Genetic and Neuropathologic Underpinnings of Sex Differences in Lewy Body Dementias

项目总结 虽然原因不明，但在路易体痴呆症中，性别差异的报道很常见。 表型差异可以用病理上的差异来描述，并且可以与 遗传风险基因座的差异。我们假设阿尔茨海默病相关的遗传风险因素 与患有路易体痴呆症的女性的痴呆症风险更高相关，因为 女性阿尔茨海默氏症的共同病理。然而，即使是患有纯路易体病变的女性， 阿尔茨海默氏症的表型比路易体痴呆表型更常见，这表明性别差异 用于临床病理对照。这可能是由于男性和女性的区域性病理负担不同所致 女人。特定的区域路易体和阿尔茨海默病的病理负担与不同的 症状；我们假设男性会有更多的新皮质路易体负担，而女性会 在内侧颞叶有更多的病理负担，因为更常见的阿尔茨海默病表型 女人。由于阿尔茨海默病是路易体痴呆患者最常见的误诊， 我们还将开发具有临床和遗传变量的性别特异性模型，以在临床上区分刘易斯 身体和阿尔茨海默氏症的病理学。这些发现将提高我们对糖尿病发病机制的理解。 路易体痴呆，协助选择未来路易体痴呆临床试验的患者和 阿尔茨海默氏症，并为这些神经退行性痴呆的精确医学提供靶点。 候选人是加州大学旧金山分校的助理项目科学家(指导职位) 迭戈。她拥有医学博士和博士学位，曾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，曾在中国进行翻译和临床研究 运动障碍，最近关注的是帕金森障碍的性别差异。她致力于一项 在翻译研究方面的研究生涯，并提出了全面的研究和五年计划 培训以获得1)遗传和基因组分析，2)解释神经病理数据，3) 利用大数据进行统计分析。在颁奖期间，贝拉姆博士将建立协作 与遗传学、神经病理学和生物信息学领域的专家的关系，以支持她作为 一名独立研究人员。该奖项还将支持拜拉姆博士的专业发展，包括 培训勇士精神、领导力和管理技能。贝拉姆博士将在 指导团队的指导包括艾琳·利特万博士(主要导师)，世界知名的 帕金森障碍中的认知下降，Sonja Scholz博士(共同导师，神经学家兼神经遗传学家，位于 NINDS)、Ali Torkamani博士(生物信息学导师)、David Salmon博士(神经心理学导师)、Dr. 丹尼斯·迪克森(顾问、病理学家)、欧文·罗斯博士(顾问、遗传学家)和亚伯拉罕·帕尔默博士 (顾问，遗传学家)，他们都是由NIH资助的知名研究人员。

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.