Biological signatures of neurodegeneration and aging associated with delirium in older adults following hip fracture surgery

髋部骨折手术后老年人与谵妄相关的神经退行性变和衰老的生物学特征

• 批准号: 10450854
• 负责人: Sara Catherine LaHue
• 金额: $ 16.15万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10450854
• 关键词: Acceleration; Acute; Address; Adipose tissue; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Alzheimer’s disease biomarker; Anesthesia procedures; Attention; Automobile Driving; Award; Biological; Biological Aging; Biological Markers; Blood; Cell Aging; Cell Cycle Arrest; Cells; Cerebrospinal Fluid; Cessation of life; Chronic Disease; Chronology; Clinical; Clinical Pathways; Cognition; Complex; Conscious; DNA Methylation; Delirium; Dependence; Development; Diagnosis; Elderly; Epidemiology; Exhibits; Foundations; Frontotemporal Lobar Degenerations; Functional disorder; Future; Geriatrics; Goals; Hip Fractures; Impaired cognition; Individual; K-Series Research Career Programs; Knowledge; Life; Light; Longevity; Measures; Nerve Degeneration; Neurology; Operative Surgical Procedures; Outcome; Participant; Pathologic; Patients; Physical Function; Plasma; Postoperative Period; Prevention; Research Personnel; Risk; Risk Assessment; Risk Factors; Site; Testing; Thinking; Tissues; United States; abeta accumulation; age difference; base; biomarker identification; bone fracture repair; cost; disorder risk; epidemiology study; high risk; innovation; mental state; mild cognitive impairment; neurofilament; novel marker; postoperative delirium; prevent; senescence; stressor; tau Proteins; tau-1

PROJECT SUMMARY/ABSTRACT Delirium is a life-threatening acute disturbance in mental status affecting more than 2.6 million hospitalized adults in the United States annually. Delirium is associated with many poor clinical outcomes, including decline in physical function, new or accelerated cognitive impairment, and death. Delirium is significantly more common in older adults, and those with mild cognitive impairment (MCI), Alzheimer's Disease, or Alzheimer's Disease Related Dementias (AD/ADRD). While delirium prevention efforts are critically important, they fail to prevent approximately 60% of cases. Insufficient knowledge of the underlying pathophysiology of delirium dramatically hinders advances in personalized delirium risk assessment, prevention, and impedes the development of delirium treatments, which do not currently exist. The complex association between delirium, cognitive impairment, and advanced age is largely established by epidemiologic studies rather than the identification of biological markers. There is growing evidence for plasma biomarkers, such as tau phosphorylated at two sites (pTau181, pTau217) and neurofilament light chain (NfL), to distinguish healthy controls from those with AD, which is an important innovation from cerebrospinal fluid testing. While advanced age is a major risk factor for both delirium and AD/ADRD, this is based on chronological age – the number of years alive. However, aging is increasingly understood to be driven by biological mechanisms that are more or less advanced in different individuals. This biological age can be distinguished from chronological age, and the difference between biological and chronologic age is “age acceleration,” which is associated with increased risk of chronic disease, including AD. One specific mechanism of biological aging is the accumulation of senescent cells in a state of cell cycle arrest that is associated with increased risk of chronic disease. This proposal is the first application of plasma pTau181, pTau217 and signatures of biological aging (age acceleration, cellular senescence) in delirious patients. The goal of this project is to identify whether elevated preoperative measures of pTau181, pTau217, NfL, and age acceleration in blood, and intraoperative measures of senescent cell burden in tissue, are associated with postoperative delirium in 100 older adults undergoing hip fracture surgery in order to advance our understanding of the pathologic drivers of delirium. We will also quantify whether these biomarkers are affected by external stressors (e.g., hip fracture surgery with anesthesia). This project will shed light on the pathological basis for the observed association between delirium, neurodegeneration and aging, and lay the foundation for my development as an early-stage clinician- investigator at the intersection of neurology and geriatrics. Findings from this study will provide the basis for a future career development award application to investigate how these markers of neurodegeneration and aging influence the trajectory of post-operative cognitive decline in older adults who develop delirium.

