Blood-Brain Barrier Dysfunction and Brain Injury in Heart Failure

心力衰竭时的血脑屏障功能障碍和脑损伤

• 批准号: 8926474
• 负责人: Rajesh Kumar
• 金额: $ 47.91万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-12 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8926474
• 关键词: Age; Alzheimer' s Disease; Antibodies; Area; Arteries; Bacteria; Blood - brain barrier anatomy; Blood capillaries; Brain; Brain Injuries; Brain region; Breathing; Cerebellum; Chemicals; Cognition; Cognitive; Contrast Media; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Edema; Emotional; Epilepsy; Functional disorder; Gender; Health; Heart failure; Hippocampus (Brain); Hypertension; Hypoxia; Image Analysis; Imaging Techniques; Impaired cognition; Infection; Injury; Investigation; Lead; Link; Lobe; Magnetic Resonance Imaging; Measures; Meningitis; Microscopic; Morbidity - disease rate; Multiple Sclerosis; Patients; Pharmaceutical Preparations; Pilot Projects; Population; Procedures; Process; Publishing; Quality of life; Radiation; Reporting; Research; Sample Size; Sampling; Site; Sodium Chloride; Spin Labels; Stroke; Symptoms; Time; Tissues; Water; base; brain tissue; capillary; diffusion weighted; effective therapy; frontal lobe; high risk; improved; mortality; nerve injury; patient population; relating to nervous system; repaired; water diffusion

DESCRIPTION (provided by applicant): Heart failure (HF) patients show brain injury in regions which control the autonomic (insular lobes), cognition (hippocampus, frontal cortex), and breathing (cerebellum) functions. Abnormalities in these sites are associated with symptoms which are linked to increased morbidity and mortality and decreased quality of life in HF. However, the underlying cause of brain injury in these areas in HF is unclear. Alteration in blood- brain barrier (BBB) function is a potential cause of brain damage in HF, as functional changes in the BBB are associated with neural injury in other diseases. However, there are no published reports of BBB changes in HF or regarding any association between BBB function and brain damage in this condition. Using non-invasive brain magnetic resonance imaging (MRI) procedures, our preliminary studies are the first to report BBB abnormalities (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures) in HF and that these BBB changes are associated with brain injury (as examined by diffusion tensor imaging based mean diffusivity [MD], an MRI measure of tissue integrity) in the insular lobes, hippocampus, frontal cortices, and cerebellar regions in HF subjects compared to controls. However, while promising, the sample size in this preliminary study was quite small and did not allow us to control for important covariates, such as age and gender. Therefore, the specific aims of this proposal are to: 1) compare global BBB function (calculated from diffusion-weighted pCASL) between HF and age- and gender-matched control subjects; 2) compare regional brain injury (assessed by MD) in the insular lobes, hippocampus, frontal cortices, and cerebellum between HF and age- and gender-matched healthy controls; 3) examine the relationship between altered BBB function (as indicated by diffusion-weighted pCASL data) and insular, hippocampal, frontal, and cerebellar injury (as indicated by MD measures) in HF patients. In summary, HF patients show significant regional brain injury in areas that control autonomic, cognitive, and breathing functions. A potential cause of this brain injury may be alterations in the BBB function. Abnormal BBB activity has not been reported previously in HF, but our preliminary studies have shown that BBB function is compromised and that this alteration is associated with brain injury in areas which control autonomic, cognitive, and breathing functions. The proposed study will examine global BBB function, assess regional tissue injury, and evaluate the relationships between BBB function and brain injury. Information from this study has the potential to disclose the processes contributing to brain injury in HF. Thus, it has important implications on identification of effectve treatments for HF by repairing BBB function, as used in other conditions (such as stroke), which could dramatically improve the mortality, morbidity, and quality of life in this high risk patient population.

描述（由申请人提供）：心力衰竭（HF）患者在控制自主神经（岛叶）、认知（海马体、额叶皮质）和呼吸（小脑）功能的区域表现出脑损伤。这些部位的异常与心力衰竭发病率和死亡率增加以及生活质量下降相关的症状相关。然而，心力衰竭这些区域脑损伤的根本原因尚不清楚。血脑屏障 (BBB) 功能的改变是心力衰竭脑损伤的潜在原因，因为 BBB 的功能改变与其他疾病中的神经损伤有关。然而，目前还没有关于心衰时血脑屏障变化的报道，也没有关于这种情况下血脑屏障功能与脑损伤之间任何关联的报道。使用非侵入性脑磁共振成像 (MRI) 程序，我们的初步研究首次报告了 HF 中的 BBB 异常（通过扩散加权伪连续动脉自旋标记 [pCASL] 程序），并且这些 BBB 变化与脑损伤相关（通过基于扩散张量成像的平均扩散率 [MD]（组织的 MRI 测量）进行检查） 与对照组相比，心力衰竭受试者的岛叶、海马、额叶皮质和小脑区域的完整性）。然而，尽管前景光明，但这项初步研究的样本量相当小，不允许我们控制重要的协变量，例如年龄和性别。因此，本提案的具体目标是： 1）比较 HF 与年龄和性别匹配的对照受试者之间的整体 BBB 功能（根据扩散加权 pCASL 计算）； 2) 比较 HF 与年龄和性别匹配的健康对照之间岛叶、海马、额叶皮质和小脑的区域性脑损伤（由 MD 评估）； 3) 检查心力衰竭患者 BBB 功能改变（如弥散加权 pCASL 数据所示）与岛叶、海马、额叶和小脑损伤（如 MD 测量所示）之间的关系。 总之，心力衰竭患者在控制自主神经、认知和呼吸功能的区域表现出明显的区域性脑损伤。这种脑损伤的一个潜在原因可能是血脑屏障功能的改变。以前在心力衰竭中没有报告过 BBB 活动异常，但我们的初步研究表明 BBB 功能受到损害，并且这种改变与控制自主神经、认知和呼吸功能的区域的脑损伤有关。拟议的研究将检查整体 BBB 功能，评估局部组织损伤，并评估 BBB 功能与脑损伤之间的关系。这项研究的信息有可能揭示导致心力衰竭脑损伤的过程。因此，它对于通过修复血脑屏障功能来确定心力衰竭的有效治疗方法具有重要意义，就像在其他疾病（如中风）中所使用的那样，这可以显着提高这一高危患者群体的死亡率、发病率和生活质量。