Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.35
P. Dušek, M. Rodinová, I. Lišková, J. Klempír, J. Zeman, J. Roth, H. Hansíková
Alterations in mitochondrial parameteres are an important hallmark of Huntington’s disease (HD). Given the ubiquitous expression of mutant huntingtin raises the prospect that mitochondrial disturbancies can be detected and monitored also in buccal epithelial cells. In a group of 34 patients with Huntington’s disease and a group of 22 age-related healthy volunteers, respiratory complex I and IV protein quantities in buccal epithelial cells were measured using dipstick immunocapture assay. The protein quantity of respiratory complex I is correlated with age (r=0.427, p=0.026, FWE-p=0.156) in the patient group, but not in the group of healthy subjects. Our non-invasive approach allows to obtain valuable materials for studies on mitochondrial biochemical parameters in patients with neurodegenerative diseases and could be be useful in epidemiological studies.
{"title":"A37 Buccal respiratory chain complexes I and IV quantities in huntington’s disease patients","authors":"P. Dušek, M. Rodinová, I. Lišková, J. Klempír, J. Zeman, J. Roth, H. Hansíková","doi":"10.1136/jnnp-2018-EHDN.35","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.35","url":null,"abstract":"Alterations in mitochondrial parameteres are an important hallmark of Huntington’s disease (HD). Given the ubiquitous expression of mutant huntingtin raises the prospect that mitochondrial disturbancies can be detected and monitored also in buccal epithelial cells. In a group of 34 patients with Huntington’s disease and a group of 22 age-related healthy volunteers, respiratory complex I and IV protein quantities in buccal epithelial cells were measured using dipstick immunocapture assay. The protein quantity of respiratory complex I is correlated with age (r=0.427, p=0.026, FWE-p=0.156) in the patient group, but not in the group of healthy subjects. Our non-invasive approach allows to obtain valuable materials for studies on mitochondrial biochemical parameters in patients with neurodegenerative diseases and could be be useful in epidemiological studies.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"37 1","pages":"A13 - A13"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79833958","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.174
J. Simpson, Alistair Smith, F. Eccles, Siofra Peeren, D. Rogers, Z. Skitt, Rachael Theed, L. Rose, Max Homberger, Kristian Glenny, D. Craufurd
Background Psychological difficulties such as low mood, anxiety and irritability are common in people with the Huntington’s disease (HD) gene, both pre-manifest and manifest. Whilst, medication can sometimes alleviate these difficulties it is not always effective or preferred. Mindfulness based cognitive therapy (MBCT) may offer an alternative or additional approach for reducing distress. Aims To see if MBCT is an acceptable and useful way of alleviating psychological distress for pre-manifest people with the HD gene and to investigate these outcomes up to one year post the intervention. Methods An 8 week course of MBCT was completed by 12 pre-manifest participants in two groups. Participants were then invited to attend 3 reunion meetings over the year in which the principles of the course were revisited. Quantitative measures of anxiety, depression, stress and mindfulness were administered pre-course, post-course, 3 months post-course, and at one year post-course. Qualitative data about participants’ experiences were collected immediately after the course and at one year. Results Significant changes in some aspects of mindfulness (particularly non-judging and non-reacting) were seen at all points in follow up, although little change was seen in measures of distress. Interviews at immediate follow up suggested that participants found the course acceptable and useful. Most participants attended the reunion meetings and found these helpful both for supporting their mindfulness practice and for maintaining connection with other pre-manifest individuals. Participants were still using some aspects of mindfulness in their daily lives at one year and for some it had resulted in marked changes in their well-being. Conclusions Learning mindfulness is possible and can be beneficial for pre-manifest individuals, with some learning and benefits retained after a year. Larger samples are needed including those with higher baseline depression, to show if it can significantly reduce psychological distress. Some recruitment difficulties were encountered and different ways of delivering the courses may need to be considered.
