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.

摘要 阿尔茨海默病（AD）和虚弱是相互作用的年龄相关疾病，具有高水平的发病率， 缺乏预后生物标志物和可以延迟和/或预防疾病进展的药物。 在老年患者中，慢性炎症通常伴随着虚弱，并增加认知能力下降的风险 以及AD的进展。血管紧张素1型受体（AT 1 RaAb）的自身抗体（aAb）是激动性的， 增加受体信号传导，这可能会增加炎症负担，从而可能加速炎症反应。 在虚弱的患者中发展AD。循环AT 1 RaAb的存在可能促进疾病的发展 和进展，这些抗体的水平可能是处于危险状态的标志物。在最近的一项研究中， 对255名社区成年人的体质进行Logistic回归分析，结果表明， AT 1 RaAb水平高于8.2 µg/ml的患者，在治疗后虚弱的可能性是对照组的3.9倍（95%CI 1.38 - 11.0）。 控制年龄（P < 0.05）。福尔斯作为AT 1 RaAb水平的函数的Logistic回归得出了比值比 对于年龄、性别、BMI和BP校正模型，为1.33（95% CI 1.06至1.66）。每增加1 µg/ml， AT 1 RaAb水平，跌倒的几率增加约30%。自然对数回归分析 在较小的验证组（n=60）中，至死亡时间的β AT 1 RaAb为-0.096（95% CI -0.255至-0.036）， 校正年龄、性别和BMI后，P < 0.01。AT 1 RaAb每增加1 µg/ml，至死亡的时间 在控制了年龄、性别、BMI和BP后下降9%。120例血清标本的病例对照研究 来自入组时认知正常的受试者，后来被分类为认知正常或诊断为 AD患者发现基线AT 1 RaAb水平与认知功能下降率相关。我们假设 （a）身体虚弱与AT 1 RaAb水平升高相关，在虚弱的老年人中， AT 1 RaAb的基线水平与认知状态恶化和AD的发展相关;并且 (b)ARB治疗将具有减轻认知能力下降和延缓进展的积极作用。 AD在虚弱的受试者中。为了验证这些假设，我们将进行一项前瞻性研究，评估 基线aAb水平和纵向结局（认知下降率、虚弱和AD发生率），以及 确定AT 1 RaAb预测进展为AD的能力。我们亦会进行一项探索性研究， 研究ARB治疗对认知能力下降率的影响。这项研究使用了500个样本 来自拉什阿尔茨海默病中心的知识库和约翰霍普金斯生物统计学的核心专业知识 中心评估一种生物标志物，可用于对虚弱患者认知能力下降的风险进行分层， 进展为AD，并确定可能从血管紧张素受体阻滞剂治疗中获益的患者。