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.98
E. Coppen, A. Hafkemeijer, J. Grond, J. B. Wolf, R. Roos
Background Striatal atrophy is associated with choreatic movements in Huntington’s disease (HD). However, other symptoms of HD might be related to cortical degeneration. Thinning of the occipital lobe has been linked to visual processing deficits, but the posterior cerebral cortex has not been the primary focus of interest in previous HD research. Aims To improve the understanding of structural and functional alterations in the posterior cerebral cortex in HD using different neuroimaging modalities and visual cognitive task performance. Methods Structural and functional MRI data were acquired from 18 healthy controls, 21 premanifest, and 20 manifest HD gene carriers. Voxel-based morphometry analysis and cortical thickness measurements were performed to assess structural changes in cortical regions that are involved in visual processing. Brain function was measured by assessing neuronal connectivity in response to visual stimulation and at rest in visual resting-state networks. Multiple linear regression analyses were performed to assess associations with visuoperceptual and visuospatial function. Results Compared to controls, pronounced atrophy and decreased neuronal function at rest were present in associative visual cortices in manifest HD. The primary visual cortex did not show group differences in cortical thickness and in functional connectivity after visual stimulation. Thinning of the associative visual cortex was related to worse visuoperceptual function. Premanifest HD gene carriers did not show any differences in brain structure or function compared to controls. Conclusion This study suggests that neurodegeneration in associative visual cortices is present in early HD and is linked to clinical visual deficits, while structure and function of the primary visual cortex remains relatively preserved. Our findings can aid in the identification of other regions than the striatum that can be used as a marker of disease severity for future clinical trials.
{"title":"E04 Structure and function of the posterior cerebral cortex in huntington’s disease","authors":"E. Coppen, A. Hafkemeijer, J. Grond, J. B. Wolf, R. Roos","doi":"10.1136/jnnp-2018-EHDN.98","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.98","url":null,"abstract":"Background Striatal atrophy is associated with choreatic movements in Huntington’s disease (HD). However, other symptoms of HD might be related to cortical degeneration. Thinning of the occipital lobe has been linked to visual processing deficits, but the posterior cerebral cortex has not been the primary focus of interest in previous HD research. Aims To improve the understanding of structural and functional alterations in the posterior cerebral cortex in HD using different neuroimaging modalities and visual cognitive task performance. Methods Structural and functional MRI data were acquired from 18 healthy controls, 21 premanifest, and 20 manifest HD gene carriers. Voxel-based morphometry analysis and cortical thickness measurements were performed to assess structural changes in cortical regions that are involved in visual processing. Brain function was measured by assessing neuronal connectivity in response to visual stimulation and at rest in visual resting-state networks. Multiple linear regression analyses were performed to assess associations with visuoperceptual and visuospatial function. Results Compared to controls, pronounced atrophy and decreased neuronal function at rest were present in associative visual cortices in manifest HD. The primary visual cortex did not show group differences in cortical thickness and in functional connectivity after visual stimulation. Thinning of the associative visual cortex was related to worse visuoperceptual function. Premanifest HD gene carriers did not show any differences in brain structure or function compared to controls. Conclusion This study suggests that neurodegeneration in associative visual cortices is present in early HD and is linked to clinical visual deficits, while structure and function of the primary visual cortex remains relatively preserved. Our findings can aid in the identification of other regions than the striatum that can be used as a marker of disease severity for future clinical trials.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"64 1","pages":"A36 - A37"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74072713","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.264
D. Claassen, M. Edmondson, R. Reilmann, N. Svrzikapa, K. Longo, J. Goyal, S. Hung, M. Panzara
Background Expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the Huntingtin (HTT) gene causes HD through production and accumulation of mutant HTT (mHTT) protein, leading to progressive loss of neurons in the brain. The pathogenic CAG repeat has been linked to certain SNPs, allowing the possibility of targeting SNPs to lower mHTT protein without impacting wild-type HTT (wtHTT) protein, which is essential for neuronal development and homeostasis. Aim To determine the frequency of the thymine (T) variant of rs362307 (SNP1) or rs362331 (SNP2) on the same HTT allele as the pathogenic CAG triplet repeat expansion in patients with HD. Methods Across 7 US sites, HD patients (aged 25–65 years) with United HD Rating Scale Total Functional Capacity scores of 7–13 are eligible to enroll. Blood samples are collected at 1 clinic visit and processed in 3 steps at a central laboratory. The first step confirms the number and size of CAG repeats in DNA samples, using polymerase chain reaction and Bioanalyzer, respectively. The second step determines the presence of SNPs (heterozygosity) via Sanger sequencing. Finally, samples with CAG repeats ≥36 and SNP heterozygosity are assessed to determine whether the SNP is present (phased) on the mHTT allele using RNA samples and a long-range sequencing investigational assay. Results A total of 203 HD patients have been enrolled and 199 DNA samples processed. All patients had confirmation of HD diagnosis with ≥36 CAG repeats (median, 44.36; range, 38–62). Heterozygosity was identified in 144 (72%) patients. Phasing results are available for 104 patients, of which, 88 (85%) had SNP1 (n=40), SNP2 (n=21), or both (n=27) present on the mHTT allele. Conclusions Results indicate that over 70% of HD patients have the targeted SNPs, which is consistent with previous reports. The ability to identify and target SNPs associated with the CAG repeat may allow personalized therapy. Final phasing results will be presented.