{"title":"F77 A pilot evaluation of mindfulness-based cognitive therapy for pre-manifest people with the huntington’s disease gene–findings at one year","authors":"J. Simpson, Alistair Smith, F. Eccles, Siofra Peeren, D. Rogers, Z. Skitt, Rachael Theed, L. Rose, Max Homberger, Kristian Glenny, D. Craufurd","doi":"10.1136/JNNP-2018-EHDN.174","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.174","url":null,"abstract":"Background Psychological difficulties such as low mood, anxiety and irritability are common in people with the Huntington’s disease (HD) gene, both pre-manifest and manifest. Whilst, medication can sometimes alleviate these difficulties it is not always effective or preferred. Mindfulness based cognitive therapy (MBCT) may offer an alternative or additional approach for reducing distress. Aims To see if MBCT is an acceptable and useful way of alleviating psychological distress for pre-manifest people with the HD gene and to investigate these outcomes up to one year post the intervention. Methods An 8 week course of MBCT was completed by 12 pre-manifest participants in two groups. Participants were then invited to attend 3 reunion meetings over the year in which the principles of the course were revisited. Quantitative measures of anxiety, depression, stress and mindfulness were administered pre-course, post-course, 3 months post-course, and at one year post-course. Qualitative data about participants’ experiences were collected immediately after the course and at one year. Results Significant changes in some aspects of mindfulness (particularly non-judging and non-reacting) were seen at all points in follow up, although little change was seen in measures of distress. Interviews at immediate follow up suggested that participants found the course acceptable and useful. Most participants attended the reunion meetings and found these helpful both for supporting their mindfulness practice and for maintaining connection with other pre-manifest individuals. Participants were still using some aspects of mindfulness in their daily lives at one year and for some it had resulted in marked changes in their well-being. Conclusions Learning mindfulness is possible and can be beneficial for pre-manifest individuals, with some learning and benefits retained after a year. Larger samples are needed including those with higher baseline depression, to show if it can significantly reduce psychological distress. Some recruitment difficulties were encountered and different ways of delivering the courses may need to be considered.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"58 1","pages":"A65 - A66"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77883643","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.236
E. Burnip, E. Wallace, Kristin Gozdzikowska, Maggie-Lee Huckabee
Background Huntington’s Disease (HD) is an autosomal dominant progressive neurodegenerative disease characterised by cognitive, motor and behavioural impairments. Corticobulbar symptoms (including speech and swallowing changes) have been reported in all stages of the disease, with aspiration pneumonia reported as the most common cause of death. There has been a recent shift to examine corticobulbar rehabilitation in other neurodegenerative conditions. Aims This systematic review will determine if evidence exists to justify rehabilitation for corticobulbar symptoms in HD. Methods Two investigators independently searched relevant electronic databases for literature related to corticobulbar rehabilitation in HD, published in English until April 2017. Included studies were critically appraised using the OCEBM Levels of Evidence, Cochrane Risk of Bias Tool and Scottish Intercollegiate Guidelines Network checklists. Primary outcomes included reported changes in function or neuromuscular physiology evidenced by validated measures. Results Sixty-eight publications were screened. Three studies were excluded as they described compensatory management only. Eight studies matched the inclusion criteria. Two randomised control trials and six intervention studies evaluated rehabilitative approaches aiming to improve corticobulbar symptoms; however; there was limited use of validated or objective outcome measures. Conclusions The few studies which focused on the effectiveness of rehabilitation programs in HD indicated no adverse effects and positive clinical outcomes were reported. As corticobulbar symptoms and associated pneumonia are among the most debilitating in terms of quality of life and caregiver burden, this review highlights the need for further research into the feasibility and potential of rehabilitation approaches for speech and swallowing changes in HD.
