Multimodal Biomarkers in Frontotemporal Lobar Degeneration

描述(由申请者提供)：这一K01奖项将支持我作为一名独立研究员的发展，我的翻译研究项目专门研究神经退行性疾病的认知和生物学基础，如额颞叶变性(FTLD)。候选人：我作为一名认知神经学家的研究经验使我能够理想地实现我的职业目标，即成为一名拥有神经退行性疾病认知和生物学基础专业知识的独立调查员。我在爱丁堡大学接受了强大的认知训练，获得了心理语言学硕士学位和心理学博士学位，在那里我获得了NRSA个人博士前奖。在宾夕法尼亚大学认知科学研究所从事IGERT博士后研究期间，我获得了NRSA个人博士后奖学金，以研究语言决策的作用。在这项研究中，我获得了对神经退行性疾病患者进行比较研究的经验，以获得补充健康成年人功能磁共振研究的趋同证据。我越来越有兴趣将我的研究转化为优化神经退行性疾病患者的诊断和治疗。最近，我获得了语言神经生物学学会博士后优秀奖，以表彰我的新研究，该研究调查了患者的社会限制如何导致话语困难。我已经致力于NIH贷款偿还计划四年的临床研究，我打算在我的职业生涯中致力于临床研究。我了解到，认知和神经成像研究对神经退行性疾病只提供了一种视角。在这项提议中，我计划在FTLD的生物学方面和相关条件方面获得必要的专业知识，以补充我过去的经验，从而实现我的目标，即成为一名拥有神经退行性疾病认知和生物学基础专业知识的多方面独立研究员。在K01的支持下，我将发展专业知识，进行神经退行性疾病的脑脊液(CSF)、遗传和神经病理学方面的研究。我最终将把从这项提案中获得的生物学专业知识与我的认知神经科学研究中的语言研究结合起来，努力识别可用于筛查患者进行临床试验的非侵入性生物标志物，并衡量疾病改良剂的疗效。环境：该奖项将在宾夕法尼亚大学佩雷尔曼医学院神经病学系、神经退行性疾病研究中心(CNDR)和宾夕法尼亚大学生物信息学中心举行，我在那里得到了强有力的机构支持。拟建的机构是一个特殊的环境，拥有神经成像、脑脊液生物标记物分析专家中心、领先的遗传研究核心、神经病理学专家、出色的生物统计学支持以及相关的临床研究实验室。与美国其他机构相比，宾夕法尼亚大学是独一无二的，因为上述所有方法都可以在一个中心使用。我的导师默里·格罗斯曼博士和我的合作导师约翰·特罗扬诺夫西博士在神经退行性疾病研究方面享有国际声誉。我的职业发展还将得到我的合作导师莱尔·昂加博士的支持，他在统计学习算法以及蛋白质组和基因组数据集分析方面拥有丰富的专业知识。总而言之，这个指导团队将通过提供现有和未来的合作者、实验室资源和特殊的培训环境，促进我作为独立调查员的发展。CNDR是世界领先的神经退行性疾病研究中心，拥有人类和动物疾病模型以及特殊的翻译科学。生物流体生物标志物经验丰富，几个国家生物流体岩心集中在宾夕法尼亚大学(例如ADNI)。宾夕法尼亚大学在宾夕法尼亚大学的成像和计算机科学实验室拥有丰富的国际公认的神经成像专业知识，我将受益于将这些设施的神经成像资源与其他形式的生物标记物研究相结合。培训：在我的导师Murray Grossman博士以及我的共同导师John Trojanowski博士和Lyle Unga博士的支持下，我将在神经退行性疾病的生物学基础上发展我的专业知识。具体地说，我将与Trojanowksi博士一起参加与FTLD的生物流体和遗传生物标记物相关的培训。我将与昂加博士一起开发高级神经成像技能和尖端生物统计学方法。这些培训方式中的每一种都将得到补充的正式课程、参加研讨会、出席会议以及与指导小组定期安排的会议的支持。研究：FTLD是一种神经退行性疾病，每10万人中约有15人受到影响。近年来，尸检中详细的神经病理学检查证实了FTLD组织病理学异常的不同来源，包括tau包涵体(FTLD-tau)和TDP-43蛋白病变(FTLD-TDP)。然而，目前还没有体内方法来区分FTLD-tau和FTLD-TDP。迫切需要改进FTLD的活体诊断，使患者适当地进入新兴的临床试验，并在试验中开发敏感和特定的终点，以量化对这些治疗的反应。这项建议的总体研究目标是开发多模式方法来提高FTLD的活体诊断。

DESCRIPTION (provided by applicant): This K01 award will support my development as an independent investigator with a translational research program that specializes in the cognitive and biological basis of neurodegenerative diseases such as frontotemporal lobar degeneration (FTLD). Candidate: My research experience as a cognitive neuroscientist ideally positions me to achieve my career goal of becoming an independent investigator with expertise on the cognitive and biological basis of neurodegenerative disease. I have strong cognitive training with an M.Sc in Psycholinguistics and Ph.D in Psychology from the University of Edinburgh, where I was supported by an NRSA Individual Predoctoral Award. During my postdoctoral IGERT fellowship at the Institute for Research in Cognitive Science at the University of Pennsylvania, I was awarded an NRSA Individual Postdoctoral Fellowship Award to investigate the role of decision-making in language. In this research I have gained experience investigating neurodegenerative disease patients comparatively in order to obtain converging evidence to complement fMRI studies of healthy adults. I have become increasingly interested in translating my research to optimize the diagnosis and treatment of patients with neurodegenerative diseases. I was recently award the Society for the Neurobiology of Language Postdoctoral Merit Award in recognition of my novel research investigating how social limitations in patients contribute to difficulty in discourse. I have committed to four years of clinical research the NIH Loan Repayment Program, and I intend to commit to clinical research for the duration of my career. I have learned that cognitive and neuroimaging studies provide only one perspective on neurodegenerative diseases. In this proposal, I plan to gain the necessary expertise in biological aspects of FTLD and related conditions to complement my past experiences, and thus achieve my goal of becoming a multifaceted independent investigator with