FGF-23 and the Risk of Stroke and Cognitive Decline

FGF-23 与中风和认知能力下降的风险

• 批准号: 8623146
• 负责人: CLINTON B WRIGHT
• 金额: $ 44.59万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-16 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623146
• 关键词: Affect; American Heart Association; Biological Markers; Blood Vessels; Blood specimen; Brain; Cardiovascular Diseases; Carotid Artery Plaques; Cause of Death; Cerebral Infarction; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Management; Cognition; Cognitive; Cohort Studies; Communities; Data; Dialysis procedure; Diet; Disease; Ethnic Origin; Event; Fibroblast Growth Factor; Future; General Population; Goals; Hispanics; Impaired cognition; Infarction; Injury; Kidney Diseases; Lesion; Life; Link; Magnetic Resonance Imaging; Measurement; Measures; Metabolism; Microvascular Dysfunction; Minerals; Modification; Myocardial Infarction; Neurological outcome; Neurologist; Neuropsychological Tests; Not Hispanic or Latino; Outcome; Participant; Patients; Phosphorus; Phosphorus Metabolism Disorders; Poverty; Prevention; Publishing; Race; Randomized Clinical Trials; Randomized Controlled Trials; Research; Research Personnel; Risk; Risk Factors; Role; Serum; Speed; Staging; Stroke; Telephone Interviews; Testing; Therapeutic; Thick; Time; Ultrasonography; United States; Vascular Diseases; Walkers; Wolves; adjudicate; base; cardiovascular disorder risk; cerebrovascular; clinical risk; cognitive function; cohort; cost effective; disability; ethnic difference; executive function; experience; fibroblast growth factor 23; follow-up; inorganic phosphate; intima media; low socioeconomic status; modifiable risk; mortality; neuropsychological; novel; population based; prospective; white matter; white matter damage

DESCRIPTION (provided by applicant): Stroke is the third leading cause of death and the number one cause of disability in the United States, and cardiovascular disease totals close to $200 billion annually. Further, subclinical vascular damage has been associated with a greater risk of clinical stroke, disability, and cognitive decline. Unfortunately, known modifiable risk factors for vascular disease do not completely explain overall risk for stroke and these other vascular outcomes, mandating the identification of novel mechanisms and biomarkers of disease. Increased levels of serum fibroblast growth factor 23 (FGF23) and phosphate have emerged as novel risk factors for cardiovascular disease (CVD) and mortality. We were the first to demonstrate that increased FGF23 levels at the initiation of dialysis are independently associated with an increased risk of mortality, and these results have now been validated in the general population. However, few studies have examined these markers in relation to stroke risk. Further, it is not understood if FGF23 and disordered phosphorus metabolism increase the risk of vascular events through small or large vessel damage and whether they are associated with subclinical cerebrovascular damage - a potent risk factor for clinical stroke and cognitive decline. In our population-based multi-ethnic Northern Manhattan Study (NOMAS) we have found subclinical infarction and cerebral small vessel disease to be prevalent and associated with poor cognitive function. Increased FGF23 and phosphate can be lowered, so demonstrating that these factors are independently associated with adverse neurological outcomes could have important therapeutic potential. We will test the hypothesis that elevated FGF23 and serum phosphate are independent risk factors for incident stroke, subclinical vascular damage, and cognitive decline. We further hypothesize that higher FGF23 levels are the key marker of phosphorus-related CVD risk. We will measure FGF23 and phosphate in the existing NOMAS cohort of 3,248 participants, initially stroke-free and now followed for an average of 10 years for carefully adjudicated vascular events, as well as in 1,290 participants of the subsample that underwent quantitative brain MRI and carotid ultrasound to measure subclinical vascular damage, and global as well as detailed neuropsychological assessments. We propose the following three aims: 1) perform the largest prospective cohort study to date to evaluate baseline FGF23 and serum phosphate levels as risk factors for incident stroke, independent of conventional CVD risk factors and kidney disease; 2) evaluate FGF23 and serum phosphate as novel risk factors for subclinical small and large vessel injury, in a subcohort who underwent brain MRI to measure white matter damage volumes and subclinical infarction, as well as quantitative carotid ultrasound measures of intima media thickness, distensibility, and carotid plaque thickness; and 3) to evaluate FGF23 and serum phosphate as predictors of cognitive decline. We anticipate that the results of this study, in concert with our ongoing projects on FGF23 in more advanced CKD, will rapidly set the stage for randomized controlled trials.

描述(申请人提供)：中风是美国第三大致死原因和第一大致残原因，心血管疾病每年的总金额接近2000亿美元。此外，亚临床血管损伤与临床中风、残疾和认知能力下降的风险更大相关。不幸的是，已知的血管疾病的可改变的危险因素并不能完全解释卒中的总体风险和这些其他血管结果，这要求确定新的疾病机制和生物标记物。血清成纤维细胞生长因子23(FGF23)和磷酸盐水平的升高已成为心血管疾病(CVD)和死亡率的新的危险因素。我们是第一个证明透析开始时FGF23水平升高与死亡风险增加独立相关的，这些结果现已在普通人群中得到验证。然而，很少有研究研究这些标志物与中风风险的关系。此外，目前尚不清楚FGF23和磷代谢紊乱是否会通过小血管或大血管损伤增加血管事件的风险，以及它们是否与亚临床脑血管损伤有关--这是临床中风和认知能力下降的一个潜在风险因素。在我们以人群为基础的北曼哈顿多民族研究(NOMAS)中，我们发现亚临床脑梗塞和脑小血管疾病普遍存在，并与认知功能低下有关。升高的FGF23和磷酸盐可以降低，因此证明这些因素与不良神经结局独立相关可能具有重要的治疗潜力。我们将检验这一假设，即FGF23升高和血磷是偶发中风、亚临床血管损伤和认知能力下降的独立危险因素。我们进一步假设，较高的FGF23水平是磷相关心血管疾病风险的关键标志。我们将在现有的3,248名NOMAS参与者中测量FGF23和磷酸盐，这些参与者最初没有中风，现在平均跟踪10年，仔细判断血管事件，以及接受定量脑MRI和颈动脉超声以测量亚临床血管损伤的1,290名参与者，以及整体和详细的神经心理评估。我们提出了以下三个目标：1)进行迄今为止最大规模的前瞻性队列研究，以评估基线FGF23和血磷水平作为发生中风的危险因素，独立于常规的心血管危险因素和肾脏疾病；2)评估FGF23和血磷作为亚临床小血管和大血管损伤的新风险因素，在接受脑MRI检查的子队列中，测量脑白质损伤体积和亚临床脑梗塞，以及定量颈动脉超声测量内膜中层厚度、扩张性和颈动脉斑块厚度；以及3)评估FGF23和血磷作为认知能力下降的预测因子。我们预计，这项研究的结果，与我们正在进行的更先进的慢性肾脏病的FGF23项目相一致，将迅速为随机对照试验奠定基础。