{"title":"H58 A systematic review of rehabilitation for corticobulbar symptoms in adults with huntington’s disease","authors":"E. Burnip, E. Wallace, Kristin Gozdzikowska, Maggie-Lee Huckabee","doi":"10.1136/jnnp-2018-EHDN.236","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.236","url":null,"abstract":"Background Huntington’s Disease (HD) is an autosomal dominant progressive neurodegenerative disease characterised by cognitive, motor and behavioural impairments. Corticobulbar symptoms (including speech and swallowing changes) have been reported in all stages of the disease, with aspiration pneumonia reported as the most common cause of death. There has been a recent shift to examine corticobulbar rehabilitation in other neurodegenerative conditions. Aims This systematic review will determine if evidence exists to justify rehabilitation for corticobulbar symptoms in HD. Methods Two investigators independently searched relevant electronic databases for literature related to corticobulbar rehabilitation in HD, published in English until April 2017. Included studies were critically appraised using the OCEBM Levels of Evidence, Cochrane Risk of Bias Tool and Scottish Intercollegiate Guidelines Network checklists. Primary outcomes included reported changes in function or neuromuscular physiology evidenced by validated measures. Results Sixty-eight publications were screened. Three studies were excluded as they described compensatory management only. Eight studies matched the inclusion criteria. Two randomised control trials and six intervention studies evaluated rehabilitative approaches aiming to improve corticobulbar symptoms; however; there was limited use of validated or objective outcome measures. Conclusions The few studies which focused on the effectiveness of rehabilitation programs in HD indicated no adverse effects and positive clinical outcomes were reported. As corticobulbar symptoms and associated pneumonia are among the most debilitating in terms of quality of life and caregiver burden, this review highlights the need for further research into the feasibility and potential of rehabilitation approaches for speech and swallowing changes in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"29 1","pages":"A88 - A88"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91540743","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.34
Petra Šmatlíková, Georgina Askeland, M. Vaškovicová, J. Klíma, J. Motlík, L. Eide, Z. Ellederová
Background Huntington´s disease (HD) is devastating neurodegenerative disorder caused by the mutation in huntingtin gene. One of the largest contributors to HD pathology represents oxidative stress, though the exact mechanism of its cause remains unclear. Molecular characterization of a unique porcine model of HD could serve for better understanding of the disease pathogenesis as well as for better evaluation of the therapeutic efficiency of preclinical studies on this large animal model. Aims In this study, we focused on the investigation of molecular and cellular features of fibroblasts isolated from transgenic minipigs expressing N-terminal part of human mutated huntingtin (TgHD) and the wild type (WT) siblings at different age, pre-symptomatic 24–36 months old and with starting behavioural symptoms at the age of 48 months. Methods We investigated the levels of oxidative stress, the expression of oxidative stress related genes, proliferation capacity along with the expression of cyclin B1 and D1 proteins, cellular permeability, as well as nuclear and mitochondrial DNA damage in these cells. Results TgHD fibroblasts isolated from 48 months old animals showed elevated levels of oxidative stress, overexpression of SOD2 gene, encoding a key mitochondria antioxidant, and NEIL3 gene, encoding DNA glycosylase involved in replication associated repair of DNA damaged by oxidative stress. These cells also displayed aberrant proliferation capacity and permeability. We further demonstrated preceded increased level of nuclear DNA damage in TgHD fibroblasts (isolated from 24–36 months old animals) indicating earlier aging of these cells. Conclusions Our results suggest the age of 48 months of TgHD minipig model to be a breakpoint in developing molecular phenotype of HD along with changes in behaviour. Furthermore, this work proposes TgHD minipigs as a suitable large animal model for studying molecular mechanisms occurring gradually in HD pathophysiology with age.
{"title":"A36 Gradual accumulation of oxidative stress and its aspects in primary porcine fibroblasts expressing mutated huntingtin","authors":"Petra Šmatlíková, Georgina Askeland, M. Vaškovicová, J. Klíma, J. Motlík, L. Eide, Z. Ellederová","doi":"10.1136/jnnp-2018-EHDN.34","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.34","url":null,"abstract":"Background Huntington´s disease (HD) is devastating neurodegenerative disorder caused by the mutation in huntingtin gene. One of the largest contributors to HD pathology represents oxidative stress, though the exact mechanism of its cause remains unclear. Molecular characterization of a unique porcine model of HD could serve for better understanding of the disease pathogenesis as well as for better evaluation of the therapeutic efficiency of preclinical studies on this large animal model. Aims In this study, we focused on the investigation of molecular and cellular features of fibroblasts isolated from transgenic minipigs expressing N-terminal part of human mutated huntingtin (TgHD) and the wild type (WT) siblings at different age, pre-symptomatic 24–36 months old and with starting behavioural symptoms at the age of 48 months. Methods We investigated the levels of oxidative stress, the expression of oxidative stress related genes, proliferation capacity along with the expression of cyclin B1 and D1 proteins, cellular permeability, as well as nuclear and mitochondrial DNA damage in these cells. Results TgHD fibroblasts isolated from 48 months old animals showed elevated levels of oxidative stress, overexpression of SOD2 gene, encoding a key mitochondria antioxidant, and NEIL3 gene, encoding DNA glycosylase involved in replication associated repair of DNA damaged by oxidative stress. These cells also displayed aberrant proliferation capacity and permeability. We further demonstrated preceded increased level of nuclear DNA damage in TgHD fibroblasts (isolated from 24–36 months old animals) indicating earlier aging of these cells. Conclusions Our results suggest the age of 48 months of TgHD minipig model to be a breakpoint in developing molecular phenotype of HD along with changes in behaviour. Furthermore, this work proposes TgHD minipigs as a suitable large animal model for studying molecular mechanisms occurring gradually in HD pathophysiology with age.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"9 1","pages":"A13 - A13"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80764601","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.203
L. McCabe, J. Eden
In partnership Scottish Huntington’s Association and Stirling University developed a Continuous Professional Development Module which delivers 200 hours of blended learning in HD. The course takes the unique approach if integrating family stories and experiences with five models of care: person centred, family systems, biopsychosocial, personalisation and palliative care. The course focuses on the lived experience of HD and how these models can assist health and social care practitioners to support and enable families to enhance their quality of life. The module won the Scottish Council for Voluntary Organisations Award for best partnership in 2015 and we are currently working with Lancashire University to extend the course to practitioners in England and Wales.
