Wenxin Song, Lauren Daneman, Alexis Cohen-Oram, Stephen Aradi
Huntington's disease (HD) is an autosomal dominant disorder that affects the basal ganglia, caused by CAG repeats in the huntingtin gene. Delusional infestation (DI) is a rare psychotic manifestation of the disease. This report presents two cases of HD patients with DI, both middle-aged females. The first patient achieved remission of DI with olanzapine, later cross-tapered to risperidone, but had spontaneous relapses. The second experienced gradual resolution of DI with risperidone in the setting of iron repletion and amantadine discontinuation, although her other psychotic symptoms remained. These cases shed light on an uncommon condition and may help guide understanding of the most effective treatment for it.
亨廷顿氏病(Huntington's disease,HD)是一种常染色体显性遗传疾病,影响基底神经节,由亨廷丁基因中的 CAG 重复序列引起。妄想性侵扰(Delusional infestation,DI)是该病的一种罕见精神病性表现。本报告介绍了两例伴有妄想症的 HD 患者,均为中年女性。第一例患者使用奥氮平治疗后,妄想症得到缓解,后来改用利培酮治疗,但自发复发。第二名患者在补铁和停用金刚烷胺的情况下,使用利培酮后DI逐渐缓解,但其他精神症状依然存在。这些病例揭示了一种不常见的病症,可能有助于指导人们了解最有效的治疗方法。
{"title":"A Case Series of Delusional Infestation in Huntington's Disease.","authors":"Wenxin Song, Lauren Daneman, Alexis Cohen-Oram, Stephen Aradi","doi":"10.3233/JHD-240013","DOIUrl":"https://doi.org/10.3233/JHD-240013","url":null,"abstract":"<p><p> Huntington's disease (HD) is an autosomal dominant disorder that affects the basal ganglia, caused by CAG repeats in the huntingtin gene. Delusional infestation (DI) is a rare psychotic manifestation of the disease. This report presents two cases of HD patients with DI, both middle-aged females. The first patient achieved remission of DI with olanzapine, later cross-tapered to risperidone, but had spontaneous relapses. The second experienced gradual resolution of DI with risperidone in the setting of iron repletion and amantadine discontinuation, although her other psychotic symptoms remained. These cases shed light on an uncommon condition and may help guide understanding of the most effective treatment for it.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436975","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}
Jin-Hui Yin, Ya-Ou Liu, Hong-Liang Li, Jean Marc Burgunder, Yue Huang
Background: Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington's disease (HD).
Objective: To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD.
Methods: 22 mutant huntingtin (mHTT) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage.
Results: Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (r = -0.80 to -0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Index = 0.786), and discerning different phase of HD (Youden Index = 0.804).
Conclusions: Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD.
背景:扩散磁共振成像(dMRI)揭示了亨廷顿氏病(HD)白质(WM)的微观结构变化:比较不同 dMRI(即扩散峰度成像(DKI)和扩散张量成像(DTI))在 HD 中的有效性。进行了临床评估和 dMRI 检查。根据 CAG 年龄乘积(CAP)得分,将 mHTT 携带者分为高 CAP 组(hCAP)和中低 CAP 组(m& lCAP)。斯皮尔曼分析用于探讨脑区成像参数与临床评估之间的相关性。受体操作特征(ROC)用于区分 mHTT 携带者和对照组,并界定晚期 HD 患者:与对照组相比,mHTT 携带者在 DKI 和 DTI 中表现出 WM 变化。与FA相比,MK检测到的HD显著差异区域多出22个。只有 5 个脑区的 MK 在任何两个组别之间存在显著差异,且与疾病负担呈负相关(r = -0.80 至 -0.71)。ROC分析显示,MK更灵敏,FA更特异,而Youden指数显示,在区分m& lCAP与对照组(Youden指数=0.786)和鉴别HD的不同阶段(Youden指数=0.804)时,FA和MK的整合具有更高的真实性:结论:WM的微结构变化发生在HD的早期阶段,并随着疾病的进展而恶化。整合 DKI 和 DTI 将为区分早期 HD 和对照组以及识别晚期 HD 提供最佳准确性。
