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

基本信息

批准号：
8444457
负责人：
CLINTON B WRIGHT
金额：
$ 37.01万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
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/8444457
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 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

项目摘要

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）：中风是美国的第三大主要原因，也是美国残疾的第一大原因，心血管疾病的总计每年接近2000亿美元。此外，亚临床血管损伤与更大的临床中风，残疾和认知能力下降有关。不幸的是，已知的可修改血管疾病的危险因素不能完全解释中风和其他血管结果的总体风险，从而鉴定了新型机制和疾病的生物标志物。血清成纤维细胞生长因子23（FGF23）和磷酸盐的水平增加已成为心血管疾病（CVD）和死亡率的新型风险因素。我们是第一个证明透析开始时FGF23水平升高与死亡率增加的独立相关的人，并且这些结果现已在一般人群中得到验证。但是，很少有研究研究这些标记与中风风险有关。此外，尚不清楚FGF23和磷代谢无序的代谢是否会通过小或大容器损害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有效风险因素。在我们基于人群的曼哈顿北部北部研究（NOMAS）中，我们发现亚临床梗塞和脑小血管疾病很普遍，并且与认知功能差有关。可以降低FGF23和磷酸盐的增加，因此证明这些因素与不良神经学结局独立相关，可能具有重要的治疗潜力。我们将检验以下假设：升高的FGF23和血清磷酸盐是事件中风，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水平是与磷相关的CVD风险的关键标记。我们将在现有的3,248名参与者的NOMAS队列中测量FGF23和磷酸盐，最初无动，现在平均遵循精心裁决的血管事件，以及在1,290名参与者中，以及在1,290名参与者中，这些参与者构成大脑MRI和CarotiD Ultrasoptiment and ne Nebymentiment and Inne and Inter and Castiral and Castiral and subsistial and Subselt and Albosit and Allbosit and细细节，并细节细节。我们提出以下三个目标：1）迄今为止，进行最大的前瞻性队列研究，以评估基线FGF23和血清磷酸盐水平作为事件中风的危险因素，而与常规的CVD危险因素和肾脏疾病无关； 2）评估FGF23和血清磷酸盐作为亚临床大小血管损伤的新风险因素，在接受大脑MRI的亚属性菌群中，以测量白质损伤的体积和亚临床梗塞，以及定量的颈动脉超声超声测量Intima Media Media Media Media介质厚度，厌恶性，颈动脉质合膜的厚度； 3）评估FGF23和血清磷酸盐作为认知下降的预测指标。我们预计，这项研究的结果与我们在更高级CKD的FGF23上正在进行的项目共同为随机对照试验奠定了基础。