Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-ehdn.120
Nikhil Ratna, S. Jain, M. Varghese, P. Pal, N. Kamble
Juvenile Huntington disease (JHD) is a distinct phenotype of Huntington disease (HD) with onset before 20 years age and/or CAG repeats >/=60 and is marked by akinetic/hypokinetic manifestations as compared to predominant hyperkinesias in adult-onset HD (AOHD). We briefly describe the profile of JHD in an Indian cohort (n=10) with detailed history of 5 patients. The CAG repeats of their upper alleles ranged from 59–113 (mean 76) and age at onset from 5–20 years (mean 12.7 years). All patients inherited mutant allele from father except one patient who inherited it from mother. Anticipation was highest in a patient with an increase of 70 CAG repeats from parent to child. 7/10 (70%) patients were a/hypokinetic with prominent dystonias and rigidity where as 30% had chorea as the presenting complaint. One child had uncontrolled seizures with myoclonic spasms and generalized dystonia. Eye movement abnormalities were common (8/10) and characteristic as compared to AOHD. Three patients had severe oculomotor apraxia. Two patients had marked cognitive decline while others had milder cognitive impairments. Behavioural abnormalities included irritability, apathy, poor self-care, stubbornness with varying severities. One patient presented with depression and past history of suicidal attempts. In summary, the phenotypes of JHD are more heterogeneous than it is believed to be and needs special attention. We aim to highlight the shared and unique clinical features across JHD patients.
{"title":"F16 Clinical profile of juvenile huntington disease: an indian cohort","authors":"Nikhil Ratna, S. Jain, M. Varghese, P. Pal, N. Kamble","doi":"10.1136/jnnp-2018-ehdn.120","DOIUrl":"https://doi.org/10.1136/jnnp-2018-ehdn.120","url":null,"abstract":"Juvenile Huntington disease (JHD) is a distinct phenotype of Huntington disease (HD) with onset before 20 years age and/or CAG repeats >/=60 and is marked by akinetic/hypokinetic manifestations as compared to predominant hyperkinesias in adult-onset HD (AOHD). We briefly describe the profile of JHD in an Indian cohort (n=10) with detailed history of 5 patients. The CAG repeats of their upper alleles ranged from 59–113 (mean 76) and age at onset from 5–20 years (mean 12.7 years). All patients inherited mutant allele from father except one patient who inherited it from mother. Anticipation was highest in a patient with an increase of 70 CAG repeats from parent to child. 7/10 (70%) patients were a/hypokinetic with prominent dystonias and rigidity where as 30% had chorea as the presenting complaint. One child had uncontrolled seizures with myoclonic spasms and generalized dystonia. Eye movement abnormalities were common (8/10) and characteristic as compared to AOHD. Three patients had severe oculomotor apraxia. Two patients had marked cognitive decline while others had milder cognitive impairments. Behavioural abnormalities included irritability, apathy, poor self-care, stubbornness with varying severities. One patient presented with depression and past history of suicidal attempts. In summary, the phenotypes of JHD are more heterogeneous than it is believed to be and needs special attention. We aim to highlight the shared and unique clinical features across JHD patients.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"26 1","pages":"A45 - A45"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79503336","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.103
M. N. Hellem, T. Vinther-Jensen, Christian Hansen, Lasse Anderberg, E. Budtz-Jørgensen, L. Hjermind, V. Larsen, I. Law, J. Nielsen
Background Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder, caused by an expansion of a trinucleotide (CAG) repeat in the huntingtin gene. There is no cure and only sparse symptomatic treatment. Structural brain imaging is the most applied and well documented technique to demonstrate longitudinal structural changes in premanifest and manifest HD gene-expansion carriers. Changes in the striatum are registered as far as 15 years before symptom onset with MRI. PET studies have found hypometabolism in the Caudate nucleus, Putamen and the temporal and frontal cortex years before clinical diagnosis along with hypermetabolism in Thalamus prior to symptom onset. Aims By a hybrid brain PET-MRI using FDG, we wished to simultaneously characterize the structural and metabolic brain changes in premanifest HD gene-expansion carriers and address the question whether changes in the metabolism precede the structural changes. Methods We recruited 21 premanifest HD gene-expansion carriers and 17 controls from the Neurogenetics Clinic, Danish Dementia Research Centre, Rigshospitalet, Denmark. We included individuals with CAG repeat ≥39 and a Unified HD Rating scale total motor score ≤5. Results We found a significantly lower (p=0.028) striatal metabolism in the HD gene expansion carrier group compared to gene-negative controls, while there was no significant striatal volume difference. We found a significant correlation between both striatal metabolism and CAP score and striatal volume and CAP score. The higher the CAP score, the lower the metabolism and striatal volume. We also found a significant positive association between striatal metabolism and MRI volume. Conclusions Our results suggest that striatal hypometabolism precedes atrophy; however longitudinal studies on larger cohorts using hybrid FDG-PET/MRI are needed to precisely assess the changes and evolution in time.
