Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.261
S. Tabrizi, B. Leavitt, B. Landwehrmeyer, E. Wild, C. Saft, R. Barker, D. Craufurd, H. Rickards, A. Rosser, J. Priller, H. Kordasiewicz, C. Czech, E. Swayze, D. Norris, T. Baumann, I. Gerlach, S. Schobel, Anne V Smith, R. Lane, C. Bennett
Background HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production. Design/methods In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent DSMB review of safety, PK and target engagement prior to dose escalation. Results IONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed. Conclusions ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD. Study Supported By: Ionis Pharmaceuticals
{"title":"J01 Effects of IONIS-HTTRX (RG6042) in patients with early huntington’s disease, results of the first htt-lowering drug trial","authors":"S. Tabrizi, B. Leavitt, B. Landwehrmeyer, E. Wild, C. Saft, R. Barker, D. Craufurd, H. Rickards, A. Rosser, J. Priller, H. Kordasiewicz, C. Czech, E. Swayze, D. Norris, T. Baumann, I. Gerlach, S. Schobel, Anne V Smith, R. Lane, C. Bennett","doi":"10.1136/jnnp-2018-EHDN.261","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.261","url":null,"abstract":"Background HD is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the HTT gene resulting in polyglutamine expansion in the mutant huntingtin protein (mHTT) with a toxic gain-of-function disease mechanism. No disease-modifying treatments are currently available. In transgenic rodent models of HD, suppressing HTT production delays disease progression and reverses disease phenotype. A drug discovery effort, including extensive preclinical testing, was undertaken to design a well-tolerated ASO with high specificity to human HTT mRNA that potently suppresses HTT production. Design/methods In this first-in-human, multi-center, double-blind clinical trial (NCT02519036), 46 patients were randomized (3:1) to receive four doses of IONIS-HTTRx or placebo by monthly bolus intrathecal (IT) injection followed by a 4-month untreated period. Five ascending-dose cohorts were enrolled with independent DSMB review of safety, PK and target engagement prior to dose escalation. Results IONIS-HTTRx was well-tolerated at all doses tested. Adverse events were mostly mild and unrelated to study drug. There were no adverse trends in laboratory parameters. No patients prematurely discontinued from treatment. ASO was measurable in CSF and plasma. Significant, dose-dependent reductions in CSF mutant HTT (mHTT) were observed. Conclusions ASO technology has the potential to provide disease-modifying benefits to patients with neurodegenerative diseases. In this Phase 1/2a trial in early stage HD patients, IONIS-HTTRx delivered via IT injection was well tolerated with no study drug-related adverse safety signals during the treatment or follow-up periods. Significant dose-dependent reductions in CSF mHTT were observed, suggesting that IONIS-HTTRx is a promising therapeutic for the treatment of HD. Study Supported By: Ionis Pharmaceuticals","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"48 1","pages":"A97 - A98"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84146703","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.11
V. Brito, R. Fernández-Santiago, M. Ezquerra, Esther Sieiro, J. Pérez-Pérez, J. Kulisevsky, S. Ginés
Background Most cellular dysfunctions in HD are associated with alterations in gene expression, with transcriptional dysregulation being a prominent feature of the disease. One of the mechanisms involved in this deregulation is the aberrant expression of microRNAs (miRNAs). Aberrant expression profiles of miRNAs have been identified as biomarkers in many different diseases. So far, several studies in the context of neurodegenerative disorders have focused on the identification and clinical application of miRNAs as biomarkers. However, the study of miRNAs in HD need to be further explored in particular related to the progression of the disease. Aims In this study we aim to explore and validate miRNA expression profiles in fibroblasts of HD patients at pre-symptomatic and symptomatic stages. Methods/techniques In a discovery phase we have assessed comprehensive genome-wide miRNA expression analysis of fibroblasts from pre-symptomatic, early symptomatic, middle/advanced symptomatic patients and controls. We have used the GeneChip miRNA 4.0 array from Affymetrix including probes for 2578 mature human miRNAs. In a validation phase we validated candidate miRNAs differentially expressed using the Taman Advance qPCR. Results/outcome Our investigations have revealed specific signatures of miRNAs expression in HD patients along the disease progression with a downregulation of miRNAs at pre-symptomatic stages and an upregulation of miRNAs at symptomatic stages. Furthermore, we identified some mRNAs as biomarkers of disease progression that might identify when a patient become symptomatic such as, miR6124, miR210 and miR493, or when patients progress to a middle or advance stage of the disease, such as miR127. Conclusions Our results indicate that miRNA alterations precede the onset of motor symptoms and highlight the potential of miRNA panels from fibroblasts as biomarkers for Huntington´s disease progression.
