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：
10447364
负责人：
Reid Spencer Alisch
金额：
$ 24.96万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10447364
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 Cognition Cognitive Cognitive deficits Complication Cytosine DNA DNA Methylation Data Dementia Development Diagnosis Elderly Enrollment 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 Measures Memory Memory impairment 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 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.

抽象的影响老年人手术后最常见的并发症是围手术期的并发症神经认知障碍。高达 30% 的 60 岁以上患者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），发生在手术后 6 周内。 POCD/NCD 的特点是记忆、注意力、学习、注意力和/或执行力受损心理测试的功能。 POCD/NCD 患者可能会经历持续的认知功能障碍手术后 7 年，独立性丧失更大，离开劳动力市场，医疗费用更高，发病率和死亡率增加。 POCD/NCD 的病因和发病机制尚不清楚。在目前，尚无 POCD/NCD 易感性生物标志物可供术前使用或指导 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手术后认知能力下降的危险因素提示重叠的病理生理学。近日，我们报道了血液样本 DNA 中超过 450 个差异甲基化位置可区分阿尔茨海默病患者来自与年龄和性别相匹配的认知健康者的疾病。 DNA甲基化调节基因的模式通过协调环境因素和遗传编码序列的影响来表达。因此，在此应用中，我们将测试手术前采集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可将手术后有 POCD/NCD 风险的患者与那些不是的人（具体目标 1）。此外，我们还将检测手术后 6 周采集的血液样本阿尔茨海默病的生物标志物与手术前的基线水平存在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 可对超过 850,000 个候选胞嘧啶位点的 DNA 甲基化状态进行分类来自患有和不患有 POCD/NCD 的患者的纵向血液样本。这些数据将提供新的预测因素 POCD/NCD 的易感性，用于 POCD/NCD 患者的诊断、预后和护理。反过来，先前未知的位点和途径的差异甲基化位置将支持更完整的研究了解 POCD/NCD 背后的遗传性和后天性机制，有可能识别新的机制治疗目标。