项目摘要/摘要 ir妄是一场危及生命的急性灾难，影响了超过260万个住院 每年在美国的成年人。 ir妄与许多临床结果不佳有关，包括下降 在身体机能，新的或加速的认知障碍和死亡方面。 ir妄明显更多 在老年人中常见，患有轻度认知障碍的人（MCI），阿尔茨海默氏病或​​阿尔茨海默氏病 与疾病相关的痴呆症（AD/ADRD）。尽管预防ir妄工作至关重要，但他们没有 预防大约60％的病例。对ir妄的潜在病理生理学的了解不足 龙在个性化的ir妄风险评估，预防中阻碍了进步，并阻碍了 ir妄疗法的发展，目前不存在。 ir妄之间的复杂关联， 认知障碍和高年龄在很大程度上是通过流行病学研究确定的 鉴定生物标记。越来越多的血浆生物标志物的证据，例如tau 在两个位置（PTAU181，PTAU217）和神经丝轻链（NFL）上磷酸化，以区分健康 来自AD的人的控制，这是脑脊液测试的重要创新。虽然先进 年龄是del妄和AD/ADRD的主要危险因素，这是基于年代年龄的 - 数量 活着。但是，越来越了解衰老是由更多或更多的生物学机制驱动的 在不同的个体中不太先进。这种生物年龄可以与年代年龄分开，而 生物学年龄和年龄之间的差异是“年龄加速”，这与增加有关 慢性病的风险，包括AD。生物衰老的一种特定机制是积累 在细胞周期停滞状态下的感觉细胞与慢性疾病风险增加有关。这 提案是血浆PTAU181，PTAU217和生物衰老的签名的第一次应用（年龄 精神病患者的加速度，细胞感应）。该项目的目的是确定是否提升 PTAU181，PTAU217，NFL和血液中年龄加速度的术前测量和术中测量 在组织中的感觉细胞伯嫩的伯嫩与术后del妄有关的100名老年人 髋部骨折手术是为了促进我们对del妄的病理驱动因素的理解。我们也会 量化这些生物标志物是否受外部压力源影响（例如，髋部骨折手术 麻醉）。该项目将阐明观察到的病理基础 del妄，神经退行性和衰老，并为我作为早期临床的发展奠定了基础 神经病学与老年医学交集的研究者。这项研究的发现将为A提供基础 未来职业发展奖的应用程序，以调查这些神经变性和衰老的标志 影响d妄的老年人的术后认知下降的轨迹。

项目成果

Opinion and Special Article: The Need for Specialized Training in Women's Neurology.

意见和特别文章：女性神经病学专业培训的需要。

• DOI: 10.1212/wnl.0000000000201451
• 发表时间: 2023
• 期刊: Neurology
• 影响因子: 9.9
• 作者: LaHue,SaraC;Paolini,Stephanie;Waters,JanetFR;O'Neal,MaryA
• 通讯作者: O'Neal,MaryA

Outcomes Following Implementation of a Hospital-Wide, Multicomponent Delirium Care Pathway.

• DOI: 10.12788/jhm.3604
• 发表时间: 2021-07
• 期刊: JOURNAL OF HOSPITAL MEDICINE
• 影响因子: 2.6
• 作者: LaHue, Sara C;Maselli, Judy;Rogers, Stephanie;Casatta, Julie;Chao, Jessica;Croci, Rhiannon;Gonzales, Ralph;Holt, Brian;Josephson, S Andrew;Lama, Sudha;Lau, Catherine;McCulloch, Charles;Newman, John C;Terrelonge, Mark;Yeager, Jan;Douglas, Vanja C
• 通讯作者: Douglas, Vanja C

KIBRA, MTNR1B, and FKBP5 genotypes are associated with decreased odds of incident delirium in elderly post-surgical patients.

• DOI: 10.1038/s41598-021-04416-z
• 发表时间: 2022-01-11
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Terrelonge M;LaHue SC;Tang C;Movsesyan I;Pullinger CR;Dubal DB;Leung J;Douglas VC
• 通讯作者: Douglas VC

Reproductive Rights in Neurology-The Supreme Court's Impact on All of Us.

• DOI: 10.1001/jamaneurol.2022.2347
• 发表时间: 2022-10-01
• 期刊: JAMA NEUROLOGY
• 影响因子: 29
• 作者: LaHue, Sara C.;Gano, Dawn;Bove, Riley
• 通讯作者: Bove, Riley

Approach to Altered Mental Status and Inpatient Delirium.

• DOI: 10.1016/j.ncl.2021.08.004
• 发表时间: 2022-03
• 期刊: NEUROLOGIC CLINICS
• 影响因子: 2.4
• 作者: LaHue, Sara C.;Douglas, Vanja C.
• 通讯作者: Douglas, Vanja C.