Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.158
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 impairment of Functional Capacity. Low mood, anxiety and irritability are common in early HD, but affective symptoms are also common in the general population and previous studies have found that the mood disorder of HD correlates poorly with motor and cognitive measures of disease progression. Apathy tends to occur later, and correlates more closely with disease progression than the mood symptoms, probably because there is no effective symptomatic treatment. Measurement of psychiatric symptoms is also confounded by anosognosia and denial, limiting the usefulness of self-report measures. Methods One of the objectives of the Repair-HD study was to validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes several psychiatric measures. These include a semi-structured interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures including the Frontal Systems Behaviour Scale (FrSBe), the Apathy Evaluation Scale (AES), the Hospital Anxiety and Depression Scale (HADS) and two PRO irritability scales. We examined correlations between the different measures of apathy, anxiety, depression, and irritability in the baseline psychiatric data. Results All four apathy measures were significantly correlated with each other (p<0.001). PBA-s irritability was significantly correlated with both PRO measures of irritability (p<0.001) but not with the FrSBe Disinhibition subscore. PBA-s and PRO measures of anxiety were also significantly correlated (p<0.001), but the PBA-s and PRO measures of depression were only weakly correlated (rs=0.19, p<0.05) suggesting that these were measuring somewhat different constructs. PBA-s depression and anxiety also correlated significantly (rs=0.38, p<0.001), as did HADS depression and anxiety (rs=0.42, p<0.001). Conclusions The interview and self-report measures used in this study were broadly consistent in this population of patients with stage 1 and stage 2 HD, with the possible exception of depression. A future analysis of changes between the baseline and 12-month assessments will examine the potential of each of these scales to measure disease progression in HD.
{"title":"F57 Psychiatric symptoms in huntington’s disease: correlations between interview and self-report measures 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.158","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.158","url":null,"abstract":"Background Psychiatric symptoms are common in Huntington’s disease (HD) and contribute significantly to impairment of Functional Capacity. Low mood, anxiety and irritability are common in early HD, but affective symptoms are also common in the general population and previous studies have found that the mood disorder of HD correlates poorly with motor and cognitive measures of disease progression. Apathy tends to occur later, and correlates more closely with disease progression than the mood symptoms, probably because there is no effective symptomatic treatment. Measurement of psychiatric symptoms is also confounded by anosognosia and denial, limiting the usefulness of self-report measures. Methods One of the objectives of the Repair-HD study was to validate a new Core Assessment Protocol for Intra-cerebral Transplantation in HD (CAPIT-HD2), which includes several psychiatric measures. These include a semi-structured interview, the Problem Behaviours Assessment for HD (PBA-s), and several Patient-Reported Outcome (PRO) measures including the Frontal Systems Behaviour Scale (FrSBe), the Apathy Evaluation Scale (AES), the Hospital Anxiety and Depression Scale (HADS) and two PRO irritability scales. We examined correlations between the different measures of apathy, anxiety, depression, and irritability in the baseline psychiatric data. Results All four apathy measures were significantly correlated with each other (p<0.001). PBA-s irritability was significantly correlated with both PRO measures of irritability (p<0.001) but not with the FrSBe Disinhibition subscore. PBA-s and PRO measures of anxiety were also significantly correlated (p<0.001), but the PBA-s and PRO measures of depression were only weakly correlated (rs=0.19, p<0.05) suggesting that these were measuring somewhat different constructs. PBA-s depression and anxiety also correlated significantly (rs=0.38, p<0.001), as did HADS depression and anxiety (rs=0.42, p<0.001). Conclusions The interview and self-report measures used in this study were broadly consistent in this population of patients with stage 1 and stage 2 HD, with the possible exception of depression. A future analysis of changes between the baseline and 12-month assessments will examine the potential of each of these scales to measure disease progression in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"49 1","pages":"A59 - A60"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86264855","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.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.73
Branduff McAllister, Thomas H. Massey, E. Rees, P. Holmans, N. Williams, L. Jones
Background CAG repeat expansions in exon 1 of the Huntingtin gene (HTT) cause Huntington’s disease (HD). Longer CAG repeat tracts correlate inversely with disease onset, but there remains considerable variation between individuals at the same repeat size (˜50%). A recent GWAS highlighted DNA repair genes as modifiers of HD onset. To improve our understanding of the effects of DNA repair genes we used whole-exome sequencing (WES) in an extreme onset cohort of HD to investigate rare coding modifiers of potentially large effect. Aims Stratify REGISTRY–HD (n˜9000) by age at motor onset Sequence the 250 earliest and 250 latest onset HD individuals Identify rare modifiers of HD onset in these patients. Methods Subjects were taken from the EHDN REGISTRY-HD study. An expected age at motor onset was calculated for each participant, and a motor onset residual was calculated by taking the CAG repeat length predicted age at onset from the observed motor onset. The 250 participants with the largest residuals at each extreme were selected for WES. Results Typical HTT alleles have a penultimate CAA triplet in their structure (5’-CAGCAACAGCCG-3’). We find individuals possessing a pure CAG tract on their expanded HTT with no interruption have exclusively early HD onset. Conversely, additional CAA interruptions are associated with late onset disease (p=0.00014). These non-canonical alleles are uncommon (5.11% MAF across all allele types) but associated with large effects (10–20 years difference in onset). Conclusions Non-canonical HTT alleles are likely cis-modifiers of disease onset. As CAG and CAA encode glutamine, these findings highlight the importance of the DNA repeat sequence itself in HD pathogenesis. We hypothesise that atypical CAG sequence modulates the propensity of the repeat to expand in neurons, affecting neurodegeneration and disease onset. We are currently exploring other next generation sequencing approaches to measure repeat instability of these atypical repeat alleles.