{"title":"E09 Hybrid brain positron emision tomography – magnetic resonance imaging using flurodeoxyglucose (FDG – PET/MRI) in premanifest huntingtons disease gene-expansion","authors":"M. N. Hellem, T. Vinther-Jensen, Christian Hansen, Lasse Anderberg, E. Budtz-Jørgensen, L. Hjermind, V. Larsen, I. Law, J. Nielsen","doi":"10.1136/jnnp-2018-EHDN.103","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.103","url":null,"abstract":"Background Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder, caused by an expansion of a trinucleotide (CAG) repeat in the huntingtin gene. There is no cure and only sparse symptomatic treatment. Structural brain imaging is the most applied and well documented technique to demonstrate longitudinal structural changes in premanifest and manifest HD gene-expansion carriers. Changes in the striatum are registered as far as 15 years before symptom onset with MRI. PET studies have found hypometabolism in the Caudate nucleus, Putamen and the temporal and frontal cortex years before clinical diagnosis along with hypermetabolism in Thalamus prior to symptom onset. Aims By a hybrid brain PET-MRI using FDG, we wished to simultaneously characterize the structural and metabolic brain changes in premanifest HD gene-expansion carriers and address the question whether changes in the metabolism precede the structural changes. Methods We recruited 21 premanifest HD gene-expansion carriers and 17 controls from the Neurogenetics Clinic, Danish Dementia Research Centre, Rigshospitalet, Denmark. We included individuals with CAG repeat ≥39 and a Unified HD Rating scale total motor score ≤5. Results We found a significantly lower (p=0.028) striatal metabolism in the HD gene expansion carrier group compared to gene-negative controls, while there was no significant striatal volume difference. We found a significant correlation between both striatal metabolism and CAP score and striatal volume and CAP score. The higher the CAP score, the lower the metabolism and striatal volume. We also found a significant positive association between striatal metabolism and MRI volume. Conclusions Our results suggest that striatal hypometabolism precedes atrophy; however longitudinal studies on larger cohorts using hybrid FDG-PET/MRI are needed to precisely assess the changes and evolution in time.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"88 1","pages":"A39 - A39"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79894648","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.269
M. Busse, L. Quinn, C. Drew, R. Williams-Thomas, P. Dimitropoulou, R. Playle, K. Hamana, B. Griffin, R. Reilmann, M. Kelson, A. Rosser
Background and aims Across the Huntington’s Disease (HD) communities, there has been some success in delivering exercise interventions in HD over the short term. In order to move the field forward we now need studies with longer term follow-up to elucidate the potential effect of exercise and physical activity on disease progression. The efficient use of existing data and consideration of patient preferences is critical for evaluation of non-drug interventions where recruitment and retention are challenging. Methods In PACE-HD we utilise a Trial-within-a-Cohort design involving six Enroll-HD sites across Europe and USA. This design involves longitudinal evaluation of physical fitness and activity in a cohort of people with manifest HD (n=120) and a nested randomized trial (RCT) at 3 sites (n=60) of 12-months exercise compared to usual care. The intervention incorporates a physical activity coaching program with goal setting, an associated workbook, and provision of exercise equipment and FitBit devices for self-monitoring of exercise. Assessments include fitness testing and the use of wearable technologies to capture and quantify dose (frequency, duration, intensity) of physical activity in a large HD cohort. Participants in the RCT allocated to usual activity and those from the observational cohort will provide reference data (n=90) from their annual Enroll-HD assessments that we will utilise to evaluate exercise effects in those randomized to supported exercise (n=30). Outcomes Should the design prove to be feasible, it will pave the way for robust evaluation of exercise in HD supported by the existing Enroll cohort.