{"title":"White Matter Microstructure Changes Revealed by Diffusion Kurtosis and Diffusion Tensor Imaging in Mutant Huntingtin Gene Carriers.","authors":"Jin-Hui Yin, Ya-Ou Liu, Hong-Liang Li, Jean Marc Burgunder, Yue Huang","doi":"10.3233/JHD-240018","DOIUrl":"https://doi.org/10.3233/JHD-240018","url":null,"abstract":"<p><strong>Background: </strong>Diffusion magnetic resonance imaging (dMRI) has revealed microstructural changes in white matter (WM) in Huntington's disease (HD).</p><p><strong>Objective: </strong>To compare the validities of different dMRI, i.e., diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI) in HD.</p><p><strong>Methods: </strong>22 mutant huntingtin (mHTT) carriers and 14 controls were enrolled. Clinical assessments and dMRI were conducted. Based on CAG-Age Product (CAP) score, mHTT carriers were categorized into high CAP (hCAP) and medium and low CAP (m& lCAP) groups. Spearman analyses were used to explore correlations between imaging parameters in brain regions and clinical assessments. Receiver operating characteristic (ROC) was used to distinguish mHTT carriers from control, and define the HD patients at advanced stage.</p><p><strong>Results: </strong>Compared to controls, mHTT carriers exhibited WM changes in DKI and DTI. There were 22 more regions showing significant differences in HD detected by MK than FA. Only MK in five brain regions showed significantly difference between any two group, and negatively correlated with the disease burden (r = -0.80 to -0.71). ROC analysis revealed that MK was more sensitive and FA was more specific, while Youden index showed that the integration of FA and MK gave rise to higher authenticities, in distinguishing m& lCAP from controls (Youden Index = 0.786), and discerning different phase of HD (Youden Index = 0.804).</p><p><strong>Conclusions: </strong>Microstructural changes in WM occur at early stage of HD and deteriorate over the disease progression. Integrating DKI and DTI would provide the best accuracies for differentiating early HD from control and identifying advanced HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436976","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}
Karlijne W Geijtenbeek, Angela Santiago Aranda, Alicia Sanz Sanz, Jolien Janzen, Aleksandra E. Bury, Suzan Kors, Nur Al Amery, Nina C.M. Schmitz, Eric Reits, Sabine Schipper-Krom
Background Huntington's disease is an inheritable autosomal dominant disorder caused by an expanded CAG trinucleotide repeat within the Huntingtin gene, leading to a polyglutamine (polyQ) expansion in the mutant protein. Objective A potential therapeutic approach for delaying or preventing the onset of the disease involves enhancing the degradation of the aggregation-prone polyQ-expanded N-terminal mutant huntingtin (mHTT) exon1 fragment. A few proteases and peptidases have been identified that are able to cleave polyQ fragments with low efficiency. This study aims to identify a potent polyQ-degrading endopeptidase. Methods Here we used quenched polyQ peptides to identify a polyQ-degrading endopeptidase. Next we investigated its role on HTT turnover, using purified polyQ-expanded HTT fragments and striatal cells expressing mHTT exon1 peptides. Results We identified insulin-degrading enzyme (IDE) as a novel endopeptidase for degrading polyQ peptides. IDE was, however, ineffective in reducing purified polyQ-expanded HTT fragments. Similarly, in striatal cells expressing mHTT exon1 peptides, IDE did not enhance mHTT turnover. Conclusions This study shows that despite IDE's efficiency in degrading polyQ peptides, it does not contribute to the direct degradation of polyQ-expanded mHTT fragments.