{"title":"A11 Skin fibroblasts from huntington´s disease patients show distinct signature of MIRNAS expression along disease progression","authors":"V. Brito, R. Fernández-Santiago, M. Ezquerra, Esther Sieiro, J. Pérez-Pérez, J. Kulisevsky, S. Ginés","doi":"10.1136/jnnp-2018-EHDN.11","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.11","url":null,"abstract":"Background Most cellular dysfunctions in HD are associated with alterations in gene expression, with transcriptional dysregulation being a prominent feature of the disease. One of the mechanisms involved in this deregulation is the aberrant expression of microRNAs (miRNAs). Aberrant expression profiles of miRNAs have been identified as biomarkers in many different diseases. So far, several studies in the context of neurodegenerative disorders have focused on the identification and clinical application of miRNAs as biomarkers. However, the study of miRNAs in HD need to be further explored in particular related to the progression of the disease. Aims In this study we aim to explore and validate miRNA expression profiles in fibroblasts of HD patients at pre-symptomatic and symptomatic stages. Methods/techniques In a discovery phase we have assessed comprehensive genome-wide miRNA expression analysis of fibroblasts from pre-symptomatic, early symptomatic, middle/advanced symptomatic patients and controls. We have used the GeneChip miRNA 4.0 array from Affymetrix including probes for 2578 mature human miRNAs. In a validation phase we validated candidate miRNAs differentially expressed using the Taman Advance qPCR. Results/outcome Our investigations have revealed specific signatures of miRNAs expression in HD patients along the disease progression with a downregulation of miRNAs at pre-symptomatic stages and an upregulation of miRNAs at symptomatic stages. Furthermore, we identified some mRNAs as biomarkers of disease progression that might identify when a patient become symptomatic such as, miR6124, miR210 and miR493, or when patients progress to a middle or advance stage of the disease, such as miR127. Conclusions Our results indicate that miRNA alterations precede the onset of motor symptoms and highlight the potential of miRNA panels from fibroblasts as biomarkers for Huntington´s disease progression.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"58 Suppl A 1","pages":"A4 - A5"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77823407","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.6
Rafael Alcala Vida, Jonathan Seguin, Anne Molitor, C. Lotz, A. Bombardier, Stéphanie Le Gras, Céline Keime, Jean-Christophe Cassel, A. Boutillier, Thomas Sexton, K. Merienne
Huntington’s disease (HD) is a progressive neurodegenerative disease, affecting primarily the striatum. Transcriptional dysregulation is believed to contribute to HD. However, the underlying mechanism is unclear. Using ChIPseq and RNAseq on the striatum of HD R6/1 transgenic mice, we found that down-regulated genes are enriched in striatal identity genes, controlled by a super-enhancer. H3K27ac, enhancer transcription and recruitment of RNA polymerase II (RNAPII) were selectively reduced at R6/1 striatal super-enhancers, indicating that altered super-enhancer activity underlies down-regulation of striatal identity genes in HD. Our 4Cseq data using R6/1 striatum further suggest that disruption of chromatin 3D architecture contributes to altered expression of striatal identity genes regulated by a super-enhancer. To investigate functional consequences of epigenetic alterations in HD, R6/1 mice were trained to learn striatum-dependent cognitive task. In contrast to wild-type (WT) animals, R6/1 mice were impaired in this task. ChIPseq data generated using the striatum of ‘trained’ and ‘home cage’ mice showed an increase of H3K27ac and RNAPII at genes implicated in synaptic plasticity and regulated by a super-enhancer, in trained vs home cage WT animals. However, this ‘plasticity’ signature was absent in trained R6/1 mice, suggesting that aberrant RNAPII dynamics and inadequate histone acetylation at these genes preclude synaptic plasticity and contribute to R6/1 behavioural deficits. Finally, we generated ChIPseq data using the striatum of HD patients and knockin mice. HD striatal ‘super-enhancer’ signature was conserved across models and our analyses further revealed that it establishes early, at presymptomatic stage.