{"title":"C02 Exome sequencing identifies differences in repeat structure as being associated with altered onset in huntington’s patients","authors":"Branduff McAllister, Thomas H. Massey, E. Rees, P. Holmans, N. Williams, L. Jones","doi":"10.1136/jnnp-2018-EHDN.73","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.73","url":null,"abstract":"Background CAG repeat expansions in exon 1 of the Huntingtin gene (HTT) cause Huntington’s disease (HD). Longer CAG repeat tracts correlate inversely with disease onset, but there remains considerable variation between individuals at the same repeat size (˜50%). A recent GWAS highlighted DNA repair genes as modifiers of HD onset. To improve our understanding of the effects of DNA repair genes we used whole-exome sequencing (WES) in an extreme onset cohort of HD to investigate rare coding modifiers of potentially large effect. Aims Stratify REGISTRY–HD (n˜9000) by age at motor onset Sequence the 250 earliest and 250 latest onset HD individuals Identify rare modifiers of HD onset in these patients. Methods Subjects were taken from the EHDN REGISTRY-HD study. An expected age at motor onset was calculated for each participant, and a motor onset residual was calculated by taking the CAG repeat length predicted age at onset from the observed motor onset. The 250 participants with the largest residuals at each extreme were selected for WES. Results Typical HTT alleles have a penultimate CAA triplet in their structure (5’-CAGCAACAGCCG-3’). We find individuals possessing a pure CAG tract on their expanded HTT with no interruption have exclusively early HD onset. Conversely, additional CAA interruptions are associated with late onset disease (p=0.00014). These non-canonical alleles are uncommon (5.11% MAF across all allele types) but associated with large effects (10–20 years difference in onset). Conclusions Non-canonical HTT alleles are likely cis-modifiers of disease onset. As CAG and CAA encode glutamine, these findings highlight the importance of the DNA repeat sequence itself in HD pathogenesis. We hypothesise that atypical CAG sequence modulates the propensity of the repeat to expand in neurons, affecting neurodegeneration and disease onset. We are currently exploring other next generation sequencing approaches to measure repeat instability of these atypical repeat alleles.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"29 1","pages":"A27 - A27"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83659458","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.29
Laura Riggall, B. Siow, X. Golay, G. Bates
Background Currently, the concept of neuroinflammation includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. However, the roles of brain-resident and peripheral immune cells in inflammatory settings are poorly understood, and neuroinflammation has not been well investigated in either Huntington’s disease (HD) patients or equivalent preclinical models. Aims This project aims to characterise the neuroinflammatory processes occurring in the R6/2 mouse model of HD over the time-course of the disease, using a number of molecular and cellular techniques in combination with in vivo imaging modalities (magnetic resonance spectroscopy [MRS] and magnetic resonance imaging [MRI]). Methods The R6/2 mouse expresses exon 1 of the human HTT gene, containing ˜180 CAGs. To begin undertaking a time-course analysis of the disease, immunohistochemistry (IHC) and western blotting were used in R6/2 and wild type (WT) mice between the ages of four- (pre-symptomatic) and 14-weeks-old (late-stage disease) to assess the neuroinflammatory processes in HD. Results Protocol optimisations to assess microglia and astrocytes (via their hallmark proteins IBA1 and GFAP respectively), two key cell types that mediate neuroinflammatory processes, have been performed for both western blotting and IHC. Subsequently, following their assessment in R6/2 mice, microglia and astrocytes were altered in terms of their reactivity, morphology and densities in comparison to WT controls. Conclusions The results of these investigations have begun to reveal changes in key neuroinflammatory cell types throughout the time-course of HD. In vivo imaging approaches and other molecular and cellular assessments will now be used to enable a more detailed characterisation of neuroinflammation in HD, and to identify robust, translational markers by which to track disease progression.
