Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-ehdn.172
A. Ehrhardt, Adam Ellenberger, E. Wild, G. Owen, S. Kwak, Elena Pak, S. Lifer, C. Sampaio
Background Earlier disease onset in subsequent generations, called anticipation, has been observed in HD families and is attributed to an increased CAG-repeat length in the HTT gene. CAG-repeat length mutations are referred to as ‘repeat instability’ and genome-wide association studies suggest that genomic variants function as genetic modifiers of disease onset, for example by affecting DNA repair mechanisms. Aims Origin-HD aims to investigate CAG repeat instability in germline and somatic cells and evaluate for correlations with putative genetic modifiers. Understanding the mechanisms affecting repeat instability may yield testable targets for future interventions. Study design Starting Q2 2019, over 1,000 male HDGECs (ages 18–55) will be recruited from Enroll-HD participants over about two years, approximately balanced between premanifest and manifest disease. Allele and genotype frequency for each pre-specified variant of interest will be assessed after about 500 participants have been recruited. If the predicted detectable effect size is d>0.35 in the final sample of 1,000 participants, a recruitment-by-genotype recruitment approach can be adopted in parallel to the ongoing recruitment. The repeat instability in DNA from sperm and blood of study participants will be analyzed, and genetic modifier variants will be determined.
{"title":"F74 Origin-hd: genetic modifiers of htt cag intergenerational repeat instability in male hdgecs","authors":"A. Ehrhardt, Adam Ellenberger, E. Wild, G. Owen, S. Kwak, Elena Pak, S. Lifer, C. Sampaio","doi":"10.1136/jnnp-2018-ehdn.172","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ehdn.172","url":null,"abstract":"Background Earlier disease onset in subsequent generations, called anticipation, has been observed in HD families and is attributed to an increased CAG-repeat length in the HTT gene. CAG-repeat length mutations are referred to as ‘repeat instability’ and genome-wide association studies suggest that genomic variants function as genetic modifiers of disease onset, for example by affecting DNA repair mechanisms. Aims Origin-HD aims to investigate CAG repeat instability in germline and somatic cells and evaluate for correlations with putative genetic modifiers. Understanding the mechanisms affecting repeat instability may yield testable targets for future interventions. Study design Starting Q2 2019, over 1,000 male HDGECs (ages 18–55) will be recruited from Enroll-HD participants over about two years, approximately balanced between premanifest and manifest disease. Allele and genotype frequency for each pre-specified variant of interest will be assessed after about 500 participants have been recruited. If the predicted detectable effect size is d>0.35 in the final sample of 1,000 participants, a recruitment-by-genotype recruitment approach can be adopted in parallel to the ongoing recruitment. The repeat instability in DNA from sperm and blood of study participants will be analyzed, and genetic modifier variants will be determined.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"75 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":"89569700","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.12
S. Kochanek, Bin Huang, Manuel Seefelder, T. Engler, Jingdong Cheng, W. Baumeister, Q. Guo, Rubén Fernándezt-Busnadiego
Huntingtin (HTT) is the protein that is altered in Huntington’s disease (HD). While HTT has been found to be essential for many cellular activities including transport of vesicles in the cell, cellular uptake of materials (endocytosis), cellular degradation of waste (autophagy), regulation of transcription, and even is important for embryonic development, an integrating understanding of HTT’s many biological functions at the molecular level is still missing. Although the HTT gene and the disease-causing mutation have been identified 25 years ago, very little data has been available on the structure of HTT. However, information on HTT’s structure would be very important for achieving an improved understand of HTT’s function in health and disease. Here we employed cryo-electron microscopy (cryo-EM) to determine the structure of full-length human HTT in a complex with another protein, HTT-associated protein 40 (HAP40). This interaction of HTT with HAP40 was instrumental in stabilizing HTT’s structure to a degree that the structure of HTT could be determined at detailed level at an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The N- and C-terminal domains contain multiple HEAT repeat elements that are arranged in a solenoid fashion. These domains are connected by a smaller bridge domain that contain different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat (TPR)-like organization. HAP40 binds in a cleft contacting the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing HTT’s conformation. These data help in the interpretation of previous biochemical results and will pave the way for the generation and testing of new research hypotheses that ultimately will lead to an improved understanding of HTT’s diverse biological functions.
