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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos 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

项目摘要

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.

抽象的手术后影响老年人的最常见并发症是围手术期的发展神经认知障碍。多达30％以上的患者发生术后认知功能障碍（POCD），手术手术后6周内，还称为神经认知功能障碍（术后）（NCD）。 POCD/NCD的特征是记忆，注意力，学习，集中和/或执行心理测试的功能。患有POCD/NCD的患者可能会出现持续的认知功能障碍手术后7年，更大的独立性丧失，离开劳动力市场，更高的医疗保健成本以及发病率和死亡率增加。 POCD/NCD的病因学和发病机理知之甚少。在目前，没有对POCD/NCD敏感的生物标志物可在手术前使用或指导 POCD/NCD的诊断和管理。轻度认知障碍和晚期阿尔茨海默氏病是手术后认知能力下降的危险因素表明病理生理重叠。最近，我们报道超过450个在DNA中与血液样本区分开的血液样本的甲基化位置认知健康的人的疾病与年龄和性别相匹配。 DNA甲基化调节基因的模式通过协调环境因素和基因编码序列的影响来表达。因此，在此应用中，我们将测试手术前获得的血液样本是否提供DNA甲基化阿尔茨海默氏病的生物标志物，该病后区分患有POCD/NCD风险的患者那些没有的人（特定目标1）。同样，我们将测试手术后6周获得的血液样本阿尔茨海默氏病的生物标志物在手术前与基线水平差异化的生物标志物患有和不具有POCD/NCD的患者（特定AIM 2）。我们的技术创新是使用Illumina Infinium 在850,000个候选胞嘧啶基因座中对DNA甲基化状态进行分类来自和没有POCD/NCD的患者的纵向血液样本。这些数据将提供新的预测指标 POCD/NCD患者的诊断，预后和护理的POCD/NCD易感性。反过来，以前未知基因座和途径在以前未知的位置差异化位置将支持更完整理解可遗传和可获得的机制，这些机制具有识别新颖的POCD/NCD的潜力治疗靶标。