{"title":"H24 Continuous professional development in hd: learning to support and empower families","authors":"L. McCabe, J. Eden","doi":"10.1136/jnnp-2018-EHDN.203","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.203","url":null,"abstract":"In partnership Scottish Huntington’s Association and Stirling University developed a Continuous Professional Development Module which delivers 200 hours of blended learning in HD. The course takes the unique approach if integrating family stories and experiences with five models of care: person centred, family systems, biopsychosocial, personalisation and palliative care. The course focuses on the lived experience of HD and how these models can assist health and social care practitioners to support and enable families to enhance their quality of life. The module won the Scottish Council for Voluntary Organisations Award for best partnership in 2015 and we are currently working with Lancashire University to extend the course to practitioners in England and Wales.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"29 1","pages":"A76 - A76"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73456115","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.157
I. Mcmillan, D. McLauchlan, M. Busse, A. Bachoud-Lévi, R. Reilmann, A. Rosser, D. Craufurd
Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to functional impairment. Low mood, anxiety and irritability can all occur many years before motor onset, but are also common in the general population. Apathy and perseveration (repetitive thinking or behavior) can occur before motor onset, but usually appear after diagnosis and are worst from stage 3 onwards. Previous studies have found that apathy correlates with motor and cognitive measures of disease progression, while the mood disorder does not. Methods One of the objectives of the Repair-HD study was to develop and validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes a psychiatric interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures. The 12-month follow-up is now complete and analysis underway. We report a preliminary analysis of data from the baseline psychiatric measures. Results Cases (N=73) and controls (N=50) differed significantly for PBA-s apathy (p<0.001), anger (p<0.05), repetitive behavior (p<0.001), modified total PBA score (mPBA) (p<0.001) and the extended 7-item PBA-s composite apathy score (p<0.001), but not for the composite affect score. In patients, Total Functional Capacity (TFC) scores correlated significantly with apathy (rs=−0.415, p<0.001), composite apathy (rs=−0.459, p<0.01), repetitive behaviours (rs=−0.326, p<0.01) and mPBA (rs=−0.265, p<0.05), but not the affect or anger scores. Significant differences between cases and controls and significant correlations with TFC scores were also found with the Apathy subscale of the Frontal Systems Behaviour Scale (FrSBe) and the Apathy Evaluation Scale (AES), but not with PRO measures of anxiety, depression or irritability. Conclusions This preliminary analysis confirms that apathy and perseveration correlate with disease stage, while disorders of mood (depression and anxiety) and irritability are more variable over time, and from person to person. This may reflect the complex aetiology of affective symptoms, involving psychological variables and variation in genetic susceptibility as well as HD. Symptomatic treatment with antidepressants may also mask any relationship with disease progression.