{"title":"J09 A new trial design for evaluating exercise outcomes in huntington’s disease","authors":"M. Busse, L. Quinn, C. Drew, R. Williams-Thomas, P. Dimitropoulou, R. Playle, K. Hamana, B. Griffin, R. Reilmann, M. Kelson, A. Rosser","doi":"10.1136/jnnp-2018-EHDN.269","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.269","url":null,"abstract":"Background and aims Across the Huntington’s Disease (HD) communities, there has been some success in delivering exercise interventions in HD over the short term. In order to move the field forward we now need studies with longer term follow-up to elucidate the potential effect of exercise and physical activity on disease progression. The efficient use of existing data and consideration of patient preferences is critical for evaluation of non-drug interventions where recruitment and retention are challenging. Methods In PACE-HD we utilise a Trial-within-a-Cohort design involving six Enroll-HD sites across Europe and USA. This design involves longitudinal evaluation of physical fitness and activity in a cohort of people with manifest HD (n=120) and a nested randomized trial (RCT) at 3 sites (n=60) of 12-months exercise compared to usual care. The intervention incorporates a physical activity coaching program with goal setting, an associated workbook, and provision of exercise equipment and FitBit devices for self-monitoring of exercise. Assessments include fitness testing and the use of wearable technologies to capture and quantify dose (frequency, duration, intensity) of physical activity in a large HD cohort. Participants in the RCT allocated to usual activity and those from the observational cohort will provide reference data (n=90) from their annual Enroll-HD assessments that we will utilise to evaluate exercise effects in those randomized to supported exercise (n=30). Outcomes Should the design prove to be feasible, it will pave the way for robust evaluation of exercise in HD supported by the existing Enroll cohort.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"100 1","pages":"A100 - A101"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73110839","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.163
Philip Pracht, R. Schubert, Pascal Barallon, Benjamin Habbel, Karin Mittmann, R. Reilmann
Background Clinical rating scales in clinical trials for Huntington’s disease (HD) have shown limited sensitivity in the premanifest stage of HD and often suffer from inter- and intra-rater variability and bias. Thus, there is an unmet need for objective and reliable assessments to serve as outcome measures in clinical trials. The Q-Motor, a sensor-based assessment battery, was developed to provide accurate and precise quantification of motor performance. During the analysis of the TRACK-HD study, a couple of variables turned out to be particularly sensitive, but further approaches on testing alternative variables have not been conducted, yet. Objective To identify novel conceptual variables for the Q-Motor digitomotography (speeded tapping) assessment, that have the potential to be more sensitive and robust particularly in the premanifest stage. The applicability of these variables should be investigated for cross-sectional and longitudinal analyses, using the TRACK-HD data. Methods Q-Motor raw-data from the TRACK-HD study was used to extract the novel variables. The data sample included 4 year follow up data from 288 participants (age: 48 ± 10 years, female: 124, number of unaffected controls: 94). Statistical analyses were conducted using R. Generalized linear mixed models and ANOVA was used for group comparisons cross-sectional and longitudinally. Correlation with clinical rating scales and imaging parameters was performed. Results Most novel identified variables allow discrimination between controls pre-HD and manifest HD groups. Some even show significance in the more subtle distinction between pre-HD subgroups. Most variables also show good correlations with the clinical Total Motor Score (TMS) and with several magnet resonance (MR) imaging variables. Conclusion The sensitivity observed in the novel variables is comparable to that of previously used variables. However, the additional information may be useful for the creation of a combined measure, which will be explored in a next step.
