Biomarkers of ischemic brain injury in adults with sickle cell disease

镰状细胞病成人缺血性脑损伤的生物标志物

• 批准号: 10365379
• 负责人: Manus J Donahue
• 金额: $ 71.22万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365379
• 关键词: Address; Adult; Age; Biological Markers; Blood; Blood Transfusion; Brain; Brain imaging; Caring; Cerebral Infarction; Cerebrovascular Circulation; Cerebrum; Child; Chronic; Clinical; Clinical Trials; Contrast Media; Core-Binding Factor; Cross-Sectional Studies; Data; Development; Enrollment; Equipment; Evaluation; Future; Genetic Diseases; Goals; Health; Hematopoietic Stem Cell Transplantation; Hemolytic Anemia; High Prevalence; Imaging Device; Imaging Techniques; Impaired cognition; Impairment; Individual; Infarction; Institutes; Intracranial Arterial Stenosis; Ischemic Brain Injury; Longevity; Longitudinal Studies; Longitudinal prospective study; Magnetic Resonance Imaging; Measurement; Measures; Medical; Metabolic; Methods; Modeling; Multi-Institutional Clinical Trial; Neuraxis; Oxygen; Oxygen Consumption; Participant; Patient Triage; Patients; Population; Prevention strategy; Prevention therapy; Procedures; Recurrence; Relaxation; Reproducibility; Rest; Retrospective cohort; Risk; Risk Assessment; Risk Factors; Role; Scanning; Screening procedure; Sickle Cell Anemia; Stem cell transplant; Stimulus; Stroke; Stroke prevention; Structure; Techniques; Testing; Time; Tissues; Transfusion; Triage; Universities; Vascular Diseases; Work; aggressive therapy; arteriole; base; brain health; brain tissue; cerebral hemodynamics; cerebrovascular; cohort; curative treatments; disability; evidence base; hemodynamics; high risk; high risk population; hydroxyurea; imaging science; improved; in vivo; metabolic profile; multidisciplinary; neuroimaging; novel; patient stratification; personalized care; prospective; public health relevance; response; screening; sex; stroke risk; stroke therapy; tool; treatment response; Address; Adult; Age; Biological Markers; Blood; Blood Transfusion; Brain; Brain imaging; Caring; Cerebral Infarction; Cerebrovascular Circulation; Cerebrum; Child; Chronic; Clinical; Clinical Trials; Contrast Media; Core-Binding Factor; Cross-Sectional Studies; Data; Development; Enrollment; Equipment; Evaluation; Future; Genetic Diseases; Goals; Health; Hematopoietic Stem Cell Transplantation; Hemolytic Anemia; High Prevalence; Imaging Device; Imaging Techniques; Impaired cognition; Impairment; Individual; Infarction; Institutes; Intracranial Arterial Stenosis; Ischemic Brain Injury; Longevity; Longitudinal Studies; Longitudinal prospective study; Magnetic Resonance Imaging; Measurement; Measures; Medical; Metabolic; Methods; Modeling; Multi-Institutional Clinical Trial; Neuraxis; Oxygen; Oxygen Consumption; Participant; Patient Triage; Patients; Population; Prevention strategy; Prevention therapy; Procedures; Recurrence; Relaxation; Reproducibility; Rest; Retrospective cohort; Risk; Risk Assessment; Risk Factors; Role; Scanning; Screening procedure; Sickle Cell Anemia; Stem cell transplant; Stimulus; Stroke; Stroke prevention; Structure; Techniques; Testing; Time; Tissues; Transfusion; Triage; Universities; Vascular Diseases; Work; aggressive therapy; arteriole; base; brain health; brain tissue; cerebral hemodynamics; cerebrovascular; cohort; curative treatments; disability; evidence base; hemodynamics; high risk; high risk population; hydroxyurea; imaging science; improved; in vivo; metabolic profile; multidisciplinary; neuroimaging; novel; patient stratification; personalized care; prospective; public health relevance; response; screening; sex; stroke risk; stroke therapy; tool; treatment response