{"title":"F56 Psychiatric symptoms in huntington’s disease: relationship to disease stage in the CAPIT-HD2 beta-testing study","authors":"I. Mcmillan, D. McLauchlan, M. Busse, A. Bachoud-Lévi, R. Reilmann, A. Rosser, D. Craufurd","doi":"10.1136/jnnp-2018-EHDN.157","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.157","url":null,"abstract":"Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to functional impairment. Low mood, anxiety and irritability can all occur many years before motor onset, but are also common in the general population. Apathy and perseveration (repetitive thinking or behavior) can occur before motor onset, but usually appear after diagnosis and are worst from stage 3 onwards. Previous studies have found that apathy correlates with motor and cognitive measures of disease progression, while the mood disorder does not. Methods One of the objectives of the Repair-HD study was to develop and validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes a psychiatric interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures. The 12-month follow-up is now complete and analysis underway. We report a preliminary analysis of data from the baseline psychiatric measures. Results Cases (N=73) and controls (N=50) differed significantly for PBA-s apathy (p<0.001), anger (p<0.05), repetitive behavior (p<0.001), modified total PBA score (mPBA) (p<0.001) and the extended 7-item PBA-s composite apathy score (p<0.001), but not for the composite affect score. In patients, Total Functional Capacity (TFC) scores correlated significantly with apathy (rs=−0.415, p<0.001), composite apathy (rs=−0.459, p<0.01), repetitive behaviours (rs=−0.326, p<0.01) and mPBA (rs=−0.265, p<0.05), but not the affect or anger scores. Significant differences between cases and controls and significant correlations with TFC scores were also found with the Apathy subscale of the Frontal Systems Behaviour Scale (FrSBe) and the Apathy Evaluation Scale (AES), but not with PRO measures of anxiety, depression or irritability. Conclusions This preliminary analysis confirms that apathy and perseveration correlate with disease stage, while disorders of mood (depression and anxiety) and irritability are more variable over time, and from person to person. This may reflect the complex aetiology of affective symptoms, involving psychological variables and variation in genetic susceptibility as well as HD. Symptomatic treatment with antidepressants may also mask any relationship with disease progression.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"127 1","pages":"A59 - A59"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72863557","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.241
Astrid Valls, C. Brouwers, Roberta Pintauro, J. Snapper, B. Bohuslavova, Marina Sogorb-González, V. Fodale, A. Bresciani, Z. Ellederová, B. Blits, J. Motlík, S. Deventer, M. Evers, P. Konstantinova
Background HTT-lowering therapies hold great promise to slow-down or halt neurodegeneration in Huntington disease (HD). We have developed an engineered microRNA targeting human huntingtin (HTT), delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT), leading to efficient HTT-lowering in vitro and in vivo in rodent models. Aim To assess the translatability of our approach in a large animal model: transgenic HD (tgHD) minipigs. Methods Animals were injected with AAV5-miHTT (1.2 × 1013 gc/brain), bilaterally into striatum (caudate and putamen) and sacrificed 6 months post-treatment. Across different brain regions, vector DNA, miHTT and mutant HTT (mHTT) mRNA were measured by Q-PCR, and mHTT protein using an ultrasensitive immunoassay. In longitudinal cerebrospinal fluid (CSF) samples, miHTT and mHTT protein expression were assessed by Q-PCR and ultrasensitive immunoassay, respectively. Results Widespread brain biodistribution of vector DNA was observed, with the highest levels in target (striatal) regions but also in thalamus and cortical regions, in both grey and white matter. Expression of miHTT was highly correlated with vector DNA in all brain areas. Corresponding to the vector DNA and miHTT expression, a reduction of mHTT mRNA and protein was observed in AAV5-miHTT treated animals with respect to controls. mHTT protein lowering was on average more than 75% in the injected areas, and between 30–50% in most of the distal regions. Translational pharmacokinetic and pharmacodynamic measures in the CSF were in line with the effects observed in the brain. We detected CSF miHTT, and CSF mHTT protein lowering up to 50% at 3 and 70% at 6 months post-dosing. Conclusions This study demonstrates widespread biodistribution and durable efficiency of AAV5-miHTT in disease-relevant regions in a large brain, and the potential of CSF translational measures to follow-up efficacy.