{"title":"A12 The cryo-electron microscopy structure of huntingtin","authors":"S. Kochanek, Bin Huang, Manuel Seefelder, T. Engler, Jingdong Cheng, W. Baumeister, Q. Guo, Rubén Fernándezt-Busnadiego","doi":"10.1136/jnnp-2018-EHDN.12","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.12","url":null,"abstract":"Huntingtin (HTT) is the protein that is altered in Huntington’s disease (HD). While HTT has been found to be essential for many cellular activities including transport of vesicles in the cell, cellular uptake of materials (endocytosis), cellular degradation of waste (autophagy), regulation of transcription, and even is important for embryonic development, an integrating understanding of HTT’s many biological functions at the molecular level is still missing. Although the HTT gene and the disease-causing mutation have been identified 25 years ago, very little data has been available on the structure of HTT. However, information on HTT’s structure would be very important for achieving an improved understand of HTT’s function in health and disease. Here we employed cryo-electron microscopy (cryo-EM) to determine the structure of full-length human HTT in a complex with another protein, HTT-associated protein 40 (HAP40). This interaction of HTT with HAP40 was instrumental in stabilizing HTT’s structure to a degree that the structure of HTT could be determined at detailed level at an overall resolution of 4 Å. HTT is largely α-helical and consists of three major domains. The N- and C-terminal domains contain multiple HEAT repeat elements that are arranged in a solenoid fashion. These domains are connected by a smaller bridge domain that contain different types of tandem repeats. HAP40 is also largely α-helical and has a tetratricopeptide repeat (TPR)-like organization. HAP40 binds in a cleft contacting the three HTT domains by hydrophobic and electrostatic interactions, thereby stabilizing HTT’s conformation. These data help in the interpretation of previous biochemical results and will pave the way for the generation and testing of new research hypotheses that ultimately will lead to an improved understanding of HTT’s diverse biological functions.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"45 1","pages":"A5 - A5"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87867515","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.129
A. Ho, M. Horton, G. Landwehrmeyer, J. Burgunder, A. Tennant
Background Understanding and measuring the impact of Huntington’s on people’s lives is important to patients, families and care providers. However, questionnaires that are generic in origin are less likely to adequately reflect patient’s experience of living with Huntington’s. The Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), is a disease-specific instrument that is fully patient-derived in order to maximise its relevance to patient’s lives. Aims The objective of this study was to refine and validate the HDQoL in a large sample of patients, and to elucidate health domains that are meaningful to patients. Methods Five-hundred and forty-one UK participants, from pre-manifest to end-stage disease completed the HDQoL, together with generic quality of life measures, and in-person motor, cognitive and behavioural assessments. The psychometric properties of the HDQoL were examined. Results The HDQoL has four domains comprising Physical-Functional, Cognitive, and two different behavioural aspects i.e. Mood-Self domain, as well as a distinct Worries domain. All domains showed good to excellent internal consistency. Known groups analyses illustrated significant and graded changes in clinical assessments and corresponding HDQoL domains across severity levels. Convergent and discriminant validity were demonstrated by the expected pattern of correlations between specific HDQoL domains and corresponding domain-relevant clinical assesments as well as patient-reported measures. The data demonstrate robust support for the refined HDQoL across disease stages. Conclusions The HDQoL is a relevant, reliable and valid patient-derived instrument to measure the impact of Huntington’s disease.
