Neurophysiological Changes in Pre-clinical Alzheimer's Disease

摘要 这是为Hannes Devos博士重新提交的K01指导研究科学家奖，Hannes Devos博士是一个早期的职业生涯， 堪萨斯大学医学院物理治疗和康复科学终身教职 中心。虽然我在博士后时期接受了临床研究培训，但我寻求扩大我的科学研究 成为阿尔茨海默病(AD)应用神经生理学的独立研究人员。 我的首要目标是获得独立，有能力领导一个多学科的小组进行调查 神经生理标记物-事件相关电位(ERP)、心跳诱发电位(HEP)和任务- 诱发的瞳孔反应(TEPR)--临床前阿尔茨海默病的早期神经退行性衰退。我正处于危急关头 在获得帕金森氏症斜视测量的初步经验后，我的职业生涯中的一个转折点 疾病。因此，我提出了一个职业发展计划，在这个计划中，我将与著名的临床专家一起接受培训 方法(Burns博士)，神经生理学(Gustafson博士)，神经成像(Brooks博士和Burns博士)，以及 研究独立性(Burns博士、Brooks博士和Mahnken博士)。 从这些专家的指导中，我将学到：(1)临床方法方面的专业知识，包括认知研究 分子、细胞和系统水平上的正常衰老和神经退化引起的变化；(2)专业知识 无创脑活动测量的神经生理学，如ERP、HEP和TEPR；(3)经验 神经成像，包括读取和分析MRI和PET数据的能力；(4)以下方面的高级经验 研究独立性，特别是复杂的统计分析、学术生产力和研究资金。 这项拟议的研究提供了一个独特的机会来(1)比较神经生理对认知的反应 健康老龄化、临床前AD和MCI/AD之间的需求；(2)将神经生理学反应与 脑结构变化；以及(3)检查受试者内神经生理反应的变异性 短期和长期。中心假说是神经生理学的变化会在 临床前阿尔茨海默病患者的神经心理表现下降，反映了一种代偿机制 过度的神经招募，以应对认知任务需求。我从职业生涯中学到的知识 开发和研究培训将使我能够竞争R01资金，以研究神经生理学 临床前阿尔茨海默病早期神经退行性、认知和功能衰退的标记物。 该项目将利用KUMC的主要研究优势：NIH指定的阿尔茨海默病 中心，霍格伦德脑成像中心，以及临床和翻译科学单位(NIH CTSA)。 总而言之，这个K01奖将把我的临床研究经验和我的应用新技能结合在一起 阿尔茨海默病的神经生理学导师团队和研究环境将在我的轨道上提供必要的支持 走向研究独立。

ABSTRACT This is a resubmission for a K01 Mentored Research Scientist Award for Dr. Hannes Devos, an Early Career, Tenure Track Faculty of Physical Therapy and Rehabilitation Science at the University of Kansas Medical Center. While I have received clinical research training in my postdoctoral years, I seek to expand my scientific foundation in becoming an independent researcher in applied neurophysiology of Alzheimer's disease (AD). My primary goal is to attain independence, capable of leading a multidisciplinary group in investigating neurophysiological markers —event-related potentials (ERP), heartbeat-evoked potentials (HEP), and task- evoked pupillary response (TEPR)— of early neurodegenerative decline in pre-clinical AD. I am at a critical point in my career to make this transition after gaining initial experience with pupillometry in Parkinson's disease. Thus, I am proposing a career development plan in which I will train with renowned experts in clinical methods (Dr. Burns), neurophysiology (Dr. Gustafson), neuro-imaging (Dr. Brooks and Dr. Burns), and research independence (Dr. Burns, Dr. Brooks, and Dr. Mahnken). From these experts' mentoring I will learn: (1) Expertise in clinical methods, including the study of cognitive changes due to normal aging and neurodegeneration on molecular, cellular, and systems level; (2) Expertise in neurophysiology of non-invasive brain activity measures such as ERP, HEP, and TEPR; (3) Experience in neuro-imaging, including the ability to read and analyze MRI and PET data; (4) Advanced experience in research independence, especially complex statistical analyses, scholarly productivity, and research funding. The proposed research offers a unique opportunity to (1) compare neurophysiological responses to cognitive demand between healthy aging, pre-clinical AD, and MCI/AD; (2) correlate neurophysiological responses to structural brain changes; and (3) examine the intrasubject variability of neurophysiological responses in the short- and long-term. The central hypothesis is that neurophysiological changes will manifest prior to decrements in neuropsychological performance in pre-clinical AD, reflecting a compensatory mechanism for excessive neural recruitment to cope with cognitive task demand. The knowledge gained from my career development and research training will enable me to compete for R01 funding to investigate neurophysiological markers of early neurodegenerative, cognitive, and functional decline in pre-clinical AD. This project will capitalize on KUMC's major research strengths: the NIH-designated Alzheimer's Disease Center, the Hoglund Brain Imaging Center, and the Clinical and Translational Science Unit (NIH CTSA). In summary, this K01-award will bring together my clinical research experience and my new skills in applied neurophysiology of AD. The mentor team and research environment will provide essential support on my track towards research independence.