{"title":"F62 Identification and verification of novel variables in quantitative motor tests (Q-motor) in huntington’s disease, using the track-hd data set","authors":"Philip Pracht, R. Schubert, Pascal Barallon, Benjamin Habbel, Karin Mittmann, R. Reilmann","doi":"10.1136/jnnp-2018-EHDN.163","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.163","url":null,"abstract":"Background Clinical rating scales in clinical trials for Huntington’s disease (HD) have shown limited sensitivity in the premanifest stage of HD and often suffer from inter- and intra-rater variability and bias. Thus, there is an unmet need for objective and reliable assessments to serve as outcome measures in clinical trials. The Q-Motor, a sensor-based assessment battery, was developed to provide accurate and precise quantification of motor performance. During the analysis of the TRACK-HD study, a couple of variables turned out to be particularly sensitive, but further approaches on testing alternative variables have not been conducted, yet. Objective To identify novel conceptual variables for the Q-Motor digitomotography (speeded tapping) assessment, that have the potential to be more sensitive and robust particularly in the premanifest stage. The applicability of these variables should be investigated for cross-sectional and longitudinal analyses, using the TRACK-HD data. Methods Q-Motor raw-data from the TRACK-HD study was used to extract the novel variables. The data sample included 4 year follow up data from 288 participants (age: 48 ± 10 years, female: 124, number of unaffected controls: 94). Statistical analyses were conducted using R. Generalized linear mixed models and ANOVA was used for group comparisons cross-sectional and longitudinally. Correlation with clinical rating scales and imaging parameters was performed. Results Most novel identified variables allow discrimination between controls pre-HD and manifest HD groups. Some even show significance in the more subtle distinction between pre-HD subgroups. Most variables also show good correlations with the clinical Total Motor Score (TMS) and with several magnet resonance (MR) imaging variables. Conclusion The sensitivity observed in the novel variables is comparable to that of previously used variables. However, the additional information may be useful for the creation of a combined measure, which will be explored in a next step.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"220 1","pages":"A61 - A62"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77558264","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.116
B. Griffin, M. Booth, M. Busse-Morris, E. Wild, C. Setodji, John H. Warner, A. Mohan
Background Although Huntington’s disease (HD) is a genetically inherited disorder, it is not clear how non-genetic factors such as environment and behavior may contribute to progression. Aims We used a causal inference approach to run simulated pseudo-randomized trials in a large (n=2,914) longitudinal dataset, to study the effects of exposure to non-genetic factors on progression of HD: education, employment status, tobacco use, alcohol use, and use of recreational and therapeutic drugs. Methods Each factor was investigated in isolation while controlling for nineteen others factors (including baseline severity of HD), to guarantee that groups were well balanced at baseline on all potential confounders using propensity score (PS) weights. Outcomes were compared several years later using doubly robust (DR) outcome models. The primary outcome was a composite HD severity measure that included assessments of motor, cognitive and functional abilities. Results We only found significant evidence that antidepressant use was detrimental to HD progression over time, compared with similarly matched individuals who were not taking antidepressants (effect size difference=0.13; 95% confidence interval=0.05,0.21). Conclusions This study is the first to examine the impact of non-genetic factors on HD using causal inference methods. We show that previously reported significant factors – including alcohol and recreational drug use – were no longer causally linked to HD progression after PS weighting. This highlights the important role PS weighting can play in examining non-genetic factors contributing to HD progression, and the caution needed when interpreting findings from studies that do not attempt to use such methods.
{"title":"F10 Environmental modifiers of huntington’s disease: using propensity scores and outcome analyses to identify causal links","authors":"B. Griffin, M. Booth, M. Busse-Morris, E. Wild, C. Setodji, John H. Warner, A. Mohan","doi":"10.1136/jnnp-2018-EHDN.116","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.116","url":null,"abstract":"Background Although Huntington’s disease (HD) is a genetically inherited disorder, it is not clear how non-genetic factors such as environment and behavior may contribute to progression. Aims We used a causal inference approach to run simulated pseudo-randomized trials in a large (n=2,914) longitudinal dataset, to study the effects of exposure to non-genetic factors on progression of HD: education, employment status, tobacco use, alcohol use, and use of recreational and therapeutic drugs. Methods Each factor was investigated in isolation while controlling for nineteen others factors (including baseline severity of HD), to guarantee that groups were well balanced at baseline on all potential confounders using propensity score (PS) weights. Outcomes were compared several years later using doubly robust (DR) outcome models. The primary outcome was a composite HD severity measure that included assessments of motor, cognitive and functional abilities. Results We only found significant evidence that antidepressant use was detrimental to HD progression over time, compared with similarly matched individuals who were not taking antidepressants (effect size difference=0.13; 95% confidence interval=0.05,0.21). Conclusions This study is the first to examine the impact of non-genetic factors on HD using causal inference methods. We show that previously reported significant factors – including alcohol and recreational drug use – were no longer causally linked to HD progression after PS weighting. This highlights the important role PS weighting can play in examining non-genetic factors contributing to HD progression, and the caution needed when interpreting findings from studies that do not attempt to use such methods.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"47 1","pages":"A43 - A44"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74137993","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.201
Bonnie Hennig-Trestman
Background There is limited research focusing on coping strategies for families living in an HD home. There is even less research focusing on the difficulties parents have discussing HD with their children. Aims The Huntington’s Disease Youth Organization (HDYO) hopes to change this. Since its inception in 2012 HDYO has received numerous inquiries requesting help from parents who are having difficulty talking to their children about HD. A grant was obtained to conduct research with parents of children in HD-affected families to determine: 1) the perceived challenges they face in talking to their children about HD and, 2) the most accessible formats for supporting materials. Method Families who have contacted HDYO from 2012 to the present were contacted inviting their participation. Additional contacts were obtained through social media platforms. Parents were asked a series of questions initially regarding demographics and subsequently targeting the perceived challenges of talking to their children about HD; if they have taken advantage of available supporting material; and whether the material accessed was written, online, or through conversation with healthcare professionals. Outcome The information collected was categorized, a data set created, and the material analyzed. A final report will be generated to enable submission of grant requests to other agencies. Conclusion The subsequent funding will allow for the creation and dissemination of materials that will include (for example) written materials, online videos, and interactive materials to assist parents and guardians in discussing HD with children.
