Blood DNA Methylation Biomarkers of Alzheimer’s Disease and Postoperative Neurocognitive Disorder

阿尔茨海默病和术后神经认知障碍的血液 DNA 甲基化生物标志物

• 批准号: 10667556
• 负责人: Reid Spencer Alisch
• 金额: $ 18.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10667556
• 关键词: Activities of Daily Living; Affect; Age; Age Years; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Anesthesia procedures; Anesthetics; Archives; Attention; Bedside Testings; Biological Markers; Blood; Blood Banks; Blood Tests; Blood specimen; Cerebrospinal Fluid; Classification; Cognition; Cognitive; Cognitive deficits; Complication; Cytosine; DNA; DNA Methylation; Data; Dementia; Development; Diagnosis; Elderly; Environmental Risk Factor; Etiology; Fostering; Foundations; Functional disorder; Funding; Gene Expression; Genes; Genetic Code; Health; Health Care Costs; Heritability; Impaired cognition; Intervention; Laboratories; Late Onset Alzheimer Disease; Learning; Marketing; Measures; Memory; Memory impairment; Methylation; Mission; Morbidity - disease rate; National Institute on Aging; Neurobehavioral Manifestations; Neurocognitive; Neurocognitive Deficit; Neuropsychological Tests; Operative Surgical Procedures; Participant; Pathogenesis; Pathway interactions; Patient Care; Patients; Pattern; Perioperative; Persons; Phenotype; Positioning Attribute; Postoperative Period; Predisposition; Prevention; Prognosis; Protocols documentation; Psychometrics; Public Health; Publishing; Quality of life; Reporting; Research; Risk; Risk Factors; Site; Syndrome; Testing; Time; United States; United States National Institutes of Health; Work; bead chip; cohort; diagnostic tool; drug discovery; epigenomics; executive function; experience; improved; innovation; methylation pattern; mild cognitive impairment; modifiable risk; mortality; neurocognitive disorder; neuropathology; new therapeutic target; novel diagnostics; novel marker; participant enrollment; phenotypic data; post-operative cognitive dysfunction; prognostic; prognostic tool; prospective; prospective test; screening; sex; therapeutic target

Abstract The most common complication to affect older adults after surgery is the development of a perioperative neurocognitive disorder. Up to 30% of patients over 60 develop postoperative cognitive dysfunction (POCD), also termed neurocognitive dysfunction (postoperative) (NCD), within 6 weeks after a surgical procedure. POCD/NCD is characterized by impairment of memory, attention, learning, concentration and/or executive function on psychometric testing. Patients with POCD/NCD may experience persistent cognitive dysfunction over 7 years after surgery, greater loss of independence, leaving the labor market, higher health care costs, and increased morbidity and mortality. The etiology and pathogenesis of POCD/NCD are poorly understood. At present, no biomarkers of susceptibility to POCD/NCD are available for use before surgery, or for guiding diagnosis and management of POCD/NCD. Mild cognitive impairment and late onset Alzheimer's disease are risk factors for cognitive decline after surgery suggesting overlapping pathophysiology. Recently, we reported over 450 differentially methylated positions in DNA from blood samples that distinguish persons with Alzheimer's disease from cognitively healthy persons matched for age and sex. Patterns of DNA methylation regulate gene expression by coordinating the influence of environmental factors and genetic coding sequences. Accordingly, in this application we will test whether blood samples acquired before surgery provide DNA methylation biomarkers of Alzheimer's disease that distinguish patients who are at risk for POCD/NCD after surgery from those who are not (Specific Aim 1). As well, we will test blood samples acquired 6 weeks after surgery for biomarkers of Alzheimer's disease that are differentially methylated from baseline levels before surgery in patients with and without POCD/NCD (Specific Aim 2). Our technical innovation is the use of the Illumina Infinium MethylationEPIC BeadChip to classify DNA methylation status at over 850,000 candidate cytosine loci in longitudinal blood samples from patients with and without POCD/NCD. These data will provide new predictors of susceptibility to POCD/NCD for the diagnosis, prognosis, and care of patients with POCD/NCD. In turn, differentially methylated positions at previously unknown loci and pathways will support a more complete understanding of heritable and acquired mechanisms that underlie POCD/NCD with potential to identify novel therapeutic targets.

摘要 影响老年人手术后最常见的并发症是围手术期的发展， 神经认知障碍60岁以上的患者中，高达30%的人会出现术后认知功能障碍（POCD）， 也称为神经认知功能障碍（术后）（NCD），在外科手术后6周内。 POCD/NCD的特征是记忆、注意力、学习、注意力和/或执行力的损害。 心理测试的功能。POCD/NCD患者可能会经历持续的认知功能障碍， 手术后7年，更大程度的丧失独立性，离开劳动力市场，更高的医疗保健费用， 发病率和死亡率增加。POCD/NCD的病因和发病机制知之甚少。在 目前，尚无POCD/NCD易感性的生物标志物可用于手术前或指导 POCD/NCD的诊断和管理。轻度认知障碍和迟发性阿尔茨海默病是 提示重叠病理生理学的手术后认知能力下降的风险因素。最近，我们报道了 从血液样本中提取的DNA中有超过450个差异甲基化位置，可以区分阿尔茨海默氏症患者 从年龄和性别相匹配的认知健康的人中获得疾病。DNA甲基化调控基因 通过协调环境因素和遗传编码序列的影响来表达。因此，委员会认为， 在本申请中，我们将测试手术前获得的血液样本是否提供DNA甲基化 阿尔茨海默病的生物标志物，区分手术后有POCD/NCD风险的患者和 没有的人（具体目标1）。同时，我们将检测术后6周采集的血液样本， 阿尔茨海默病的生物标志物，从手术前的基线水平差异甲基化， 患有和不患有POCD/NCD的患者（具体目标2）。我们的技术创新是使用Illumina Infinium 甲基化EPIC BeadChip用于对超过850，000个候选胞嘧啶位点的DNA甲基化状态进行分类， 纵向血液样本来自患有和不患有POCD/NCD的患者。这些数据将提供新的预测指标 POCD/NCD的易感性，用于POCD/NCD患者的诊断、预后和护理。反过来， 在以前未知的基因座和途径的差异甲基化位置将支持一个更完整的 了解POCD/NCD的遗传和获得性机制，有可能发现新的 治疗目标