{"title":"A06 Huntington’s disease striatal super-enhancer signature","authors":"Rafael Alcala Vida, Jonathan Seguin, Anne Molitor, C. Lotz, A. Bombardier, Stéphanie Le Gras, Céline Keime, Jean-Christophe Cassel, A. Boutillier, Thomas Sexton, K. Merienne","doi":"10.1136/jnnp-2018-EHDN.6","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.6","url":null,"abstract":"Huntington’s disease (HD) is a progressive neurodegenerative disease, affecting primarily the striatum. Transcriptional dysregulation is believed to contribute to HD. However, the underlying mechanism is unclear. Using ChIPseq and RNAseq on the striatum of HD R6/1 transgenic mice, we found that down-regulated genes are enriched in striatal identity genes, controlled by a super-enhancer. H3K27ac, enhancer transcription and recruitment of RNA polymerase II (RNAPII) were selectively reduced at R6/1 striatal super-enhancers, indicating that altered super-enhancer activity underlies down-regulation of striatal identity genes in HD. Our 4Cseq data using R6/1 striatum further suggest that disruption of chromatin 3D architecture contributes to altered expression of striatal identity genes regulated by a super-enhancer. To investigate functional consequences of epigenetic alterations in HD, R6/1 mice were trained to learn striatum-dependent cognitive task. In contrast to wild-type (WT) animals, R6/1 mice were impaired in this task. ChIPseq data generated using the striatum of ‘trained’ and ‘home cage’ mice showed an increase of H3K27ac and RNAPII at genes implicated in synaptic plasticity and regulated by a super-enhancer, in trained vs home cage WT animals. However, this ‘plasticity’ signature was absent in trained R6/1 mice, suggesting that aberrant RNAPII dynamics and inadequate histone acetylation at these genes preclude synaptic plasticity and contribute to R6/1 behavioural deficits. Finally, we generated ChIPseq data using the striatum of HD patients and knockin mice. HD striatal ‘super-enhancer’ signature was conserved across models and our analyses further revealed that it establishes early, at presymptomatic stage.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"28 1","pages":"A2 - A3"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78192361","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.2
Julia Dancourt, Morgane Fontaine, C. Néri
Although the length of CAG repeat expansion may highly anticorrelates with the age at onset of Huntington disease (HD), genetic modifiers may have a significant impact in HD. One class of modifiers that has recently drawn attention is DNA repair genes. Although some DNA repair genes may be associated with somatic CAG expansion, the involvement of DNA repair genes might reach far beyond that phenomenon, notably in terms of stress response and compensation. HD is marked by neurodegeneration but also has an increasingly studied neurodevelopmental component. Recent advances in stem cells technologies now allow for a comprehensive study of neurodevelopmental processes in vitro, enabling to investigate the role of stress response mechanisms such as DNA repair in the earliest phases of the HD process and test whether DNA damage and repair features established at the time of neuronal differentiation might be conserved in adult neurons. To this end, we study DNA damage and DNA Damage Response (DDR) in human HD stem cells including an isogenic pair of patient-derived Neural Stem Cells (NSCs) and its genetically corrected counterpart differentiated in vitro from induced Pluripotent Stem Cells (iPSCs). To this end, we use markers of DNA damage levels and reporters of DDR pathway activities in response to Single Strand Breaks (SSB) and Double Strand Breaks (DSB). We will present results on the alteration of SSB and DSB responses in human HD NSCs, discussing how understanding the specificities of DDR alterations during neuronal differentiation may shed light on disease mechanisms, seminal effects and potential therapeutic targets.