{"title":"H22 Developing an evidenced-based model to optimize parental support for discussing huntington’s disease (hd) with children","authors":"Bonnie Hennig-Trestman","doi":"10.1136/jnnp-2018-EHDN.201","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.201","url":null,"abstract":"Background There is limited research focusing on coping strategies for families living in an HD home. There is even less research focusing on the difficulties parents have discussing HD with their children. Aims The Huntington’s Disease Youth Organization (HDYO) hopes to change this. Since its inception in 2012 HDYO has received numerous inquiries requesting help from parents who are having difficulty talking to their children about HD. A grant was obtained to conduct research with parents of children in HD-affected families to determine: 1) the perceived challenges they face in talking to their children about HD and, 2) the most accessible formats for supporting materials. Method Families who have contacted HDYO from 2012 to the present were contacted inviting their participation. Additional contacts were obtained through social media platforms. Parents were asked a series of questions initially regarding demographics and subsequently targeting the perceived challenges of talking to their children about HD; if they have taken advantage of available supporting material; and whether the material accessed was written, online, or through conversation with healthcare professionals. Outcome The information collected was categorized, a data set created, and the material analyzed. A final report will be generated to enable submission of grant requests to other agencies. Conclusion The subsequent funding will allow for the creation and dissemination of materials that will include (for example) written materials, online videos, and interactive materials to assist parents and guardians in discussing HD with children.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"1 1","pages":"A75 - A75"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86320251","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.42
R. Cheong, S. Cuellar-Baena, Barbara Baldo, R. I. Zandt, D. Kirik, Å. Petersén
Background Alterations in the modulatory function of dopamine in the striatum have been a consistent finding in Huntington’s disease. The dopamine D2 receptor-expressing GABAergic enkephalin neurons of the indirect striatal pathway are thought to be most vulnerable and the ultimate loss of inhibitory control of this circuitry may directly be related to motor, cognitive and behavioral deficits associated with the disease. Aim The aim of this study was to investigate whether behavioral and neurochemical changes in the BACHD mouse model are directly related to the expression of mutant huntingtin protein in the indirect striatal pathway. Methods/techniques We crossed BACHD mice with mice expressing Cre-recombinase under the adenosine A2a promoter. As adenosine A2a and dopamine D2 receptors are co-expressed in the striatum, this crossing generated BACHD mice without expression of mutant HTT in the indirect striatal pathway. We evaluated striatal metabolite changes with 9.4T 1H-magnetic resonance spectroscopy and behavioral changes with the accelerating rotarod, footprints test, elevated plus maze, Porsolt forced swim test, open field test as readouts. Mice were tested at 6 months of age. Results/outcome Our results show that motor deficits, body weight changes and depressive-like behavior are present in BACHD mice of the C57BL6/J strain at 6 months of age. Notably, these impairments remain in the absence of mutant HTT in A2a-expressing cells. Analyses of striatal metabolite changes revealed alterations in metabolites involved in energy metabolism and neurotransmission such as lactate, myo-inositol, N-acetylaspartate. Finally, gene expression analyses reveal reversal in genes of the citric acid cycle with the deletion of mutant huntingtin from A2a neurons. Conclusions Together, these observations suggest that motor and psychiatric impairments in the BACHD mice at the behavioral level are not due to effects on the adenosine A2a pathway despite changes at the gene expression level.
