Delirium, Alzheimer's Disease Biomarkers, and Long-Term Cognitive Decline

摘要 虽然精神错乱和痴呆症是老年人认知障碍的最常见原因，但他们的 相互关系是复杂的，也是很难理解的。许多问题仍然没有解决：预先存在的 阿尔茨海默病(AD)的病理增加了精神错乱的易感性？精神错乱会增加认知功能衰退吗？ 在那些有AD病理的人身上？阿尔茨海默病的病理和精神错乱是否相互作用，从而促进认知能力下降或痴呆？ 项目1将调查精神错乱和长期认知衰退(LTCD)的相互关系。 AD病理的分子生物标志物根据新的ATN的3个一般成分(淀粉样蛋白−β[Aβ]， 神经退行性变)AD生物标志物的描述性分类方案。我们提出以下建议 具体目的：(1)研究基线脑脊液(CSF)与AD生物标志物(CSF)之间的关系 Aβ42，总tau[t-tau]，磷酸tau tau/Aβ42比率，和神经丝光线[nfl])，在脊髓之前取样 一种新的18-36个月的麻醉和术后精神错乱和认知能力下降的发展 接受关节置换手术的400名老年人的队列(SAGES II)；(2)评估 精神错乱和脑脊液AD生物标记物的病史(近4年随访采样)LTCD(至少8 年)在SAGES I(N=128)的概率样本中：患者在最初的时间里发展为精神错乱 住院和，在最初或以后的住院期间没有出现精神错乱；以及 在将脑脊液和血浆中t-tau和NFL的新的SiMoA分析结果相关联后，在 SAGES I概率样本(N=128)，以检验术前这些标记物水平的关系 从储存的血浆中获得，包括精神错乱的发生率/严重程度和精神错乱后的LTCD。我们已经进行了 确保拟议工作的可行性的详细试点工作，包括确保足够数量的 可获得的患者及其参与意愿，并验证所有研究的可行性和耐受性 程序。我们已经证明了足够的统计能力来检查我们的目标。的成功之路 拟议的工作得到了一个高技能的跨学科研究调查团队的进一步保证，他们已经 在一起工作2-11年，通过证明实现了之前的所有目标，并通过注册 在最初的周期中，包括560多名手术患者和119名非手术对照的大型复杂队列。 该项目将探索液体生物标记物是否能识别更易患精神错乱的患者，以及 最有可能在精神错乱后出现认知衰退。通过对精神错乱与阿尔茨海默病关系的探讨 生物标志物，我们将处于有利地位，以促进我们的机械理解并开发更多 有效的干预策略以预防LTCD与神志不清和AD相关。此外，这项研究可能 为识别AD和相关痴呆(ADRD)的潜在血浆生物标志物奠定基础。如果 我们的假设得到了证实，这项研究将为预防糖尿病的重要性提供令人信服的支持 精神错乱预防AD/ADRD认知功能衰退的进展。

ABSTRACT While delirium and dementia are the most common causes of cognitive impairment in older adults, their interrelationship is complex and poorly understood. Many questions remain unresolved: Does pre-existing Alzheimer's disease (AD) pathology increase vulnerability to delirium? Does delirium increase cognitive decline in those with AD pathology? Do AD pathology and delirium interact to promote cognitive decline or dementia? Project 1 will investigate the inter-relationship of delirium and long-term cognitive decline (LTCD) with molecular biomarkers of AD pathology according to 3 general components of the new "ATN" (Amyloid−β [Aβ], Tau, Neurodegeneration) descriptive classification scheme for AD biomarkers. We propose the following specific aims: (1) to examine the relationship between baseline cerebrospinal fluid (CSF) AD biomarkers (CSF Aβ42, total tau [t-tau], phospho-tau tau/Aβ42 ratios, and neurofilament light [NFL]), sampled prior to spinal anesthesia, and development of post-operative delirium and cognitive decline over 18-36 months in a new cohort of 400 older persons undergoing joint replacement surgery (SAGES II); (2) to evaluate associations of history of delirium and CSF AD biomarkers (sampled near 4 year follow-up) with LTCD (over a minimum of 8 years) in a probability sample from SAGES I (N=128): 64 patients who developed delirium during the initial hospitalization and 64 who did not develop delirium during the initial or subsequent hospitalizations; and (3) after correlating CSF and plasma levels of novel SiMoA assays of t-tau and NFL obtained at follow-up in the SAGES I probability sample (N=128), to examine the relationship of pre-operative levels of these markers obtained from stored plasma with delirium incidence/severity and LTCD following delirium. We have conducted detailed pilot work ensuring the feasibility of the proposed work, including assuring adequate numbers of available patients and their willingness to participate, and verifying feasibility and tolerability of all study procedures. We have demonstrated adequate statistical power to examine our aims. The success of the proposed work is further assured by a highly skilled interdisciplinary team of study investigators who have been working together for 2-11 years, by the demonstrated attainment of all of the previous aims, and by enrolling a large, complex cohort of over 560 surgical patients along with 119 non-surgical controls during the initial cycle. This project will probe whether fluid biomarkers identify patients who are more vulnerable to delirium, and are most likely to have cognitive decline following delirium. By probing the relationship of delirium and AD biomarkers, we will be well positioned to advance our mechanistic understanding and to develop more effective intervention strategies to forestall LTCD associated with delirium and AD. Moreover, this study may lay the groundwork for identification of potential plasma biomarkers for AD and related dementias (ADRD). If our hypotheses are confirmed, this study will offer compelling support for the importance of prevention of delirium to forestall the progression of cognitive decline in AD/ADRD.