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STAGING PRECLINICAL AD WITH CSF BIOMARKERS

使用脑脊液生物标志物进行临床前广告

基本信息

批准号：
9910355
负责人：
Suzanne Elizabeth Schindler
金额：
$ 15.71万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-15 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9910355
关键词：
Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease pathology Alzheimer’s disease biomarker Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid deposition Biological Markers Brain Brain Pathology Brain imaging Calcium Calmodulin-Binding Proteins Categories Cerebrospinal Fluid Clinic Clinical Clinical Chemistry Clinical Research Clinical assessments Cognitive Complex Data Dementia Deposition Development Development Plans Disease Disease Progression Doctor of Philosophy Early treatment Enrollment Event Faculty Family Functional disorder Funding Future Generations Goals Hippocampus (Brain)Image Imaging Techniques Impaired cognition Individual Inflammation Inherited Injury Institution K-Series Research Career Programs Knowledge Late Onset Alzheimer Disease Learning Liquid substance Magnetic Resonance Imaging Measures Medial Medical Memory Mentors Modeling Mutation Neurology Neurons Neurosciences Pathologic Pathology Patients Performance Pharmaceutical Preparations Pharmacotherapy Plasma Positioning Attribute Positron-Emission Tomography Prevention trial Process Proteins Psychometrics Research Research Personnel Residencies Risk S-nitro-N-acetylpenicillamine Sampling Senile Plaques Specialist Staging Staging System Statistical Computing Statistical Data Interpretation Structure Synapses Temporal Lobe Testing Time Training Training Activity Translating Universities Washington aged base career career development cognitive testing cohort college experience high risk high school imaging biomarker imaging modality improved inflammatory marker interest meetings member multidisciplinary mutation carrier neocortical neurogranin neuron loss pre-clinical programs repository research study sensor skills statistics symposium synaptosomal-associated protein 25 tau Proteins tau aggregation visinin

项目摘要

Staging preclinical Alzheimer disease with CSF biomarkers Career development plan I have been interested in Alzheimer's disease (AD) since high school. I did research on AD in college, completed a PhD in Neurosciences focused on AD, underwent medical training and a neurology residency, and became a dementia specialist. I currently see patients with memory problems in the clinic, perform clinical assessments for AD research and assist with two drug trials for prevention of AD. Although my research background was in a wet lab doing basic neuroscience, at the end of 2015 I decided to make a major career change to align my clinical training and research interests. I have been learning new skills, including statistical analysis, so that I can perform meaningful clinical research. I still have much to learn and would benefit tremendously from a four year mentored career development award. There is a major need in the AD field for a test that reliably predicts if and when cognitively normal individuals will develop AD dementia. I believe that I am uniquely positioned to investigate this topic. I am a junior faculty member at Washington University's Knight Alzheimer's Disease Research Center (ADRC), which has one of the largest and best characterized repositories of AD cerebrospinal fluid (CSF) and plasma in the world. My mentors include Dr. John Morris, a world expert on longitudinal clinical research studies of AD, and Dr. Anne Fagan, a leader in CSF biomarkers of AD. I have assembled a group of collaborators, at Washington University and at other institutions, with expertise in clinical chemistry, statistics, brain imaging, and cognitive testing. All these individuals will serve to advise and guide me as I develop my skills and experience. I have formulated a training plan that will increase my knowledge of fluid biomarkers, statistics and statistical computing, imaging, and psychometrics. Training activities include formal coursework, conferences, meetings and seminars. The research plan I have detailed will provide opportunities to measure emerging biomarkers in CSF samples, perform complex statistical analyses of biomarker levels, learn about the generation of various types of brain imaging measures and evaluate performance on multiple cognitive tests. At the conclusion of the four year career development award, I expect to be a skilled, multidisciplinary investigator with independent funding and an independent research program. Research plan We propose to develop and validate a staging system for preclinical Alzheimer disease (AD) using a panel of seven cerebrospinal fluid (CSF) biomarkers. Improved staging of preclinical AD would be helpful to clinicians and patients who desire to know their risk for development of AD dementia within the next 20, 10, 5 or 2 years. Further, more precise staging of preclinical AD in clinical drug trials would allow refinement of enrollment criteria and determination of when treatments are most effective at slowing progression of the disease. It is unlikely that a single brain imaging modality or fluid biomarker could reflect the complex pathophysiology of AD. However, a single sample of cerebrospinal fluid (CSF) offers an opportunity to measure many of the processes occurring along the AD pathologic cascade, from amyloid deposition to tau aggregation/release to injury/destruction of synapses to inflammation to neuronal cell death. The potentially rich information offered by CSF, including on processes not well reflected by current imaging techniques, may allow better staging of preclinical AD and improve our ability to predict when individuals will develop dementia. We will formulate a biomarker defined preclinical AD staging system using levels of CSF Aβ42, tau, ptau, the pre-synaptic protein synaptosomal-associated protein-25 (SNAP-25), the post-synaptic calmodulin binding protein neurogranin, the neuronal calcium sensor visinin-like protein 1 (VILIP-1) and the inflammatory marker YKL-40. With CSF biomarker data from a cohort of families carrying Autosomal Dominant Alzheimer Disease (ADAD) mutations, we will plot a time course of biomarker changes in ADAD mutation carriers versus non-carriers. We will use the biomarker data to create a CSF biomarker defined staging system for preclinical AD. We will examine whether this staging system accurately estimates the time until dementia onset using longitudinal data. We will then translate and optimize this staging system, created in an ADAD cohort, to a cohort at risk for late onset AD (LOAD) from Washington University. Next we will validate the LOAD staging system in an independent cohort at risk for LOAD from Johns Hopkins University. Finally, we will evaluate how well the staging system correlates with imaging biomarkers of AD, including hippocampal volume, amyloid PET, and tau PET.

