Pub Date : 2018-09-01DOI: 10.1136/jnnp-2018-EHDN.83
A. Ehrhardt, C. Sampaio
Background and aim For select samples from Enroll-HD platform studies, standardized core services, including preparation of derived samples and commonly requested analysis are being planned. The goal is to provide consistent quality, use the samples efficiently, and build a data collection providing larger context on the samples to create synergies, which will be enabling more, and more efficient HD research from the samples. Plans The plans consist of two main parts: Centralized and standardized core preparations when samples are requested (e.g. DNA and RNA isolation from PBMCs, cell line generation [only when needed], etc.) Discussions about an optimized core panel are ongoing, i.e. a set of analytes to be measured in all CSF samples, their matched plasma samples, and possibly additional samples. The panel is meant to cover commonly requested sample analysis (e.g. mHTT, HTT, NFL, tau, etc.).
{"title":"D01 Centralized sample preparation and analysis considerations","authors":"A. Ehrhardt, C. Sampaio","doi":"10.1136/jnnp-2018-EHDN.83","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.83","url":null,"abstract":"Background and aim For select samples from Enroll-HD platform studies, standardized core services, including preparation of derived samples and commonly requested analysis are being planned. The goal is to provide consistent quality, use the samples efficiently, and build a data collection providing larger context on the samples to create synergies, which will be enabling more, and more efficient HD research from the samples. Plans The plans consist of two main parts: Centralized and standardized core preparations when samples are requested (e.g. DNA and RNA isolation from PBMCs, cell line generation [only when needed], etc.) Discussions about an optimized core panel are ongoing, i.e. a set of analytes to be measured in all CSF samples, their matched plasma samples, and possibly additional samples. The panel is meant to cover commonly requested sample analysis (e.g. mHTT, HTT, NFL, tau, etc.).","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"46 1","pages":"A31 - A31"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73754852","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.148
A. D. Paepe, Joanna Sierpowska, C. García-Gorro, S. Martínez-Horta, J. Pérez-Pérez, J. Kulisevsky, N. Rodríguez-Dechicha, I. Vaquer, S. Subirà, M. Calopa, E. Muñoz, P. Santacruz, Jesús Ruiz-Idiago, C. Mareca, R. D. Diego-Balaguer, E. Càmara
Along with motor and cognitive deterioration, neuropsychiatric symptoms form a common feature of Huntington’s disease. Of these, apathy has been shown to most highly correlate with disease progression, often emerging prior to clinical diagnosis. However, due to the multidimensional nature of apathy, its elusive etiology, and the lack of operative diagnostic criteria, treatment options are limited. The present study combine diffusion tensor imaging (DTI) with precise apathy scales to investigate the relationship between white matter microstructural change and apathy in premanifest (n=22) and early manifest Huntington’s disease (n=24) compared with controls (n=35).Global apathy was measured using both the short Problem Behavior Assessment and the Lille Apathy Rating Scale, short-form. Principle component analysis of the LARS-s produced three apathy subtypes: emotional, cognitive, and auto-activation deficit. We found that premanifest participant’s portrayed significantly higher auto-activation deficit apathy, with early manifest patients additionally showing significantly increased apathy in cognitive apathy as well as global apathy. Analysis by DTI showed a significant rightward disturbance in the uncinate fasciculus (UF), the frontostriatal tract (FST), and the dorsolateral prefrontal cortex to caudate nucleus tract (dlPFC-cn). Importantly, specific apathy subtypes were found to be associated with discrete tracts. Specifically, higher levels of subtype-specific apathy correlated with a lateralized decrease in structural connectivity in the dlPFC-cn and FST for the cognitive domain of apathy and in the UF for auto-activation deficit, predominantly on the right side. That apathy subtypes are associated with distinct white matter substrates supports the importance of an individualized approach to its diagnosis and treatment.
