Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.104
N. Georgiou‐Karistianis, M. Soloveva, D. Velakoulis, G. Poudel, S. Jamadar
Background Cognitive reserve and physical exercise has been found to have positive function and brain effects in a number of neurodegenerative disorders. No study to date has examined whether these factors can beneficially modulate functional brain activity during the premanifest stages of Huntington’s disease (pre-HD). Aims We examined the relationship between cognitive reserve, level of physical exercise and functional brain activity in pre-HD, compared with healthy controls, using functional MRI (fMRI) while individuals performed a visuospatial working memory task. Methods Pre-HD (n=15; M=37.33; SD=10.82) and age- and gender-matched healthy controls (n=15; M=35.60; SD=10.69), completed the Cognitive Reserve Index Questionnaire (CRIq) and the International Physical Activity Questionnaire Long (IPAQ-L). Participants also performed an 18 min fMRI visuospatial working memory task with low (2 items), intermediate-1 (3 items), intermediate-2 (4 items), and high (5 items) memory loads. Results Pearson’s correlation revealed that greater cognitive reserve (CRIq) was associated with decreased functional brain activity in the left posterior medial frontal cortex in pre-HD at intermediate-1 memory load (r=−0.52, p=0.045) and intermediate-2 memory load (r=−0.56, p=0.030), compared with healthy controls. Higher level of physical exercise (IPAQ-L) was also related to reduced functional brain activity in pre-HD, including in left (r=−0.52, p=0.050) and right (r=−0.65, p=0.009) anterior insula, left (r=−0.69, p=0.004) and right (r=−0.72, p=0.002) inferior frontal gyrus, left intraparietal sulcus (r=−0.64, p=0.01) and left dorsolateral prefrontal cortex (r=−0.57, p=0.03) at low memory load; and, right intraparietal sulcus (r=−0.61, p=0.015) at intermediate-1 memory load, compared with healthy controls. Conclusions These findings demonstrate that cognitive reserve and level of physical exercise can modulate functional brain reorganisation in pre-HD.
{"title":"E10 Cognitive reserve and physical exercise modulate functional brain reorganisation in premanifest huntington’s disease: preliminary findings","authors":"N. Georgiou‐Karistianis, M. Soloveva, D. Velakoulis, G. Poudel, S. Jamadar","doi":"10.1136/jnnp-2018-EHDN.104","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.104","url":null,"abstract":"Background Cognitive reserve and physical exercise has been found to have positive function and brain effects in a number of neurodegenerative disorders. No study to date has examined whether these factors can beneficially modulate functional brain activity during the premanifest stages of Huntington’s disease (pre-HD). Aims We examined the relationship between cognitive reserve, level of physical exercise and functional brain activity in pre-HD, compared with healthy controls, using functional MRI (fMRI) while individuals performed a visuospatial working memory task. Methods Pre-HD (n=15; M=37.33; SD=10.82) and age- and gender-matched healthy controls (n=15; M=35.60; SD=10.69), completed the Cognitive Reserve Index Questionnaire (CRIq) and the International Physical Activity Questionnaire Long (IPAQ-L). Participants also performed an 18 min fMRI visuospatial working memory task with low (2 items), intermediate-1 (3 items), intermediate-2 (4 items), and high (5 items) memory loads. Results Pearson’s correlation revealed that greater cognitive reserve (CRIq) was associated with decreased functional brain activity in the left posterior medial frontal cortex in pre-HD at intermediate-1 memory load (r=−0.52, p=0.045) and intermediate-2 memory load (r=−0.56, p=0.030), compared with healthy controls. Higher level of physical exercise (IPAQ-L) was also related to reduced functional brain activity in pre-HD, including in left (r=−0.52, p=0.050) and right (r=−0.65, p=0.009) anterior insula, left (r=−0.69, p=0.004) and right (r=−0.72, p=0.002) inferior frontal gyrus, left intraparietal sulcus (r=−0.64, p=0.01) and left dorsolateral prefrontal cortex (r=−0.57, p=0.03) at low memory load; and, right intraparietal sulcus (r=−0.61, p=0.015) at intermediate-1 memory load, compared with healthy controls. Conclusions These findings demonstrate that cognitive reserve and level of physical exercise can modulate functional brain reorganisation in pre-HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"43 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":"84669897","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.227
K. Doleckova, P. Dušek, R. Konvalinková, J. Roth, J. Klempír