{"title":"F25 Huntington’s disease health-related quality of life questionnaire (HDQOL): further validation","authors":"A. Ho, M. Horton, G. Landwehrmeyer, J. Burgunder, A. Tennant","doi":"10.1136/jnnp-2018-EHDN.129","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.129","url":null,"abstract":"Background Understanding and measuring the impact of Huntington’s on people’s lives is important to patients, families and care providers. However, questionnaires that are generic in origin are less likely to adequately reflect patient’s experience of living with Huntington’s. The Huntington’s Disease health-related Quality of Life questionnaire (HDQoL), is a disease-specific instrument that is fully patient-derived in order to maximise its relevance to patient’s lives. Aims The objective of this study was to refine and validate the HDQoL in a large sample of patients, and to elucidate health domains that are meaningful to patients. Methods Five-hundred and forty-one UK participants, from pre-manifest to end-stage disease completed the HDQoL, together with generic quality of life measures, and in-person motor, cognitive and behavioural assessments. The psychometric properties of the HDQoL were examined. Results The HDQoL has four domains comprising Physical-Functional, Cognitive, and two different behavioural aspects i.e. Mood-Self domain, as well as a distinct Worries domain. All domains showed good to excellent internal consistency. Known groups analyses illustrated significant and graded changes in clinical assessments and corresponding HDQoL domains across severity levels. Convergent and discriminant validity were demonstrated by the expected pattern of correlations between specific HDQoL domains and corresponding domain-relevant clinical assesments as well as patient-reported measures. The data demonstrate robust support for the refined HDQoL across disease stages. Conclusions The HDQoL is a relevant, reliable and valid patient-derived instrument to measure the impact of Huntington’s disease.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"124 1","pages":"A48 - A49"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87904856","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.254
Talya Shacham, Gerardo Lederkrember
Protein aggregation stands at the center of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease (HD). HD is caused by a mutation in the huntingtin gene, resulting in expansion of poly-glutamine repeats, causing aggregation of the huntingtin protein in the cell. One of the consequences of this aggregation is endoplasmic reticulum (ER) stress, which interferes with cell function and eventually leads to cell death, predominantly in the brain striatum. In recent years, a key pathway of the unfolded protein response (UPR)- the PERK pathway, has been targeted as a possible therapeutic approach for neurodegenerative diseases. Previous research in neurodegenerative diseases showed positive effects of PERK inhibition, suggesting that decreasing phosphorylation of its substrate, eIF2α, interferes with the initiation of the apoptotic pathway upon long term ER stress. However, other studies suggested that, paradoxically, the opposite strategy, increasing eIF2α phosphorylation by PERK activation or by inhibition of the phosphatase subunit GADD34, is also beneficial for cell survival. Higher levels of eIF2α-P lead to inhibition of protein translation, and as a result, reduce accumulation of damaged proteins in the cell. In our recent work, treatment with a PERK activator developed in our lab – MK-28, was attempted on cellular HD models and on the R6/2 transgenic mouse HD model. Cells in culture expressing polyglutamine-expanded huntingtin showed significantly increased survival, upon ER stress. MK-28 treated mice showed significant improvement in their motor performance and physiologic measurements, suggesting that PERK activation postponed the appearance of HD symptoms. These findings suggest a new possible therapy for HD, and possibly open a new approach for treatment of other neurodegenerative diseases.
{"title":"I18 Perk activation therapy in huntington’s disease","authors":"Talya Shacham, Gerardo Lederkrember","doi":"10.1136/jnnp-2018-EHDN.254","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.254","url":null,"abstract":"Protein aggregation stands at the center of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease (HD). HD is caused by a mutation in the huntingtin gene, resulting in expansion of poly-glutamine repeats, causing aggregation of the huntingtin protein in the cell. One of the consequences of this aggregation is endoplasmic reticulum (ER) stress, which interferes with cell function and eventually leads to cell death, predominantly in the brain striatum. In recent years, a key pathway of the unfolded protein response (UPR)- the PERK pathway, has been targeted as a possible therapeutic approach for neurodegenerative diseases. Previous research in neurodegenerative diseases showed positive effects of PERK inhibition, suggesting that decreasing phosphorylation of its substrate, eIF2α, interferes with the initiation of the apoptotic pathway upon long term ER stress. However, other studies suggested that, paradoxically, the opposite strategy, increasing eIF2α phosphorylation by PERK activation or by inhibition of the phosphatase subunit GADD34, is also beneficial for cell survival. Higher levels of eIF2α-P lead to inhibition of protein translation, and as a result, reduce accumulation of damaged proteins in the cell. In our recent work, treatment with a PERK activator developed in our lab – MK-28, was attempted on cellular HD models and on the R6/2 transgenic mouse HD model. Cells in culture expressing polyglutamine-expanded huntingtin showed significantly increased survival, upon ER stress. MK-28 treated mice showed significant improvement in their motor performance and physiologic measurements, suggesting that PERK activation postponed the appearance of HD symptoms. These findings suggest a new possible therapy for HD, and possibly open a new approach for treatment of other neurodegenerative diseases.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"27 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":"87438630","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.48
