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

谵妄、阿尔茨海默病生物标志物和长期认知能力下降

• 批准号: 10405117
• 负责人: SHARON K. INOUYE
• 金额: $ 44.09万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10405117
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Amyloid beta-42; Amyloid beta-Protein; Biological Assay; Biological Markers; Brain; Cerebrospinal Fluid; Classification Scheme; Cognitive; Complex; Delirium; Dementia; Development; Elderly; Enrollment; Ensure; Goals; Hospitalization; Impaired cognition; Incidence; Intervention; Light; Liquid substance; Longitudinal cohort; Longterm Follow-up; Molecular; Nerve Degeneration; Older Population; Operative Surgical Procedures; Participant; Patients; Plasma; Positioning Attribute; Prevention; Probability Samples; Procedures; Recording of previous events; Replacement Arthroplasty; Research Personnel; Risk; Risk Factors; Sample Size; Sampling; Severities; Spinal Anesthesia; Work; cognitive function; cohort; effective intervention; follow-up; high risk; innovation; mild cognitive impairment; molecular marker; neurofilament; novel; postoperative delirium; prospective; single molecule; success; tau Proteins; tau-1; willingness

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.

抽象的 虽然del妄和痴呆症是老年人认知障碍的最常见原因，但他们 相互关系是复杂的，并且理解不足。许多问题仍未解决：确实存在 阿尔茨海默氏病（AD）病理学增加了对妄想的脆弱性？ ir妄会增加认知能力下降吗 在患有广告病理学的人中？ AD病理学和ir妄性是否相互作用以促进认知能力下降或痴呆？ 项目1将研究ir妄与长期认知下降（LTCD）的关系 根据新“ ATN”（淀粉样蛋白-β[Aβ]，AD病理的分子生物标志物 Tau，神经变性）AD生物标志物的描述性分类方案。我们提出以下内容 具体目的：（1）检查基线脑脊液（CSF）AD生物标志物（CSF）之间的关系 Aβ42，总tau [t-tau]，磷酸tau/aβ42比和神经丝[NFL]），在脊柱之前进行采样 麻醉，以及在新的一个新月中的术后del妄和认知能力下降的发展 共有400名接受关节置换手术的老年人（SAGES II）； （2）评估关联 LTCD的del妄和CSF AD生物标志物的历史（接近4年的随访）（至少超过8年 年份）在鼠尾草I（n = 128）的概率样本中：64例在初始del妄的患者 住院和64人在初次或随后的住院期间没有发展ir妄； （3） 在将CSF和血浆水平相关联之后 圣人I概率样本（n = 128），以检查这些标记的术前级别的关系 从del妄后，从del妄发病率/严重程度和LTCD中获得的血浆获得。我们进行了 详细的飞行员工作确保了拟议工作的可行性，包括确保足够的数量 可用的患者及其参与的意愿，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。成功的成功 提议的工作是由一支高技能的跨学科研究调查人员的跨学科工作的工作 通过所有以前目标的属性，共同努力2-11年，并通过注册 在初始周期内，超过560名手术患者的大型复杂队列以及119个非手术对照。 该项目将探测流体生物标志物是否识别出更容易受到ir妄的患者，并且 del妄后，最有可能的认知能力下降。通过探测del妄与广告的关系 生物标志物，我们将有能力提高我们的机械理解并发展更多 有效的干预策略，以阻止与del妄和AD相关的LTCD。而且，这项研究可能 为识别AD和相关痴呆症（ADRD）的潜在等离子体生物标志物（ADRD）的基础。如果 我们的假设得到了证实，这项研究将为预防的重要性提供令人信服的支持 del妄，以阻止AD/ADRD认知下降的进展。