The potentional benefit of symptomatic treatment of motor impairment in Huntington´s disease (HD) is still discussed. The aim of this study was to find out the effect of medication at different stages of this disease, In our Registry database containing 309 examinations of patients (aged 50.3±13.4 years, disease duration 9.13±3.51 years, CAG ranging from 40 to 70 repeats) was analysed usage of different drugs in comparison. To objectify performance of patients, Unified Huntington´s Disease Rating Scale – total motor score, motor scale subscores (voluntary, occulomotor, chorea, dystonia, rigidity), Total Functional Capacity and Functional Assessment were used. Risperidone was the most used medication with 154 assessements with this treatment and 155 without. Other preparates with the strongest representation were amantadine (97:212 events), clonazepam (56:253), tiapride (49:260), tetrabenazine (13:296) and haloperidol (11:298). Statistically (Mann-Whitney U-test) were compared patients with and without particular medical treatement, with only significant results in patients with clonazepam therapy, who had only significantly higher voluntary motor subscore (p<0.001). Additionally, we performed a linear model using ordinary least squares calculation to count for the effect of disease progression (age, disease duration, CAG repeats). The difference in voluntary motor subscore was independent on the disease progression. Although a longitudinal study should be performed to prove causality of clonazepam, caution should be used when prescribing clonazepam in HD.
{"title":"H49 Effectivness of pharmacotherapy in huntington’s disease","authors":"K. Doleckova, P. Dušek, R. Konvalinková, J. Roth, J. Klempír","doi":"10.1136/JNNP-2018-EHDN.227","DOIUrl":"https://doi.org/10.1136/JNNP-2018-EHDN.227","url":null,"abstract":"The potentional benefit of symptomatic treatment of motor impairment in Huntington´s disease (HD) is still discussed. The aim of this study was to find out the effect of medication at different stages of this disease, In our Registry database containing 309 examinations of patients (aged 50.3±13.4 years, disease duration 9.13±3.51 years, CAG ranging from 40 to 70 repeats) was analysed usage of different drugs in comparison. To objectify performance of patients, Unified Huntington´s Disease Rating Scale – total motor score, motor scale subscores (voluntary, occulomotor, chorea, dystonia, rigidity), Total Functional Capacity and Functional Assessment were used. Risperidone was the most used medication with 154 assessements with this treatment and 155 without. Other preparates with the strongest representation were amantadine (97:212 events), clonazepam (56:253), tiapride (49:260), tetrabenazine (13:296) and haloperidol (11:298). Statistically (Mann-Whitney U-test) were compared patients with and without particular medical treatement, with only significant results in patients with clonazepam therapy, who had only significantly higher voluntary motor subscore (p<0.001). Additionally, we performed a linear model using ordinary least squares calculation to count for the effect of disease progression (age, disease duration, CAG repeats). The difference in voluntary motor subscore was independent on the disease progression. Although a longitudinal study should be performed to prove causality of clonazepam, caution should be used when prescribing clonazepam in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"53 1","pages":"A83 - A84"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88622239","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.108
F. Squitieri, M. Dema, C. Borrelli, F. Consoli, A. Luca, S. Migliore
Background Huntington’s disease (HD) prevalence is variable and depends on genetic background. However, culture, environment and other, yet unknown, biological factors may also play a role in determining its frequency. In Italy we estimate a prevalence of 11/100.000 (Squitieri et al., 2016). Methods LIRH Foundation started to collect clinical and genealogical data together with DNA samples from patients and family members since 2001. Recently, we got in touch with a family from Calabria, Southern Italy, showing a high number of interrelationships and consequent increased risk of transmission of the mutation among people. Results The family includes about 25 affected people with ascertained HD and hundreds at risk. However, there were two generations of people with homozygous CAG repeat expansion due to two intermarriages of mutation carrier people. The main kindred showed a homozygous mother married with a heterozygous father and 5 children whose four had an homozygous condition. They showed a different HD stage and were included into ENROLL-HD. These people had several 100% risk children. Conclusion Nevertheless the large experience and the number of publications on genetic and psychological counseling in HD, the scientific community remains still unprepared on how to communicate such unusual risk of HD transmission. These conditions, moreover, contribute to an unpredictable frequency of the disease in some geographical areas.