J. Stricker-Shaver, B. Fabry, L. Yu-Taeger, E. Singer, L. Stanek, C. Calaminus, B. Pichler, L. Shihabuddin, O. Riess, H. Nguyen
Background In Huntington disease (HD), the negative impacts of metabolic dysfunctions heavily affects the quality of life of patients. As energy metabolism is centrally regulated by the hypothalamus via a number of proteins, we hypothesize that mutant huntingtin (mHTT) disrupts selective proteins resulting in metabolic disturbances. Aims To investigate disruptions of energy metabolism caused by mHTT in the hypothalamus. Methods A viral-mediated microRNA that could downregulate both wild-type and mutant HTT was administered to the hypothalamus of BACHD rats using bilateral stereotaxic injections. To compare the effects of mHTT downregulation at the time of intervention, BACHD rats were treated at 1 and 6 months of age, which correspond to the early disease and symptomatic stages respectively. Wild-type littermates treated with vector formulation buffer and BACHD rats treated with an empty vector were included as control groups. Brain tissues were harvested 5 months post-treatment for protein analyses. Results Our findings showed that, protein expressions of neuropeptide Y receptor 5 (NPY5R), orexin receptor 1 (OX1R) and leptin receptor were significantly altered in at least one of the disease stages in the hypothalamus of the empty vector-treated BACHD rats when compared to the wild-type littermates. Downregulation of mHTT in the hypothalamus restored the protein expressions of NPY5R, OX1R and leptin receptor in the hypothalamus to respective levels as in the wild-type littermates. Conclusions The physiological functions of the hypothalamus are disrupted by mHTT in HD. Nevertheless, mHTT suppression in the hypothalamus can be an effective approach for restoring the perturbed neuroendocrine axes regulating energy metabolism.
{"title":"A50 Hypothalamic suppression of mutant huntingtin restored proteins involved in energy metabolism","authors":"J. Stricker-Shaver, B. Fabry, L. Yu-Taeger, E. Singer, L. Stanek, C. Calaminus, B. Pichler, L. Shihabuddin, O. Riess, H. Nguyen","doi":"10.1136/jnnp-2018-EHDN.48","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.48","url":null,"abstract":"Background In Huntington disease (HD), the negative impacts of metabolic dysfunctions heavily affects the quality of life of patients. As energy metabolism is centrally regulated by the hypothalamus via a number of proteins, we hypothesize that mutant huntingtin (mHTT) disrupts selective proteins resulting in metabolic disturbances. Aims To investigate disruptions of energy metabolism caused by mHTT in the hypothalamus. Methods A viral-mediated microRNA that could downregulate both wild-type and mutant HTT was administered to the hypothalamus of BACHD rats using bilateral stereotaxic injections. To compare the effects of mHTT downregulation at the time of intervention, BACHD rats were treated at 1 and 6 months of age, which correspond to the early disease and symptomatic stages respectively. Wild-type littermates treated with vector formulation buffer and BACHD rats treated with an empty vector were included as control groups. Brain tissues were harvested 5 months post-treatment for protein analyses. Results Our findings showed that, protein expressions of neuropeptide Y receptor 5 (NPY5R), orexin receptor 1 (OX1R) and leptin receptor were significantly altered in at least one of the disease stages in the hypothalamus of the empty vector-treated BACHD rats when compared to the wild-type littermates. Downregulation of mHTT in the hypothalamus restored the protein expressions of NPY5R, OX1R and leptin receptor in the hypothalamus to respective levels as in the wild-type littermates. Conclusions The physiological functions of the hypothalamus are disrupted by mHTT in HD. Nevertheless, mHTT suppression in the hypothalamus can be an effective approach for restoring the perturbed neuroendocrine axes regulating energy metabolism.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"318 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":"78926608","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.46
Jinqiu Zhang, J. Ooi, S. Langley, O. Aning, M. Renner, C. F. Cheok, E. Petretto, J. Knoblich, M. Pouladi
Huntington disease (HD) manifests in both adult and juvenile forms. A widely accepted view posits that mutant HTT gene carriers undergo normal brain development followed some years later by a degenerative phase that ultimately results in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD raise the possibility of abnormal neurodevelopment. Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Furthermore, the impact of CAG repeat length on neurodevelopment has not been addressed to date. Using a panel of isogenic HD hESCs and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in a HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids. We confirmed this finding using HD patient-derived hiPSCs. Mechanistically, we show using chimerism experiments that this phenomenon is driven largely by cell intrinsic processes. Transcriptional profiling of cerebral organoids and time-lapse imaging of neural stem cells further reveal impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors which collectively contribute to premature neuronal differentiation. Overall, our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our study further supports the notion that HD may not be a purely neurodegenerative disorder and that abnormal neurodevelopment may be a component of HD pathophysiology.