{"title":"A44 Analysis of the deletion of mutant huntingtin from A2A-receptor expressing neurons","authors":"R. Cheong, S. Cuellar-Baena, Barbara Baldo, R. I. Zandt, D. Kirik, Å. Petersén","doi":"10.1136/jnnp-2018-EHDN.42","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.42","url":null,"abstract":"Background Alterations in the modulatory function of dopamine in the striatum have been a consistent finding in Huntington’s disease. The dopamine D2 receptor-expressing GABAergic enkephalin neurons of the indirect striatal pathway are thought to be most vulnerable and the ultimate loss of inhibitory control of this circuitry may directly be related to motor, cognitive and behavioral deficits associated with the disease. Aim The aim of this study was to investigate whether behavioral and neurochemical changes in the BACHD mouse model are directly related to the expression of mutant huntingtin protein in the indirect striatal pathway. Methods/techniques We crossed BACHD mice with mice expressing Cre-recombinase under the adenosine A2a promoter. As adenosine A2a and dopamine D2 receptors are co-expressed in the striatum, this crossing generated BACHD mice without expression of mutant HTT in the indirect striatal pathway. We evaluated striatal metabolite changes with 9.4T 1H-magnetic resonance spectroscopy and behavioral changes with the accelerating rotarod, footprints test, elevated plus maze, Porsolt forced swim test, open field test as readouts. Mice were tested at 6 months of age. Results/outcome Our results show that motor deficits, body weight changes and depressive-like behavior are present in BACHD mice of the C57BL6/J strain at 6 months of age. Notably, these impairments remain in the absence of mutant HTT in A2a-expressing cells. Analyses of striatal metabolite changes revealed alterations in metabolites involved in energy metabolism and neurotransmission such as lactate, myo-inositol, N-acetylaspartate. Finally, gene expression analyses reveal reversal in genes of the citric acid cycle with the deletion of mutant huntingtin from A2a neurons. Conclusions Together, these observations suggest that motor and psychiatric impairments in the BACHD mice at the behavioral level are not due to effects on the adenosine A2a pathway despite changes at the gene expression level.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"10 1","pages":"A16 - A16"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90536402","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.115
Clare A. Gibbons, Sherali Esmail, Harrison Mah, W. Fung
Background Huntington disease (HD) and amyotrophic lateral sclerosis (ALS) are clinically distinct neurodegenerative disorders; however, there are reports of the coexistence of the two conditions. This has led to a debate about whether these cases are a coincidental occurrence of both diseases or whether an expanded HD allele could be a risk factor for developing ALS in a rare subset of HD patients. Case history We report a male patient with onset of HD motor symptoms at 64 years of age who then developed ALS at 74 years of age. The patient has multiple family members with HD including his father who developed symptoms in his early 70’s. The patient had predictive testing for HD in 1998 which revealed an expanded HTT allele of 39 CAG repeats. He has no family history of ALS. The patient reported HD symptoms began about 8 years ago and recently some mild cognitive decline. A motor exam in 2014 found mild chorea in all extremities, head and neck. Swallowing difficulties, worsening chorea and balance were noted in 2016. By November 2017, the patient presented with rapidly progressing proximal weakness in the arms and legs, as well as, distal weakness and atrophy in the right hand intrinsics and weakness at both ankle dorsiflexors. The degree of weakness and wasting was higher than typically seen in HD. Further examination found fasciculation in the distal hands. Needle EMG examination showed mild denervation in the right C5/C6 myotome and severe denervation in the right tibialis anterior. In addition, there was evidence of wide spread denervation in the thoracic paraspinal muscles in keeping with active and chronic motor neuron disease. Conclusion We present a patient with early manifest HD who developed ALS to contribute to the literature in this area.