{"title":"F02 A cluster of HD in italy with several subjects carrying cag expansion homozygousity in different generations and genetic risk over 50%","authors":"F. Squitieri, M. Dema, C. Borrelli, F. Consoli, A. Luca, S. Migliore","doi":"10.1136/jnnp-2018-EHDN.108","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.108","url":null,"abstract":"Background Huntington’s disease (HD) prevalence is variable and depends on genetic background. However, culture, environment and other, yet unknown, biological factors may also play a role in determining its frequency. In Italy we estimate a prevalence of 11/100.000 (Squitieri et al., 2016). Methods LIRH Foundation started to collect clinical and genealogical data together with DNA samples from patients and family members since 2001. Recently, we got in touch with a family from Calabria, Southern Italy, showing a high number of interrelationships and consequent increased risk of transmission of the mutation among people. Results The family includes about 25 affected people with ascertained HD and hundreds at risk. However, there were two generations of people with homozygous CAG repeat expansion due to two intermarriages of mutation carrier people. The main kindred showed a homozygous mother married with a heterozygous father and 5 children whose four had an homozygous condition. They showed a different HD stage and were included into ENROLL-HD. These people had several 100% risk children. Conclusion Nevertheless the large experience and the number of publications on genetic and psychological counseling in HD, the scientific community remains still unprepared on how to communicate such unusual risk of HD transmission. These conditions, moreover, contribute to an unpredictable frequency of the disease in some geographical areas.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"44 1","pages":"A41 - A41"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86675431","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.213
P. D. Vreede, F. Veldkamp, W. Achterberg, A. Heemskerk
Background Involuntary weight loss and malnutrition is a well-known and frequent outcome in patients with HD. Nowadays the therapy of a dietitian during or after a period of involuntary weight loss is focused on gaining weight by increasing calorie intake. Finally to achieve a reference Body Mass Index (BMI) between 23–28. In fact, the BMI range does not include the body composition, which includes the fat free mass and fat mass. A low fat free mass is for example associated with a higher mortality. Aim The aim of this study is therefore to create a better insight into the body composition changes of HD patients. Methods Fifty patients with HD will be included. The following aspects will be measured four times in one year: Bioelectrical impedance Analyses Nutritional history Calculation of energy requirement based on the Harris and Benedict formula Body Mass Index Length measurement based on knee height, Hand grip strength Calculation nutritional intake Phase of the disease Results The outcomes of this study are not known at this moment, but can be used to describe what changes occur in the body composition of HD patients during one year. Conclusion This study gives a better insight into the body composition changes in HD patients. This will be the first step to analyze what changes occur. This study makes it also possible to design a better balanced diet focusing on maintaining fat free mass.
{"title":"H35 Measuring body composition changes in huntington’s disease","authors":"P. D. Vreede, F. Veldkamp, W. Achterberg, A. Heemskerk","doi":"10.1136/jnnp-2018-EHDN.213","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.213","url":null,"abstract":"Background Involuntary weight loss and malnutrition is a well-known and frequent outcome in patients with HD. Nowadays the therapy of a dietitian during or after a period of involuntary weight loss is focused on gaining weight by increasing calorie intake. Finally to achieve a reference Body Mass Index (BMI) between 23–28. In fact, the BMI range does not include the body composition, which includes the fat free mass and fat mass. A low fat free mass is for example associated with a higher mortality. Aim The aim of this study is therefore to create a better insight into the body composition changes of HD patients. Methods Fifty patients with HD will be included. The following aspects will be measured four times in one year: Bioelectrical impedance Analyses Nutritional history Calculation of energy requirement based on the Harris and Benedict formula Body Mass Index Length measurement based on knee height, Hand grip strength Calculation nutritional intake Phase of the disease Results The outcomes of this study are not known at this moment, but can be used to describe what changes occur in the body composition of HD patients during one year. Conclusion This study gives a better insight into the body composition changes in HD patients. This will be the first step to analyze what changes occur. This study makes it also possible to design a better balanced diet focusing on maintaining fat free mass.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"306 1","pages":"A79 - A79"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79684667","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.204
Chandler Swope, Catherine A. Martin, M. Ellison
Background There are many camps available to support young people who are currently suffering from symptoms from an illness or condition, but little availability of camps for those with parents suffering from an illness where the young people are at risk for developing the same illness. The Huntington’s Disease Youth Organization (HDYO) has hosted eight camps around the world over the course of five years for young people impacted by HD. The aim of these camps is to provide the camper respite, a space for peer and professional support as well as access to education that is age and stage appropriate. Case history Campers overwhelming spoke to camp helping them feel less isolated and more in control of their journey with HD. Over 50% of campers in our study (only 10 campers completed all pre and post surveys) stated they had more specific knowledge about HD, there was also a statistically significant increase in the campers sense of social support and an increase positive sense of self-esteem (Kavanaugh et al, 2017). Conclusion There is still limited data on camps for young people at-risk of HD, but early information points to the existence of these camps to be hugely important for healthy outcomes. Furthermore, feeling educated about the disease, and research leads to young people feeling empowered and less afraid of the disease. They can also get practical information to help them make critical decisions (testing, family planning, symptom management etc) for their own journey with HD.
