Neurobiological Predictors of Huntington's Disease

亨廷顿病的神经生物学预测因素

• 批准号: 8636255
• 负责人: Jane S Paulsen
• 金额: $ 4.93万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636255
• 关键词: Activities of Daily Living; Affect; Anisotropy; Award; Behavioral; Biological; Biological Markers; Brain imaging; CAG repeat; Clinical; Clinical Trials; Cognitive; Collaborations; Companions; Corpus striatum structure; Databases; Development; Diagnosis; Disease; Disease Marker; Disease Progression; Etiology; Functional disorder; Funding; Future; Genes; Genetic; Genetic screening method; Goals; Health; Huntington Disease; Image; Individual; International; Knowledge; Measurement; Measures; Modeling; Motor; Natural History; Neurobiology; Neurodegenerative Disorders; Neurologic; Observational Study; Onset of illness; Participant; Performance; Persons; Pharmaceutical Preparations; Phase; Phase I/II Trial; Plant Roots; Plasma; Recruitment Activity; Research Infrastructure; Resources; Risk; Safety; Sample Size; Sampling; Site; Speed; Spottings; Staging; Standardization; Subjects Selections; Surrogate Endpoint; Symptoms; Testing; Therapeutic; Time; Training; Validity and Reliability; candidate identification; catalyst; clinical Diagnosis; cohort; disease diagnosis; efficacy trial; functional disability; human Huntingtin protein; improved; innovation; longitudinal course; multi-site trial; neuroimaging; predictive modeling; prevent; tool; volunteer; white matter

DESCRIPTION (provided by applicant): PREDICT-HD is an international 30-site observational study of persons at-risk for Huntington's disease (HD). PREDICT-HD capitalizes on two unique aspects of HD among neurodegenerative disorders the ability to know in advance who will develop the disease and the knowledge that all affected individuals have the same etiology (a CAG expansion in the huntingtin gene). PREDICT-HD has become part of a world-wide effort and offers an unprecedented opportunity to examine the pathophysiology and neurobiology of early HD. We seek renewal of this project to maximize the impact of this resource and test new and refined hypotheses to advance clinical trials in HD. The ultimate goal of PREDICT-HD is to define the neurobiology of HD sufficiently to allow clinical trials of potential disease-modifying therapies before at-risk individuals have diagnosable symptoms of the disease. By identifying disease state markers that are useful during this early period, PREDICT-HD will make it possible to test putative neuroprotective therapies that could delay or prevent the manifestations of disease. PREDICT-HD has successfully recruited over 1000 healthy participants who had previously undergone genetic testing for the HD expansion. Annual measures of plasma, brain imaging, cognitive performance, psychiatric symptoms, and functional capacity are obtained in concert with other demographic, clinical and genetic information. We have already identified markers of disease that are present 15 years prior to traditional motor diagnosis. The requested 5-year longitudinal continuation of PREDICT-HD will result in six products: (1) Characterization of the early longitudinal course of functional, cognitive, motor, and psychiatric change in the period encompassing 10-20 years before to 0-3 years after the traditional point of clinical diagnosis. (2) Identification of candidate biological and neuroimaging markers that have potential as useful biomarkers and possibly as surrogate endpoints in clinical trials. Developed appropriately, markers identified in PREDICT-HD could be used to reduce dramatically the number of subjects needed in future clinical trials, and/or to stratify subjects for selection in studies. (3) Refinement and standardization of the measurement of neurological and functional impairment in the earliest stages of HD development, including the point of traditional clinical diagnosis. (4) Provision of a cohort from which sub samples may volunteer for early (phase I and II) trials of candidate therapies as well as phase III efficacy trials. (5) Examination of available compounds for safety and tolerability and of their impact on newly developed disease state markers in this presymptomatic cohort. (6) Innovations in infrastructure and worldwide collaboration to serve as a model and catalyst for clinical trials in other neurodegenerative diseases.