{"title":"F09 Huntington disease and amyotrophic lateral sclerosis: a case study","authors":"Clare A. Gibbons, Sherali Esmail, Harrison Mah, W. Fung","doi":"10.1136/jnnp-2018-EHDN.115","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.115","url":null,"abstract":"Background Huntington disease (HD) and amyotrophic lateral sclerosis (ALS) are clinically distinct neurodegenerative disorders; however, there are reports of the coexistence of the two conditions. This has led to a debate about whether these cases are a coincidental occurrence of both diseases or whether an expanded HD allele could be a risk factor for developing ALS in a rare subset of HD patients. Case history We report a male patient with onset of HD motor symptoms at 64 years of age who then developed ALS at 74 years of age. The patient has multiple family members with HD including his father who developed symptoms in his early 70’s. The patient had predictive testing for HD in 1998 which revealed an expanded HTT allele of 39 CAG repeats. He has no family history of ALS. The patient reported HD symptoms began about 8 years ago and recently some mild cognitive decline. A motor exam in 2014 found mild chorea in all extremities, head and neck. Swallowing difficulties, worsening chorea and balance were noted in 2016. By November 2017, the patient presented with rapidly progressing proximal weakness in the arms and legs, as well as, distal weakness and atrophy in the right hand intrinsics and weakness at both ankle dorsiflexors. The degree of weakness and wasting was higher than typically seen in HD. Further examination found fasciculation in the distal hands. Needle EMG examination showed mild denervation in the right C5/C6 myotome and severe denervation in the right tibialis anterior. In addition, there was evidence of wide spread denervation in the thoracic paraspinal muscles in keeping with active and chronic motor neuron disease. Conclusion We present a patient with early manifest HD who developed ALS to contribute to the literature in this area.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"1 1","pages":"A43 - A43"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89977832","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.90
L. Byrne, F. B. Rodrigues, K. Blennow, A. Durr, B. Leavitt, R. Roos, R. Scahill, S. Tabrizi, H. Zetterberg, D. Langbehn, E. Wild
Background Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington’s disease. We investigated whether neurofilament light protein (NfL) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington’s disease. Methods In the 3 year, 298-participant TRACK-HD cohort, we did a retrospective analysis of the relationship between plasma NfL and clinical and neuroimaging measures previously identified as being the strongest predictors of HD progression. Cross-sectional and longitudinal relationships were analysed using random effect models of within-subject correlation. In a separate 37-participant cohort we quantified NfL in cerebrospinal fluid (CSF) and plasma. Findings Mean concentrations of plasma NfL at baseline were significantly higher in HTT mutation carriers than in controls and the difference increased with disease stage. At any given timepoint, plasma NfL correlated with clinical and MRI findings. In longitudinal analyses, baseline plasma NfL correlated significantly with subsequent decline in cognition (SDMT r=–0.374, p<0.0001; SWR r=–0.248, p=0.0033), TFC (r=–0.289, p=0.0264), and brain atrophy (caudate r=0.178, p=0.0087; whole-brain r=0.602, p<0.0001; grey matter r=0.518, p<0.0001; white matter r=0.588, p<0.0001; and ventricular expansion r=–0.589, p<0.0001). All changes except SWR and TFC remained significant after adjustment for age and CAG repeat. In premanifest HD individuals, plasma NfL at baseline was associated with subsequent clinical onset during the 3 year follow-up period. Concentrations of NfL in CSF and plasma were correlated in mutation carriers. Interpretation NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington’s disease.
{"title":"D08 Neurofilament light protein in blood as a potential biomarker of neurodegeneration in hungtington’s disease: a retrospective cohort analysis","authors":"L. Byrne, F. B. Rodrigues, K. Blennow, A. Durr, B. Leavitt, R. Roos, R. Scahill, S. Tabrizi, H. Zetterberg, D. Langbehn, E. Wild","doi":"10.1136/jnnp-2018-EHDN.90","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.90","url":null,"abstract":"Background Blood biomarkers of neuronal damage could facilitate clinical management of and therapeutic development for Huntington’s disease. We investigated whether neurofilament light protein (NfL) in blood is a potential prognostic marker of neurodegeneration in patients with Huntington’s disease. Methods In the 3 year, 298-participant TRACK-HD cohort, we did a retrospective analysis of the relationship between plasma NfL and clinical and neuroimaging measures previously identified as being the strongest predictors of HD progression. Cross-sectional and longitudinal relationships were analysed using random effect models of within-subject correlation. In a separate 37-participant cohort we quantified NfL in cerebrospinal fluid (CSF) and plasma. Findings Mean concentrations of plasma NfL at baseline were significantly higher in HTT mutation carriers than in controls and the difference increased with disease stage. At any given timepoint, plasma NfL correlated with clinical and MRI findings. In longitudinal analyses, baseline plasma NfL correlated significantly with subsequent decline in cognition (SDMT r=–0.374, p<0.0001; SWR r=–0.248, p=0.0033), TFC (r=–0.289, p=0.0264), and brain atrophy (caudate r=0.178, p=0.0087; whole-brain r=0.602, p<0.0001; grey matter r=0.518, p<0.0001; white matter r=0.588, p<0.0001; and ventricular expansion r=–0.589, p<0.0001). All changes except SWR and TFC remained significant after adjustment for age and CAG repeat. In premanifest HD individuals, plasma NfL at baseline was associated with subsequent clinical onset during the 3 year follow-up period. Concentrations of NfL in CSF and plasma were correlated in mutation carriers. Interpretation NfL in plasma shows promise as a potential prognostic blood biomarker of disease onset and progression in Huntington’s disease.