{"title":"F44 Disentangling apathy subtypes in huntington’s disease: a white matter biomarker of disease profile and progression","authors":"A. D. Paepe, Joanna Sierpowska, C. García-Gorro, S. Martínez-Horta, J. Pérez-Pérez, J. Kulisevsky, N. Rodríguez-Dechicha, I. Vaquer, S. Subirà, M. Calopa, E. Muñoz, P. Santacruz, Jesús Ruiz-Idiago, C. Mareca, R. D. Diego-Balaguer, E. Càmara","doi":"10.1136/jnnp-2018-EHDN.148","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.148","url":null,"abstract":"Along with motor and cognitive deterioration, neuropsychiatric symptoms form a common feature of Huntington’s disease. Of these, apathy has been shown to most highly correlate with disease progression, often emerging prior to clinical diagnosis. However, due to the multidimensional nature of apathy, its elusive etiology, and the lack of operative diagnostic criteria, treatment options are limited. The present study combine diffusion tensor imaging (DTI) with precise apathy scales to investigate the relationship between white matter microstructural change and apathy in premanifest (n=22) and early manifest Huntington’s disease (n=24) compared with controls (n=35).Global apathy was measured using both the short Problem Behavior Assessment and the Lille Apathy Rating Scale, short-form. Principle component analysis of the LARS-s produced three apathy subtypes: emotional, cognitive, and auto-activation deficit. We found that premanifest participant’s portrayed significantly higher auto-activation deficit apathy, with early manifest patients additionally showing significantly increased apathy in cognitive apathy as well as global apathy. Analysis by DTI showed a significant rightward disturbance in the uncinate fasciculus (UF), the frontostriatal tract (FST), and the dorsolateral prefrontal cortex to caudate nucleus tract (dlPFC-cn). Importantly, specific apathy subtypes were found to be associated with discrete tracts. Specifically, higher levels of subtype-specific apathy correlated with a lateralized decrease in structural connectivity in the dlPFC-cn and FST for the cognitive domain of apathy and in the UF for auto-activation deficit, predominantly on the right side. That apathy subtypes are associated with distinct white matter substrates supports the importance of an individualized approach to its diagnosis and treatment.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"49 1","pages":"A55 - A56"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84491005","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.150
A. Nair, N. Aziz, R. Rutledge, G. Rees, S. Tabrizi
Introduction Disrupted gating of motor control through striatal pathways is thought to drive the development of motor symptoms in Huntington’s disease (HD). The range of motor symptoms, from chorea to bradykinesia, is thought to be driven by disruption in different striatal pathways. Aside from motor control, striatal pathways are also thought to play a key role in the expression of motivated behaviour. On this basis we asked whether the association between apathy and specific motor symptoms is in keeping with the hypothesis that apathy in HD is another manifestation of dysfunctional striatal gating. Methods Clinical data on 2608 patients with manifest HD disease was retrieved from the ENROLL-HD database. A linear mixed model was built to assess the relationship between motor symptoms and apathy (measured using the PBA and square root transformed) controlling for cognitive impairment, depression, medication use, disease duration, CAG repeat size and age. In a separate analysis the bradykinesia item was replaced by voluntary finger tapping performance. Results Although both bradykinesia and chorea were significantly associated with apathy, their effects were in opposite directions. Bradykinesia was associated with greater apathy (β=0.14, p<0.001) whereas chorea was associated with lower apathy (β=−0.12, p<0.001). By comparison rigidity had no significant effect in this large cohort (β=−0.04, p=0.08). In a similar model, slower finger tapping performance was also associated with greater apathy (β=0.07, p=0.001). Depression, medication use and cognitive slowing were also associated with apathy. Conclusion This analysis suggests that the processes driving distinct motor symptoms in HD may also underlie hard-to-treat psychiatric symptoms such as apathy. A common substrate and likely target for this shared mechanism is the disruption of specific striatal pathways that gate actions, decisions and motivated behaviour.