{"title":"H25 The social and educational impact of attending an huntington’s disease specific camp","authors":"Chandler Swope, Catherine A. Martin, M. Ellison","doi":"10.1136/jnnp-2018-EHDN.204","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.204","url":null,"abstract":"Background There are many camps available to support young people who are currently suffering from symptoms from an illness or condition, but little availability of camps for those with parents suffering from an illness where the young people are at risk for developing the same illness. The Huntington’s Disease Youth Organization (HDYO) has hosted eight camps around the world over the course of five years for young people impacted by HD. The aim of these camps is to provide the camper respite, a space for peer and professional support as well as access to education that is age and stage appropriate. Case history Campers overwhelming spoke to camp helping them feel less isolated and more in control of their journey with HD. Over 50% of campers in our study (only 10 campers completed all pre and post surveys) stated they had more specific knowledge about HD, there was also a statistically significant increase in the campers sense of social support and an increase positive sense of self-esteem (Kavanaugh et al, 2017). Conclusion There is still limited data on camps for young people at-risk of HD, but early information points to the existence of these camps to be hugely important for healthy outcomes. Furthermore, feeling educated about the disease, and research leads to young people feeling empowered and less afraid of the disease. They can also get practical information to help them make critical decisions (testing, family planning, symptom management etc) for their own journey with HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"33 1","pages":"A76 - A76"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89910150","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.232
Kate L Harris, S. Mason, R. Barker
Whilst the diagnosis of Huntington’s disease (HD) is reliant on the presence of motor disturbances, progressive cognitive impairments can precede overt motor features by up to 15 years (Paulsen, 2011) and often place the greatest burden on both HD patients and their families (Brandt and Butters, 1986). It has been hypothesised that there is an increase in DA transmission in early stages of HD as drugs that block DA receptors help alleviate the chorea (Cepeda, 2015). However, despite knowing that DA is critical for cognition in a healthy population, little is understood about the consequences of these early changes on cognition in HD. Importantly, it is not known this process if influenced by the DA antagonists used to treat motor features of HD. In this study we use the dataset from Enroll-HD, the world’s largest observational study for Huntington’s disease families, to assess the effects of dopamine antagonist medication on cognitive decline. Participants were grouped into those taking dopamine antagonist medication during the assessment period and a control group who were not taking DA medication but were matched for age, gender and disease stage using propensity score matching. Results showed that participants taking DA antagonists had a significantly greater annual decline in performance on the enrol cognitive task battery than those who were not on DA medication. Furthermore, a group of participants who came off dopamine antagonists during the assessment period did not differ from the control group in rate of cognitive decline during the period they were off the medication. Together these results suggest that dopamine antagonist medication may be detrimental to cognition, which has important implications for the clinical management of cognitive symptoms.