expertise in the cognitive and biological basis for neurodegenerative diseases. With the support of this K01, I will develop expertise to conduct investigations of cerebrospinal fluid (CSF), genetic, and neuropathological aspects of neurodegenerative diseases. I will ultimately integrate the biological expertise gained in this proposal with language studies from my cognitive neuroscience research in an effort to identify non-invasive biomarkers that can be used to screen patients for clinical trials and to measure the efficacy of disease-modifying agents. Environment: This award will be conducted at the Perelman School of Medicine at the University of Pennsylvania in the Department of Neurology, the Center for Neurodegenerative Disease Research (CNDR), and the Penn Bioinformatics Center where I have strong institutional support. The proposed institution is an exceptional environment that has expert centers for neuroimaging, cerebrospinal fluid biomarker analysis, a leading genetic research core, expert neuropathology, outstanding biostatisical support, and relevant clinical research laboratories. The University of Pennsylvania is unique in comparison to other institutions in the country because all of the above methods are available in one center. My mentor, Dr. Murray Grossman, and my co-mentor, Dr. John Trojanowksi, have international reputations for neurodegenerative disease research. My career development will also be supported by my co-mentor, Dr. Lyle Ungar, who has extensive expertise in statistical learning algorithms and in the analysis of proteomic and genomics datasets. Together, this mentorship team will facilitate my development as an independent investigator by providing access to existing and future collaborators, laboratory resources, and exceptional training environments. The CNDR is a world- leading center for neurodegenerative disease research with human and animal models of disease and exceptional translational science. Biofluid biomarker experience is extensive, and several national biofluid cores are centered at Penn (e.g. ADNI). There is a wealth of internationally-recognized neuroimaging expertise at the University of Pennsylvania in the Penn Imaging and Computer Science Laboratory, and I will benefit by integrating neuroimaging resources from these facilities with other modalities of biomarker research. Training: I will develop my expertise in the biological basis of neurodegenerative disease with the support of my mentor, Dr. Murray Grossman, and my co-mentors, Dr. John Trojanowski and Dr. Lyle Ungar. Specifically, with Dr. Trojanowksi I will engage in training related to biofluid and genetic biomarkers of FTLD. I will develop advanced neuroimaging skills and cutting-edge biostatistical methods with Dr. Ungar. Each of these training modalities will be supported by complementary formal coursework, participation in seminars, attendance of conferences, and regularly scheduled meetings with mentorship team. Research: FTLD is a neurodegenerative disease affecting approximately 15 out of 100,000 individuals. In recent years detailed neuropathological investigations at autopsy have demonstrated distinct sources of histopathological abnormalities in FTLD, including the presence of tau inclusions (FTLD-tau) and TDP-43 proteinopathies (FTLD-TDP). However, there are currently no in vivo methods for discriminating between FTLD-tau and FTLD-TDP. There is an urgent need to improve the in vivo diagnosis of FTLD to appropriately enter patients into emerging clinical trials, and to develop sensitive and specific endpoints in trials that can quantify response to these treatments. The overall research aim of this proposal is to develop multimodal methods to improve in vivo diagnosis of FTLD.