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.

项目总结