Genetic and Neuropathologic Underpinnings of Sex Differences in Lewy Body Dementias

路易体痴呆性别差异的遗传和神经病理学基础

• 批准号: 10448638
• 负责人: ECE BAYRAM
• 金额: $ 12.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448638
• 关键词: Affect; Alzheimer' s Disease; Alzheimer' s disease pathology; Award; Big Data; Bioinformatics; Biological Markers; Body Burden; Brain; California; Clinic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Data; Data Set; Dementia; Dementia with Lewy Bodies; Development; Doctor of Philosophy; Elderly; Five-Year Plans; Foundations; Frequencies; Functional disorder; Funding; Future; Genetic; Genetic Risk; Genomics; Goals; Gold; Hippocampus (Brain); Impaired cognition; Individual; Institution; Leadership; Lewy Bodies; Lewy Body Dementia; Lewy body pathology; Life; Medial; Medical Genetics; Medicine; Mentors; Modeling; Movement Disorders; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurodegenerative Disorders; Neurologist; Neuropsychology; Parkinson Disease; Parkinsonian Disorders; Pathologic; Pathologist; Pathology; Pathway interactions; Patient Selection; Patients; Phase; Phenotype; Positioning Attribute; Positron-Emission Tomography; Prevalence; Productivity; Recording of previous events; Reporting; Research; Research Personnel; Research Project Grants; Research Training; Resources; Salmon; Sampling; Scientist; Senile Plaques; Series; Sex Differences; Statistical Data Interpretation; Symptoms; Temporal Lobe; Training; Translational Research; United States National Institutes of Health; Universities; Visual Hallucination; Woman; Work; alpha synuclein; career; clinical diagnosis; clinical diagnostics; clinical phenotype; clinical predictors; cohort; dementia risk; diagnosis standard; diagnostic accuracy; disease phenotype; experience; genetic predictors; genetic risk factor; genetic variant; genome sequencing; improved; men; morphogens; neocortical; neurodegenerative dementia; neuroimaging; neuropathology; non-demented; precision medicine; predictive modeling; public-private partnership; regional difference; risk variant; sex; skills; success; tau Proteins; whole genome

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.

项目摘要 性别差异通常在路易体内痴呆症中报道，尽管原因尚不清楚。 表型差异可以通过病理学的差异来描述，并且可以与 遗传风险基因座的差异。我们假设阿尔茨海默氏病与疾病相关的遗传危险因素将是 鉴于较高的可能性，与Lewy身体痴呆症女性的痴呆症风险更高有关 阿尔茨海默氏症女性的竞选。但是，即使对于具有纯Lewy身体病理学的女性， 阿尔茨海默氏症的表型比路易身体痴呆表型更普遍，表明性别差异 用于临床病理相关性。这可能是由于男性区域病理负担的差异以及 女性。特定的区域路易尸体和阿尔茨海默氏病的病理负担与不同 症状;我们假设男人会有更多的新皮层路易义务，而妇女将 考虑到更常见的阿尔茨海默氏症表型，内侧颞叶有更多的病理负担 女性。由于阿尔茨海默氏病是路易痴呆患者最常见的误诊，所以 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Lewy 身体和阿尔茨海默氏病的病理。这些发现将提高我们对 Lewy身体痴呆症，协助患者选择Lewy身体痴呆和未来的临床试验 阿尔茨海默氏病，并为这些神经退行性痴呆症提供了精确医学的靶标。 候选人是加利福尼亚大学SAN的助理项目科学家（指导职位） 迭戈。她拥有一家医学博士学位和博士学位，并在神经退行性疾病，神经心理学和 神经影像学。她有生产力的历史，已经进行了翻译和临床研究 运动障碍，最近关注帕金森氏症的性别差异。她致力于 翻译研究的研究职业，并提出了一项综合的五年研究计划和 培训以获取技能1）遗传和基因组分析，2）解释神经病理学数据，3） 用大数据进行统计分析。在奖励期间，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的关系，以支持她的工作 独立研究人员。该奖项还将支持Bayram博士的专业发展 培训授予技巧，领导和行政技能。 Bayram博士将达到她的目标 指导团队的指导，包括Irene Litvan博士（主要导师），这是世界知名的专家 帕金森氏症的认知能力下降，Sonja Scholz博士（神经科医生 - 神经源性主义者的联合学家 Ninds），Ali Torkamani博士（生物信息学导师），David Salmon博士（神经心理学导师），博士 丹尼斯·迪克森（Dennis Dickson）（病理学家顾问），欧文·罗斯（Owen Ross）博士（遗传学家顾问）和亚伯拉罕·帕尔默（Abraham Palmer）博士 （遗传学家顾问），所有这些都是成就良好且由NIH资助的研究人员。