{"title":"F46 Relationship between distinct motor symptoms and apathy in huntington’s disease: clues to mechanism","authors":"A. Nair, N. Aziz, R. Rutledge, G. Rees, S. Tabrizi","doi":"10.1136/jnnp-2018-EHDN.150","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.150","url":null,"abstract":"Introduction Disrupted gating of motor control through striatal pathways is thought to drive the development of motor symptoms in Huntington’s disease (HD). The range of motor symptoms, from chorea to bradykinesia, is thought to be driven by disruption in different striatal pathways. Aside from motor control, striatal pathways are also thought to play a key role in the expression of motivated behaviour. On this basis we asked whether the association between apathy and specific motor symptoms is in keeping with the hypothesis that apathy in HD is another manifestation of dysfunctional striatal gating. Methods Clinical data on 2608 patients with manifest HD disease was retrieved from the ENROLL-HD database. A linear mixed model was built to assess the relationship between motor symptoms and apathy (measured using the PBA and square root transformed) controlling for cognitive impairment, depression, medication use, disease duration, CAG repeat size and age. In a separate analysis the bradykinesia item was replaced by voluntary finger tapping performance. Results Although both bradykinesia and chorea were significantly associated with apathy, their effects were in opposite directions. Bradykinesia was associated with greater apathy (β=0.14, p<0.001) whereas chorea was associated with lower apathy (β=−0.12, p<0.001). By comparison rigidity had no significant effect in this large cohort (β=−0.04, p=0.08). In a similar model, slower finger tapping performance was also associated with greater apathy (β=0.07, p=0.001). Depression, medication use and cognitive slowing were also associated with apathy. Conclusion This analysis suggests that the processes driving distinct motor symptoms in HD may also underlie hard-to-treat psychiatric symptoms such as apathy. A common substrate and likely target for this shared mechanism is the disruption of specific striatal pathways that gate actions, decisions and motivated behaviour.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"13 1","pages":"A56 - A56"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82063238","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.248
M. Melone, Francesca Di Cristo, F. A. Digilio, S. Paladino, A. Valentino, M. Finicelli, T. Squillaro, F. Napolitano, F. Scialò, U. Galderisi, A. Giordano, G. Peluso
Background Mitochondrial dysfunction, characterized by abnormalities of mitochondrial biogenesis, dynamics, trafficking, and alterations in the synthesis of high-energy molecules, seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington’s disease (HD). Meldonium is a small molecule that inhibits endogenous carnitine synthesis and carnitine cell uptake. The decrease of carnitine availability inside the cell induces a significant reprogramming of cell metabolic pathways that apparently counters the mitochondrial dysfunction, at least in the case of heart or brain ischemia. Aims To evaluate neuroprotective actions of meldonium in both in vitro and in vivo HD models. Methods We used STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein (mHtt), and a transgenic Drosophila model of HD in which the expression of Htt, with a 128Q expansion (Q128HD-FL) in the nervous system, led to progressive motor performance deficits. Results We found that meldonium could prevent cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells. Meldonium could also reduce the accumulation of mHtt aggregates inside the cell. In addition, meldonium was able to upregulate the expression of PGC-1α, which is a master co-regulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, as well as a potential HD target. As expected, the increase of PGC-1α was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Interestingly, when given per os, meldonium significantly alleviated motor dysfunction and prolonged the survival of transgenic Drosophila model of HD. Conclusions Our study strongly suggests, after considering these factors together, that meldonium (itself or as a lead structure for the synthesis of novel drugs) is a potential treatment for the management of HD.
{"title":"I12 Are mitochondria a possible therapeutic target in huntington’s disease?","authors":"M. Melone, Francesca Di Cristo, F. A. Digilio, S. Paladino, A. Valentino, M. Finicelli, T. Squillaro, F. Napolitano, F. Scialò, U. Galderisi, A. Giordano, G. Peluso","doi":"10.1136/jnnp-2018-EHDN.248","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.248","url":null,"abstract":"Background Mitochondrial dysfunction, characterized by abnormalities of mitochondrial biogenesis, dynamics, trafficking, and alterations in the synthesis of high-energy molecules, seems to play a fundamental role in the pathogenesis of neurodegeneration in Huntington’s disease (HD). Meldonium is a small molecule that inhibits endogenous carnitine synthesis and carnitine cell uptake. The decrease of carnitine availability inside the cell induces a significant reprogramming of cell metabolic pathways that apparently counters the mitochondrial dysfunction, at least in the case of heart or brain ischemia. Aims To evaluate neuroprotective actions of meldonium in both in vitro and in vivo HD models. Methods We used STHdhQ111/Q111 cells expressing a mutated form of the huntingtin protein (mHtt), and a transgenic Drosophila model of HD in which the expression of Htt, with a 128Q expansion (Q128HD-FL) in the nervous system, led to progressive motor performance