{"title":"A02 Studying the dynamics of DNA damage response in human huntington’s disease neural stem cells","authors":"Julia Dancourt, Morgane Fontaine, C. Néri","doi":"10.1136/jnnp-2018-EHDN.2","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.2","url":null,"abstract":"Although the length of CAG repeat expansion may highly anticorrelates with the age at onset of Huntington disease (HD), genetic modifiers may have a significant impact in HD. One class of modifiers that has recently drawn attention is DNA repair genes. Although some DNA repair genes may be associated with somatic CAG expansion, the involvement of DNA repair genes might reach far beyond that phenomenon, notably in terms of stress response and compensation. HD is marked by neurodegeneration but also has an increasingly studied neurodevelopmental component. Recent advances in stem cells technologies now allow for a comprehensive study of neurodevelopmental processes in vitro, enabling to investigate the role of stress response mechanisms such as DNA repair in the earliest phases of the HD process and test whether DNA damage and repair features established at the time of neuronal differentiation might be conserved in adult neurons. To this end, we study DNA damage and DNA Damage Response (DDR) in human HD stem cells including an isogenic pair of patient-derived Neural Stem Cells (NSCs) and its genetically corrected counterpart differentiated in vitro from induced Pluripotent Stem Cells (iPSCs). To this end, we use markers of DNA damage levels and reporters of DDR pathway activities in response to Single Strand Breaks (SSB) and Double Strand Breaks (DSB). We will present results on the alteration of SSB and DSB responses in human HD NSCs, discussing how understanding the specificities of DDR alterations during neuronal differentiation may shed light on disease mechanisms, seminal effects and potential therapeutic targets.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"121 1","pages":"A1 - A1"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82584711","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.38
Morgane Louessard, M. Jarrige, Julie Bigarreau, Michel Cailleret, Gabriel Vachey, N. Déglon, A. Perrier
In Huntington disease (HD), the most affected cells are the GABA-releasing medium spiny neurons (MSN) of the striatum, the subcortical brain structure that controls body movement. DARPP32 (dopamine- and 3’,5’-cyclic adenosine monophosphate-regulated phosphoprotein, 32 kDa) is a class defining protein marker for striatal MSNs and a central mediator of dopamine signalling and other first messengers in these cells. DARPP-32 is expressed in 97% of the MSNs, several cortical layers, and cerebellar Purkinje cells. This protein has the capacity to function as either a kinase or a phosphatase inhibitor, depending on the phosphorylation state of key amino acid residues. DARPP32 is highly down-regulated in the striatum of HD patient and in the majority of mouse models of HD. The rational of our work is to use derivatives of several types of HD and WT-human Pluripotent Stem Cell (hPSC) lines challenged or not with HTT-targeting RNA interference (shRNA lentiviral vectors) or HTT-targeting CRISPR-Cas9 complex to decipher possible wt-HTT dosage, mut-HTT dominant-negative, mut-HTT de novo toxic or CAG repeat length effects on DARPP32 homeostasis. Using lentiviral vectors, we investigated the role of HTT isoforms on DARPP-32 protein levels measured by Western Blot and immunocytochemistry. We observed changes in DARPP32 and phopsho-DARPP32 protein level in hPSC derivatives treated with shHTT lentivirus. Next, we generated a series of CRISPER-CAS9 HTT-gene edited clones of HD-iPSC and WT-iPSC. Either or both allele of HTT gene was inactivated in those cells and the MSN derived from those clones. Exploration of DARPP32 protein levels in undifferentiated cells and MSN derived from these clones is ongoing. This study should help understand the role of HTT isoforms on human MSN homeostasis.
{"title":"A40 Modulation of DARPP32 homeostasis by htt protein in derivatives of disease-specific and control human pluripotent stem cells","authors":"Morgane Louessard, M. Jarrige, Julie Bigarreau, Michel Cailleret, Gabriel Vachey, N. Déglon, A. Perrier","doi":"10.1136/jnnp-2018-EHDN.38","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.38","url":null,"abstract":"In Huntington disease (HD), the most affected cells are the GABA-releasing medium spiny neurons (MSN) of the striatum, the subcortical brain structure that controls body movement. DARPP32 (dopamine- and 3’,5’-cyclic adenosine monophosphate-regulated phosphoprotein, 32 kDa) is a class defining protein marker for striatal MSNs and a central mediator of dopamine signalling and other first messengers in these cells. DARPP-32 is expressed in 97% of the MSNs, several cortical layers, and cerebellar Purkinje cells. This protein has the capacity to function as either a kinase or a phosphatase inhibitor, depending on the phosphorylation state of key amino acid residues. DARPP32 is highly down-regulated in the striatum of HD patient and in the majority of mouse models of HD. The rational of our work is to use derivatives of several types of HD and WT-human Pluripotent Stem Cell (hPSC) lines challenged or not with HTT-targeting RNA interference (shRNA lentiviral vectors) or HTT-targeting CRISPR-Cas9 complex to decipher possible wt-HTT dosage, mut-HTT dominant-negative, mut-HTT de novo toxic or CAG repeat length effects on DARPP32 homeostasis. Using lentiviral vectors, we investigated the role of HTT isoforms on DARPP-32 protein levels measured by Western Blot and immunocytochemistry. We observed changes in DARPP32 and phopsho-DARPP32 protein level in hPSC derivatives treated with shHTT lentivirus. Next, we generated a series of CRISPER-CAS9 HTT-gene edited clones of HD-iPSC and WT-iPSC. Either or both allele of HTT gene was inactivated in those cells and the MSN derived from those clones. Exploration of DARPP32 protein levels in undifferentiated cells and MSN derived from these clones is ongoing. This study should help understand the role of HTT isoforms on human MSN homeostasis.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"89 1","pages":"A14 - A14"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82309290","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.229