{"title":"Insulin-Degrading Enzyme Efficiently Degrades polyQ Peptides but not Expanded polyQ Huntingtin Fragments.","authors":"Karlijne W Geijtenbeek, Angela Santiago Aranda, Alicia Sanz Sanz, Jolien Janzen, Aleksandra E. Bury, Suzan Kors, Nur Al Amery, Nina C.M. Schmitz, Eric Reits, Sabine Schipper-Krom","doi":"10.3233/jhd-230583","DOIUrl":"https://doi.org/10.3233/jhd-230583","url":null,"abstract":"Background\u0000Huntington's disease is an inheritable autosomal dominant disorder caused by an expanded CAG trinucleotide repeat within the Huntingtin gene, leading to a polyglutamine (polyQ) expansion in the mutant protein.\u0000\u0000\u0000Objective\u0000A potential therapeutic approach for delaying or preventing the onset of the disease involves enhancing the degradation of the aggregation-prone polyQ-expanded N-terminal mutant huntingtin (mHTT) exon1 fragment. A few proteases and peptidases have been identified that are able to cleave polyQ fragments with low efficiency. This study aims to identify a potent polyQ-degrading endopeptidase.\u0000\u0000\u0000Methods\u0000Here we used quenched polyQ peptides to identify a polyQ-degrading endopeptidase. Next we investigated its role on HTT turnover, using purified polyQ-expanded HTT fragments and striatal cells expressing mHTT exon1 peptides.\u0000\u0000\u0000Results\u0000We identified insulin-degrading enzyme (IDE) as a novel endopeptidase for degrading polyQ peptides. IDE was, however, ineffective in reducing purified polyQ-expanded HTT fragments. Similarly, in striatal cells expressing mHTT exon1 peptides, IDE did not enhance mHTT turnover.\u0000\u0000\u0000Conclusions\u0000This study shows that despite IDE's efficiency in degrading polyQ peptides, it does not contribute to the direct degradation of polyQ-expanded mHTT fragments.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140696921","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}
A. Snow, Abagail E. Ciriegio, Kelly H Watson, Anna C. Pfalzer, Spencer Diehl, Lisa M Hale, Katherine E. McDonell, Daniel O. Claassen, Bruce E Compas
Background Huntington's disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms. Objective This study examined frequencies of specific stressors in HD patients and at-risk individuals and the correlates of these stressors with demographics, disease characteristics, and symptoms of depression and anxiety. Methods HD patients (n = 57) and at-risk individuals (n = 81) completed the Responses to Stress Questionnaire -Huntington's Disease Version to assess HD-related stressors. Participants completed measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics. Results Patients endorsed a mean number of 5.05 stressors (SD = 2.74) out of the 10-item list. Demographics were not related to total stressors, but disease characteristics were significantly related to specific stressors. At-risk individuals endorsed a mean number of 3.20 stressors (SD = 2.65) out of the 11-item list. Age and sex were significantly related to specific stressors. Total number of stressors was significantly related to depression (β=0.67, p < 0.001) and anxiety symptoms (β=0.58, p < 0.001) in patients and at-risk individuals (β=0.35, p = 0.003 and β=0.32, p = 0.006, respectively). Conclusions hese findings emphasize the significant burden of stress experienced by HD patients and at-risk individuals. We highlight a need for more specific stress-based measures and psychosocial support interventions for HD-affected families.