{"title":"A48 Expanded HTT cag repeats disrupt the balance between neural progenitor expansion and differentiation in isogenic human cerebral organoids","authors":"Jinqiu Zhang, J. Ooi, S. Langley, O. Aning, M. Renner, C. F. Cheok, E. Petretto, J. Knoblich, M. Pouladi","doi":"10.1136/jnnp-2018-EHDN.46","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.46","url":null,"abstract":"Huntington disease (HD) manifests in both adult and juvenile forms. A widely accepted view posits that mutant HTT gene carriers undergo normal brain development followed some years later by a degenerative phase that ultimately results in progressive clinical manifestations. However, recent studies in children and prodromal individuals at risk for HD raise the possibility of abnormal neurodevelopment. Although key findings in rodent models support this notion, direct evidence in the context of human physiology remains lacking. Furthermore, the impact of CAG repeat length on neurodevelopment has not been addressed to date. Using a panel of isogenic HD hESCs and cerebral organoids, we investigated the impact of mutant HTT on early neurodevelopment. We find that ventricular zone-like neuroepithelial progenitor layer expansion is blunted in a HTT CAG repeat length-dependent manner due to premature neurogenesis in HD cerebral organoids. We confirmed this finding using HD patient-derived hiPSCs. Mechanistically, we show using chimerism experiments that this phenomenon is driven largely by cell intrinsic processes. Transcriptional profiling of cerebral organoids and time-lapse imaging of neural stem cells further reveal impaired cell cycle regulatory processes, increased G1 length, and increased asymmetric division of apical progenitors which collectively contribute to premature neuronal differentiation. Overall, our findings suggest that CAG repeat length regulates the balance between neural progenitor expansion and differentiation during early neurodevelopment. Our study further supports the notion that HD may not be a purely neurodegenerative disorder and that abnormal neurodevelopment may be a component of HD pathophysiology.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"10 1","pages":"A17 - A17"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81090002","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.200
C. Hvalstedt, A. Carlsson
Background We all face new challenges as Huntington’s disease have a progress and people with the disease loses their abilities as time passes. We therefore wanted to gather knowledge from professionals and develop support that is easily accessible to all concerned during the entire course of the disease. Aims We wanted to try new ways and methods to raise the level of knowledge about the disease. There is a lot of information available online but it is not always reliable. We wanted to ensure the accuracy of the information with a close cooperation with professionals with specific knowledge about HD in Sweden. We wanted to make sure that we reach the target groups with specific information for everyone both gene carriers, people with HD, relatives and professionals. Methods We started to create a responsive website as a platform on the internet to meet all target groups. To gain access to valuable knowledge workshops with professionals was set up in a number of important topics such as; medical treatment, genetic counselling, communication, physiotherapy, occupational therapy, dental care and nursing. Together with personal interviews and knowledge presented by professionals the specific material were produced as text, films and practical instructions. Results/outcome Two web-based education programs were presented: Basics about Huntington’s disease and symptoms for the public and nursing at Huntington’s disease for the profession. The programs are available at www.huntington.se At present approximately 5000 people have visited the web-based courses. Conclusions As a conclusion we have succeeded with the project as planned. During the project, we have linked many contacts with both professionals and others in our constant work to raise the level of knowledge for both gene carriers, people with HD, relatives and professionals.