Ahmed Elaswed, R. Dasi
Background Our multi- disciplinary team offer assessment and treatment for a wide range of mental health problems and neuropsychiatric disorders such as Huntington’s disease (HD). Although HD is a disease of the central nervous system, mortality surveys indicate that heart disease is a leading cause of death.1 The previous audit about the ECG monitoring was conducted in July 2013 (Project 2057). The monitoring of ECG abnormalities of inpatients involves an ECG which expected to be performed at admission, and repeated when patients are commenced on high-dose antipsychotics. The QTc is considered the most appropriate measure for ventricular repolarization. Interpretation of case reports of arrhythmia and sudden death in patients receiving these drugs is complicated because psychiatric patients are known to be at a high risk of cardiovascular death.2 Researchers assessed ECGs from a large cohort of patients with early HD found increased prevalence in cardiac conduction abnormalities and bradycardia. These results suggest caution is indicated in using medications that may have additive cardiac toxicity.3 Aims and objectives To establish the number of patients on the ward who have had ECGs done and documented. To investigate how long does it take for staff to apply the first ECG following admission? Standards There are currently no specific standards for monitoring ECGs in patients on antipsychotics. However, we used the same standards from the previous Audit which included; the trust guidelines for physical assessment for patients,4 The Royal College of Psychiatrists (RCPsych Consensus statement on high-dose antipsychotic medication5 and NICE guidance for Schizophrenia March 2009.6 Methodology Sample: A total of 23 patients were on our inpatients list during the 8 days period from 06/10/17 to 13/10/17 (included). The age of patient was ranged from 22 to 64 (Mean=38) years. 2 patients were admitted to the department with psychotic symptoms to HD during this period. Search Strategy: All of the information were collected from Amigos (patient’s electronic data). A manual search through patient’s clinical paper notes was also conducted. Findings/results All patients (23) audited were on a form of Antipsychotic medication (7 were on IM Antipsychotics Injection). 6 out of 23 did not have an ECG done (1 patient was agitated, 3 had refused and no documentation on why ECG was not done for 2 patients). The average time between admission and performing an ECG ranged from day 1 to day 174 (with a mean of 28 days and a median of 27 days). We noticed good documentation about ECG’s finding in Amigos, though only few ECG6 were documented in full details and included QTc. ECG machines become more readily available. Conclusion and recommendation Doctors should be made aware and reminded that ECGs are important in monitoring for any cardiac abnormality which could be detrimental in patients taking antipsychotics, and patients at high risk of developing cardiovascular pr
{"title":"H51 Project 564: monitoring electrocardiogram (ECG) in patients on antipsychotic medication admitted to psychiatric ward during admission period in october 2017 (re-audit of project 2057)","authors":"Ahmed Elaswed, R. Dasi","doi":"10.1136/JNNP-2018-EHDN.229","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.229","url":null,"abstract":"Background Our multi- disciplinary team offer assessment and treatment for a wide range of mental health problems and neuropsychiatric disorders such as Huntington’s disease (HD). Although HD is a disease of the central nervous system, mortality surveys indicate that heart disease is a leading cause of death.1 The previous audit about the ECG monitoring was conducted in July 2013 (Project 2057). The monitoring of ECG abnormalities of inpatients involves an ECG which expected to be performed at admission, and repeated when patients are commenced on high-dose antipsychotics. The QTc is considered the most appropriate measure for ventricular repolarization. Interpretation of case reports of arrhythmia and sudden death in patients receiving these drugs is complicated because psychiatric patients are known to be at a high risk of cardiovascular death.2 Researchers assessed ECGs from a large cohort of patients with early HD found increased prevalence in cardiac conduction abnormalities and bradycardia. These results suggest caution is indicated in using medications that may have additive cardiac toxicity.3 Aims and objectives To establish the number of patients on the ward who have had ECGs done and documented. To investigate how long does it take for staff to apply the first ECG following admission? Standards There are currently no specific standards for monitoring ECGs in patients on antipsychotics. However, we used the same standards from the previous Audit which included; the trust guidelines for physical assessment for patients,4 The Royal College of Psychiatrists (RCPsych Consensus statement on high-dose antipsychotic medication5 and NICE guidance for Schizophrenia March 2009.6 Methodology Sample: A total of 23 patients were on our inpatients list during the 8 days period from 06/10/17 to 13/10/17 (included). The age of patient was ranged from 22 to 64 (Mean=38) years. 