deficits. Results We found that meldonium could prevent cytotoxicity induced by serum deprivation in STHdhQ111/Q111 cells. Meldonium could also reduce the accumulation of mHtt aggregates inside the cell. In addition, meldonium was able to upregulate the expression of PGC-1α, which is a master co-regulator of mitochondrial biogenesis, energy homeostasis, and antioxidant defense, as well as a potential HD target. As expected, the increase of PGC-1α was accompanied by the increment of mitochondrial mass and by the rebalancing of mitochondrial dynamics with a promotion of the mitochondrial fusion. Interestingly, when given per os, meldonium significantly alleviated motor dysfunction and prolonged the survival of transgenic Drosophila model of HD. Conclusions Our study strongly suggests, after considering these factors together, that meldonium (itself or as a lead structure for the synthesis of novel drugs) is a potential treatment for the management of HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"36 11 1","pages":"A92 - A92"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79445964","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.44
Christiana C. Christodoulou, C. Demetriou, Kleitos Sokratous, G. Spyrou, E. Zamba-Papanicolaou
Background Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder. Common pathological molecular mechanisms contributing to HD include reactive oxygen species (ROS), mitochondrial dysfunction and neuro-inflammation.1 Exposure to the Mediterranean Diet (MD) provides neuroprotection and has anti-oxidant and anti-inflammatory properties.2–4 Adherence to the MD could positively influence age of onset and progression of HD. Aims to address gaps in understanding on how neurodegeneration mechanisms influence phenoconversion and clinical characteristics of HD, particularly age of onset to investigate how adherence to the Mediterranean diet may modify these associations to delay phenoconversion. Methods This is a case-control study, where HD cases, pre-symptomatic, early symptomatic and later stage and age-matched controls will be recruited. Questionnaires will be used to collect data. A blood sample will be collected for untargeted metabolomic investigation into the pathways involved in HD and pathways affected by the MD. An attempt was made to integrate existing publically available data on HD, to identify pathways which, play a role in disease pathology of HD. Enrichment analysis was performed and seven clusters with pathways involved in HD were obtained.5 Results/outcomes Some of the pathways identified through publicly available datasets were cAMP, TGF-beta, Ca2+, and VEGF. These are likely to play a role in contributing to disease pathogenesis of HD. Conclusions Given the existing results and those that will emerge from the untargeted metabolomic analysis, we hope to identify pathways that can differentiate between different HD disease stages and whose aberrant changes can be positively influenced by adherence to the MD. References . Mo C, Hannan A, Renoir T. Environmental factors as modulators of neurodegeneration: Insights from gene–environment interactions in Huntington’s disease. Neuroscience & Biobehavioral2015;52:178–192. . Sofi F, Macchi C, Casini A. Mediterranean diet and minimizing neurodegeneration. Curr Nutr Rep2013;2:75–80. . Valls-Pedret C, et al. Mediterranean diet and age-related cognitive decline. JAMA Internal Medicine2015;175(7):1094. . Casamenti F, Stefani M. Olive polyphenols: New promising agents to combat aging-associated neurodegeneration. Expert Review of Neurotherapeutics2016;17(4):345–358. . Andrea C, Kakouri, Christiana C, Christodoulou, et al. Revealing clusters of connected pathways through multisource data integration in Huntington’s disease and Spastic Ataxia (paper is currently under review) 2018.
{"title":"A46 Neurodegenerative markers in hd: association with clinical charactersitcs, triplet expansion, phenoconversion and mediterranean diet adherence","authors":"Christiana C. Christodoulou, C. Demetriou, Kleitos Sokratous, G. Spyrou, E. Zamba-Papanicolaou","doi":"10.1136/jnnp-2018-EHDN.44","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.44","url":null,"abstract":"Background Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder. Common pathological molecular mechanisms contributing to HD include reactive oxygen species (ROS), mitochondrial dysfunction and neuro-inflammation.1 Exposure to the Mediterranean Diet (MD) provides neuroprotection and has anti-oxidant and anti-inflammatory properties.2–4 Adherence to the MD could positively influence age of onset and progression of HD. Aims to address gaps in understanding on how neurodegeneration mechanisms influence phenoconversion and clinical characteristics of HD, particularly age of onset to investigate how adherence to the Mediterranean diet may modify these associations to delay phenoconversion. Methods This is a case-control study, where HD cases, pre-symptomatic, early symptomatic and later stage and age-matched controls will be recruited. Questionnaires will be used to collect data. A blood sample will be collected for untargeted metabolomic investigation into the pathways involved in HD and pathways affected by the MD. An attempt was made to integrate existing publically available data on HD, to identify pathways which, play a role in disease pathology of HD. Enrichment analysis was performed and seven clusters with pathways involved in HD were obtained.5 Results/outcomes Some of the pathways identified through publicly available datasets were cAMP, TGF-beta, Ca2+, and VEGF. These are likely to play a role in contributing to disease pathogenesis of HD. Conclusions Given the existing results and