背景亨廷顿氏病(HD)是一种神经退行性疾病,会给家庭带来大量的压力事件。然而,关于受 HD 影响的家庭成员所遇到的压力及其与心理症状的相关性的实证研究却相对较少。本研究调查了 HD 患者和高危人群中特定压力的频率,以及这些压力与人口统计学、疾病特征、抑郁和焦虑症状的相关性。参与者还完成了抑郁和焦虑症状的测量。我们还调阅了患者的健康记录,以获取与疾病特征相关的信息。人口统计学特征与总压力无关,但疾病特征与特定压力显著相关。在 11 个项目中,高危人群认可的压力源平均为 3.20 个(标准差 = 2.65)。年龄和性别与特定压力源有明显关系。患者和高危人群的压力源总数与抑郁(β=0.67,p < 0.001)和焦虑症状(β=0.58,p < 0.001)明显相关(分别为β=0.35,p = 0.003和β=0.32,p = 0.006)。我们强调需要为受 HD 影响的家庭提供更多基于压力的具体措施和社会心理支持干预。
{"title":"Stress in Huntington's Disease: Characteristics and Correlates in Patients and At-Risk Individuals.","authors":"A. Snow, Abagail E. Ciriegio, Kelly H Watson, Anna C. Pfalzer, Spencer Diehl, Lisa M Hale, Katherine E. McDonell, Daniel O. Claassen, Bruce E Compas","doi":"10.3233/JHD-231515","DOIUrl":"https://doi.org/10.3233/JHD-231515","url":null,"abstract":"Background\u0000Huntington's disease (HD) is a neurodegenerative disease that presents families with significant numbers of stressful events. However, relatively little empirical research has characterized the stressors encountered by members of HD-affected families and their correlations with psychological symptoms.\u0000\u0000\u0000Objective\u0000This study examined frequencies of specific stressors in HD patients and at-risk individuals and the correlates of these stressors with demographics, disease characteristics, and symptoms of depression and anxiety.\u0000\u0000\u0000Methods\u0000HD patients (n = 57) and at-risk individuals (n = 81) completed the Responses to Stress Questionnaire -Huntington's Disease Version to assess HD-related stressors. Participants completed measures of depression and anxiety symptoms. Patient health records were accessed to obtain information related to disease characteristics.\u0000\u0000\u0000Results\u0000Patients endorsed a mean number of 5.05 stressors (SD = 2.74) out of the 10-item list. Demographics were not related to total stressors, but disease characteristics were significantly related to specific stressors. At-risk individuals endorsed a mean number of 3.20 stressors (SD = 2.65) out of the 11-item list. Age and sex were significantly related to specific stressors. Total number of stressors was significantly related to depression (β=0.67, p < 0.001) and anxiety symptoms (β=0.58, p < 0.001) in patients and at-risk individuals (β=0.35, p = 0.003 and β=0.32, p = 0.006, respectively).\u0000\u0000\u0000Conclusions\u0000hese findings emphasize the significant burden of stress experienced by HD patients and at-risk individuals. We highlight a need for more specific stress-based measures and psychosocial support interventions for HD-affected families.","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140748491","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}
Karen E Anderson, Lakshmi Arbatti, Abhishek Hosamath, Andrew Feigin, Jody Goldstein, Elise Kayson, Brett L Kinsler, Lauren Falanga, Lynn Denise, Noelle E Carlozzi, Samuel Frank, Katie Jackson, Sandra Kostyk, Jennifer L Purks, Kenneth P Serbin, Shari Kinel, Christopher A Beck, Ira Shoulson
Background: Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement.
Objective: We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words.
Methods: Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms.
Results: All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common.
Conclusions: Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.
