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（由申请人提供）：中风是美国第三大死亡原因和第一大残疾原因，每年心血管疾病的总价值接近 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更大风险相关。不幸的是，已知的可改变的血管疾病危险因素并不能完全解释中风和这些其他血管结果的总体风险，需要识别疾病的新机制和生物标志物。血清成纤维细胞生长因子 23 (FGF23) 和磷酸盐水平升高已成为心血管疾病 (CVD) 和死亡的新危险因素。我们首次证明透析开始时 FGF23 水平升高与死亡风险增加独立相关，并且这些结果现已在普通人群中得到验证。然而，很少有研究检查这些标志物与中风风险的关系。此外，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（临床中风和认知能力下降的潜在危险因素）相关。在我们基于人口的多种族北曼哈顿研究 (NOMAS) 中，我们发现亚临床梗塞和脑小血管疾病普遍存在，并且与认知功能不良有关。增加的 FGF23 和磷酸盐可以降低，因此证明这些因素与不良神经系统结果独立相关可能具有重要的治疗潜力。我们将检验以下假设：FGF23 和血清磷酸盐升高是中风、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 CVD 风险的关键标志。我们将测量现有 NOMAS 队列中 3,248 名参与者的 FGF23 和磷酸盐，这些参与者最初没有中风，现在平均随访 10 年以仔细判断血管事件，以及子样本中 1,290 名参与者的 FGF23 和磷酸盐，这些参与者接受了定量脑 MRI 和颈动脉超声以测量亚临床血管损伤，以及全面和详细的神经心理学评估。我们提出以下三个目标：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 和血清磷酸盐水平作为中风风险因素，独立于传统的 CVD 风险因素和肾脏疾病； 2) 在接受脑 MRI 测量白质损伤体积和亚临床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的亚队列中，评估 FGF23 和血清磷酸盐作为亚临床小血管和大血管损伤的新危险因素； 3) 评估 FGF23 和血清磷酸盐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 FGF23 在更晚期 CKD 中的项目相结合，将迅速为随机对照试验奠定基础。