Brain blood flow, oxygenation, and cognition in adult onset iron deficiency anemia

成人缺铁性贫血的脑血流量、氧合和认知

基本信息

批准号：
10735765
负责人：
JOHN C WOOD
金额：
$ 68.08万
依托单位：
CHILDREN'S HOSPITAL OF LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735765
关键词：
Address Adult Age Anemia Area Benign Biological Markers Blood Blood - brain barrier anatomy Blood Vessels Blood capillaries Blood flow Brain Brain region Caring Carrying Capacities Cerebrovascular Circulation Cerebrum Child Childhood Cognition Cognitive Cognitive deficits Data Deposition Development Diabetes Mellitus Diagnosis Electron Transport Employment Exclusion Fibroid Tumor General Population Goals Hemoglobin Hemoglobin concentration result Hemorrhage Hippocampus Hispanic Hypertension Impaired cognition Impairment Individual Intelligence Intervention Intestinal Absorption Intravenous Iron Iron deficiency anemia Knowledge Liquid substance Literature Los Angeles Magnetic Resonance Imaging Medical Memory Menstruation Metabolic Metabolism Microvascular Dysfunction Minority Groups Mitochondria Monitor Moods National Health and Nutrition Examination Survey Neurocognition Neurocognitive Neurocognitive Deficit Neurons Neurosciences Oral Oxygen Oxygen Consumption Patient Outcomes Assessments Patients Performance Perfusion Permeability Persons Phenotype Physicians Physiological Population Primary Care Physician Randomized Recording of previous events Regulation Replacement Therapy Reporting Risk Factors Service delivery model Severities Sleep Sleep Apnea Syndromes Surface Synapses Toxic effect United States Verbal Learning Visual Visuospatial Water Woman Work arm blood product blood-brain barrier function blood-brain barrier permeabilization cerebrovascular cognitive function cohort competitive environment effectiveness clinical trial endometriosis follow-up global health gray matter hazard improved insight iron deficiency medical attention metabolic rate middle age morphometry neurocognitive test neurogenesis primary endpoint primary outcome recruit response restoration screening social media standard of care therapy duration tissue oxygenation treatment duration treatment response verbal white matter white matter damage

项目摘要

Moderate anemia (hemoglobin < 11 g/dl) occurs 1.5% – 2.0% of the general population. In young and middle- aged adults, iron deficiency from blood loss represents the dominant mechanism and is heavily over- represented in women and minority populations. Iron deficiency anemia’s (IDA) negative impact on pediatric brain function is well established, but its consequences on adult brains are underappreciated. Our preliminary data demonstrates significant (one standard deviation) deficits in visual and verbal memory, fluid and visuospatial reasoning, and verbal learning. We also demonstrate decreased cerebral metabolic rate of oxygen and abnormal blood brain barrier permeability to water that suggest impaired microvascular blood flow regulation in the brain. The overarching goal for this study is to deeply phenotype the cognitive and cerebrovascular derangements caused by adult-onset IDA and to determine their reversibility with iron replacement therapies. We will recruit 96 women ages 14-60 years diagnosed with moderate IDA, and 40 healthy control subjects from four donor centers in the Los Angeles area as well as women recruited from social media. Most of these subjects will be otherwise entirely healthy but we will exclude individuals with other mechanisms for their anemia as well as risk factors for small vessel disease including hypertension, sleep disordered breathing, and diabetes. All anemic and control subjects will undergo comprehensive cerebrovascular MRI, baseline bloodwork, patient reported outcomes, and neurocognitive testing. Aims 1 and 2 focus on careful characterization of the cognitive, metabolic, flow, oxygenation, and connectivity changes in response to IDA. These data will provide new insights into the neuroscientific basis for cognitive dysfunction in IDA. Aim 3 is interventional; we will restudy all the previously acquired biomarkers after normalizing hemoglobin level to prove reversibility/irreversibility of the MRI and cognitive deficits. All patients with confirmed moderate IDA will be randomized to intravenous ferric carboxymaltose versus standard-of-care therapy (referral to primary care physician for oral iron therapy). The primary endpoint will be the cerebral metabolic rate by MRI and neurocognition at 12 months. Secondary markers include regional brain blood flow, cerebrovascular reactivity, tissue oxygenation, blood-brain barrier function, and functional connectivity. Exploratory markers include brain iron deposition, white matter damage, and brain morphometry. We will exploit the rapid correction of iron sufficiency in the IV iron treated subjects to uncouple the relative impacts of iron and anemia. We posit that all subjects who successfully replace their iron stores will normalize their MRI and cognitive function. However, we anticipate that iron restoration and durability in the standard-of- care arm will not be as robust as for intravenous iron because of poor compliance, insufficient therapy duration, and/or lack of adequate medical follow-up. Taken together, this study will determine the urgency of identifying and correcting IDA in adults, the mechanisms of brain toxicity, and potential targets to improve care practices.

中度贫血（血红蛋白<11 g/dL）发生1.5％ - 2.0％的普通人群。在年轻和中间老年人，失血导致的铁缺乏症代表了主要机制，并且大量过度代表妇女和少数民族。铁缺乏症贫血（IDA）对小儿的负面影响大脑功能已经建立得很好，但其对成人大脑的后果被低估了。我们的初步数据显示出显着（一个标准偏差）在视觉和言语记忆，流体和视觉推理和言语学习。我们还证明了氧气的大脑代谢率降低和血液脑屏障对水的异常，这表明微血管血流受损大脑中的调节。这项研究的总体目标是深层表型认知和由成人发作的IDA引起的脑血管演变，并确定其用铁的可逆性替代疗法。我们将招募96名14-60岁的女性诊断中等IDA，40岁来自洛杉矶地区四个捐助者中心的健康控制对象以及从社交媒体。这些主题中的大多数将完全健康，但我们将排除其他人其贫血的机制以及小血管疾病的风险因素，包括高血压，睡眠呼吸无序和糖尿病。所有的贫血和控制学科都将经历全面脑血管MRI，基线血液调查，患者报告的结局和神经认知测试。目标1和2关注认知，代谢，流动，氧合和连通性的仔细表征响应IDA的变化。这些数据将为认知的神经科学基础提供新的见解 IDA功能障碍。目标3是介入的；我们将在此之后审查所有先前获得的生物标志物将血红蛋白水平归一化，以证明MRI和认知缺陷的可逆性/不可逆性。所有确认的中度IDA患者将被随机分为静脉输铁羧蛋白酶与护理标准疗法（转介给初级保健医师口服铁治疗）。主要终点将是在12个月时，MRI和神经认知的大脑代谢率。次要标记包括区域脑血流，脑血管反应性，组织氧合，血脑屏障功能和功能连接性。探索性标记包括脑铁沉积，白质损伤和脑形态计量学。我们将利用IV铁治疗受试者的铁足够快速校正以使相对铁和贫血的影响。我们指出，所有成功取代铁店的受试者都将正常化他们的MRI和认知功能。但是，我们预计铁在标准标准中的恢复和耐用性由于依从性差，治疗持续时间不足，护理臂对静脉铁不如静脉输液和/或缺乏足够的医学随访。综上所述，这项研究将确定识别的紧迫性并纠正成人IDA，大脑毒性的机制以及改善护理实践的潜在目标。