{"title":"H54 Investigation of the effects of dopamine antagonist medication on cognition in huntington’s disease","authors":"Kate L Harris, S. Mason, R. Barker","doi":"10.1136/jnnp-2018-EHDN.232","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.232","url":null,"abstract":"Whilst the diagnosis of Huntington’s disease (HD) is reliant on the presence of motor disturbances, progressive cognitive impairments can precede overt motor features by up to 15 years (Paulsen, 2011) and often place the greatest burden on both HD patients and their families (Brandt and Butters, 1986). It has been hypothesised that there is an increase in DA transmission in early stages of HD as drugs that block DA receptors help alleviate the chorea (Cepeda, 2015). However, despite knowing that DA is critical for cognition in a healthy population, little is understood about the consequences of these early changes on cognition in HD. Importantly, it is not known this process if influenced by the DA antagonists used to treat motor features of HD. In this study we use the dataset from Enroll-HD, the world’s largest observational study for Huntington’s disease families, to assess the effects of dopamine antagonist medication on cognitive decline. Participants were grouped into those taking dopamine antagonist medication during the assessment period and a control group who were not taking DA medication but were matched for age, gender and disease stage using propensity score matching. Results showed that participants taking DA antagonists had a significantly greater annual decline in performance on the enrol cognitive task battery than those who were not on DA medication. Furthermore, a group of participants who came off dopamine antagonists during the assessment period did not differ from the control group in rate of cognitive decline during the period they were off the medication. Together these results suggest that dopamine antagonist medication may be detrimental to cognition, which has important implications for the clinical management of cognitive symptoms.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"61 1","pages":"A86 - A86"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78245816","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.262
S. Schobel, G. Palermo, D. Trundell, T. Kremer, P. Sanwald-Ducray, Anne V Smith, L. Boak, R. Doody
Background RG6042 (formerly IONIS-HTTRx) is a non-allele-specific, huntingtin mRNA-targeting antisense oligonucleotide which reversibly suppresses production of all forms of Huntingtin protein (HTT). In a first-in-human test of this approach, RG6042 safely lowered the pathogenic mutant HTT (mHTT) in early Huntington’s disease (HD) patients, prompting Roche to begin a Global Development Program. Questions to be answered in the next phase of development include: what is the ultimate sustained magnitude of lowering of mHTT that can be achieved over long-term dosing; will lowering of mHTT be associated with clinical benefit and what are the best ways to measure such benefit; and will the approach prove to be safe and well tolerated over longer-term dosing? Method/results This Global Development Program includes a single, pivotal, 24-month efficacy study designed to demonstrate clinical efficacy and safety of RG6042 in early manifest HD patients, and examine the effects on slowing or stopping clinical progression of HD. The program also includes an ongoing, open-label extension study of the completed Phase I/IIa study (NCT03342053), and an observational natural history study, both being conducted in a limited number of sites. The rationale for the target population, pivotal study design, endpoints and digital monitoring tools will be discussed. Conclusion The Roche Global Development Program will provide valuable information on the clinical benefit and safety of the huntingtin lowering treatment RG6042 for patients with HD, as well as further longitudinal evidence of the causal role of mHTT in disease progression.