those that will emerge from the untargeted metabolomic analysis, we hope to identify pathways that can differentiate between different HD disease stages and whose aberrant changes can be positively influenced by adherence to the MD. References . Mo C, Hannan A, Renoir T. Environmental factors as modulators of neurodegeneration: Insights from gene–environment interactions in Huntington’s disease. Neuroscience & Biobehavioral2015;52:178–192. . Sofi F, Macchi C, Casini A. Mediterranean diet and minimizing neurodegeneration. Curr Nutr Rep2013;2:75–80. . Valls-Pedret C, et al. Mediterranean diet and age-related cognitive decline. JAMA Internal Medicine2015;175(7):1094. . Casamenti F, Stefani M. Olive polyphenols: New promising agents to combat aging-associated neurodegeneration. Expert Review of Neurotherapeutics2016;17(4):345–358. . Andrea C, Kakouri, Christiana C, Christodoulou, et al. Revealing clusters of connected pathways through multisource data integration in Huntington’s disease and Spastic Ataxia (paper is currently under review) 2018.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"10 1","pages":"A16 - A17"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81739543","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.96
David G. Anderson, M. Haagensen, Aline Ferreira-Correia, R. Pierson, J. Carr, A. Krause, R. Margolis
Background Huntington’s Disease-Like 2 (HDL2) is one of the most common Huntington’s Disease (HD) phenocopies. Clinical similarities between these genetically different diseases are remarkable and the MRIs between them have been indistinguishable. Objective To compare MRIs between HDL2 and HD against unaffected controls using semiautomated volumetric analysis and morphometry. Methods Participants with a mixed or African ancestry were enrolled from an area with the world’s highest frequency of HDL2. All MRIs were performed on 1.5T and processed by Brain Image Analysis, LLC as described in previous HD studies. Analysis was done blind to the participants diagnosis. Results There were nine HDL2, ten HD, and 9 controls enrolled. Volume loss was greater in HDL2 patients when compared to HD, however significantly more thalamic volume loss was seen in HDL2 relative to HD and controls when controlled across multiple covariances. Conclusion Our findings suggest selective thalamic atrophy in HDL2 compared to HD.
{"title":"E02 Selective thalamic volume loss in huntington’s disease-like 2; a novel MRI finding compared to huntington’s disease","authors":"David G. Anderson, M. Haagensen, Aline Ferreira-Correia, R. Pierson, J. Carr, A. Krause, R. Margolis","doi":"10.1136/jnnp-2018-EHDN.96","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.96","url":null,"abstract":"Background Huntington’s Disease-Like 2 (HDL2) is one of the most common Huntington’s Disease (HD) phenocopies. Clinical similarities between these genetically different diseases are remarkable and the MRIs between them have been indistinguishable. Objective To compare MRIs between HDL2 and HD against unaffected controls using semiautomated volumetric analysis and morphometry. Methods Participants with a mixed or African ancestry were enrolled from an area with the world’s highest frequency of HDL2. All MRIs were performed on 1.5T and processed by Brain Image Analysis, LLC as described in previous HD studies. Analysis was done blind to the participants diagnosis. Results There were nine HDL2, ten HD, and 9 controls enrolled. Volume loss was greater in HDL2 patients when compared to HD, however significantly more thalamic volume loss was seen in HDL2 relative to HD and controls when controlled across multiple covariances. Conclusion Our findings suggest selective thalamic atrophy in HDL2 compared to HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"32 1","pages":"A36 - A36"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81767752","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.65
C. Casey, Yichen Qiu, Matthew Bentham, Edward J. Smith, G. Lignani, R. Andre, A. Wood‐Kaczmar, S. Tabrizi
Background The corticostriatal (CS) pathway, comprising layer V cortical projection neurons (CPN) and medium spiny neurons (MSN), is one of the first brain pathways to succumb to Huntington’s disease (HD) pathology. As a result, disrupted CS connectivity is evident and contributes to the motor and cognitive symptoms experienced by HD patients. Aims The aim of this work is to investigate the CS pathway using a purely human tissue-derived in vitro system. Methods This project utilizes two familial iPSC lines; the control line, with 20/20 HTT CAG repeat lengths (20Q), and a juvenile HD line, with 20/73 CAG repeats (73Q). These lines were differentiated in parallel to either MSNs or CPNs, and co-cultured in microfluidic chambers to physically recapitulate the human CS pathway. Results High-resolution fluorescence microscopy has revealed the formation of CS synapses within MFC co-cultures, complimented by live cell imaging with calcium binding dye Fluo4, which demonstrates the successful transmission of calcium between neuronal populations within MFCs. CPN cultures show a HD phenotype in their cytoskeletal dynamics, as axon projection efficiency is drastically reduced in 73Q CPNs compared to 20Q. Furthermore, 73Q MSNs exhibit enhanced cell death after BDNF-withdrawal compared to 20Q cultures. Finally, the intrinsic membrane properties of iPSC-derived MSNs also differ with disease state, as 73Q MSNs are hyper-excitable, with an extended latency to fire and extended refractory period. Conclusion These results provide a novel insight into the human CS pathway and suggest subtle differences in both the development and function of the CS pathway in HD.