使用CSF生物标志物对临床前阿尔茨海默病进行分期职业发展计划我从高中开始就对阿尔茨海默病（AD）感兴趣。我在大学里研究过AD，完成了专注于AD的神经科学博士学位，接受了医学培训和神经病学住院医师，成为了一名痴呆症专家我目前在诊所看到有记忆问题的患者，评估AD研究，并协助两项预防AD的药物试验。虽然我的研究我的背景是在一个湿实验室做基础神经科学，在2015年底，我决定做一个主要的职业生涯改变，使我的临床培训和研究兴趣保持一致。我一直在学习新的技能，包括统计分析，以便我可以进行有意义的临床研究。我还有很多东西要学，四年的职业发展奖。在AD领域中存在对可靠地预测认知是否正常以及何时正常的测试的主要需求个体将发展成AD痴呆。我相信我是唯一能够研究这个话题的人。我是一个他是华盛顿大学奈特阿尔茨海默病研究中心（ADRC）的一名初级教员，该中心拥有世界上最大和最具特征的AD脑脊液（CSF）和血浆储存库之一，世界我的导师包括John Morris博士，他是AD纵向临床研究的世界专家，博士Anne Fagan是AD CSF生物标志物的领导者。我在华盛顿召集了一群合作者大学和其他机构，具有临床化学，统计学，脑成像和认知方面的专业知识试验.所有这些人都将在我发展技能和经验的过程中为我提供建议和指导。我制定了一个培训计划，这将增加我对液体生物标志物、统计数据和统计计算成像和心理测量学培训活动包括正式课程、会议、会议和研讨会。我所详述的研究计划将提供机会来衡量新兴的 CSF样本中的生物标志物，对生物标志物水平进行复杂的统计分析，了解生成各种类型的大脑成像措施，并评估在多种认知测试中的表现。在四年的职业发展奖结束时，我希望成为一个熟练的，多学科的，独立的研究机构，独立的研究项目。研究计划我们建议开发和验证临床前阿尔茨海默病（AD）的分期系统，一组七种脑脊液（CSF）生物标志物。改善临床前AD的分期将有助于临床医生和患者希望了解他们在未来20、10、5年内患AD痴呆的风险或两年。此外，临床药物试验中临床前AD的更精确分期将允许改进临床试验。入组标准和确定何时治疗在减缓疾病进展方面最有效。疾病单一的脑成像方式或液体生物标志物不太可能反映复杂的 AD的病理生理学然而，脑脊液（CSF）的单一样本提供了一个机会，测量AD病理级联反应中沿着发生的许多过程，从淀粉样蛋白沉积到tau蛋白聚集/释放到损伤/破坏突触到炎症到神经元细胞死亡。潜在 CSF提供的丰富信息，包括当前成像技术不能很好反映的过程，允许更好地对临床前AD进行分期，并提高我们预测个体何时发展为痴呆症的能力。我们将使用CSF Aβ42，tau， ptau，突触前蛋白突触体相关蛋白-25（SNAP-25），突触后钙调蛋白结合蛋白神经颗粒蛋白、神经元钙传感器视见素样蛋白1（VILIP-1）和炎性标记YKL-40。来自常染色体显性遗传阿尔茨海默病家族队列的CSF生物标志物数据疾病（ADAD）突变，我们将绘制ADAD突变携带者与非携带者。我们将使用生物标志物数据创建CSF生物标志物定义的临床前分期系统， AD.我们将研究这种分期系统是否能准确地估计痴呆发作的时间，纵向数据然后，我们将翻译和优化这个分期系统，在ADAD队列中创建，来自华盛顿大学的迟发性AD风险队列（LOAD）。接下来，我们将验证LOAD分段来自约翰霍普金斯大学的LOAD风险独立队列中的系统。最后，我们将评估如何分期系统与AD的影像学生物标志物相关，包括海马体积、淀粉样蛋白 PET和tau PET。