{"title":"J02 A global development program testing RG6042, an anti-sense oligonucleotide, for the treatment of early manifest huntington’s disease (hd)","authors":"S. Schobel, G. Palermo, D. Trundell, T. Kremer, P. Sanwald-Ducray, Anne V Smith, L. Boak, R. Doody","doi":"10.1136/jnnp-2018-EHDN.262","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.262","url":null,"abstract":"Background RG6042 (formerly IONIS-HTTRx) is a non-allele-specific, huntingtin mRNA-targeting antisense oligonucleotide which reversibly suppresses production of all forms of Huntingtin protein (HTT). In a first-in-human test of this approach, RG6042 safely lowered the pathogenic mutant HTT (mHTT) in early Huntington’s disease (HD) patients, prompting Roche to begin a Global Development Program. Questions to be answered in the next phase of development include: what is the ultimate sustained magnitude of lowering of mHTT that can be achieved over long-term dosing; will lowering of mHTT be associated with clinical benefit and what are the best ways to measure such benefit; and will the approach prove to be safe and well tolerated over longer-term dosing? Method/results This Global Development Program includes a single, pivotal, 24-month efficacy study designed to demonstrate clinical efficacy and safety of RG6042 in early manifest HD patients, and examine the effects on slowing or stopping clinical progression of HD. The program also includes an ongoing, open-label extension study of the completed Phase I/IIa study (NCT03342053), and an observational natural history study, both being conducted in a limited number of sites. The rationale for the target population, pivotal study design, endpoints and digital monitoring tools will be discussed. Conclusion The Roche Global Development Program will provide valuable information on the clinical benefit and safety of the huntingtin lowering treatment RG6042 for patients with HD, as well as further longitudinal evidence of the causal role of mHTT in disease progression.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"87 1","pages":"A98 - A98"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78254829","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.26
AP Gómez-Escribano, J. Bono-Yagüe, I. Real-Arévalo, Q. Chengzhang, M. Seco, M. Sequedo, J. Blanca, J. Cañizares, J. Burguera, C. Peiró, A. Laoz, O. Nicholas, J. Millán, R. Vázquez-Manrique
Toxicity induced by proteins containing polyglutamines (polyQs) is the cause of different neurodegenerative diseases, such as Huntington’s disease (HD). Mutant huntingtin (mHtt) is prone to aggregation, due to an abnormally long polyQ at the N-terminal region, which is believed to cause aggregation of other molecules, and contributes to the toxicity in patients of HD. Despite HD is a monogenic disease, there may be genes that modify the dynamics of mHtt aggregation and clearance, and therefore may modulate the onset and the progression of the disease in HD patients. To look for modifier genes that modulate the dynamics of aggregation of polyQ-containing proteins, we performed random chemical mutagenesis in Caenorhabditis elegans (C. elegans) worms that expresses 40 glutamines (40Q) fused in frame with YFP in muscle cells. 40Q::YFP aggregates in an age-dependent fashion, producing inclusion bodies that can be easily followed using a dissecting microscope equipped with fluorescence. We isolated a mutation that enhances the aggregation phenotype of 40Q::YFP worms. We identified the responsible mutation, vlt10, in the unc-1/Stomatin like protein gene by means of NGS. To verify the role of unc-1(vlt10) in the dynamics of aggregation, we have analysed different unc-1 mutations (e719, e1598) which confirmed that unc-1 is a modulator of aggregation. In addition, the product of unc-1 (UNC-1) works in nervous system to regulate protein homeostasis in muscle cells, suggesting that UNC-1 acts non-cell autonomously. To shed light into potential mechanisms of protein homeostasis modulation by unc-1, we performed genetic interaction studies. Among genes and pathways tested, we observed that the unc-1 phenotype is rescued by loss of function of ssu-1, a gene encoding a sulfotransferase enzyme which expression is restricted to the ASJ neurons. It is believed that SSU-1 adds sulphur to hormones produced by ASJ, to facilitate distribution among tissues by hormonal signalling. A steroid nuclear receptor, NHR-1, has been related with hormonal signalling from SSU-1. So we have analysed the ablation of this receptor in unc-1 mutant background to elucidate the mechanism.