{"title":"H21 RHS, the lay association huntington’s disease in sweden approaches their target group in a creative and unique way using the web","authors":"C. Hvalstedt, A. Carlsson","doi":"10.1136/jnnp-2018-ehdn.200","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ehdn.200","url":null,"abstract":"Background We all face new challenges as Huntington’s disease have a progress and people with the disease loses their abilities as time passes. We therefore wanted to gather knowledge from professionals and develop support that is easily accessible to all concerned during the entire course of the disease. Aims We wanted to try new ways and methods to raise the level of knowledge about the disease. There is a lot of information available online but it is not always reliable. We wanted to ensure the accuracy of the information with a close cooperation with professionals with specific knowledge about HD in Sweden. We wanted to make sure that we reach the target groups with specific information for everyone both gene carriers, people with HD, relatives and professionals. Methods We started to create a responsive website as a platform on the internet to meet all target groups. To gain access to valuable knowledge workshops with professionals was set up in a number of important topics such as; medical treatment, genetic counselling, communication, physiotherapy, occupational therapy, dental care and nursing. Together with personal interviews and knowledge presented by professionals the specific material were produced as text, films and practical instructions. Results/outcome Two web-based education programs were presented: Basics about Huntington’s disease and symptoms for the public and nursing at Huntington’s disease for the profession. The programs are available at www.huntington.se At present approximately 5000 people have visited the web-based courses. Conclusions As a conclusion we have succeeded with the project as planned. During the project, we have linked many contacts with both professionals and others in our constant work to raise the level of knowledge for both gene carriers, people with HD, relatives and professionals.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"16 1","pages":"A75 - A75"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77162449","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.9
Aynur Sönmez, K. Kojer, R. Mustafa, S. Spieth, Christian Litke, J. Koch, T. Hering, B. Liss, M. Orth, R. Parlato
Background Transcriptional and metabolic dysregulation are known to occur in Huntington’s disease (HD). Mutant huntingtin (mHTT) protein affects several cellular functions hindering the identification of the primary pathogenic event. Impaired transcription of ribosomal DNA (rDNA) genes in the nucleolus – a major non-membrane bound sub-nuclear compartment – represents an emerging mechanism underlying progressive neurodegeneration Aims To identify a sensitive transcriptional and metabolic marker associated with mHTT and disease progression, we tested the hypothesis that changes in rDNA transcription in the nucleolus are early signs of transcriptional dysregulation by mHTT in HD models and human tissue biopsies. Methods/techniques We analyzed by real-time quantitative PCR, RNA in situ hybridization, and immunofluorescence the activity and integrity of the nucleolus in the striatum and skeletal muscle of zQ175 knock-in mice at various ages as well as of patient tissue biopsies at early neuropathological stages. Results/outcome Here, we show that rDNA transcription and distribution of the nucleolar chaperone protein nucleophosmin (NPM1) are differentially altered in brain and muscle tissues from HD mouse models and in muscle biopsies from HD patients. Conclusions Our results indicate that mHTT nuclear inclusions interfere with nucleolar function in a stage- and cell-specific fashion by altering NPM1 in striatal cells. Moreover these studies demonstrate that NPM1 in muscle cells constitutes a molecular signature of the initial stages of HD. These findings could help to provide novel tools to test the functional efficacy of ongoing therapeutic strategies aiming at lowering mHTT levels in specific cells. Funding This work was supported by EHDN seed-fund project 0753, DFG PA 1529/2–1, CEMMA Graduate School
