Genetic and Neuropathologic Underpinnings of Sex Differences in Lewy Body Dementias

项目摘要 在路易体痴呆症中，性别差异是常见的，尽管原因尚不清楚。 表型差异可以通过病理学差异来描述，并且可以与 遗传风险位点的差异。我们假设阿尔茨海默病相关的遗传风险因素将是 与路易体痴呆症女性的痴呆风险较高相关，因为 老年痴呆症在女性中的共同病理学。然而，即使对于患有单纯路易体病的女性， 阿尔茨海默氏症表型比路易体痴呆表型更常见，表明性别差异 临床病理相关性。这可能是由于男性和女性的区域病理学负担存在差异， 妇女特定区域的路易体和阿尔茨海默病的病理负担与不同的 我们假设男性会有更多的新皮质路易体负担，女性会有更多的新皮质路易体负担。 由于老年痴呆症的表型更为常见， 妇女由于阿尔茨海默病是路易体痴呆症患者最常见的误诊， 我们还将开发具有临床和遗传变量的性别特异性模型， 身体和阿尔茨海默病的病理学。这些发现将有助于我们了解的发病机制， 路易体痴呆症，协助患者选择未来的临床试验在路易体痴呆症和 阿尔茨海默病，并为这些神经退行性痴呆症的精确医学提供目标。 候选人是加州大学旧金山分校的助理项目科学家（一个受指导的职位）。 迪亚哥她拥有医学博士和博士学位，之前接受过神经退行性疾病、神经心理学和 神经成像她有生产力的历史，在1999年进行了转化和临床研究。 运动障碍，最近集中在帕金森病的性别差异。她致力于 研究职业生涯中的转化研究，并提出了一个全面的五年计划的研究和 培训以获得以下技能：1）遗传和基因组分析，2）解释神经病理学数据，3） 利用大数据进行统计分析。在颁奖期间，Bayram博士将建立合作 与遗传学、神经病理学和生物信息学领域的专家建立了关系，以支持她的工作， 独立研究员。该奖项还将支持Bayram博士的专业发展，包括 培训财务、领导和行政技能。Bayram博士将根据 一个指导团队的指导，包括Irene Litvan博士（主要导师），世界知名的专家， 帕金森病认知功能下降，Sonja Scholz博士（共同导师，神经学家-神经遗传学家， NINDS），Ali Torkamani博士（生物信息学导师），大卫萨尔蒙博士（神经心理学导师）， Dennis Dickson（顾问，病理学家），Owen Ross博士（顾问，遗传学家）和Abraham Palmer博士 （顾问，遗传学家），他们都是知名的和NIH资助的研究人员。

PROJECT SUMMARY Sex differences are commonly reported in Lewy body dementia, although the reasons are unknown. Phenotypic differences can be described by differences in the pathology and can be associated with differences in genetic risk loci. We hypothesize that Alzheimer's disease-related genetic risk factors will be associated with higher dementia risk in women with Lewy body dementia, given the higher likelihood of Alzheimer's co-pathology in women. However, even for women with pure Lewy body pathology, Alzheimer's phenotype is more common than Lewy body dementia phenotype, indicating sex differences for clinicopathologic correlations. This may be due to differences in regional pathology burden for men and women. Specific regional Lewy body and Alzheimer's pathology burden have been associated with different symptoms; and we hypothesize that men will have more neocortical Lewy body burden and women will have more pathology burden in the medial temporal lobe given the more common Alzheimer's phenotype in women. As Alzheimer's disease is the most common misdiagnosis for patients with Lewy body dementia, we will also develop sex-specific models with clinical and genetic variables to clinically differentiate Lewy body and Alzheimer's pathology. These findings will improve our understanding of the etiopathogenesis of Lewy body dementia, assist with patient selection for future clinical trials in both Lewy body dementia and Alzheimer's disease, and provide targets for precision medicine in these neurodegenerative dementias. The candidate is an Assistant Project Scientist (a mentored position) at the University of California San Diego. She has an MD and a PhD with prior training in neurodegenerative disorders, neuropsychology, and neuroimaging. She has a history of productivity, having conducted translational and clinical research in movement disorders, recently focusing on sex differences in Parkinsonian disorders. She is committed to a research career in translational research and proposes a comprehensive five-year plan of research and training to acquire skills in 1) genetic and genomic analysis, 2) interpreting neuropathological data, 3) performing statistical analyses with big data. During the award period, Dr. Bayram will build collaborative relationships with experts in the field of genetics, neuropathology, and bioinformatics to support her work as an independent researcher. This award will also support Dr. Bayram's professional development including training for grantsmanship, leadership, and administrative skills. Dr. Bayram will meet her goals under the guidance of a mentoring team including Dr. Irene Litvan (primary mentor), a world-renowned expert in cognitive decline in Parkinsonian disorders, Dr. Sonja Scholz (co-mentor, neurologist-neurogeneticist at NINDS), Dr. Ali Torkamani (bioinformatics mentor), Dr. David Salmon (neuropsychology mentor), Dr. Dennis Dickson (advisor, pathologist), Dr. Owen Ross (advisor, geneticist) and Dr. Abraham Palmer (advisor, geneticist), all of whom are well-established and NIH-funded researchers.