studies in HD are tempted.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"260 1","pages":"A95 - A95"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76549006","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.218
Jessica Bent, A. Heemskerk, W. Achterberg
Background In 2010 Topaz Huntington Centre Overduin introduced a weekly Brisk-walking program. The intervention, that was developed, was an one hour program based on endurance, balance (static and dynamic) and muscle force training. TOPAZ Overduin is located in the middle of a perfect place to train these aspects outside, in a sandy hilly environment. At the moment 17 HD-patients, (11 male) participate in this program every week or once every two weeks, 16 patients completed a questionnaire about their experiences with this program. Aims Aim of the study is to examine on which of thirteen QOL aspects the patients experienced benefits and to find out whether this program improves the quality of life. Another aim was to investigate whether patients would perform this activity independently on their own. Methods All 17 HD-patients who participate in this program were asked to fill in a questionnaire. Percentages of benefits were calculated of 13 QOL aspects (coordination, range of motion, endurance, muscle force, velocity of moving, pleasure, concentration, contact with other HD patients, memory, bowel movements, sleep, mood and self confidence). Results Participants had the most benefit on the aspects endurance, self confidence and contact with other HD patients. Less benefit was experienced on memory, sleep and bowel movements. Most patients (75%) would not continue a similar program on their own. Conclusion This Brisk walking program has a positive influence on endurance, pleasure and self-confidence. On the aspects of sleep, bowel movements and memory the effect were not so clearly felt.
2010年，Topaz Huntington Centre Overduin推出了每周快步走项目。这种干预是一种基于耐力、平衡(静态和动态)和肌肉力量训练的一小时计划。TOPAZ Overduin位于一个完美的地方，在一个多沙的丘陵环境中训练这些方面。目前有17例hd患者(11例男性)每周或每两周参加一次该项目，其中16例患者完成了关于他们在该项目中的经历的问卷调查。目的研究的目的是检查患者在13个生活质量方面哪些方面受益，并找出该计划是否提高了生活质量。另一个目的是调查患者是否会独立完成这项活动。方法对17例hd患者进行问卷调查。从13个生活质量方面(协调性、运动范围、耐力、肌肉力量、运动速度、愉悦感、注意力、与其他HD患者的接触、记忆力、排便、睡眠、情绪和自信)计算获益百分比。结果参与者在耐力、自信心和与其他HD患者的接触方面获益最大。在记忆力、睡眠和排便方面则没有那么明显的改善。大多数患者(75%)不会自己继续类似的计划。结论快走运动对耐力、愉悦感和自信心有积极影响。在睡眠、排便和记忆方面，效果并不明显。
{"title":"H40 Experiences of huntington patients, who participate in a challenging briskwalking program","authors":"Jessica Bent, A. Heemskerk, W. Achterberg","doi":"10.1136/jnnp-2018-ehdn.218","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ehdn.218","url":null,"abstract":"Background In 2010 Topaz Huntington Centre Overduin introduced a weekly Brisk-walking program. The intervention, that was developed, was an one hour program based on endurance, balance (static and dynamic) and muscle force training. TOPAZ Overduin is located in the middle of a perfect place to train these aspects outside, in a sandy hilly environment. At the moment 17 HD-patients, (11 male) participate in this program every week or once every two weeks, 16 patients completed a questionnaire about their experiences with this program. Aims Aim of the study is to examine on which of thirteen QOL aspects the patients experienced benefits and to find out whether this program improves the quality of life. Another aim was to investigate whether patients would perform this activity independently on their own. Methods All 17 HD-patients who participate in this program were asked to fill in a questionnaire. Percentages of benefits were calculated of 13 QOL aspects (coordination, range of motion, endurance, muscle force, velocity of moving, pleasure, concentration, contact with other HD patients, memory, bowel movements, sleep, mood and self confidence). Results Participants had the most benefit on the aspects endurance, self confidence and contact with other HD patients. Less benefit was experienced on memory, sleep and bowel movements. Most patients (75%) would not continue a similar program on their own. Conclusion This Brisk walking program has a positive influence on endurance, pleasure and self-confidence. On the aspects of sleep, bowel movements and memory the effect were not so clearly felt.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"39 1","pages":"A81 - A81"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74902876","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.69
Edward J. Smith, K. Sathasivam, G. Bates
Background There is a need for improved human and mouse cell models of Huntington’s disease. Neural stem cells (NSCs) are a pool of stem cell like progenitors responsible for self-renewal and differentiation in the developing CNS leading to the formation of the mature brain. Aims To generate neural progenitor cell lines from the R6/2 mouse model of HD and to investigate these for HD-related phenotypes. Methods Cell lines have been established from E14.5 R6/2 and wild type mouse embryos and cultured in bespoke culture media with growth factors to expand the population. Progenitor populations have been harvested from distinct cortical and striatal progenitors. NSCs have been successfully maintained in a proliferative state for multiple passages and differentiated into neurons and glia that express proteins indicative of mature cell types. Results Neurons show evidence of synaptophysin expression at junctions between cell neurites suggesting synaptic functionality and the formation of rudimentary neural networks. After 14–28 days of differentiation, induced by removal of growth factors, mutant huntingtin (mHTT) aggregation is detectable in R6/2 cell nuclei recapitulating a phenotype found in the mouse model and by clinical histopathology. Initial aggregation can be detected in cell nuclei from 14 days of differentiation in 5% of cells rising to around 10% after 28 days. Detection of mHTT-aggregated protein was also validated via western blot. Super high resolution cell imaging shows earlier aggregation of mHTT and that this occurs in both the cytoplasm and the nucleus. Conclusions This cell model will be used to explore the misfolding and aggregation of mHTT and how this affects cellular function. We have assessed the utility of these cell lines in screening for approaches to modulation mHTT aggregation. Funding Medical Research Council, CHDI Foundation