背景:直接面向参与者的在线报告通过增加患者参与的机会和临床意义,促进了临床研究的开展:我们评估了从已确诊亨廷顿氏病(HD)的成人患者处收集在线数据的可行性,他们直接用自己的话报告了自己的问题和影响:我们通过在线方式收集了美国居民的数据,这些居民自称:1)已被确诊为亨廷顿氏病;2)能够独立行走;3)能够满足大部分日常需求。这项试点研究的数据是通过亨廷顿研究小组的 myHDstory 在线研究平台收集的。亨廷顿病患者问题报告(HD-PROP)是一份开放式问卷,用于逐字记录困扰患者的问题和对患者功能的影响。自然语言处理、由临床和经验专家参与的逐字报告环内人工整理以及机器学习将逐字报告分类为有临床意义的症状:345名参与者完成了在线试点研究的全部8份问卷,其中60.9%为男性,年龄为34.5±9.9(平均±SD)岁,确诊HD的时间为9.5±8.4年。他们的种族自我认同为:46.4% 白种人、28.7% 非裔美国人、15.4% 美洲印第安人/阿拉斯加原住民和 9.5% 其他。逐字分类的准确率为 99%。非运动性问题是最常报告的症状;抑郁和认知障碍是最常见的症状:对于自我报告确诊为 HD 并主要出现与情绪和认知相关的非运动症状的不同成人群体来说,参与在线研究是可行的。在线研究工具有助于了解 HD 患者的困扰,确定有临床意义的结果,并促进不同人群和代表性不足人群的参与。
{"title":"What Huntington's Disease Patients Say About Their Illness: An Online Direct-to-Participant Pilot Study.","authors":"Karen E Anderson, Lakshmi Arbatti, Abhishek Hosamath, Andrew Feigin, Jody Goldstein, Elise Kayson, Brett L Kinsler, Lauren Falanga, Lynn Denise, Noelle E Carlozzi, Samuel Frank, Katie Jackson, Sandra Kostyk, Jennifer L Purks, Kenneth P Serbin, Shari Kinel, Christopher A Beck, Ira Shoulson","doi":"10.3233/JHD-231520","DOIUrl":"10.3233/JHD-231520","url":null,"abstract":"<p><strong>Background: </strong>Direct-to-participant online reporting facilitates the conduct of clinical research by increasing access and clinically meaningful patient engagement.</p><p><strong>Objective: </strong>We assessed feasibility of online data collection from adults with diagnosed Huntington's disease (HD) who directly reported their problems and impact in their own words.</p><p><strong>Methods: </strong>Data were collected online from consenting United States residents who self-identified as 1) having been diagnosed with Huntington's disease, 2) able to ambulate independently, and 3) self-sufficient for most daily needs. Data for this pilot study were collected using the Huntington Study Group myHDstory online research platform. The Huntington Disease Patient Report of Problems (HD-PROP), an open-ended questionnaire, was used to capture verbatim bothersome problems and functional impact. Natural language processing, human-in-the-loop curation of verbatim reports involving clinical and experience experts, and machine learning classified verbatim-reports into clinically meaningful symptoms.</p><p><strong>Results: </strong>All 8 questionnaires in the online pilot study were completed by 345 participants who were 60.9% men, 34.5±9.9 (mean±SD) years old, and 9.5±8.4 years since HD diagnosis. Racial self-identification was 46.4% Caucasian, 28.7% African American, 15.4% American Indian/Alaska Native, and 9.5% other. Accuracy of verbatim classification was 99%. Non-motor problems were the most frequently reported symptoms; depression and cognitive impairment were the most common.</p><p><strong>Conclusions: </strong>Online research participation was feasible for a diverse cohort of adults who self-reported an HD diagnosis and predominantly non-motor symptoms related to mood and cognition. Online research tools can help inform what bothers HD patients, identify clinically meaningful outcomes, and facilitate participation by diverse and under-represented populations.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857282","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}
Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT in multiple organs may contribute to the neurological and psychiatric symptoms observed in Huntington's disease (HD). The proteostasis and neurotoxicity of mutant HTT are influenced by the intracellular milieu and responses to environmental signals. Recent research has highlighted a prominent role of gut microbiota in brain and immune system development, aging, and the progression of neurological disorders. Several studies suggest that mutant HTT might disrupt the homeostasis of gut microbiota (known as dysbiosis) and impact the pathogenesis of HD. Dysbiosis has been observed in HD patients, and in animal models of the disease it coincides with mutant HTT aggregation, abnormal behaviors, and reduced lifespan. This review article aims to highlight the potential toxicity of mutant HTT in organs and pathways within the microbiota-gut-immune-central nervous system (CNS) axis. Understanding the functions of Wild-Type (WT) HTT and the toxicity of mutant HTT in these organs and the associated networks may elucidate novel pathogenic pathways, identify biomarkers and peripheral therapeutic targets for HD.