{"title":"A28 Steroid hormone signaling may regulate homeostasis of polyq-containing proteins in c. elegans","authors":"AP Gómez-Escribano, J. Bono-Yagüe, I. Real-Arévalo, Q. Chengzhang, M. Seco, M. Sequedo, J. Blanca, J. Cañizares, J. Burguera, C. Peiró, A. Laoz, O. Nicholas, J. Millán, R. Vázquez-Manrique","doi":"10.1136/jnnp-2018-EHDN.26","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.26","url":null,"abstract":"Toxicity induced by proteins containing polyglutamines (polyQs) is the cause of different neurodegenerative diseases, such as Huntington’s disease (HD). Mutant huntingtin (mHtt) is prone to aggregation, due to an abnormally long polyQ at the N-terminal region, which is believed to cause aggregation of other molecules, and contributes to the toxicity in patients of HD. Despite HD is a monogenic disease, there may be genes that modify the dynamics of mHtt aggregation and clearance, and therefore may modulate the onset and the progression of the disease in HD patients. To look for modifier genes that modulate the dynamics of aggregation of polyQ-containing proteins, we performed random chemical mutagenesis in Caenorhabditis elegans (C. elegans) worms that expresses 40 glutamines (40Q) fused in frame with YFP in muscle cells. 40Q::YFP aggregates in an age-dependent fashion, producing inclusion bodies that can be easily followed using a dissecting microscope equipped with fluorescence. We isolated a mutation that enhances the aggregation phenotype of 40Q::YFP worms. We identified the responsible mutation, vlt10, in the unc-1/Stomatin like protein gene by means of NGS. To verify the role of unc-1(vlt10) in the dynamics of aggregation, we have analysed different unc-1 mutations (e719, e1598) which confirmed that unc-1 is a modulator of aggregation. In addition, the product of unc-1 (UNC-1) works in nervous system to regulate protein homeostasis in muscle cells, suggesting that UNC-1 acts non-cell autonomously. To shed light into potential mechanisms of protein homeostasis modulation by unc-1, we performed genetic interaction studies. Among genes and pathways tested, we observed that the unc-1 phenotype is rescued by loss of function of ssu-1, a gene encoding a sulfotransferase enzyme which expression is restricted to the ASJ neurons. It is believed that SSU-1 adds sulphur to hormones produced by ASJ, to facilitate distribution among tissues by hormonal signalling. A steroid nuclear receptor, NHR-1, has been related with hormonal signalling from SSU-1. So we have analysed the ablation of this receptor in unc-1 mutant background to elucidate the mechanism.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"26 1","pages":"A10 - A10"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75619836","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.102
H. Furby, James Ralph, A. Rosser, P. O'Callaghan, K. Murphy, R. Wise, J. Steventon
Background Preclinical and post-mortem studies reveal cerebrovascular abnormalities in the HD brain. Arterial spin labelling (ASL) MRI can be used to non-invasively measure cerebral blood flow (CBF) in the HD brain, a factor known to reflect cerebrovascular health. Lower CBF has been reported in cortical and subcortical grey matter (GM) regions in early HD patients and reductions in CBF exceed changes in GM volume (Chen et al., 2012). Reduced CBF may contribute to neuronal dysfunction and cognitive performance. Alterations in CBF need to be probed earlier in the disease course. Aims To assess early signs of cerebrovascular pathology in a pre-/early-symptomatic HD cohort, by measuring cerebral blood flow (CBF) using ASL MRI. Methods 3T MRI was performed at Cardiff University Brain Research Imaging Centre (CUBRIC). Fourteen pre-/early-HD gene carriers and 19 matched control volunteers were recruited. ASL MRI was used to quantify CBF across global grey matter (GM) and subcortical regions (caudate, putamen, thalamus and hippocampus). GM volume was measured from T1 weighted anatomical scans. Cognitive tests included the SDMT, STROOP, Trailmaking, SCOLP, Forward digit span and verbal fluency tests. Results/outcome CBF was lower in HD carriers than controls in the right thalamus and right caudate, but not across global GM (p<0.05). However, global GM and left thalamus CBF was related to disease burden score (Age x (CAG −35.5), where those later in the disease showed elevated CBF. Volume was significantly lower in HD carriers than controls in caudate, putamen and thalamus, but not the hippocampus. Regional volume did not predict CBF differences. Cognitive performance was generally lower in HD group, and bilateral caudate CBF predicted performance on SDMT and SCOLP tasks, but this effect was similar in both groups. Conclusions Apparent alterations in CBF can be detected in pre-/early-HD. CBF was related to cognition, but not to GM volume. A CBF reduction in distinct subcortical regions suggest that early abnormalities are not global, and may first occur locally in key regions in HD. A disease related increase in CBF may reflect an early compensatory elevation in CBF. How CBF is related to HD pathology remains to be elucidated. Findings highlight the additional value of ASL MRI as a non-invasive measure of HD pathology that complements typical anatomical MRI approaches.