{"title":"B13 Huntington’s disease phenotypes and disrupted corticostriatal connectivity observed in a novel ipsc-derived in vitro co-culture model","authors":"C. Casey, Yichen Qiu, Matthew Bentham, Edward J. Smith, G. Lignani, R. Andre, A. Wood‐Kaczmar, S. Tabrizi","doi":"10.1136/jnnp-2018-EHDN.65","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.65","url":null,"abstract":"Background The corticostriatal (CS) pathway, comprising layer V cortical projection neurons (CPN) and medium spiny neurons (MSN), is one of the first brain pathways to succumb to Huntington’s disease (HD) pathology. As a result, disrupted CS connectivity is evident and contributes to the motor and cognitive symptoms experienced by HD patients. Aims The aim of this work is to investigate the CS pathway using a purely human tissue-derived in vitro system. Methods This project utilizes two familial iPSC lines; the control line, with 20/20 HTT CAG repeat lengths (20Q), and a juvenile HD line, with 20/73 CAG repeats (73Q). These lines were differentiated in parallel to either MSNs or CPNs, and co-cultured in microfluidic chambers to physically recapitulate the human CS pathway. Results High-resolution fluorescence microscopy has revealed the formation of CS synapses within MFC co-cultures, complimented by live cell imaging with calcium binding dye Fluo4, which demonstrates the successful transmission of calcium between neuronal populations within MFCs. CPN cultures show a HD phenotype in their cytoskeletal dynamics, as axon projection efficiency is drastically reduced in 73Q CPNs compared to 20Q. Furthermore, 73Q MSNs exhibit enhanced cell death after BDNF-withdrawal compared to 20Q cultures. Finally, the intrinsic membrane properties of iPSC-derived MSNs also differ with disease state, as 73Q MSNs are hyper-excitable, with an extended latency to fire and extended refractory period. Conclusion These results provide a novel insight into the human CS pathway and suggest subtle differences in both the development and function of the CS pathway in HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"68 1","pages":"A24 - A24"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81324898","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.223
D. Kegelmeyer, S. Kostyk, David M Kline, K. Ambrogi, A. Kloos
Individuals with HD have progressive motor, cognitive and behavioral impairments that contribute to difficulty with stair negotiation leading to falls on stairs. To assess stair safety, we developed a tool called the Step Test Evaluation of Performance on Stairs (STEPS) that allows systematic observation of movement and analysis of stair performance. The purpose of this study was to examine 1) the agreement of STEPs ratings between healthcare professionals who were experienced versus novice in movement analysis, and 2) STEPS items with the lowest ratings indicating areas to target fall prevention interventions. Methods Forty ambulatory individuals with a diagnosis of HD (mean age 50.35) participated. Three observers (2 experienced physical therapists (PTs) and one nurse with minimal experience in movement analysis) concurrently rated live performances of the STEPS. Results The nurse’s average total STEPS ratings did not significantly differ from the experienced PTs’ ratings with a difference of -0.05 (CI=-0.53, 0.43; p=0.83). Out of 16 items, the agreement between all raters was less than 75% for continuity of ascent (69%) and descent (72%), foot placement during ascent (74%) and eccentric control of the knee during descent (74%). Individuals with HD were most likely to have difficulty during ascent/descent of stairs with foot placement and trunk stability. Additionally many clients exhibited deficits in balance and eccentric control of the knee during descent. Conclusions Observation for continuity of movement has greater inter-rater variability than other STEPS items. Principal impairments that may negatively impact stair performance in HD are foot placement and control of descent along with trunk stability. Healthcare providers other than PTs can quickly be trained to use the STEPS tool reliably. Future areas to study would be whether therapy aimed at improving foot placement, trunk control and eccentric quadriceps strength would improve safety on stairs.