{"title":"I05 Sustained mutant huntingtin lowering in the brain and cerebrospinal fluid of huntington disease minipigs mediated by AAV5-MIHTT gene therapy","authors":"Astrid Valls, C. Brouwers, Roberta Pintauro, J. Snapper, B. Bohuslavova, Marina Sogorb-González, V. Fodale, A. Bresciani, Z. Ellederová, B. Blits, J. Motlík, S. Deventer, M. Evers, P. Konstantinova","doi":"10.1136/jnnp-2018-EHDN.241","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.241","url":null,"abstract":"Background HTT-lowering therapies hold great promise to slow-down or halt neurodegeneration in Huntington disease (HD). We have developed an engineered microRNA targeting human huntingtin (HTT), delivered via adeno-associated viral vector serotype 5 (AAV5-miHTT), leading to efficient HTT-lowering in vitro and in vivo in rodent models. Aim To assess the translatability of our approach in a large animal model: transgenic HD (tgHD) minipigs. Methods Animals were injected with AAV5-miHTT (1.2 × 1013 gc/brain), bilaterally into striatum (caudate and putamen) and sacrificed 6 months post-treatment. Across different brain regions, vector DNA, miHTT and mutant HTT (mHTT) mRNA were measured by Q-PCR, and mHTT protein using an ultrasensitive immunoassay. In longitudinal cerebrospinal fluid (CSF) samples, miHTT and mHTT protein expression were assessed by Q-PCR and ultrasensitive immunoassay, respectively. Results Widespread brain biodistribution of vector DNA was observed, with the highest levels in target (striatal) regions but also in thalamus and cortical regions, in both grey and white matter. Expression of miHTT was highly correlated with vector DNA in all brain areas. Corresponding to the vector DNA and miHTT expression, a reduction of mHTT mRNA and protein was observed in AAV5-miHTT treated animals with respect to controls. mHTT protein lowering was on average more than 75% in the injected areas, and between 30–50% in most of the distal regions. Translational pharmacokinetic and pharmacodynamic measures in the CSF were in line with the effects observed in the brain. We detected CSF miHTT, and CSF mHTT protein lowering up to 50% at 3 and 70% at 6 months post-dosing. Conclusions This study demonstrates widespread biodistribution and durable efficiency of AAV5-miHTT in disease-relevant regions in a large brain, and the potential of CSF translational measures to follow-up efficacy.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"35 1","pages":"A89 - A90"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76654298","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.183
D. Rae, A. McDermott, Z. Miedzybrodzka, K. Gillies
Background The production of meaningful evidence about the effectiveness of complex care delivery interventions requires clear definition and consistent use of outcomes that matter to key stakeholders (service users and professionals). Outcomes for the evaluation of such interventions in multifaceted neurodegenerative progressive conditions, such as Huntington’s disease (HD) have not been previously reviewed. Objective The objectives of this article are 1) to comprehensively map outcomes reported in the existing literature on care delivery interventions in HD and 2) to identify any convergences/divergences in patterns and stakeholder perspectives across the identified outcomes. Main results A total of 16 studies and supplementary documents were identified measuring 48 outcomes. These were categorised into three outcome categories, 34 outcome types and 47 variables. Only two outcome types, ’Specialist Knowledge and understanding’ and ’Confidence’, previously suggested by service users as important (n=10) were considered in formal care delivery evaluations. Conclusion A large number of outcomes are currently measured and suggested in the evaluation and description of care delivery in HD. This outcome map highlights the inconsistent use of outcomes important to and suggested by key stakeholders. Clear understanding of what intervention mechanisms and interactions may be relevant (and to whom) and produce desired outcomes is missing in existing literature.
{"title":"H02 Outcome mapping for care delivery interventions for huntington’s disease patients in the community","authors":"D. Rae, A. McDermott, Z. Miedzybrodzka, K. Gillies","doi":"10.1136/jnnp-2018-EHDN.183","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.183","url":null,"abstract":"Background The production of meaningful evidence about the effectiveness of complex care delivery interventions requires clear definition and consistent use of outcomes that matter to key stakeholders (service users and professionals). Outcomes for the evaluation of such interventions in multifaceted neurodegenerative progressive conditions, such as Huntington’s disease (HD) have not been previously reviewed. Objective The objectives of this article are 1) to comprehensively map outcomes reported in the existing literature on care delivery interventions in HD and 2) to identify any convergences/divergences in patterns and stakeholder perspectives across the identified outcomes. Main results A total of 16 studies and supplementary documents were identified measuring 48 outcomes. These were categorised into three outcome categories, 34 outcome types and 47 variables. Only two outcome types, ’Specialist Knowledge and understanding’ and ’Confidence’, previously suggested by service users as important (n=10) were considered in formal care delivery evaluations. Conclusion A large number of outcomes are currently measured and suggested in the evaluation and description of care delivery in HD. This outcome map highlights the inconsistent use of outcomes important to and suggested by key stakeholders. Clear understanding of what intervention mechanisms and interactions may be relevant (and to whom) and produce desired outcomes is missing in existing literature.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"172 1","pages":"A69 - A69"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85564308","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.52