亨廷汀(HTT)蛋白在大多数细胞系中都有表达,突变型 HTT 在多个器官中的毒性可能导致亨廷顿氏病(HD)的神经和精神症状。突变型 HTT 的蛋白稳态和神经毒性受到细胞内环境和对环境信号反应的影响。最近的研究强调了肠道微生物群在大脑和免疫系统发育、衰老以及神经系统疾病进展中的重要作用。一些研究表明,突变型 HTT 可能会破坏肠道微生物群的平衡(称为菌群失调),并影响 HD 的发病机制。在 HD 患者中已经观察到了菌群失调,而在该病的动物模型中,它与突变型 HTT 的聚集、异常行为和寿命缩短相吻合。这篇综述文章旨在强调突变型 HTT 在微生物群-肠道-免疫-中枢神经系统(CNS)轴的器官和通路中的潜在毒性。了解野生型(WT)HTT的功能和突变型HTT在这些器官及相关网络中的毒性,可以阐明新的致病途径、确定生物标志物和HD的外围治疗靶点。
{"title":"Gut Microbiota as a Modifier of Huntington's Disease Pathogenesis.","authors":"Ali Khoshnan","doi":"10.3233/JHD-240012","DOIUrl":"10.3233/JHD-240012","url":null,"abstract":"<p><p>Huntingtin (HTT) protein is expressed in most cell lineages, and the toxicity of mutant HTT in multiple organs may contribute to the neurological and psychiatric symptoms observed in Huntington's disease (HD). The proteostasis and neurotoxicity of mutant HTT are influenced by the intracellular milieu and responses to environmental signals. Recent research has highlighted a prominent role of gut microbiota in brain and immune system development, aging, and the progression of neurological disorders. Several studies suggest that mutant HTT might disrupt the homeostasis of gut microbiota (known as dysbiosis) and impact the pathogenesis of HD. Dysbiosis has been observed in HD patients, and in animal models of the disease it coincides with mutant HTT aggregation, abnormal behaviors, and reduced lifespan. This review article aims to highlight the potential toxicity of mutant HTT in organs and pathways within the microbiota-gut-immune-central nervous system (CNS) axis. Understanding the functions of Wild-Type (WT) HTT and the toxicity of mutant HTT in these organs and the associated networks may elucidate novel pathogenic pathways, identify biomarkers and peripheral therapeutic targets for HD.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140904492","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marian DiFiglia, Blair R Leavitt, Douglas Macdonald, Leslie M Thompson
The field of Huntington's disease research covers many different scientific disciplines, from molecular biology all the way through to clinical practice, and as our understanding of the disease has progressed over the decades, a great deal of different terminology has accrued. The field is also renowned for its collaborative spirit and use of standardized reagents, assays, datasets, models, and clinical measures, so the use of standardized terms is especially important. We have set out to determine, through a consensus exercise involving basic and clinical scientists working in the field, the most appropriate language to use across disciplines. Nominally, this article will serve as the style guide for the Journal of Huntington's Disease (JHD), the only journal devoted exclusively to HD, and we lay out the preferred and standardized terminology and nomenclature for use in JHD publications. However, we hope that this article will also serve as a useful resource to the HD research community at large and that these recommended naming conventions will be adopted widely.
