Pathological and cognitive correlations of real time quaking induced conversion in LBD and AD

实时震动引起的 LBD 和 AD 转变的病理和认知相关性

• 批准号: 10665720
• 负责人: David G Coughlin
• 金额: $ 16.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-15 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665720
• 关键词: Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Antibodies; Autopsy; Award; Biological Assay; Biological Markers; Brain; California; Clinical; Clinical Research; Clinical Trials Design; Cognition; Cognitive; Coupled; Dementia; Dementia with Lewy Bodies; Development; Diagnosis; Disease; Doctor of Philosophy; Episodic memory; Epitopes; Fellowship; Five-Year Plans; Fluorescence; Functional disorder; Future; Goals; Histologic; Histopathology; Immunohistochemistry; Impaired cognition; International; K-Series Research Career Programs; Laboratories; Learning; Lewy Body Disease; Life; Measurement; Measures; Mentors; Mentorship; Methods; Molecular; Motor; Movement Disorders; Names; National Institute of Allergy and Infectious Disease; Nerve Degeneration; Neurodegenerative Disorders; Neuropsychology; Neurosciences; Outcome; Parkinson Disease; Pathogenicity; Pathologic; Pathology; Patients; Pennsylvania; Positioning Attribute; Productivity; Progressive Disease; Proteins; Recording of previous events; Research; Research Support; Resources; Salmon; Sampling; Scientist; Sensitivity and Specificity; Statistical Data Interpretation; Statistical Methods; TNFSF15 gene; Techniques; Testing; Time; Tissues; Training; Translational Research; United States National Institutes of Health; Universities; Use of New Techniques; Visuospatial; Western Blotting; alpha synuclein; biomarker signature; career; clinical diagnosis; clinically significant; cognitive performance; cognitive testing; cohort; diagnostic accuracy; digital; experimental study; improved; molecular pathology; multimodality; neuropathology; novel; professor; programs; self-directed learning; skill acquisition; skills; statistical learning; tau Proteins; validation studies

Project Summary/Abstract The accurate clinical diagnosis of Lewy body diseases (LBD: Parkinson’s disease (PD), dementia with Lewy bodies (DLB)), and Alzheimer’s disease (AD) is challenged by overlapping clinical features. Novel biofluid biomarkers including real time quaking induced conversion (RT-QuIC) offer the ability to diagnose patients with greater accuracy during life by identifying pathologic α-synuclein (a-syn) or tau seeds. However, in LBD, approximately 50% of cases will harbor significant AD pathology, and in AD up to 50% harbor limbic a-syn which can complicate interpretation of biomarker signatures. Therefore, comprehensive pathological validation studies are essential to understand the utility of these new assays and their association with histopathologic burden and clinical correlations. If RT-QuIC metrics relate to pathological burden or cognitive outcomes, they could be used as an objective biomarker in LBD, an ongoing critical need. The aims of this proposal are to test whether a-syn and tau RT-QuIC is associated with 1) histopathological features and 2) cognitive outcomes in LBD and AD. The hypotheses are that a-syn and tau RT-QuIC will be able to predict primary and co-pathologies in LBD and AD and that higher degrees of RT-QuIC activity will associate with greater neuropathological burden and worse cognitive outcomes. The proposed experiments will leverage pre-existing autopsy cohorts with antemortem CSF and cognitive testing collected at the University of California San Diego (UCSD) and the University of Pennsylvania with the RT-QuIC expertise of the NIH/NIAID Rocky Mountain Laboratories. The K23 candidate is an Assistant Professor of Neurosciences at the UCSD, having previously completed movement disorders fellowship and a NIH TL1-supported Masters of Translational Research. He has a history of productivity, having conducted translational and clinical research in neuroscience, recently focusing on the neuropathology of PD, DLB, and AD. The candidate is committed to a career in translational research and proposes a comprehensive five year plan of mentorship, formal training, self-directed learning, and research. This K23 career development award will support Dr. Coughlin’s short-term goals, including 1) developing a detailed understanding of RT-QuIC and its association with histopathological and cognitive outcomes, 2) acquisition of skills for multimodal tissue characterization using immunohistochemistry and Western blotting techniques, 3) learning the neuropsychology of dementia with a focus on LBD and AD, and 4) learning the statistical methods to carry out these and future studies. Dr. Coughlin will meet these objectives under the guidance of a mentorship team, including Dr. Douglas Galasko, an expert in biofluid biomarkers, Dr. Robert Rissman PhD, an expert in the molecular pathology of neurodegenerative disease and Dr. David Salmon PhD expert neuropsychologist with a long research track record in LBD and AD. This award will support Dr. Coughlin’s development towards becoming an independent clinician-scientist with expertise in biomarker-pathological validation studies and a unique research program in translational neuropathology.