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"20 23","pages":"A33 - A34"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91442604","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.50
S. Gabery, Barbara Baldo, R. Soylu-Kucharz, R. Cheong, J. Henningsen, E. Englund, C. Mclean, D. Kirik, G. Halliday, Å. Petersén
Background Metabolic dysfunction is part of the neurodegenerative Huntington disease (HD) and may be involved in modulating the disease process. The underlying mechanisms are not known. The metabolic regulators sirtuins have been suggested to play a role in HD but the published results are conflicting. It is not known to what extent sirtuins are affected in different brain regions in HD. Aims Metabolic dysfunction is involved in modulating the disease process in HD but the underlying mechanisms are not known. We aimed at investigating whether or not the metabolic regulators sirtuins are affected in HD. Methods qRT-PCR and immunohistochemistry were used to assess levels of SIRT1–3 and downstream targets in postmortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin using recombinant adeno-associated viral vectors in mice. Results We show that mRNA levels of the metabolic regulator SIRT1 are upregulated in the striatum and the cerebral cortex in postmortem HD brain but not in the less affected cerebellum in postmortem HD brain. Levels of SIRT2 are only upregulated in the striatum and SIRT3 is not affected in HD. Interestingly, both mRNA and protein levels of SIRT1 were increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets as well as downregulation of the neuropeptides orexin (hypocretin), dynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant huntingtin suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes of SIRT1 require more widespread expression of mutant huntingtin. Conclusions We show that SIRT1 expression is increased in HD affected brain regions, impacting metabolic pathways in specific nuclei of the hypothalamus in HD.
{"title":"A52 SIRT1 is increased in affected brain regions in huntington disease impacting hypothalamic metabolic pathways","authors":"S. Gabery, Barbara Baldo, R. Soylu-Kucharz, R. Cheong, J. Henningsen, E. Englund, C. Mclean, D. Kirik, G. Halliday, Å. Petersén","doi":"10.1136/jnnp-2018-EHDN.50","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.50","url":null,"abstract":"Background Metabolic dysfunction is part of the neurodegenerative Huntington disease (HD) and may be involved in modulating the disease process. The underlying mechanisms are not known. The metabolic regulators sirtuins have been suggested to play a role in HD but the published results are conflicting. It is not known to what extent sirtuins are affected in different brain regions in HD. Aims Metabolic dysfunction is involved in modulating the disease process in HD but the underlying mechanisms are not known. We aimed at investigating whether or not the metabolic regulators sirtuins are affected in HD. Methods qRT-PCR and immunohistochemistry were used to assess levels of SIRT1–3 and downstream targets in postmortem brain tissue from HD patients and control cases as well as after selective hypothalamic expression of mutant huntingtin using recombinant adeno-associated viral vectors in mice. Results We show that mRNA levels of the metabolic regulator SIRT1 are upregulated in the striatum and the cerebral cortex in postmortem HD brain but not in the less affected cerebellum in postmortem HD brain. Levels of SIRT2 are only upregulated in the striatum and SIRT3 is not affected in HD. Interestingly, both mRNA and protein levels of SIRT1 were increased in the lateral hypothalamic area (LHA) and ventromedial hypothalamus (VMH) in HD. Further analyses of the LHA and VMH confirmed pathological changes in these regions including effects on SIRT1 downstream targets as well as downregulation of the neuropeptides orexin (hypocretin), dynorphin and melanin-concentrating hormone (MCH) in the LHA and of brain-derived neurotrophic factor (BDNF) in the VMH. Analyses after selective hypothalamic expression of mutant huntingtin suggest that effects on BDNF, orexin, dynorphin and MCH are early and direct, whereas changes of SIRT1 require more widespread expression of mutant huntingtin. Conclusions We show that SIRT1 expression is increased in HD affected brain regions, impacting metabolic pathways in specific nuclei of the hypothalamus in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"36 1","pages":"A19 - A19"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81428888","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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