2 patients were admitted to the department with psychotic symptoms to HD during this period. Search Strategy: All of the information were collected from Amigos (patient’s electronic data). A manual search through patient’s clinical paper notes was also conducted. Findings/results All patients (23) audited were on a form of Antipsychotic medication (7 were on IM Antipsychotics Injection). 6 out of 23 did not have an ECG done (1 patient was agitated, 3 had refused and no documentation on why ECG was not done for 2 patients). The average time between admission and performing an ECG ranged from day 1 to day 174 (with a mean of 28 days and a median of 27 days). We noticed good documentation about ECG’s finding in Amigos, though only few ECG6 were documented in full details and included QTc. ECG machines become more readily available. Conclusion and recommendation Doctors should be made aware and reminded that ECGs are important in monitoring for any cardiac abnormality which could be detrimental in patients taking antipsychotics, and patients at high risk of developing cardiovascular pr","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"25 1","pages":"A84 - A85"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76398301","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.185
Alistair Haw
Background Government commissioned SHA to develop a National Care Framework for HD followed by localised versions for each health region. Aims To develop a measureable, integrated health and social care model that guides providers and empowers HD families. Online format allows Framework to be kept up to date. Method/techniques Developed by expert group representing families, psychiatry, psychology, neurology, neuropsychology, genetics, rehabilitation, dentistry, GPs, speech and language therapy, dietetics, physiotherapy, occupational therapy, care homes, palliative care, social work and academia. Then subject to national consultation. Results/outcome National Framework backed and launched by Government. Localised versions published in 3 regions. Baseline surveys of staff and families conducted – to be repeated in 3 years to determine impact. Conclusions Framework widely welcomed, both nationally and internationally, as excellent model for HD and other conditions.
{"title":"H04 National care framework for huntington’s disease","authors":"Alistair Haw","doi":"10.1136/jnnp-2018-EHDN.185","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.185","url":null,"abstract":"Background Government commissioned SHA to develop a National Care Framework for HD followed by localised versions for each health region. Aims To develop a measureable, integrated health and social care model that guides providers and empowers HD families. Online format allows Framework to be kept up to date. Method/techniques Developed by expert group representing families, psychiatry, psychology, neurology, neuropsychology, genetics, rehabilitation, dentistry, GPs, speech and language therapy, dietetics, physiotherapy, occupational therapy, care homes, palliative care, social work and academia. Then subject to national consultation. Results/outcome National Framework backed and launched by Government. Localised versions published in 3 regions. Baseline surveys of staff and families conducted – to be repeated in 3 years to determine impact. Conclusions Framework widely welcomed, both nationally and internationally, as excellent model for HD and other conditions.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"47 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":"88415449","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.187
M. Musilová, Z. Vondrackova, P. Šašinková
Background The project focuses on the education of carers, employees of social facilities and students and staff of educational institutions. Huntington’s disease (HD) is a very specific neurodegenerative disease and the care of HD patients is complicated. HD patients acceptance to social facilities is very problematic. Most institutions are not familiar with HD or have not enough experience. Particularly in the illness terminal stages institutional care is very much needed. Aims From the experiences in the Czech Republic and abroad we know the care for HD patients can be handled if the staff is well trained. During the lectures the staff is familiar with the issue of HD and the care specifics. Afterwards the institution can accept HD patients as their residents. This improves the quality of life not only of the patients themselves but also of their families which are heavily burdened in the home environment. Methods/techniques Czech Huntington Association has a multidisciplinary team of experts, collaborating physicians and therapists who can provide lectures on the specifics of HD care. Lectures and seminars for social facilities and educational institutions raise awareness of HD. The lectures and workshops materials are freely available to all participants. Results/outcome This training project started in 2014. Since then, lectures have been held in 17 social facilities and at the Faculty of Education at Charles University in Prague. All care institutions can accept HD patients depending on their actual availabilities. Conclusion The aim of the project is to create a network of special social facilities throughout the Czech Republic that can accept HD patients. The social facility fulfils these criteria: The offered care is professional, the staff is well informed and acquainted with the specifics of HD patients care. Thanks to wide network of possible care institutions the patients’ social contact with the family can be maintained.