J. Henningsen, Barbara Baldo, M. Björkqvist, Å. Petersén
Background In Huntington disease (HD), the typical motor symptoms are associated with selective degeneration of striatal neurons. Importantly, non-motor aspects develop earlier and include changes in sleep and circadian rhythm, metabolic dysfunction and psychiatric symptoms. Recent studies point to selective vulnerability also of the lateral hypothalamic area (LHA) in HD, which may mediate several of the non-motor features of HD. Excitotoxicity, i.e. excessive glutamate signaling, has been linked to striatal degeneration in HD. Similar to the striatum, LHA receives glutamatergic synaptic inputs and excitotoxicity could thus be an important driving force in the development of LHA neuropathology. Aims The aim of the study is to determine if excitotoxicity plays a role in the development of LHA neuropathology. Methods Quantitative real time polymerase chain reaction (qRT-PCR) was used to assess mRNA levels of different components of the glutamate signaling machinery in the LHA of tissue dissected from the transgenic R6/2 and the BACHD mouse models as well as from mice expressing mutant huntingtin selectively in the hypothalamus using an adeno-associated viral vector approach. Vulnerability to exposure of intra-hypothalamic injections of the excitotoxin quinolinic acid was moreover evaluated in the same HD mouse models. Results We detected changes in mRNA levels of several markers involved in glutamate signaling in the LHA. In our model of LHA excitotoxicity, we found that neurons expressing melanin concentrating hormone but not orexin were sensitive to excitotoxicity. Interestingly, orexin neurons in the R6/2 mouse model displays increased sensitivity to excitotoxicity. Conclusions Excitotoxicity may play a role in the vulnerability of orexin neurons to the expression of mutant huntingtin in HD.
{"title":"A54 The role of excitotoxicity for neuropathology in the lateral hypothalamus in mouse models of huntington disease","authors":"J. Henningsen, Barbara Baldo, M. Björkqvist, Å. Petersén","doi":"10.1136/jnnp-2018-EHDN.52","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.52","url":null,"abstract":"Background In Huntington disease (HD), the typical motor symptoms are associated with selective degeneration of striatal neurons. Importantly, non-motor aspects develop earlier and include changes in sleep and circadian rhythm, metabolic dysfunction and psychiatric symptoms. Recent studies point to selective vulnerability also of the lateral hypothalamic area (LHA) in HD, which may mediate several of the non-motor features of HD. Excitotoxicity, i.e. excessive glutamate signaling, has been linked to striatal degeneration in HD. Similar to the striatum, LHA receives glutamatergic synaptic inputs and excitotoxicity could thus be an important driving force in the development of LHA neuropathology. Aims The aim of the study is to determine if excitotoxicity plays a role in the development of LHA neuropathology. Methods Quantitative real time polymerase chain reaction (qRT-PCR) was used to assess mRNA levels of different components of the glutamate signaling machinery in the LHA of tissue dissected from the transgenic R6/2 and the BACHD mouse models as well as from mice expressing mutant huntingtin selectively in the hypothalamus using an adeno-associated viral vector approach. Vulnerability to exposure of intra-hypothalamic injections of the excitotoxin quinolinic acid was moreover evaluated in the same HD mouse models. Results We detected changes in mRNA levels of several markers involved in glutamate signaling in the LHA. In our model of LHA excitotoxicity, we found that neurons expressing melanin concentrating hormone but not orexin were sensitive to excitotoxicity. Interestingly, orexin neurons in the R6/2 mouse model displays increased sensitivity to excitotoxicity. Conclusions Excitotoxicity may play a role in the vulnerability of orexin neurons to the expression of mutant huntingtin in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"34 1","pages":"A19 - A20"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88160542","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.78
J. Sipilä, S. Ylönen, K. Majamaa
Background Variation in the prevalence of Huntington’s disease (HD) is associated with differences in chromosome 4 haplogroup proportions between populations. No data have been published on mutant HTT (mHTT) repeat stability in different haplogroups. Aim To study intergenerational CAG repeat stability in different mHTT haplotypes. Methods A previously identified Finnish cohort of 207 HD patients and data on mHTT repeat lengths obtained from the diagnostic laboratories were used as a basis to identify parent-offspring pairs using several national registries. DNA remaining from diagnostic testing was analysed to determine haplogroups defined by the SNPs rs762855 and rs4690073. Haplogroup A haplotypes were further defined using four additional SNPs, rs2857936, rs363096, rs2276881 and rs362307. (Warby et al. 2009) The SNPs were determined either with restriction fragment analysis, allele specific amplification using locked nucleic acid primers or by sequencing. Results mHTT haplogroup and CAG repeat could be phased in 49 transmissions (haplogroup A, 38; haplogroup C, 10; other haplogroup, 1). The mean change in the length of CAG repeats differed between haplogroups A and C in paternal inheritances (p=0.038), but not in maternal inheritances (p=0.17). The change in haplogroup C was negative in paternal as well as maternal transmissions (p=0.74 for difference; figure 1), whereas the repeats in haplogroup A expanded in paternal transmissions in comparison to maternal transmissions (p=0.008). The difference was most obvious in haplotype A1 inheritances (p=0.022).Abstract C07 Figure 1 The mean change (%) in the length of CAG repeats in haplogroups A and C in paternal and maternal transmissions Conclusions Intergenerational stability of the CAG repeat differed between mHTT haplogroups in a sex-dependent manner.