已知在亨廷顿舞蹈病(HD)中发生转录和代谢失调。突变的亨廷顿蛋白(mHTT)影响几种细胞功能，阻碍了原发性致病事件的鉴定。核仁(主要的非膜结合亚核区室)中核糖体DNA (rDNA)基因的转录受损代表了进行性神经退行性变的一种新兴机制目的为了确定与mHTT和疾病进展相关的敏感转录和代谢标志物，我们在HD模型和人体组织活检中验证了核仁中rDNA转录的变化是mHTT转录失调的早期迹象的假设。方法/技术采用实时定量PCR、RNA原位杂交和免疫荧光分析不同年龄zQ175敲入小鼠纹状体和骨骼肌核仁的活性和完整性，以及早期神经病理阶段的患者组织活检。结果/结果在这里，我们发现rDNA转录和核仁伴侣蛋白核磷蛋白(NPM1)的分布在HD小鼠模型的大脑和肌肉组织以及HD患者的肌肉活检中发生了差异。结论mHTT核包涵体通过改变纹状体细胞中的NPM1，以阶段和细胞特异性的方式干扰核仁功能。此外，这些研究表明，肌肉细胞中的NPM1构成了HD初始阶段的分子特征。这些发现可能有助于提供新的工具来测试正在进行的旨在降低特定细胞中mHTT水平的治疗策略的功能功效。本研究得到了EHDN种子基金项目0753,DFG PA 1529/2-1, CEMMA研究生院的支持
{"title":"A09 Stage- and cell-specific changes of nucleolar activity and integrity are associated with the progression of huntington’s disease","authors":"Aynur Sönmez, K. Kojer, R. Mustafa, S. Spieth, Christian Litke, J. Koch, T. Hering, B. Liss, M. Orth, R. Parlato","doi":"10.1136/jnnp-2018-EHDN.9","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.9","url":null,"abstract":"Background Transcriptional and metabolic dysregulation are known to occur in Huntington’s disease (HD). Mutant huntingtin (mHTT) protein affects several cellular functions hindering the identification of the primary pathogenic event. Impaired transcription of ribosomal DNA (rDNA) genes in the nucleolus – a major non-membrane bound sub-nuclear compartment – represents an emerging mechanism underlying progressive neurodegeneration Aims To identify a sensitive transcriptional and metabolic marker associated with mHTT and disease progression, we tested the hypothesis that changes in rDNA transcription in the nucleolus are early signs of transcriptional dysregulation by mHTT in HD models and human tissue biopsies. Methods/techniques We analyzed by real-time quantitative PCR, RNA in situ hybridization, and immunofluorescence the activity and integrity of the nucleolus in the striatum and skeletal muscle of zQ175 knock-in mice at various ages as well as of patient tissue biopsies at early neuropathological stages. Results/outcome Here, we show that rDNA transcription and distribution of the nucleolar chaperone protein nucleophosmin (NPM1) are differentially altered in brain and muscle tissues from HD mouse models and in muscle biopsies from HD patients. Conclusions Our results indicate that mHTT nuclear inclusions interfere with nucleolar function in a stage- and cell-specific fashion by altering NPM1 in striatal cells. Moreover these studies demonstrate that NPM1 in muscle cells constitutes a molecular signature of the initial stages of HD. These findings could help to provide novel tools to test the functional efficacy of ongoing therapeutic strategies aiming at lowering mHTT levels in specific cells. Funding This work was supported by EHDN seed-fund project 0753, DFG PA 1529/2–1, CEMMA Graduate School","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"04 1","pages":"A4 - A4"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89714832","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.165
Vincent Poile, Gregory Youdan, L. Sheeran, L. Quinn, M. Busse
Background Wearable technology can provide detailed information about physical activity (PA) in Huntington’s disease (HD). Most commercially available devices are however limited by the lack of disease specific validation and consideration of wear time. Aim To develop a methodology for accurate profiling of PA in HD. Methods We recruited 29 people with early stage HD (mean (SD) age 51.76 (10.27); 14 males) and 17 healthy controls (mean (SD) age 52.95 (10.76); 10 male) to a cross sectional multi-centre observational study. Participants used a wrist worn accelerometer for 7 days following the completion of a laboratory-based validation study. PA profiles (percentage time sedentary, low, moderate and high PA) were produced. Differences were assessed when accounting for wear time based on body temperature trends. Results HD mean (SD) device wear time over 7 days was 9783 mins (2192.84) (approx. 23.3 hours per day) and controls 7965 mins (1200.34) approx. 18.9 hours per day). When accounting for wear time HD participants were sedentary for 54% of the time and participated in light, moderate and vigorous PA for 27.2%, 17.4% and 0.43% of the time respectively. Control participants were sedentary for 61% of the time and participated in light, moderate and vigorous PA 26.6%, 11.2% and 1.2% of the time respectively. Conclusions Surprisingly HD participants were less sedentary than age matched controls. The impact of involuntary movements on the assessment of PA in HD needs to be explored. Critical to this is the importance of a wear time algorithm to identify true sedentary behaviour in comparison to non-wear.