{"title":"H45 The steps tool: an easy to use assessment measure that highlights impairments impacting stair safety","authors":"D. Kegelmeyer, S. Kostyk, David M Kline, K. Ambrogi, A. Kloos","doi":"10.1136/jnnp-2018-EHDN.223","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.223","url":null,"abstract":"Individuals with HD have progressive motor, cognitive and behavioral impairments that contribute to difficulty with stair negotiation leading to falls on stairs. To assess stair safety, we developed a tool called the Step Test Evaluation of Performance on Stairs (STEPS) that allows systematic observation of movement and analysis of stair performance. The purpose of this study was to examine 1) the agreement of STEPs ratings between healthcare professionals who were experienced versus novice in movement analysis, and 2) STEPS items with the lowest ratings indicating areas to target fall prevention interventions. Methods Forty ambulatory individuals with a diagnosis of HD (mean age 50.35) participated. Three observers (2 experienced physical therapists (PTs) and one nurse with minimal experience in movement analysis) concurrently rated live performances of the STEPS. Results The nurse’s average total STEPS ratings did not significantly differ from the experienced PTs’ ratings with a difference of -0.05 (CI=-0.53, 0.43; p=0.83). Out of 16 items, the agreement between all raters was less than 75% for continuity of ascent (69%) and descent (72%), foot placement during ascent (74%) and eccentric control of the knee during descent (74%). Individuals with HD were most likely to have difficulty during ascent/descent of stairs with foot placement and trunk stability. Additionally many clients exhibited deficits in balance and eccentric control of the knee during descent. Conclusions Observation for continuity of movement has greater inter-rater variability than other STEPS items. Principal impairments that may negatively impact stair performance in HD are foot placement and control of descent along with trunk stability. Healthcare providers other than PTs can quickly be trained to use the STEPS tool reliably. Future areas to study would be whether therapy aimed at improving foot placement, trunk control and eccentric quadriceps strength would improve safety on stairs.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"93 1","pages":"A82 - A82"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82448293","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.244
S. Rohiwal, J. Klíma, M. Vaškovicová, F. Šenigl, M. Šlouf, E. Pavlova, P. Štěpánek, K. Stieger, Z. Ellederová
Background The CRISPR/Cas system represents a pioneering gene editing technology for the treatment of monogenic disorders, employing R-Cas9 to target repetitive RNAs such as CAGN repeats suggests suitability in Huntingotn´s disease (HD) therapy. Till date, gene editing has been mediated primarily by viral vectors, but nanoparticles recently gained importance as carriers for delivery systems. They represent a promising technology to transfer RNA, protein and template to the targeted cells, due to their capacity to carry large sizes when used as vehicle. Moreover, the unlimited number of particles can be transferred with minimum host immune response and the potential to the cross blood brain barrier. Aim We aim to develop a non-viral delivery system using nanoparticles for the in vitro and in vivo delivery of the R-Cas9 system and sgRNAs to enable genome editing in HD. Methods We engineered CRISPR/Cas9 encapsulated poly (l-lactic) glycolic acid (PLGA) nanoparticles (NPs) by double emulsion and human serum albumin (HSA) NPs by desolvation method. The NPs were characterized by dynamic light scattering, zeta potential measurements and transmission electron microscopy. Next, we used a stable HEK293 cell line expressing the traffic light reporter (TLR-3) system to show efficient homology- directed repair (HDR) and non-homologous end joining (NHEJ) events following transfection with NPs. Results CRISPR/Cas9 encapsulated PLGA NPs as well as HSA NPs have been synthesized with the particle size around ˜ 100–200 nm in diameter. The dynamic light scattering and zeta potential measurements showed that both NPs were monodispersed and have good colloidal stability. Nevertheless, the PLGA NPs showed a higher transfection efficiency and HDR as well as NHEJ events compared to HSA NPs. Conclusions This study represents a promising step in the development of safe gene therapy approach for HD.