{"title":"A31 The development of translational biomarkers of neuroinflammation in a mouse model of huntington’s disease","authors":"Laura Riggall, B. Siow, X. Golay, G. Bates","doi":"10.1136/jnnp-2018-EHDN.29","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.29","url":null,"abstract":"Background Currently, the concept of neuroinflammation includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. However, the roles of brain-resident and peripheral immune cells in inflammatory settings are poorly understood, and neuroinflammation has not been well investigated in either Huntington’s disease (HD) patients or equivalent preclinical models. Aims This project aims to characterise the neuroinflammatory processes occurring in the R6/2 mouse model of HD over the time-course of the disease, using a number of molecular and cellular techniques in combination with in vivo imaging modalities (magnetic resonance spectroscopy [MRS] and magnetic resonance imaging [MRI]). Methods The R6/2 mouse expresses exon 1 of the human HTT gene, containing ˜180 CAGs. To begin undertaking a time-course analysis of the disease, immunohistochemistry (IHC) and western blotting were used in R6/2 and wild type (WT) mice between the ages of four- (pre-symptomatic) and 14-weeks-old (late-stage disease) to assess the neuroinflammatory processes in HD. Results Protocol optimisations to assess microglia and astrocytes (via their hallmark proteins IBA1 and GFAP respectively), two key cell types that mediate neuroinflammatory processes, have been performed for both western blotting and IHC. Subsequently, following their assessment in R6/2 mice, microglia and astrocytes were altered in terms of their reactivity, morphology and densities in comparison to WT controls. Conclusions The results of these investigations have begun to reveal changes in key neuroinflammatory cell types throughout the time-course of HD. In vivo imaging approaches and other molecular and cellular assessments will now be used to enable a more detailed characterisation of neuroinflammation in HD, and to identify robust, translational markers by which to track disease progression.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"112 1","pages":"A11 - A11"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89452713","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.126
P. Wijeratne, E. Johnson, S. Gregory, A. Mohan, C. Sampaio, R. Scahill, S. Tabrizi, D. Alexander
Background The TRACK, PREDICT and IMAGE-HD studies provide rich and varied datasets with which to identify robust imaging and clinical biomarkers of Huntington’s disease (HD) progression. A comparative analysis of biomarkers between studies has potential use in observational study design. Estimating the sequence in which these biomarkers become abnormal can provide important insights into HD pathology and a mechanism for disease staging. Aims We have, for the first time, analysed and statistically compared structural imaging and phenotypic clinical data from these three observational studies. We hence aim to identify a common set of robust biomarkers, and explain observational differences between studies. We also propose how to use these biomarkers to inform a model of HD progression. Methods We analysed structural imaging, clinical and behavioural data from a total of 357 TRACK, 1091 PREDICT, and 96 IMAGE-HD participants at baseline. The imaging data were segmented and parcellated using a common framework. Groupwise comparisons were made between controls, pre-manifest and manifest groups, and effect sizes compared between studies. An event-based model1 was trained to infer the most likely sequence of biomarker abnormality, and to stage participants. Results We identified a core set of significant imaging, clinical and behavioural biomarkers common to all studies, plus biomarkers that were significant within, but not between studies. Consequently, the disease progression model reveals a distinct, cross-validated pattern of imaging and phenotypic abnormality. Conclusions We successfully identified a set of robust biomarkers common to all studies, explored observational differences, and demonstrated that these biomarkers can be used to model HD progression. Reference . Wijeratne, et al. Ann Clin Trans Neurol2018. doi:10.1002/acn3.558
{"title":"F22 Robust biomarkers of huntington’s disease progression: observations from the track-hd, predict-hd and image-hd studies","authors":"P. Wijeratne, E. Johnson, S. Gregory, A. Mohan, C. Sampaio, R. Scahill, S. Tabrizi, D. Alexander","doi":"10.1136/jnnp-2018-EHDN.126","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.126","url":null,"abstract":"Background The TRACK, PREDICT and IMAGE-HD studies provide rich and varied datasets with which to identify robust imaging and clinical biomarkers of Huntington’s disease (HD) progression. A comparative analysis of biomarkers between studies has potential use in observational study design. Estimating the sequence in which these biomarkers become abnormal can provide important insights into HD pathology and a mechanism for disease staging. Aims We have, for the first time, analysed and statistically compared structural imaging and phenotypic clinical data from these three observational studies. We hence aim to identify a common set of robust biomarkers, and explain observational differences between studies. We also propose how to use these biomarkers to inform a model of HD progression. Methods We analysed structural imaging, clinical and behavioural data from a total of 357 TRACK, 1091 PREDICT, and 96 IMAGE-HD participants at baseline. The imaging data were segmented and parcellated using a common framework. Groupwise comparisons were made between controls, pre-manifest and manifest groups, and effect sizes compared between studies. An event-based model1 was trained to infer the most likely sequence of biomarker abnormality, and to stage participants. Results We identified a core set of significant imaging, clinical and behavioural biomarkers common to all studies, plus biomarkers that were significant within, but not between studies. Consequently, the disease progression model reveals a distinct, cross-validated pattern of imaging and phenotypic abnormality. Conclusions We successfully identified a set of robust biomarkers common to all studies, explored observational differences, and demonstrated that these biomarkers can be used to model HD progression. Reference . Wijeratne, et al. Ann Clin Trans Neurol2018. doi:10.1002/acn3.558","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"18 1","pages":"A47 - A47"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90069404","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.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.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.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}
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