Antemortem White Matter Integrity Quantification from DTI and Relationship with Postmortem TDP-43

项目总结/摘要 痴呆综合征是全球性的健康问题，影响着全世界5500多万人， 估计每年有1000万新病例。如果没有治愈或治疗药物来阻止疾病的进展， 虽然老年痴呆症是一种严重的疾病，但它仍然是一种需要大量探索的毁灭性疾病。白色物质 微结构在痴呆症中受到显着影响，然而，基础疾病之间的关系 和微结构完整性知之甚少。事实上，了解潜在的神经生物学基础 神经变性疾病中的认知下降仍然是一个未解决的挑战。目前缺乏关于 生前脑特征与死后疾病负担之间的关系。tar dna结合 蛋白43（TDP-43）蛋白质病是许多神经退行性疾病的共同特征，已知影响 白色物质的结构完整性，需要在体内探索。虽然除了神经病理学，TDP- TDP-43也高度参与白色物质，因此，研究TDP-43和白色之间的关系 物质结构的完整性可以更好地理解神经变性过程。利用 来自拉什阿尔茨海默病中心的两项队列研究的基于社区的老年人样本， 计划测量死后TDP-43病理学和空间死前白色物质之间的关系 结构完整性，并进一步探讨其对认知的影响。白色物质完整性的传统测量 假设整个区域保持类似的特征，然而，先进的计算研究已经 发现白色物质的完整性在沿着束的定型模式中变化。通过研究 在死后TDP-43负荷和死前白色物质完整性的空间模式之间，我们可以评估 局部白色物质完整性，因为它与疾病负担有关。然后我将探索白色物质 通过相关分析和中介分析，以前的研究都没有利用死后 神经病理学负荷量化，以测量疾病对体内空间白色物质完整性的影响。通过 探讨TDP-43负荷量与生前白色物质结构的关系 完整性，我们可以提高我们的理解疾病的神经退行性过程中的作用。未来 研究可以扩大这项研究，作为一个潜在的非侵入性的，现成的， 指示死后疾病的生物标志物。

Project Summary/Abstract Dementia syndromes are global health concerns affecting more than 55 million people worldwide, with an estimated 10 million new cases each year. Without a cure or therapeutic agents to stop the progression of disease, dementia remains a devastating illness which requires significant exploration. White matter microstructure is significantly affected within dementia, however, the relationship between underlying disease and microstructural integrity is poorly understood. Indeed, understanding neurobiological basis underlying cognitive decline in neurodegenerative disease remains an unmet challenge. There is a dearth of research on the relationship between antemortem brain characteristics and postmortem disease burden. TAR DNA-binding protein 43 (TDP-43) proteinopathy is a common feature of many neurodegenerative diseases, is known to affect white matter structural integrity, and needs to be explored in-vivo. While in addition to neuronal pathology, TDP- 43 is also highly involved in white matter and therefore, studying the relationships between TDP-43 and white matter structural integrity can allow for a better understanding of the neurodegenerative process. Utilizing a community-based sample of older adults from two cohort studies from the Rush Alzheimer’s Disease Center, I plan to measure the relationship between postmortem TDP-43 pathology and spatial antemortem white matter structural integrity and additionally explore its effect on cognition. Traditional measures of white matter integrity assume the entire tract to maintain similar characteristics, however, advanced computational research has identified that white matter integrity varies in stereotyped patterns along the tract. By studying the relationship between postmortem TDP-43 burden and spatial patterns of antemortem white matter integrity, we can assess localized white matter integrity as it relates to disease burden. I will then explore the association of white matter integrity and cognition through correlation and mediation analysis. No previous research has utilized postmortem neuropathological burden quantification to measure disease effects on in-vivo spatial white matter integrity. By exploring the relationship of postmortem quantification of TDP-43 burden and antemortem white matter structural integrity, we may enhance our understanding of the role of disease within the neurodegenerative process. Future research can expand this research to be used as a potential noninvasive, readily available, antemortem biomarker indicative of postmortem disease.