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，具有很高的发病率和 缺乏预后生物标志物和可延缓和/或预防疾病进展的药物的死亡率。 在老年患者中，慢性炎症通常伴随着虚弱，并增加认知能力下降的风险。 以及AD的进展。自身抗体(AABS)血管紧张素1型受体(AT1RaAb)是激动型和 增加受体信号，这可能会增加炎症负担，从而潜在地加速 衰弱患者阿尔茨海默病的发生。循环中AT1RaAbbs的存在可能促进疾病的发展 进展和这些AABS的水平可能是高危状态的标志。在我们最近的一项研究中 完成了255个社区居住成年人的Logistic回归分析，发现个体的脆弱性 当AT1RaAb水平高于8.2微克/毫升时，发生以下疾病的可能性是后者的3.9倍(95%可信区间1.38-11.0 控制年龄(p&lt；0.05)。AT1RaAb水平与跌倒的Logistic回归得出优势比 调整了年龄、性别、BMI和BP的模型为1.33(95%可信区间1.06~1.66)。每改变1微克/毫升 AT1RaAb水平，下降的几率增加约30%。自然对数的回归分析 在较小的验证组(n=60)中，死亡时间的βAT1RaAb为-0.096(95%CI-0.255到-0.036) 经年龄、性别和体重指数调整后的P&lt；0.01。AT1RaAbs每增加1微克/毫升，死亡时间 在控制了年龄、性别、BMI和BP后，下降了9%。120份血清标本的病例对照研究 来自注册时认知正常的受试者，后来被归类为认知正常或确诊的受试者 AD患者AT1RaAb基线水平与认知功能减退率相关。我们假设 (A)身体虚弱与AT1RaAb水平升高有关，在虚弱的老年人中，AT1RaAb水平最高 AT1RaAbbs的基线水平与认知状况恶化和AD的发展有关；以及 (B)ARB治疗将具有减轻认知衰退和延缓病情进展的积极作用 在虚弱的对象中做广告。为了检验这些假设，我们将进行一项前瞻性研究，评估 基线AAB水平与纵向结果(认知减退率、虚弱和AD发生率)，以及 确定AT1RaAb预测进展为AD的能力。我们还将进行探索性研究，以 研究ARB治疗对认知功能减退率的影响。拟议中的研究使用了500个样本 来自拉什阿尔茨海默病中心知识库和约翰·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记物，可用于对虚弱患者认知能力下降和 进展到阿尔茨海默病，并确定谁可能受益于血管紧张素受体阻滞剂治疗。