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

中度贫血（血红蛋白< 11 g/dl）发生在一般人群的1.5% - 2.0%。在年轻人和中年人- 老年人，失血引起的铁缺乏是主要机制，并且严重过度， 在妇女和少数民族人口中的代表性。缺铁性贫血（IDA）对儿童的负面影响 大脑功能已经得到了很好的建立，但它对成年人大脑的影响却没有得到充分的认识。我们的初步 数据显示视觉和语言记忆、流体和 视觉空间推理和语言学习。我们还证明了大脑的氧代谢率降低 以及血脑屏障对水的异常渗透性，这表明微血管血流受损 大脑的调节。这项研究的首要目标是深入表型的认知和 成人发病IDA引起的脑血管紊乱，并确定其与铁的可逆性 替代疗法我们将招募96名14-60岁诊断为中度IDA的女性， 来自洛杉矶地区四个供者中心的健康对照受试者以及来自 社交媒体这些受试者中的大多数在其他方面都是完全健康的，但我们将排除患有其他 他们贫血的机制以及小血管疾病的危险因素，包括高血压，睡眠 呼吸紊乱和糖尿病所有贫血和对照受试者将接受全面的 脑血管MRI、基线血液检查、患者报告的结局和神经认知测试。 目标1和2重点关注认知、代谢、流量、氧合和连接的仔细表征 对IDA的回应。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是干预性的;我们将重新研究所有先前获得的生物标志物， 使血红蛋白水平正常化，以证明MRI和认知缺陷的可逆性/不可逆性。 所有确诊为中度IDA的患者将随机接受静脉内羧基麦芽糖铁治疗， 标准治疗（转诊至初级保健医生进行口服铁剂治疗）。主要终点将是 12个月时MRI和神经认知的脑代谢率。次要标志包括区域 脑血流量、脑血管反应性、组织氧合、血脑屏障功能和功能 连通性。探索性标志物包括脑铁沉积、白色物质损伤和脑形态测定。 我们将利用静脉铁剂治疗受试者中铁充足的快速校正来解除相对的偶联。 铁和贫血的影响。我们认为，所有成功补充铁储备的受试者都会恢复正常。 核磁共振成像和认知功能然而，我们预计，铁恢复和耐久性的标准- 护理臂将不像静脉内铁剂那样稳健，因为依从性差，治疗持续时间不足， 和/或缺乏适当的医疗后续行动。综上所述，本研究将确定确定 和纠正成人缺铁性贫血，脑毒性的机制，以及改善护理实践的潜在目标。

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.