背景亨廷顿氏病(HD)患病率的差异与人群间4号染色体单倍群比例的差异有关。在不同单倍群中，没有关于突变HTT (mHTT)重复稳定性的数据发表。目的研究不同mHTT单倍型CAG重复序列的代际稳定性。方法使用先前确定的207名芬兰HD患者队列和从诊断实验室获得的mHTT重复长度数据作为使用几个国家登记处识别父母-后代对的基础。分析诊断测试留下的DNA以确定snp rs762855和rs4690073定义的单倍群。单倍群A单倍型进一步定义了另外四个snp, rs2857936, rs363096, rs2276881和rs362307。(Warby et al. 2009)通过限制性内切酶片段分析、锁定核酸引物进行等位基因特异性扩增或测序来确定snp。结果mHTT单倍群和CAG重复序列可分49次传递(单倍群A, 38次;C单倍群，10;A和C单倍群在父系遗传中CAG重复序列长度的平均变化差异较大(p=0.038)，而在母系遗传中无差异(p=0.17)。单倍群C在父本和母本传播中均为负变化(p=0.74;图1)，而单倍群A的重复数在父系传播中比母系传播中增加(p=0.008)。单倍型A1遗传差异最明显(p=0.022)。图1父系和母系遗传中单倍群A和C中CAG重复序列长度的平均变化(%)结论mHTT单倍群之间CAG重复序列的代际稳定性存在性别依赖性。
{"title":"C07 Intergenerational cag stability across chromosome 4 haplogroups","authors":"J. Sipilä, S. Ylönen, K. Majamaa","doi":"10.1136/jnnp-2018-EHDN.78","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.78","url":null,"abstract":"Background Variation in the prevalence of Huntington’s disease (HD) is associated with differences in chromosome 4 haplogroup proportions between populations. No data have been published on mutant HTT (mHTT) repeat stability in different haplogroups. Aim To study intergenerational CAG repeat stability in different mHTT haplotypes. Methods A previously identified Finnish cohort of 207 HD patients and data on mHTT repeat lengths obtained from the diagnostic laboratories were used as a basis to identify parent-offspring pairs using several national registries. DNA remaining from diagnostic testing was analysed to determine haplogroups defined by the SNPs rs762855 and rs4690073. Haplogroup A haplotypes were further defined using four additional SNPs, rs2857936, rs363096, rs2276881 and rs362307. (Warby et al. 2009) The SNPs were determined either with restriction fragment analysis, allele specific amplification using locked nucleic acid primers or by sequencing. Results mHTT haplogroup and CAG repeat could be phased in 49 transmissions (haplogroup A, 38; haplogroup C, 10; other haplogroup, 1). The mean change in the length of CAG repeats differed between haplogroups A and C in paternal inheritances (p=0.038), but not in maternal inheritances (p=0.17). The change in haplogroup C was negative in paternal as well as maternal transmissions (p=0.74 for difference; figure 1), whereas the repeats in haplogroup A expanded in paternal transmissions in comparison to maternal transmissions (p=0.008). The difference was most obvious in haplotype A1 inheritances (p=0.022).Abstract C07 Figure 1 The mean change (%) in the length of CAG repeats in haplogroups A and C in paternal and maternal transmissions Conclusions Intergenerational stability of the CAG repeat differed between mHTT haplogroups in a sex-dependent manner.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"29 1","pages":"A29 - A29"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88633748","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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