{"title":"F64 Wearable technologies for assessment of physical activity in hd: preliminary analysis of movement variability and wear time","authors":"Vincent Poile, Gregory Youdan, L. Sheeran, L. Quinn, M. Busse","doi":"10.1136/jnnp-2018-EHDN.165","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.165","url":null,"abstract":"Background Wearable technology can provide detailed information about physical activity (PA) in Huntington’s disease (HD). Most commercially available devices are however limited by the lack of disease specific validation and consideration of wear time. Aim To develop a methodology for accurate profiling of PA in HD. Methods We recruited 29 people with early stage HD (mean (SD) age 51.76 (10.27); 14 males) and 17 healthy controls (mean (SD) age 52.95 (10.76); 10 male) to a cross sectional multi-centre observational study. Participants used a wrist worn accelerometer for 7 days following the completion of a laboratory-based validation study. PA profiles (percentage time sedentary, low, moderate and high PA) were produced. Differences were assessed when accounting for wear time based on body temperature trends. Results HD mean (SD) device wear time over 7 days was 9783 mins (2192.84) (approx. 23.3 hours per day) and controls 7965 mins (1200.34) approx. 18.9 hours per day). When accounting for wear time HD participants were sedentary for 54% of the time and participated in light, moderate and vigorous PA for 27.2%, 17.4% and 0.43% of the time respectively. Control participants were sedentary for 61% of the time and participated in light, moderate and vigorous PA 26.6%, 11.2% and 1.2% of the time respectively. Conclusions Surprisingly HD participants were less sedentary than age matched controls. The impact of involuntary movements on the assessment of PA in HD needs to be explored. Critical to this is the importance of a wear time algorithm to identify true sedentary behaviour in comparison to non-wear.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"AES-2 1","pages":"A62 - A62"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84443011","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.216
A. Nuzzi
Motor speech disorder, linguistic and cognitive difficulties, and behavioral changes significantly affect communication ability in Huntington’s disease. This progressive decline in communicative effectiveness negatively impacts social interactions resulting in diminished quality of life. However, these difficulties may vary over time and from person to person, requiring different intervention strategies based especially on the daily communication needs of HD patients and their families. The aims of this presentation are to: 1) highlight the need of a centered-person assessment of communication using the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) model; 2) overview the available speech therapy interventions in HD to support communicative abilities and participation in everyday life even in late stage. Particular attention will also be paid to the use of new technologies in Teletherapy and Augmentative and Alternative Communication (AAC).
{"title":"H38 Managing communication difficulties in huntington’s disease","authors":"A. Nuzzi","doi":"10.1136/jnnp-2018-EHDN.216","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.216","url":null,"abstract":"Motor speech disorder, linguistic and cognitive difficulties, and behavioral changes significantly affect communication ability in Huntington’s disease. This progressive decline in communicative effectiveness negatively impacts social interactions resulting in diminished quality of life. However, these difficulties may vary over time and from person to person, requiring different intervention strategies based especially on the daily communication needs of HD patients and their families. The aims of this presentation are to: 1) highlight the need of a centered-person assessment of communication using the World Health Organization’s International Classification of Functioning, Disability and Health (ICF) model; 2) overview the available speech therapy interventions in HD to support communicative abilities and participation in everyday life even in late stage. Particular attention will also be paid to the use of new technologies in Teletherapy and Augmentative and Alternative Communication (AAC).","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"4 1","pages":"A80 - A80"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88352562","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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