亨廷顿氏病研究领域涵盖了从分子生物学到临床实践等多个不同的科学学科,随着几十年来我们对该疾病认识的不断深入,积累了大量不同的术语。该领域也因其合作精神和使用标准化试剂、检测方法、数据集、模型和临床测量方法而闻名,因此使用标准化术语尤为重要。我们已着手通过与从事该领域工作的基础和临床科学家达成共识,确定跨学科使用的最合适语言。从名义上讲,这篇文章将作为《亨廷顿氏病杂志》(JHD)的风格指南,该杂志是唯一专门研究HD的杂志,我们为JHD的出版物列出了首选的标准化术语和命名法。不过,我们希望这篇文章也能成为整个 HD 研究界的有用资源,并希望这些建议的命名规则能被广泛采用。
{"title":"Towards Standardizing Nomenclature in Huntington's Disease Research.","authors":"Marian DiFiglia, Blair R Leavitt, Douglas Macdonald, Leslie M Thompson","doi":"10.3233/JHD-240044","DOIUrl":"10.3233/JHD-240044","url":null,"abstract":"<p><p>The field of Huntington's disease research covers many different scientific disciplines, from molecular biology all the way through to clinical practice, and as our understanding of the disease has progressed over the decades, a great deal of different terminology has accrued. The field is also renowned for its collaborative spirit and use of standardized reagents, assays, datasets, models, and clinical measures, so the use of standardized terms is especially important. We have set out to determine, through a consensus exercise involving basic and clinical scientists working in the field, the most appropriate language to use across disciplines. Nominally, this article will serve as the style guide for the Journal of Huntington's Disease (JHD), the only journal devoted exclusively to HD, and we lay out the preferred and standardized terminology and nomenclature for use in JHD publications. However, we hope that this article will also serve as a useful resource to the HD research community at large and that these recommended naming conventions will be adopted widely.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11307060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141537925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Russell G Wells, Azzam F Azzam, Amie L Hiller, Michael F Sardinia
Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD.
Objective: The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent.
Methods: Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis.
Results: Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity.
Conclusions: Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.
背景:亨廷顿氏病(Huntington's disease,HD)是一种神经退行性疾病,其特征是由突变亨廷蛋白引起的运动、认知和精神功能障碍。众所周知,全身服用线粒体毒素 3-硝基丙酸(3-NP)会导致新陈代谢活动紊乱,从而模拟 HD 的病理过程并诱发大鼠出现类似 HD 的症状。N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408),又称 Dihexa,已被证明在阿尔茨海默氏症和帕金森氏症动物模型中具有神经保护和促进认知的特性。鉴于其作用机制以及在其他神经退行性疾病中的成功应用,我们认为这是一种适合进一步研究 HD 的化合物:本研究旨在测试血管紧张素 IV 类似物 PNB-0408 能否减轻 3-NP 诱导的大鼠 HD 类症状,并作为一种潜在的治疗药物:将 40 只雄性 Wistar 大鼠随机分为三组,包括 "载体 "组、"3-NP "组和 "3-NP + PNB-0408" 组。PNB-0408 与 3-NP 的慢性暴露同时给药。在安乐死和组织病理学分析之前,对动物的体重、运动功能和认知能力进行了为期五周的测量:结果:暴露于 3-NP 会降低大鼠的体重增加量,损害空间学习和记忆巩固,并导致明显的运动功能障碍。根据我们的观察和分析,PNB-0408 不能保护大鼠免受 3-NP 神经毒性引起的缺陷的影响:我们的研究结果表明,在临床前模型中,PNB-0408 可能不是预防 3-NP 引起的类似 HD 症状的有效治疗策略。这些数据突出表明,有必要在替代模型和/或替代方法中进一步研究这种化合物,以治疗这种疾病。
{"title":"Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.","authors":"Russell G Wells, Azzam F Azzam, Amie L Hiller, Michael F Sardinia","doi":"10.3233/JHD-231507","DOIUrl":"10.3233/JHD-231507","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD.</p><p><strong>Objective: </strong>The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent.</p><p><strong>Methods: </strong>Forty male Wistar rats were randomized into three groups consisting of a \"vehicle\" group, a \"3-NP\" group, and a \"3-NP + PNB-0408\" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis.</p><p><strong>Results: </strong>Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity.</p><p><strong>Conclusions: </strong>Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136908","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}
Harry Knights, Annabelle Coleman, Nicola Z Hobbs, Sarah J Tabrizi, Rachael I Scahill
Background: The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy.