{"title":"I08 Nanoparticle based CRSIPR/CAS gene editing system to treat huntington’s disease","authors":"S. Rohiwal, J. Klíma, M. Vaškovicová, F. Šenigl, M. Šlouf, E. Pavlova, P. Štěpánek, K. Stieger, Z. Ellederová","doi":"10.1136/jnnp-2018-EHDN.244","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.244","url":null,"abstract":"Background The CRISPR/Cas system represents a pioneering gene editing technology for the treatment of monogenic disorders, employing R-Cas9 to target repetitive RNAs such as CAGN repeats suggests suitability in Huntingotn´s disease (HD) therapy. Till date, gene editing has been mediated primarily by viral vectors, but nanoparticles recently gained importance as carriers for delivery systems. They represent a promising technology to transfer RNA, protein and template to the targeted cells, due to their capacity to carry large sizes when used as vehicle. Moreover, the unlimited number of particles can be transferred with minimum host immune response and the potential to the cross blood brain barrier. Aim We aim to develop a non-viral delivery system using nanoparticles for the in vitro and in vivo delivery of the R-Cas9 system and sgRNAs to enable genome editing in HD. Methods We engineered CRISPR/Cas9 encapsulated poly (l-lactic) glycolic acid (PLGA) nanoparticles (NPs) by double emulsion and human serum albumin (HSA) NPs by desolvation method. The NPs were characterized by dynamic light scattering, zeta potential measurements and transmission electron microscopy. Next, we used a stable HEK293 cell line expressing the traffic light reporter (TLR-3) system to show efficient homology- directed repair (HDR) and non-homologous end joining (NHEJ) events following transfection with NPs. Results CRISPR/Cas9 encapsulated PLGA NPs as well as HSA NPs have been synthesized with the particle size around ˜ 100–200 nm in diameter. The dynamic light scattering and zeta potential measurements showed that both NPs were monodispersed and have good colloidal stability. Nevertheless, the PLGA NPs showed a higher transfection efficiency and HDR as well as NHEJ events compared to HSA NPs. Conclusions This study represents a promising step in the development of safe gene therapy approach for HD.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"37 31 1","pages":"A90 - A91"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82753132","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.234
M. Jacobs, E. Hart, Y. Miranda, G. Groeneveld, J. Gerven, R. Roos
Background In patients with Huntington’s disease (HD), instrumental daily activities such as working and driving become affected at a relatively young age. For most patients, the decision to quit driving is difficult and affects their independence and social activities. Aims To investigate if differences in driving performance between HD gene carriers and healthy individuals can be detected with a driving simulator. Furthermore, we wanted to determine which cognitive and motor symptoms contribute to driving performance in HD. Methods We included 58 HD gene carriers (28 premanifest HD, 30 manifest HD) and 29 controls in this cross-sectional study. All participants were active drivers and underwent neuropsychological, motor, and psychiatric evaluations. A driving simulator, including an urban and motorway scenario, was used to assess driving performance. Results Manifest HD drove slower compared to controls and premanifest HD when speed limits increased (80 and 100 km/h) and they had a less steady speed compared to premanifest HD on the motorway and in a 30 km/h zone. Manifest HD also had a larger standard deviation of the lateral position (i.e., more weaving of the car) compared to controls and premanifest HD on the motorway. Postural instability and slower speed of processing were predictors of the driving simulator outcome measures. There were no significant differences between premanifest HD and controls. Conclusions Manifest HD drive more cautious in a driving simulator when speed limits increase compared to premanifest HD and controls and they have less vehicle control on the motorway. Increased postural instability and slower speed of processing are predictive of worse driving simulator performance in manifest HD. This might assist clinicians in their referral for an official on-road driving test. More studies are necessary to determine if a driving simulator can be used to monitor longitudinal changes in fitness to drive.
{"title":"H56 Driving performance of huntington’s disease gene carriers","authors":"M. Jacobs, E. Hart, Y. Miranda, G. Groeneveld, J. Gerven, R. Roos","doi":"10.1136/jnnp-2018-EHDN.234","DOIUrl":"https://doi.org/10.1136/jnnp-2018-EHDN.234","url":null,"abstract":"Background In patients with Huntington’s disease (HD), instrumental daily activities such as working and driving become affected at a relatively young age. For most patients, the decision to quit driving is difficult and affects their independence and social activities. Aims To investigate if differences in driving performance between HD gene carriers and healthy individuals can be detected with a driving simulator. Furthermore, we wanted to determine which cognitive and motor symptoms contribute to driving performance in HD. Methods We included 58 HD gene carriers (28 premanifest HD, 30 manifest HD) and 29 controls in this cross-sectional study. All participants were active drivers and underwent neuropsychological, motor, and psychiatric evaluations. A driving simulator, including an urban and motorway scenario, was used to assess driving performance. Results Manifest HD drove slower compared to controls and premanifest HD when speed limits increased (80 and 100 km/h) and they had a less steady speed compared to premanifest HD on the motorway and in a 30 km/h zone. Manifest HD also had a larger standard deviation of the lateral position (i.e., more weaving of the car) compared to controls and premanifest HD on the motorway. Postural instability and slower speed of processing were predictors of the driving simulator outcome measures. There were no significant differences between premanifest HD and controls. Conclusions Manifest HD drive more cautious in a driving simulator when speed limits increase compared to premanifest HD and controls and they have less vehicle control on the motorway. Increased postural instability and slower speed of processing are predictive of worse driving simulator performance in manifest HD. This might assist clinicians in their referral for an official on-road driving test. More studies are necessary to determine if a driving simulator can be used to monitor longitudinal changes in fitness to drive.","PeriodicalId":16509,"journal":{"name":"Journal of Neurology, Neurosurgery & Psychiatry","volume":"21 1","pages":"A87 - A87"},"PeriodicalIF":0.0,"publicationDate":"2018-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82818499","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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