PROJECT SUMMARY Sickle cell anemia (SCA) is a chronic hemolytic anemia that dramatically increases the risk of central nervous system complications including silent cerebral infarcts (SCI), overt strokes, and intracranial stenosis. Stroke risk screening procedures for adults with SCA are considerably underdeveloped compared to procedures for children with SCA and other populations of adults at risk for stroke. However, SCI and overt stroke risk persists across the lifespan, and SCIs occur in more than 50% of adults with SCA by age 30 years, representing a frequent cause of long-term disability. The absence of an approach to identify adults at risk for new or recurrent cerebral infarcts is a major limitation in adult SCA care, as treatments for SCA continue to improve and lifespan is increasing. The critical barrier to addressing stroke risk and prevention in adults rests with our inability to identify underlying brain tissue-level impairment as a part of routine medical care and our need to develop new screening tools to triage adults with SCA for appropriate stroke prevention therapies. The overall goal of this work is to utilize recently identified biomarkers of inadequate cerebral hemodynamic compensatory mechanisms to test fundamental hypotheses about stroke risk and treatment response in adults with SCA in a longitudinal study. Over the past seven years, we have established a multidisciplinary team to systematically evaluate adults with SCA, assessing known stroke risk factors in sequence with more novel pathophysiological indicators including: (i) oxygen extraction fraction (OEF; ratio of oxygen consumed to oxygen delivered), (ii) cerebral blood flow (CBF; rate of blood delivery to tissue), (iii) flow velocity, and (iv) cerebrovascular reactivity (CVR; ability of arterioles to respond to a vasoactive challenge). This work led to the findings that (i) OEF is elevated in adults with SCA and clinical impairment (prior stroke, intracranial stenosis, or monthly transfusions), (ii) OEF is elevated in adults with SCA and evidence of new or progressive infarcts (retrospective data), and (iii) CBF response to treatment with blood transfusion appears to be less robust in adults than children with SCA. We have developed methods to measure these hypothesized stroke risk biomarkers using MRI approaches that do not require exogenous contrast agents, making them a possible tool for SCI surveillance and for evaluating treatment response. Here, we propose to extend this work to (Aim 1) a longitudinal, prospective study, to evaluate how metabolic and hemodynamic stroke risk factors can be used to identify which adults with SCA will have new infarcts; (Aim 2) to quantify the impact of stem cell transplant, an emerging curative treatment, on brain tissue health; and (Aim 3) to compare OEF values obtained from the two most popular non-invasive MRI methods thereby informing their collective or individual use in future multi-site clinical trials. The long-term goal is to identify underlying brain tissue-level impairment that may provide evidence-based biomarkers to assess stroke risk, treatment response, and guide therapy decisions in adults with SCA, with the goal of reducing stroke and cognitive dysfunction in this high-risk population for which validated stroke screening tools do not exist.

项目摘要 镰状细胞贫血（SCA）是一种慢性溶血性贫血，可显着增加中枢神经的风险 系统并发症，包括无声脑梗塞（SCI），明显的中风和颅内狭窄。中风风险 与儿童的手术相比 SCA和其他有中风风险的成年人人群。但是，SCI和公开中风风险持续存在 寿命和SCI发生在超过50％的SCA成年人到30岁的成年人中，代表经常 长期残疾的原因。缺乏识别有新脑或经常性脑风险的成年人的方法 梗塞是成人SCA护理的主要限制，因为SCA的治疗继续改善，寿命为 增加。解决成年人中风风险和预防的关键障碍是我们无法确定的 基本的脑组织水平损害是常规医疗护理的一部分，我们需要开发新的筛查 具有SCA的分类成人的工具，可进行适当的中风预防疗法。这项工作的总体目标是 利用最近确定的脑血液动力补偿机制不足的生物标志物测试 在一项纵向研究中，关于SCA成年人的中风风险和治疗反应的基本假设。 在过去的七年中，我们建立了一个多学科团队，以系统地评估成人 SCA，通过更新颖的病理生理指标评估已知的中风风险因素，包括： （i）提取氧气馏分（OEF；所消耗的氧与输送的氧之比），（ii）大脑血流（CBF； 血液输送到组织的速率），（iii）流速度和（iv）脑血管反应性（CVR；小动脉的能力 应对血管活性挑战）。这项工作导致发现（i）OEF在患有SCA和 临床障碍（先前中风，颅内狭窄或每月输血），（ii）OEF在成年人中升高 SCA和新的或进行性梗阻的证据（回顾性数据），以及（iii）CBF对治疗的反应 与患有SCA的儿童相比，成年人的输血似乎不那么健壮。我们已经开发了方法 使用不需要外源的MRI方法测量这些假设的中风风险生物标志物 对比剂，使其成为SCI监视和评估治疗反应的可能工具。这里， 我们建议将这项工作扩展到（目标1）纵向，前瞻性研究，以评估代谢和 血液动力学危险因素可用于确定哪些患有SCA的成年人将具有新的梗塞。 （目标2） 量化干细胞移植（一种新兴的治疗方法）对脑组织健康的影响； （目标3） 比较从两种最受欢迎​​的非侵入性MRI方法中获得的OEF值，从而告知他们 在将来的多站点临床试验中的集体或个人用途。长期目标是识别潜在的大脑 组织水平的障碍可能会提供基于证据的生物标志物来评估中风风险，治疗反应， SCA成人的指导疗法决策，目的是减少中风和认知功能障碍 不存在经过验证的中风筛查工具的高风险人群。