{"title":"B17 Establishing a neural progenitor cell model of huntington’s disease","authors":"Edward J. Smith, K. Sathasivam, G. Bates","doi":"10.1136/jnnp-2018-EHDN.69","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.69","url":null,"abstract":"Background There is a need for improved human and mouse cell models of Huntington’s disease. Neural stem cells (NSCs) are a pool of stem cell like progenitors responsible for self-renewal and differentiation in the developing CNS leading to the formation of the mature brain. Aims To generate neural progenitor cell lines from the R6/2 mouse model of HD and to investigate these for HD-related phenotypes. Methods Cell lines have been established from E14.5 R6/2 and wild type mouse embryos and cultured in bespoke culture media with growth factors to expand the population. Progenitor populations have been harvested from distinct cortical and striatal progenitors. NSCs have been successfully maintained in a proliferative state for multiple passages and differentiated into neurons and glia that express proteins indicative of mature cell types. Results Neurons show evidence of synaptophysin expression at junctions between cell neurites suggesting synaptic functionality and the formation of rudimentary neural networks. After 14–28 days of differentiation, induced by removal of growth factors, mutant huntingtin (mHTT) aggregation is detectable in R6/2 cell nuclei recapitulating a phenotype found in the mouse model and by clinical histopathology. Initial aggregation can be detected in cell nuclei from 14 days of differentiation in 5% of cells rising to around 10% after 28 days. Detection of mHTT-aggregated protein was also validated via western blot. Super high resolution cell imaging shows earlier aggregation of mHTT and that this occurs in both the cytoplasm and the nucleus. Conclusions This cell model will be used to explore the misfolding and aggregation of mHTT and how this affects cellular function. We have assessed the utility of these cell lines in screening for approaches to modulation mHTT aggregation. Funding Medical Research Council, CHDI Foundation","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"51 1","pages":"A25 - A26"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75072887","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.105
S. Gregory, J. Long, S. Kloppel, Adeel Razi, E. Scheller, Lora Minkova, E. Johnson, A. Durr, R. Roos, B. Leavitt, J. Mills, J. Stout, R. Scahill, S. Tabrizi, G. Rees
Background Compensation accounts for the dissociation between pathology and absence of behavioural change during premanifest stages of Huntington’s disease (HD). Despite neuronal loss, individuals with premanifest HD function at a level similar to that of a healthy population. Neural mechanisms underlying compensation, however, are generally poorly understood due to the lack of an operational definition of compensation. Here, we describe the first example of the modelling and empirical testing of compensation in HD. Aims We hypothesise that compensation occurs where increased brain activation is required to maintain normal levels of behaviour until pathology becomes too severe. A compensatory relationship is thus characterised by non-linear longitudinal trajectories of brain activity and behaviour as disease load increases linearly across sequential phases of disease progression. Methods We tested our model in a large cohort of premanifest and early HD gene-carriers from the TrackOn-HD study. Focusing on both cognitive and motor networks, brain activity was measured using task and resting-state fMRI, volumetric loss by structural MRI and behaviour by task performance. Compensation was tested for across three sequential phases of disease progression. Results Maintained global cognition was associated with increased effective connectivity between the left and right dorsolateral prefrontal cortex, an important region for cognitive processing, while maintained motor performance was associated with increased connectivity between bilateral premotor cortex. Conclusions Our empirical findings demonstrate theoretically-defined compensation in HD in networks central to the HD phenotype and can now be used to test both cross-sectional and longitudinal compensation in other neurodegenerative disease with similar patterns to HD.
{"title":"E11 Compensation in huntington’s disease","authors":"S. Gregory, J. Long, S. Kloppel, Adeel Razi, E. Scheller, Lora Minkova, E. Johnson, A. Durr, R. Roos, B. Leavitt, J. Mills, J. Stout, R. Scahill, S. Tabrizi, G. Rees","doi":"10.1136/jnnp-2018-EHDN.105","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.105","url":null,"abstract":"Background Compensation accounts for the dissociation between pathology and absence of behavioural change during premanifest stages of Huntington’s disease (HD). Despite neuronal loss, individuals with premanifest HD function at a level similar to that of a healthy population. Neural mechanisms underlying compensation, however, are generally poorly understood due to the lack of an operational definition of compensation. Here, we describe the first example of the modelling and empirical testing of compensation in HD. Aims We hypothesise that compensation occurs where increased brain activation is required to maintain normal levels of behaviour until pathology becomes too severe. A compensatory relationship is thus characterised by non-linear longitudinal trajectories of brain activity and behaviour as disease load increases linearly across sequential phases of disease progression. Methods We tested our model in a large cohort of premanifest and early HD gene-carriers from the TrackOn-HD study. Focusing on both cognitive and motor networks, brain activity was measured using task and resting-state fMRI, volumetric loss by structural MRI and behaviour by task performance. Compensation was tested for across three sequential phases of disease progression. Results Maintained global cognition was associated with increased effective connectivity between the left and right dorsolateral prefrontal cortex, an important region for cognitive processing, while maintained motor performance was associated with increased connectivity between bilateral premotor cortex. Conclusions Our empirical findings demonstrate theoretically-defined compensation in HD in networks central to the HD phenotype and can now be used to test both cross-sectional and longitudinal compensation in other neurodegenerative disease with similar patterns to HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"9 1","pages":"A39 - A40"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74733349","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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