项目总结/摘要 路易体病（LBD：帕金森病（PD）、路易痴呆）的准确临床诊断 阿尔茨海默病（AD）受到重叠临床特征的挑战。新型生物流体 包括真实的时间震动诱导转换（RT-QuIC）在内的生物标志物提供了诊断患者的能力， 通过识别病理性α-突触核蛋白（a-syn）或tau种子，在生命期间获得更高的准确性。然而，在LBD中， 大约50%的病例具有显著的AD病理学，并且在AD中高达50%具有边缘a-syn， 会使生物标记的解释复杂化。因此，全面的病理学验证研究 对于了解这些新检测方法的实用性及其与组织病理学负荷的相关性至关重要， 临床相关性如果RT-QuIC指标与病理负担或认知结果相关，则可以使用它们 作为LBD的客观生物标志物，这是一个持续的关键需求。这项建议的目的是测试是否a-syn 并且tau RT-QuIC与LBD和AD中的1）组织病理学特征和2）认知结果相关。的 假设a-syn和Tau RT-QuIC将能够预测LBD和AD中原发和共同病理 并且更高程度的RT-QuIC活性将与更大的神经病理学负担和更差的 认知结果。拟议的实验将利用预先存在的尸检队列和死前CSF 和认知测试收集在加州圣地亚哥大学（UCSD）和 宾夕法尼亚州的NIH/NIAID落基山实验室的RT-QuIC专业知识。 K23候选人是UCSD神经科学助理教授，此前已完成 运动障碍奖学金和NIH TL 1支持的转化研究硕士学位。他有一段历史 生产力，在神经科学方面进行了转化和临床研究，最近专注于 PD、DLB和AD的神经病理学。候选人致力于从事翻译研究， 提出了一个全面的五年计划的导师，正规培训，自我导向的学习，和研究。 这个K23职业发展奖将支持考夫林博士的短期目标，包括1）开发一个 详细了解RT-QuIC及其与组织病理学和认知结果的相关性，2） 获得使用免疫组织化学和蛋白质印迹进行多模式组织表征的技能 技术，3）学习痴呆症的神经心理学，重点是LBD和AD，以及4）学习 统计方法来进行这些和未来的研究。考夫林博士将根据 导师团队的指导，包括生物流体生物标志物专家道格拉斯加拉斯科博士，罗伯特博士 Rissman博士，神经退行性疾病分子病理学专家和大卫萨尔蒙博士 神经心理学家专家，在LBD和AD方面有长期的研究记录。该奖项将支持考夫林博士的 发展成为一名独立的临床科学家，具有生物标志物病理学方面的专业知识 验证研究和转化神经病理学的独特研究计划。

项目成果

Long-standing multiple system atrophy-Parkinsonism with limbic and FTLD-type α-synuclein pathology.

• DOI: 10.1111/nan.12783
• 发表时间: 2022-04
• 期刊: NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY
• 影响因子: 5
• 作者: Coughlin, David G.;Dryden, Ian;Goodwill, Vanessa S.;Pizzo, Donald P.;Wright, Brenton;Lessig, Stephanie;Galasko, Douglas;MacKenzie, Ian R.;Hiniker, Annie
• 通讯作者: Hiniker, Annie

Fluid and Biopsy Based Biomarkers in Parkinson's Disease.

• DOI: 10.1007/s13311-023-01379-z
• 发表时间: 2023-07
• 期刊: NEUROTHERAPEUTICS
• 影响因子: 5.7
• 作者: Coughlin, David G.;Irwin, David J.
• 通讯作者: Irwin, David J.

Perception of Fragmented Letters by Patients With Pathologically Confirmed Dementia With Lewy Bodies or Alzheimer Disease.

病理证实患有路易体痴呆或阿尔茨海默病的患者对碎片字母的感知。

• DOI: 10.1212/wnl.0000000000201068
• 发表时间: 2022
• 期刊: Neurology
• 影响因子: 9.9
• 作者: Salmon,DavidP;Smirnov,DenisS;Coughlin,DavidG;Hamilton,JoanneM;Landy,KellyM;Filoteo,JVincent;Hiniker,Annie;Hansen,LawrenceA;Galasko,Douglas
• 通讯作者: Galasko,Douglas