Autoantibodies, Frailty and Cognitive Decline

自身抗体、虚弱和认知能力下降

• 批准号: 9371387
• 负责人: NEAL S FEDARKO
• 金额: $ 24.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9371387
• 关键词: Address; Adult; Age; Aging; Algorithms; Alzheimer' s Disease; Alzheimer' s disease risk; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor; Antinuclear Antibodies; Attenuated; Autoantibodies; Binding; Biological; Biological Markers; Biometry; Case-Control Studies; Cessation of life; Chronic; Cognition; Cognitive; Communities; Data; Data Set; Dementia; Development; Diagnosis; Disease; Disease Progression; Enrollment; Evaluation; Frail Elderly; Funding; Gender; Goals; Hand Strength; Immunoglobulin G; Impaired cognition; Incidence; Individual; Inflammation; Inflammatory; Intervention; Linear Models; Link; Logistic Regressions; Longitudinal Studies; Measures; Mediating; Mediator of activation protein; Memory; Modeling; Morbidity - disease rate; Odds Ratio; Outcome; Participant; Pathogenesis; Patients; Persons; Pharmaceutical Preparations; Population; Prospective Studies; Randomized Controlled Trials; Receptor Signaling; Receptor, Angiotensin, Type 1; Regression Analysis; Religion and Spirituality; Research; Resources; Rheumatoid Factor; Risk; Risk stratification; Sampling; Serum; Specificity; Structure; Testing; Time; Translating; United States National Institutes of Health; Validation; adverse outcome; age related; cognitive function; cognitive testing; falls; frailty; logarithm; mortality; older patient; outcome forecast; prevent; repository; research clinical testing; sex

Abstract Alzheimer's disease (AD) and frailty are interacting age-related disorders with a high level of morbidity and mortality that both lack biomarkers for prognosis and drugs that can delay and/or prevent disease progression. In older patients, chronic inflammation commonly accompanies frailty and increases risk of cognitive decline and the progression of AD. Autoantibodies (aAbs) angiotensin type 1 receptor (AT1RaAb) are agonistic and increase receptor signaling, which may increase inflammatory burden and thus potentially accelerate the development of AD in frail patients. The presence of circulating AT1RaAbs may facilitate disease development and progression and the levels of these aAbs may be markers of at-risk status. In a study we recently completed of 255 community dwelling adults, Logistic regression analysis of frailty revealed that individuals with AT1RaAb levels above 8.2 µg/ml were 3.9 (95% CI 1.38 - 11.0) times more likely to be frail after controlling for age (p < 0.05). Logistic regression of falls as a function of AT1RaAb levels yielded an odds ratio of 1.33 (95% CI 1.06 to 1.66) for an age, gender, BMI and BP adjusted model. For every 1 µg/ml change in AT1RaAb levels, the odds of falling increased approximately 30%. Regression analysis of the natural logarithm of time to death in a smaller validation group (n=60) yielded a βAT1RaAb of -0.096 (95% CI -0.255 to -0.036) with P < 0.01 after adjusting for age, gender and BMI. For every 1 µg/ml increase in AT1RaAbs, the time to death decreased by 9% after controlling for age, gender, BMI and BP. A case control study of 120 serum samples from subjects with normal cognition on enrollment and later classified as either cognitively normal or diagnosed with AD found baseline AT1RaAb levels were associated with the rate of cognitive decline. We hypothesize that (a) physical frailty is associated with increased levels of AT1RaAb and that, in frail elderly, the highest baseline levels of AT1RaAbs are associated with worsening cognitive status and the development of AD; and (b) ARB treatment would have a positive effect of lessening cognitive decline and delaying the progression to AD in frail subjects. To test these hypotheses we will perform a prospective study assessing the association of baseline aAb levels with longitudinal outcomes (rate of cognitive decline, incidence of frailty and of AD), and determine the capacity of AT1RaAb to predict progression to AD. We will also carry out an exploratory study to investigate the impact of ARB treatment on rate of cognitive decline. The proposed research uses 500 samples from the Rush Alzheimer's Disease Center Repository and core expertise of the Johns Hopkins Biostatistics Center to evaluate a biomarker that could be used to stratify the risk of frail patients for cognitive decline and progression to AD and to identify patients who might benefit from angiotensin receptor blocker treatment.

抽象的 阿尔茨海默氏病（AD）和脆弱的是与年龄相关的疾病，发病率很高 死亡率都缺乏预后的生物标志物和可能延迟和/或预防疾病进展的药物的死亡率。 在老年患者中，慢性炎症通常可容纳脆弱并增加认知能力下降的风险 和AD的进展。自身抗体（AABS）血管紧张素1型受体（AT1RAAB）是激动性的，并且 增加接收器信号传导，这可能会增加炎症性燃烧，从而可能加速 脆弱患者的广告发展。循环AT1RAAB的存在可能有助于疾病发展 和进展以及这些AAB的水平可能是处于危险状态的标志。在一项研究中，我们最近 完成的255名社区居住成年人，对脆弱的逻辑回归分析表明，个人 AT1RAAB水平高于8.2 µg/ml的水平为3.9（95％CI 1.38-11.0），其可能性脆弱的可能性高于 控制年龄（p <0.05）。跌落的逻辑回归作为AT1RAAB水平的函数产生的优势比 年龄，性别，BMI和BP调整模型的1.33（95％CI 1.06至1.66）中的1.33（95％至1.66）。每1 µg/ml更改 AT1RAAB水平，下降的几率大约增加了30％。自然对数的回归分析 在较小的验证组中死亡的时间（n = 60）产生-0.096的βAT1RAAB（95％CI -0.255至-0.036），使用 调整年龄，性别和BMI后的p <0.01。每增加1 µg/ml的AT1RAAB，死亡的时间 控制年龄，性别，BMI和BP后，下降了9％。 120个血清样品的案例控制研究 来自患有正常认知的受试者，后来被归类为认知正常或被诊断 发现AD发现基线AT1RAAB水平与认知能力下降率有关。我们假设 （a）物理脆弱与At1raab的水平增加有关，而在脆弱的情况下，最高的 At1raabs的基线水平与后悔的认知状况和AD的发展有关。和 （b）ARB治疗将具有降低认知能力下降并延迟发展为 脆弱的主题中的广告。为了检验这些假设，我们将进行一项前瞻性研究，以评估 具有纵向结果的基线AAB水平（认知能力下降的速度，脆弱和AD的发生率）和 确定AT1RAAB预测AD进展的能力。我们还将进行探索性研究 研究ARB治疗对认知率下降速度的影响。拟议的研究使用500个样本 来自阿尔茨海默氏病中心疾病中心的存储库和约翰·霍普金斯生物统计学的核心专业知识 评估可用于分层脆弱患者认知能力下降的风险和的中心 进展为AD并确定可能受益于血管紧张素受体阻滞剂治疗的患者。