Cognitive and Neural Moderators of Longitudinal Decline in Frontotemporal Degeneration

项目摘要 这个K99/R 00奖将支持我作为一个独立的研究者的发展， 计划设计个性化干预措施，以减缓认知能力下降的人， 神经退行性疾病是基于潜在的神经生物学机制。 候选人：我作为一名护士的临床经验和认知神经科学的研究经验 理想地定位我，以实现我的职业目标，成为一个独立的调查员，在专业知识， 神经退行性疾病如额颞叶变性（FTD）的认知和生物学基础。我 我在宾夕法尼亚大学接受过很强的神经科学训练，在那里我得到了NRSA的支持 博士前奖，以调查冷漠的神经基础，在行为变异额颞叶变性 （bvFTD）。我随后被授予个人NRSA博士后奖学金，以调查生活方式如何 因素导致冷漠的纵向恶化。在这项研究中，我获得了经验， 纵向设计，并了解了其他MRI测量，如白色的扩散张量成像 物质束我对纵向认知能力下降以及生活方式和 生物学因素导致bvFTD的下降速率不同。在这个提议中，我计划获得必要的 在神经退行性疾病症状进展的生物学基础方面的专业知识， bvFTD干预。我将继续接受干预设计和方法方面的培训，为随后的 R 01，我将使用从K99/R 00中获得的知识来设计和测试认知干预措施， 增强神经代偿以减缓bvFTD的下降。 环境：该奖项将在宾夕法尼亚州立大学（PSU），护理学院进行 以及宾夕法尼亚大学额颞叶变性中心（UPenn FTDC）。PSU和UPenn 神经退行性疾病研究的领先中心，我得到了两者的强有力的机构支持 高校PSU是一个特殊的环境，拥有老化研究和方法的专家中心 包括对神经退行性疾病患者的非药物干预研究。我 导师，唐娜菲克博士，是一个护士研究与认知衰退的专业知识，她有一个富有成效的 一项研究计划，根据认知能力为谵妄和痴呆患者制定量身定制的干预措施， 储备理论考虑到我未来发展认知干预的目标，PSU是一个理想的环境， 进行干预方法的培训。宾夕法尼亚大学FTDC是生物研究的领先中心， 神经退行性疾病，包括遗传和神经影像学研究专家中心和相关 临床研究实验室。UPenn FTDC是世界上最大的神经退行性疾病之一， 数据集，包括各种模态，如MRI、弥散张量成像、动脉自旋 标签、遗传学、脑脊髓和神经心理学测试。我的共同导师默里·格罗斯曼博士是 宾夕法尼亚大学FTDC的主任，因此将促进我作为一个独立的调查员的发展， 提供对这一独特数据集以及实验室资源的访问，并与其他 神经影像学和遗传学专家 培训：我将发展我在纵向衰退的认知和神经基础方面的专业知识。 我的导师Donna Fick博士和我的共同导师Murray博士的支持下， 格罗斯曼具体来说，我将从事纵向统计方法，遗传学，高级 神经影像学技能和干预设计和方法。将支持每一种培训方式 通过补充正式课程，参加研讨会，出席会议，并定期 和我的导师团队安排了会议 研究：bvFTD是慢性神经退行性疾病的常见原因， 大约7年，但这是高度可变的。最近的研究表明， 生活方式和遗传因素对bvFTD临床病程的影响。神经解剖学因素也可能在 补偿功能的神经实现，例如支持替代大脑网络以实现最佳的 性能这项建议的总体研究目标是更好地了解 生活方式和生物学因素对慢性痴呆纵向下降的影响， 这种情况发生的机制。这些知识对于认知干预措施的设计至关重要 它利用代偿机制来增强认知功能， 神经退行性疾病

Project Summary This K99/R00 award will support my development as an independent investigator with a research program designing individualized interventions to slow cognitive decline in persons with neurodegenerative disease that are based on underlying neurobiological mechanisms. Candidate: My clinical experience as a nurse practitioner and research experience in cognitive neuroscience ideally position me to achieve my career goal of becoming an independent investigator with expertise in the cognitive and biologic basis of neurodegenerative conditions such as Frontotemporal Degeneration (FTD). I had strong neuroscience training at the University of Pennsylvania, where I was supported by an NRSA Predoctoral Award to investigate the neural basis of apathy in behavioral variant Frontotemporal Degeneration (bvFTD). I was subsequently awarded an Individual NRSA Postdoctoral Fellowship to investigate how lifestyle factors contribute to longitudinal worsening in apathy. In this research, I have gained experience with longitudinal design and learned about additional MRI measures such as diffusion tensor imaging of white matter tracts. I have become increasingly interested in longitudinal cognitive decline and how lifestyle and biologic factors contribute to the variable rate of decline in bvFTD. In this proposal, I plan to gain the necessary expertise in the biological basis for symptom progression in neurodegenerative disease in order to design interventions for bvFTD. I will pursue training in intervention design and methods to prepare for a subsequent R01 where I will use the knowledge gained from this K99/R00 to design and test cognitive interventions that boost neural compensation to slow decline in bvFTD. Environment: This award will be conducted at The Pennsylvania State University (PSU), College of Nursing and the University of Pennsylvania, Frontotemporal Degeneration Center (UPenn FTDC). PSU and UPenn are leading centers for the study of neurodegenerative disease and I have strong institutional support from both universities. PSU is an exceptional environment that has expert centers for aging research and methodology including, non-pharmacological intervention research for individuals with neurodegenerative disease. My mentor, Dr. Donna Fick, is a nurse researcher with expertise in cognitive decline and she has a productive research program developing tailored interventions for persons with delirium and dementia based on cognitive reserve theory. Given my future goal of developing cognitive interventions, PSU is the ideal environment to pursue training in intervention methods. The UPenn FTDC is a leading center for biologic research in neurodegenerative disease including expert centers for genetic and neuroimaging research and relevant clinical research laboratories. The UPenn FTDC maintains one of the largest neurodegenerative disease datasets that includes a diverse range of modalities such as MRI, diffusion tensor imaging, arterial spin labeling, genetics, cerebrospinal and neuropsychological testing. My co-mentor, Dr. Murray Grossman, is the Director of the UPenn FTDC and thus will facilitate my development as an independent investigator by providing access to this unique dataset as well as laboratory resources and collaborations with other neuroimaging and genetic experts at UPenn. Training: I will develop my expertise in the cognitive and neural basis of longitudinal decline in neurodegenerative disease with the support of my mentor, Dr. Donna Fick, and my co-mentor, Dr. Murray Grossman. Specifically, I will engage in training related to longitudinal statistical methods, genetics, advanced neuroimaging skills and intervention design and methods. Each of these training modalities will be supported by complementary formal coursework, participation in seminars, attendance of conferences, and regularly scheduled meetings with my mentorship team. Research: bvFTD is a common cause of young-onset neurodegenerative disease and life expectancy is approximately 7 years, but this is highly variable. Recent studies have demonstrated the moderating effects of lifestyle and genetic factors on the clinical course of bvFTD. Neuroanatomic factors may also play a role in neural implementation of compensatory function, such as supporting alternate brain networks for optimal performance. The overall research aim of this proposal is to better understand the moderating effects of lifestyle and biologic factors on longitudinal decline in young-onset dementia, and an account of the mechanisms by which this occurs. This knowledge is crucial for the design of cognitive interventions that take advantage of compensatory mechanisms to enhance cognitive function and slow decline in neurodegenerative disease.