{"title":"H06 Training in care specifics of huntington´s disease","authors":"M. Musilová, Z. Vondrackova, P. Šašinková","doi":"10.1136/jnnp-2018-EHDN.187","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.187","url":null,"abstract":"Background The project focuses on the education of carers, employees of social facilities and students and staff of educational institutions. Huntington’s disease (HD) is a very specific neurodegenerative disease and the care of HD patients is complicated. HD patients acceptance to social facilities is very problematic. Most institutions are not familiar with HD or have not enough experience. Particularly in the illness terminal stages institutional care is very much needed. Aims From the experiences in the Czech Republic and abroad we know the care for HD patients can be handled if the staff is well trained. During the lectures the staff is familiar with the issue of HD and the care specifics. Afterwards the institution can accept HD patients as their residents. This improves the quality of life not only of the patients themselves but also of their families which are heavily burdened in the home environment. Methods/techniques Czech Huntington Association has a multidisciplinary team of experts, collaborating physicians and therapists who can provide lectures on the specifics of HD care. Lectures and seminars for social facilities and educational institutions raise awareness of HD. The lectures and workshops materials are freely available to all participants. Results/outcome This training project started in 2014. Since then, lectures have been held in 17 social facilities and at the Faculty of Education at Charles University in Prague. All care institutions can accept HD patients depending on their actual availabilities. Conclusion The aim of the project is to create a network of special social facilities throughout the Czech Republic that can accept HD patients. The social facility fulfils these criteria: The offered care is professional, the staff is well informed and acquainted with the specifics of HD patients care. Thanks to wide network of possible care institutions the patients’ social contact with the family can be maintained.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"52 1","pages":"A70 - A70"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83855693","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.59
S. Flunkert, T. Loeffler, B. Fabry, H. Nguyen, R. Wronski, B. Hutter-Paier
Background The BACHD rat is by now a well characterized animal model of Huntington’s disease (HD), presenting several disease relevant symptoms and pathologies. The BACHD rat represents one of the few animal models that overexpresses the full length human mutant huntingtin (mHTT) and is thus of great value for HD research. Aims The aim of this study was to compare the metabolic properties of primary striatal, hypothalamic and cortical neurons of BACHD rats with the l-glutamate or MPP+ induced rat striatal lesion models to establish BACHD primary cells as valuable in vitro HD model. Methods BACHD rat pups, as well as wildtype pups, were dissected at embryonic day 19 and primary neurons of the striatum, hypothalamus and cortex were cultivated. Cells were analyzed after 1, 7 and 14 days in vitro. For the lesion models, primary striatal embryonic day 19 rat neurons were cultivated for 15 days and lesioned with l-glutamate or MPP+ for 24 hours. All samples were analyzed with the MTT- and LDH-assay. Results Our data show that primary neurons of embryonic BACHD rats show a significantly decreased metabolic activity in the striatum and hypothalamus. These results are comparable with data obtained by l-glutamate or MTT+ lesions in primary striatal neurons of wildtype rats. Conclusions We conclude that the BACHD rat model is a valuable tool for the in vitro evaluation of HD-related metabolic properties.