{"title":"J04 A prospective observational study of the frequency of single nucleotide polymorphisms (SNP) in patients with huntington’s disease (hd)","authors":"D. Claassen, M. Edmondson, R. Reilmann, N. Svrzikapa, K. Longo, J. Goyal, S. Hung, M. Panzara","doi":"10.1136/JNNP-2018-EHDN.264","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.264","url":null,"abstract":"Background Expansion of a cytosine-adenine-guanine (CAG) triplet repeat in the Huntingtin (HTT) gene causes HD through production and accumulation of mutant HTT (mHTT) protein, leading to progressive loss of neurons in the brain. The pathogenic CAG repeat has been linked to certain SNPs, allowing the possibility of targeting SNPs to lower mHTT protein without impacting wild-type HTT (wtHTT) protein, which is essential for neuronal development and homeostasis. Aim To determine the frequency of the thymine (T) variant of rs362307 (SNP1) or rs362331 (SNP2) on the same HTT allele as the pathogenic CAG triplet repeat expansion in patients with HD. Methods Across 7 US sites, HD patients (aged 25–65 years) with United HD Rating Scale Total Functional Capacity scores of 7–13 are eligible to enroll. Blood samples are collected at 1 clinic visit and processed in 3 steps at a central laboratory. The first step confirms the number and size of CAG repeats in DNA samples, using polymerase chain reaction and Bioanalyzer, respectively. The second step determines the presence of SNPs (heterozygosity) via Sanger sequencing. Finally, samples with CAG repeats ≥36 and SNP heterozygosity are assessed to determine whether the SNP is present (phased) on the mHTT allele using RNA samples and a long-range sequencing investigational assay. Results A total of 203 HD patients have been enrolled and 199 DNA samples processed. All patients had confirmation of HD diagnosis with ≥36 CAG repeats (median, 44.36; range, 38–62). Heterozygosity was identified in 144 (72%) patients. Phasing results are available for 104 patients, of which, 88 (85%) had SNP1 (n=40), SNP2 (n=21), or both (n=27) present on the mHTT allele. Conclusions Results indicate that over 70% of HD patients have the targeted SNPs, which is consistent with previous reports. The ability to identify and target SNPs associated with the CAG repeat may allow personalized therapy. Final phasing results will be presented.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"13 1","pages":"A99 - A99"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75747055","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.222
L. Brabcová, J. Roth, O. Ulmanová, J. Rusz, J. Klempír, O. Horáček, M. Kolářová, P. Košková, P. Rolková, H. Božková, L. Szabó, M. Inemanová, K. Lísalová, F. Jančok, E. Růžička, H. Brožová
Background Postural and gait instability in Huntington’s disease (HD) is an essential part of the motor symptomatology causing falls which contribute to morbidity and mortality. Rehabilitation (RHB) is considered beneficial in postural and gait stability treatment. Aims We aimed to evaluate the short- and long-term effects of an inpatient multidisciplinary rehabilitation program on postural and gait stability in HD. Methods A sample of 13 subjects with HD with no severe cognitive deficit or depression underwent a 3-week specific inpatient multidisciplinary rehabilitation program focused on postural and gait stability according to a steady protocol based on typical gait and stability problems in HD. The subjects were examined at the baseline, after the completion of the RHB, and 1 month and 3 months after the program. The testing included: gait stability examination (Dynamic Gait Index; DGI), posturography examination of postural stability- Limits of Stability, tested on a stable (PSS) and 20% unstable (PSU) platform and the total motor score evaluation by Unified Huntington’s Disease Rating Scale (UHDRS). Results There was a significant 3 months lasting improvement in PSS and a significant improvement in DGI immediately after the RHB. There was no significant improvement in PSU and UHDRS total motor score. Conclusions Specific RHB methods may improve postural and gait instability in patients with early and mid-stage HD. The postural instability improvement measured by PSS persisted for at least 3 months. The gait stability improvement in DGI did not persist after 1 month. We found no improvement in PSU. This study offers a specific RHB protocol for stability training in HD.
{"title":"H44 The effects of a specific inpatient multidisciplinary rehabilitation program on postural and gait stability in huntington´s disease- a pilot study","authors":"L. Brabcová, J. Roth, O. Ulmanová, J. Rusz, J. Klempír, O. Horáček, M. Kolářová, P. Košková, P. Rolková, H. Božková, L. Szabó, M. Inemanová, K. Lísalová, F. Jančok, E. Růžička, H. Brožová","doi":"10.1136/jnnp-2018-EHDN.222","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.222","url":null,"abstract":"Background Postural and gait instability in Huntington’s disease (HD) is an essential part of the motor symptomatology causing falls which contribute to morbidity and mortality. Rehabilitation (RHB) is considered beneficial in postural and gait stability treatment. Aims We aimed to evaluate the short- and long-term effects of an inpatient multidisciplinary rehabilitation program on postural and gait stability in HD. Methods A sample of 13 subjects with HD with no severe cognitive deficit or depression underwent a 3-week specific inpatient multidisciplinary rehabilitation program focused on postural and gait stability according to a steady protocol based on typical gait and stability problems in HD. The subjects were examined at the baseline, after the completion of the RHB, and 1 month and 3 months after the program. The testing included: gait stability examination (Dynamic Gait Index; DGI), posturography examination of postural stability- Limits of Stability, tested on a stable (PSS) and 20% unstable (PSU) platform and the total motor score evaluation by Unified Huntington’s Disease Rating Scale (UHDRS). Results There was a significant 3 months lasting improvement in PSS and a significant improvement in DGI immediately after the RHB. There was no significant improvement in PSU and UHDRS total motor score. Conclusions Specific RHB methods may improve postural and gait instability in patients with early and mid-stage HD. The postural instability improvement measured by PSS persisted for at least 3 months. The gait stability improvement in DGI did not persist after 1 month. We found no improvement in PSU. This study offers a specific RHB protocol for stability training in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"88 1","pages":"A82 - A82"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79933173","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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