{"title":"E08 Cerebral blood flow is associated with disease severity and cognitive defecits in pre/early huntington’s disease","authors":"H. Furby, James Ralph, A. Rosser, P. O'Callaghan, K. Murphy, R. Wise, J. Steventon","doi":"10.1136/jnnp-2018-EHDN.102","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.102","url":null,"abstract":"Background Preclinical and post-mortem studies reveal cerebrovascular abnormalities in the HD brain. Arterial spin labelling (ASL) MRI can be used to non-invasively measure cerebral blood flow (CBF) in the HD brain, a factor known to reflect cerebrovascular health. Lower CBF has been reported in cortical and subcortical grey matter (GM) regions in early HD patients and reductions in CBF exceed changes in GM volume (Chen et al., 2012). Reduced CBF may contribute to neuronal dysfunction and cognitive performance. Alterations in CBF need to be probed earlier in the disease course. Aims To assess early signs of cerebrovascular pathology in a pre-/early-symptomatic HD cohort, by measuring cerebral blood flow (CBF) using ASL MRI. Methods 3T MRI was performed at Cardiff University Brain Research Imaging Centre (CUBRIC). Fourteen pre-/early-HD gene carriers and 19 matched control volunteers were recruited. ASL MRI was used to quantify CBF across global grey matter (GM) and subcortical regions (caudate, putamen, thalamus and hippocampus). GM volume was measured from T1 weighted anatomical scans. Cognitive tests included the SDMT, STROOP, Trailmaking, SCOLP, Forward digit span and verbal fluency tests. Results/outcome CBF was lower in HD carriers than controls in the right thalamus and right caudate, but not across global GM (p<0.05). However, global GM and left thalamus CBF was related to disease burden score (Age x (CAG −35.5), where those later in the disease showed elevated CBF. Volume was significantly lower in HD carriers than controls in caudate, putamen and thalamus, but not the hippocampus. Regional volume did not predict CBF differences. Cognitive performance was generally lower in HD group, and bilateral caudate CBF predicted performance on SDMT and SCOLP tasks, but this effect was similar in both groups. Conclusions Apparent alterations in CBF can be detected in pre-/early-HD. CBF was related to cognition, but not to GM volume. A CBF reduction in distinct subcortical regions suggest that early abnormalities are not global, and may first occur locally in key regions in HD. A disease related increase in CBF may reflect an early compensatory elevation in CBF. How CBF is related to HD pathology remains to be elucidated. Findings highlight the additional value of ASL MRI as a non-invasive measure of HD pathology that complements typical anatomical MRI approaches.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"21 1","pages":"A38 - A38"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72900491","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.268
J. Vesper, A. Schnitzler, L. Wojtecki, P. Kleger, B. Landwehrmeyer
Deep brain stimulation is an approved treatment for several neurodegenerative disorders but not for Huntington’s Disease. Because of the striking effects of pallidal deep brain stimulation (DBS) on choreodystonic movements induced by L-dopa in Parkinson’s disease and on dystonic symptoms, DBS of the GPi has recently been applied to a few single cases of HD. These off-label case studies report significant improvements of medically intractable chorea. Our previous randomised prospective pilot trial on 6 HD patients confirms the beneficial effects of pallidal stimulation on choreodystonic symptoms and suggests the optimal target site in the Globus pallidus to be at the GPi/GPe border zone rather than targeting the GPi alone.
脑深部刺激被批准用于治疗几种神经退行性疾病，但不适用于亨廷顿氏病。由于pallidal deep brain stimulation (DBS)对帕金森病患者左旋多巴诱导的神经张力障碍运动和神经张力障碍症状的显著影响，GPi的DBS最近已被应用于少数HD病例。这些标签外病例研究报告了医学上难治性舞蹈病的显著改善。我们之前对6名HD患者进行的随机前瞻性试验证实了苍白球刺激对舞蹈症张力障碍症状的有益作用，并建议苍白球的最佳靶点是GPi/GPe边界区，而不是单独针对GPi。
{"title":"J08 Deep brain stimulation (DBS) of the globus pallidus (GP) in huntington’s disease (HD): a prospective, randomised, controlled, international, multi-centre study (HD-DBS)","authors":"J. Vesper, A. Schnitzler, L. Wojtecki, P. Kleger, B. Landwehrmeyer","doi":"10.1136/jnnp-2018-EHDN.268","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.268","url":null,"abstract":"Deep brain stimulation is an approved treatment for several neurodegenerative disorders but not for Huntington’s Disease. Because of the striking effects of pallidal deep brain stimulation (DBS) on choreodystonic movements induced by L-dopa in Parkinson’s disease and on dystonic symptoms, DBS of the GPi has recently been applied to a few single cases of HD. These off-label case studies report significant improvements of medically intractable chorea. Our previous randomised prospective pilot trial on 6 HD patients confirms the beneficial effects of pallidal stimulation on choreodystonic symptoms and suggests the optimal target site in the Globus pallidus to be at the GPi/GPe border zone rather than targeting the GPi alone.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"21 1","pages":"A100 - A100"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73151925","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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