{"title":"B07 Metabolic characteristics of primary neuron cultures from bachd rats compared to induced lesion models","authors":"S. Flunkert, T. Loeffler, B. Fabry, H. Nguyen, R. Wronski, B. Hutter-Paier","doi":"10.1136/jnnp-2018-EHDN.59","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.59","url":null,"abstract":"Background The BACHD rat is by now a well characterized animal model of Huntington’s disease (HD), presenting several disease relevant symptoms and pathologies. The BACHD rat represents one of the few animal models that overexpresses the full length human mutant huntingtin (mHTT) and is thus of great value for HD research. Aims The aim of this study was to compare the metabolic properties of primary striatal, hypothalamic and cortical neurons of BACHD rats with the l-glutamate or MPP+ induced rat striatal lesion models to establish BACHD primary cells as valuable in vitro HD model. Methods BACHD rat pups, as well as wildtype pups, were dissected at embryonic day 19 and primary neurons of the striatum, hypothalamus and cortex were cultivated. Cells were analyzed after 1, 7 and 14 days in vitro. For the lesion models, primary striatal embryonic day 19 rat neurons were cultivated for 15 days and lesioned with l-glutamate or MPP+ for 24 hours. All samples were analyzed with the MTT- and LDH-assay. Results Our data show that primary neurons of embryonic BACHD rats show a significantly decreased metabolic activity in the striatum and hypothalamus. These results are comparable with data obtained by l-glutamate or MTT+ lesions in primary striatal neurons of wildtype rats. Conclusions We conclude that the BACHD rat model is a valuable tool for the in vitro evaluation of HD-related metabolic properties.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"31 1","pages":"A21 - A22"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83050605","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.127
D. Trundell, G. Palermo, S. Schobel, J. Long, B. Leavitt, S. Tabrizi
Background The composite Unified Huntington’s Disease Ratings Scale (cUHDRS) is a combined score of measures of motor function (TMS), cognition (SDMT and SWR) and overall functional capacity (TFC). The cUHDRS was developed to assess multi-domain clinical progression in Huntington’s disease (HD), and was shown to be a sensitive, reliable, and valid. To support its use in clinical studies, further evidence is required. This includes estimates of clinically meaningful change of the cUHDRS and its individual measures. Aims To assess the reliability, validity and ability to detect change of the cUHDRS and to estimate minimal clinically meaningful within-patient cUHDRS change. Methods Data from an early manifest HD population (TFC≥5) from two multi-national registries (ENROLL-HD and REGISTRY) were used. Test-retest reliability was assessed by calculating the intraclass correlation coefficient (ICC) in a subset of patients with no change in Clinical Global Impression of Severity (CGI-S) score. Convergent validity was assessed by Spearman rank order correlations. Known-groups validity was assessed by analysis of covariance (ANCOVA) between groups defined by CGI-S. Ability to detect change was assessed by ANCOVA comparing groups based on CGI-S score change. Regression analyses were conducted to estimate meaningful change, using CGI-S and Independence Scale (IS) as anchors. Results Strong evidence of test-retest reliability, known-groups validity and ability to detect change was demonstrated. Convergent validity was supported by stronger correlations with measures that are more similar. Meaningful within-patient change was estimated. Conclusions cUHDRS is valid, reliable and able to detect change in patients with early manifest HD. Analyses anchored against CGI-S and IS support that a decline on the cUHDRS is clinically meaningful. Acknowledgements Funded by F. Hoffmann-La Roche.
{"title":"F23 Validity, reliability, ability to detect change and meaningful within-patient change of the CUHDRS","authors":"D. Trundell, G. Palermo, S. Schobel, J. Long, B. Leavitt, S. Tabrizi","doi":"10.1136/jnnp-2018-EHDN.127","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.127","url":null,"abstract":"Background The composite Unified Huntington’s Disease Ratings Scale (cUHDRS) is a combined score of measures of motor function (TMS), cognition (SDMT and SWR) and overall functional capacity (TFC). The cUHDRS was developed to assess multi-domain clinical progression in Huntington’s disease (HD), and was shown to be a sensitive, reliable, and valid. To support its use in clinical studies, further evidence is required. This includes estimates of clinically meaningful change of the cUHDRS and its individual measures. Aims To assess the reliability, validity and ability to detect change of the cUHDRS and to estimate minimal clinically meaningful within-patient cUHDRS change. Methods Data from an early manifest HD population (TFC≥5) from two multi-national registries (ENROLL-HD and REGISTRY) were used. Test-retest reliability was assessed by calculating the intraclass correlation coefficient (ICC) in a subset of patients with no change in Clinical Global Impression of Severity (CGI-S) score. Convergent validity was assessed by Spearman rank order correlations. Known-groups validity was assessed by analysis of covariance (ANCOVA) between groups defined by CGI-S. Ability to detect change was assessed by ANCOVA comparing groups based on CGI-S score change. Regression analyses were conducted to estimate meaningful change, using CGI-S and Independence Scale (IS) as anchors. Results Strong evidence of test-retest reliability, known-groups validity and ability to detect change was demonstrated. Convergent validity was supported by stronger correlations with measures that are more similar. Meaningful within-patient change was estimated. Conclusions cUHDRS is valid, reliable and able to detect change in patients with early manifest HD. Analyses anchored against CGI-S and IS support that a decline on the cUHDRS is clinically meaningful. Acknowledgements Funded by F. Hoffmann-La Roche.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"21 1","pages":"A48 - A48"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83241921","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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