描述（由申请方提供）：PREDICT-HD是一项在亨廷顿病（HD）高危人群中开展的国际30家临床试验机构观察性研究。PREDICT-HD利用了神经退行性疾病中HD的两个独特方面，即提前知道谁将发展疾病的能力和所有受影响个体具有相同病因的知识（亨廷顿基因中的CAG扩增）。PREDICT-HD已成为全球努力的一部分，并提供了一个前所未有的机会来检查早期HD的病理生理学和神经生物学。我们寻求更新该项目，以最大限度地发挥这一资源的影响，并测试新的和完善的假设，以推进HD的临床试验。PREDICT-HD的最终目标是充分定义HD的神经生物学，以便在高危个体出现可诊断的疾病症状之前进行潜在疾病缓解疗法的临床试验。通过识别在早期阶段有用的疾病状态标志物，PREDICT-HD将有可能测试可能延迟或预防疾病表现的假定神经保护疗法。PREDICT-HD已成功招募了1000多名健康参与者，他们之前曾接受过HD扩展的基因检测。血浆、脑成像、认知能力、精神症状和功能能力的年度测量与其他人口统计学、临床和遗传信息一起获得。我们已经确定了在传统运动诊断之前15年存在的疾病标志物。PREDICT-HD要求的5年纵向延续将产生6种产品：（1）在传统临床诊断点之前10-20年至之后0-3年期间，表征功能、认知、运动和精神变化的早期纵向过程。(2)识别候选生物学和神经影像学标志物，这些标志物有可能作为有用的生物标志物，并可能作为临床试验中的替代终点。通过适当开发，PREDICT-HD中鉴定的标志物可用于大幅减少未来临床试验所需的受试者数量，和/或对研究中选择的受试者进行分层。(3)在HD发展的最早阶段，包括传统临床诊断点，对神经和功能损害的测量进行细化和标准化。(4)提供一个队列，子样本可自愿参加候选治疗的早期（I期和II期）试验以及III期疗效试验。(5)检查可用化合物的安全性和耐受性及其对该症状前队列中新开发的疾病状态标志物的影响。(6)基础设施的创新和全球合作，作为其他神经退行性疾病临床试验的模型和催化剂。

项目成果

Robust automated constellation-based landmark detection in human brain imaging.

• DOI: 10.1016/j.neuroimage.2017.04.012
• 发表时间: 2018-04-15
• 期刊: NeuroImage
• 影响因子: 5.7
• 作者: Ghayoor A;Vaidya JG;Johnson HJ
• 通讯作者: Johnson HJ

Perception, experience, and response to genetic discrimination in Huntington disease: the international RESPOND-HD study.

• DOI: 10.1002/ajmg.b.31079
• 发表时间: 2010-07
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS
• 影响因子: 2.8
• 作者: Erwin, Cheryl;Williams, Janet K.;Juhl, Andrew R.;Mengeling, Michelle;Mills, James A.;Bombard, Yvonne;Hayden, Michael R.;Quaid, Kimberly;Shoulson, Ira;Taylor, Sandra;Paulsen, Jane S.
• 通讯作者: Paulsen, Jane S.

Early changes in the hypothalamic region in prodromal Huntington disease revealed by MRI analysis.

• DOI: 10.1016/j.nbd.2010.07.013
• 发表时间: 2010-12
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Soneson, Charlotte;Fontes, Magnus;Zhou, Yongxia;Denisov, Vladimir;Paulsen, Jane S.;Kirik, Deniz;Petersen, Asa
• 通讯作者: Petersen, Asa

Cerebral cortex structure in prodromal Huntington disease.

• DOI: 10.1016/j.nbd.2010.07.014
• 发表时间: 2010-12
• 期刊: NEUROBIOLOGY OF DISEASE
• 影响因子: 6.1
• 作者: Nopoulos, Peggy C.;Aylward, Elizabeth H.;Ross, Christopher A.;Johnson, Hans J.;Magnotta, Vincent A.;Juhl, Andrew R.;Pierson, Ronald K.;Mills, James;Langbehn, Douglas R.;Paulsen, Jane S.
• 通讯作者: Paulsen, Jane S.

Cognitive decline in prodromal Huntington Disease: implications for clinical trials.

前驱亨廷顿疾病的认知能力下降：对临床试验的影响。

• DOI: 10.1136/jnnp-2013-305114
• 发表时间: 2013-11
• 期刊: Journal of neurology, neurosurgery, and psychiatry
• 作者: Paulsen JS;Smith MM;Long JD;PREDICT HD investigators and Coordinators of the Huntington Study Group
• 通讯作者: PREDICT HD investigators and Coordinators of the Huntington Study Group