Objective: Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS.
Methods: Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis.
Results: Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes.
Conclusions: As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.
{"title":"Freesurfer Software Update Significantly Impacts Striatal Volumes in the Huntington's Disease Young Adult Study and Will Influence HD-ISS Staging.","authors":"Harry Knights, Annabelle Coleman, Nicola Z Hobbs, Sarah J Tabrizi, Rachael I Scahill","doi":"10.3233/JHD-231512","DOIUrl":"10.3233/JHD-231512","url":null,"abstract":"<p><strong>Background: </strong>The Huntington's Disease Integrated Staging System (HD-ISS) defined disease onset using volumetric cut-offs for caudate and putamen derived from FreeSurfer 6 (FS6). The impact of the latest software update (FS7) on volumes remains unknown. The Huntington's Disease Young Adult Study (HD-YAS) is appropriately positioned to explore differences in FS bias when detecting early atrophy.</p><p><strong>Objective: </strong>Explore the relationships and differences between raw caudate and putamen volumes, calculated total intracranial volumes (cTICV), and adjusted caudate and putamen volumes, derived from FS6 and FS7, in HD-YAS.</p><p><strong>Methods: </strong>Images from 123 participants were segmented and quality controlled. Relationships and differences between volumes were explored using intraclass correlation (ICC) and Bland-Altman analysis.</p><p><strong>Results: </strong>Across the whole cohort, ICC for raw caudate and putamen was 0.99, cTICV 0.93, adjusted caudate 0.87, and adjusted putamen 0.86 (all p < 0.0005). Compared to FS6, FS7 calculated: i) larger raw caudate (+0.8%, p < 0.00005) and putamen (+1.9%, p < 0.00005), with greater difference for larger volumes; and ii) smaller cTICV (-5.1%, p < 0.00005), with greater difference for smaller volumes. The systematic and proportional difference in cTICV was greater than raw volumes. When raw volumes were adjusted for cTICV, these effects compounded (adjusted caudate +7.0%, p < 0.00005; adjusted putamen +8.2%, p < 0.00005), with greater difference for larger volumes.</p><p><strong>Conclusions: </strong>As new software is released, it is critical that biases are explored since differences have the potential to significantly alter the findings of HD trials. Until conversion factors are defined, the HD-ISS must be applied using FS6. This should be incorporated into the HD-ISS online calculator.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136909","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}
Morgane Louessard, Michel Cailleret, Margot Jarrige, Julie Bigarreau, Sophie Lenoir, Noëlle Dufour, Maria Rey, Frédéric Saudou, Nicole Deglon, Anselme L Perrier
Background: Mutations in the Huntingtin (HTT) gene cause Huntington's disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood.
Objective: To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations.
Methods: We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic HTT knock-out human induced pluripotent stem cell (iPSC) clones.
Results: We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons.
Conclusions: We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons.
{"title":"Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.","authors":"Morgane Louessard, Michel Cailleret, Margot Jarrige, Julie Bigarreau, Sophie Lenoir, Noëlle Dufour, Maria Rey, Frédéric Saudou, Nicole Deglon, Anselme L Perrier","doi":"10.3233/JHD-231509","DOIUrl":"10.3233/JHD-231509","url":null,"abstract":"<p><strong>Background: </strong>Mutations in the Huntingtin (HTT) gene cause Huntington's disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood.</p><p><strong>Objective: </strong>To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations.</p><p><strong>Methods: </strong>We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic HTT knock-out human induced pluripotent stem cell (iPSC) clones.</p><p><strong>Results: </strong>We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons.</p><p><strong>Conclusions: </strong>We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons.</p>","PeriodicalId":16042,"journal":{"name":"Journal of Huntington's disease","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11091579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}