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

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.

项目概要 镰状细胞性贫血（SCA）是一种慢性溶血性贫血，会显着增加中枢神经系统疾病的风险 系统并发症包括无症状性脑梗塞（SCI）、显性中风和颅内狭窄。中风风险 与儿童的筛查程序相比，成人 SCA 的筛查程序相当不发达 SCA 和其他有中风风险的成年人群。然而，SCI 和明显的中风风险仍然存在 超过 50% 的 30 岁以上患有 SCA 的成年人会发生 SCI，这是一种常见的 造成长期残疾的原因。缺乏识别有新发或复发性脑病风险的成年人的方法 梗死是成人 SCA 护理的一个主要限制，因为 SCA 的治疗方法不断改进，寿命也缩短了。 增加。解决成人中风风险和预防的关键障碍在于我们无法识别 作为常规医疗护理一部分的潜在脑组织水平损伤以及我们需要开发新的筛查 对患有 SCA 的成人进行分类以进行适当的中风预防治疗的工具。这项工作的总体目标是 利用最近发现的脑血流动力学代偿机制不足的生物标志物来测试 一项纵向研究中关于患有 SCA 的成人中风风险和治疗反应的基本假设。 在过去的七年里，我们建立了一个多学科团队来系统地评估成人 SCA，使用更多新颖的病理生理指标依次评估已知的中风危险因素，包括： (i) 氧提取分数（OEF；消耗的氧气与输送的氧气的比率），(ii) 脑血流量（CBF； 血液输送到组织的速率），（iii）流速，以及（iv）脑血管反应性（CVR；小动脉的能力） 应对血管活性挑战）。这项工作得出以下结论：(i) 患有 SCA 的成人中 OEF 升高，并且 临床损伤（既往中风、颅内狭窄或每月输血），(ii) 成人中 OEF 升高 SCA 和新发或进展性梗塞的证据（回顾性数据），以及 (iii) CBF 对治疗的反应 成人输血似乎不如患有 SCA 的儿童有效。我们开发了方法 使用不需要外源性的 MRI 方法来测量这些假设的中风风险生物标志物 造影剂，使其成为 SCI 监测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）一项纵向、前瞻性研究，以评估代谢和 血流动力学卒中危险因素可用于确定哪些患有 SCA 的成年人会出现新的梗塞； （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；和（目标 3） 比较从两种最流行的非侵入性 MRI 方法获得的 OEF 值，从而了解它们的 在未来的多中心临床试验中集体或个人使用。长期目标是识别潜在的大脑 组织水平损伤，可以提供基于证据的生物标志物来评估中风风险、治疗反应、 并指导成人 SCA 的治疗决策，目标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危人群。