Blood-Brain Barrier Deficit and Brain Injury in Obstructive Sleep Apnea

阻塞性睡眠呼吸暂停中的血脑屏障缺陷和脑损伤

• 批准号: 9038446
• 负责人: Rajesh Kumar
• 金额: $ 51.95万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038446
• 关键词: Acute; Affective; Affective Symptoms; Age; Alzheimer' s Disease; Antibodies; Anxiety; Area; Arteries; Bacteria; Beck depression inventory; Blood - brain barrier anatomy; Blood Pressure; Blood capillaries; Body mass index; Brain; Brain Injuries; Breathing; Cerebellum; Chemicals; Chronic; Cognition; Cognitive; Cognitive deficits; Continuous Positive Airway Pressure; Contrast Media; Cortical Dysplasia; Data; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Emotional; Epilepsy; Equipment and supply inventories; Experimental Autoimmune Encephalomyelitis; Gender; Health; Hippocampus (Brain); Hypoxemia; Image Analysis; Imaging Techniques; Impairment; Infection; Injury; Insula of Reil; Lead; Link; Magnetic Resonance Imaging; Measures; Meningitis; Methods; Microscopic; Moods; Morbidity - disease rate; Multiple Sclerosis; Neurobehavioral Manifestations; Obstructive Sleep Apnea; Outcome; Patients; Pharmaceutical Preparations; Pilot Projects; Procedures; Process; Publishing; Quality of life; Radiation; Reporting; Sample Size; Sampling; Site; Sodium Chloride; Spin Labels; Stroke; Study of magnetics; Symptoms; Syndrome; Testing; Time; Tissues; Traumatic Brain Injury; Water; acute stroke; anxiety symptoms; associated symptom; base; brain tissue; capillary; cognitive change; cognitive function; cognitive testing; diffusion weighted; effective intervention; effective therapy; frontal lobe; hypoperfusion; improved; mild cognitive impairment; mood symptom; mortality; nerve injury; patient population; relating to nervous system; repaired; treatment response; water diffusion

 DESCRIPTION (provided by applicant): Obstructive sleep apnea (OSA) patients show brain damage in areas that regulate autonomic (insular sites), cognition (hippocampus and frontal cortex), and breathing (cerebellum) functions. Structural deficits in these regions in OSA are associated with symptoms that are linked to increased morbidity, mortality, and decreased quality of life. However, the underlying processes contributing to brain injury in these sites in OSA are unknown. [Altered blood-brain barrier (BBB) function in OSA] is a potential cause of brain damage, as functional alterations in the BBB are linked with neural injury in other disease conditions. However, no reports of BBB changes are published in OSA or associated with any relationship between BBB function and brain injury in this condition. Using non-invasive magnetic resonance imaging (MRI) procedures, our preliminary studies are the first to show BBB abnormalities (via diffusion-weighted pseudo-continuous arterial spin labeling [pCASL] procedures) in OSA and that these BBB changes are associated with brain damage (as assessed by diffusion tensor imaging based mean diffusivity [MD], an MRI measure of tissue integrity) in the insular, hippocampal, frontal, and cerebellar areas, [and affective and cognitive changes in OSA over controls]. However, [the sample size in this pilot study did not allow us to control for significant covariates, such as age, gender, body mass index (BMI), and blood pressure]. Therefore, the specific [aims are to:] 1) compare BBB status (calculated from diffusion-weighted pCASL) between untreated, moderate-to-severe OSA and age-, gender, [BMI-matched] controls; 2) compare brain damage (assessed by MD) in the [insula, hippocampus, frontal cortices, and cerebellum, and affective and cognitive functions] between OSA and age-, gender-, and [BMI-matched] controls; 3) examine the relationships between altered BBB function (assessed by diffusion- weighted pCASL data) and insular, hippocampal, frontal, and cerebellar structural integrity (as indicated by MD) in OSA subjects; [and 4) in an exploratory aim, examine BBB integrity in a subset of OSA at 3 and 9 months of continuous positive airway pressure treatment and compare to pre-treatment responses and controls]. In summary, OSA subjects show brain damage in sites that control autonomic, cognitive, and breathing functions. A potential reason of this brain injury in OSA may be changes in the BBB function, [which has not been reported previously in OSA]. Our initial studies have shown that BBB function is altered, and this alteration is associated with brain damage in autonomic, cognitive, and breathing control sites. Information from this study has the potential to uncover the processes contributing to brain damage in OSA. Thus, it has important implications on identification of effective treatments for OSA by repairing BBB function, as used in other [acute (e.g., stroke, traumatic brain injury, and multiple sclerosis) and chronic (e.g., Alzheimer's disease, chronic hypoperfusion, cortical dysplasia, and autoimmune encephalomyelitis) onset conditions], which could dramatically improve the morbidity, mortality, and quality of life in this patient population.

 描述（由申请人提供）： 阻塞性睡眠呼吸暂停（OSA）患者在调节自主神经（岛叶部位）、认知（海马和额叶皮质）和呼吸（小脑）功能的区域显示脑损伤。OSA患者这些区域的结构缺陷与发病率、死亡率增加和生活质量下降相关的症状有关。然而，导致OSA中这些部位脑损伤的潜在过程尚不清楚。[OSA中血脑屏障（BBB）功能改变]是脑损伤的潜在原因，因为BBB的功能改变与其他疾病中的神经损伤有关。然而，在OSA中没有关于BBB变化的报道，也没有关于这种情况下BBB功能与脑损伤之间的任何关系的报道。使用非侵入性磁共振成像（MRI）程序，我们的初步研究是第一个显示血脑屏障异常（通过弥散加权伪连续动脉自旋标记[pCASL]程序），这些BBB变化与脑损伤有关（如通过基于扩散张量成像的平均扩散率[MD]，组织完整性的MRI测量所评估的）在岛叶、海马、额叶，和小脑区域，[以及情感和认知 OSA相对于对照组的变化]。然而，[这项初步研究的样本量不允许我们控制显著的协变量，如年龄，性别，体重指数（BMI）和血压]。因此，具体的[目的是：] 1）比较BBB状态（根据弥散加权pCASL计算）未治疗的中度至重度OSA与年龄、性别、[BMI匹配]对照之间的脑损伤; 2）比较（通过MD评估）OSA与年龄、性别和[BMI匹配]对照组之间的[小脑、海马、额叶皮质和小脑，以及情感和认知功能]; 3）研究BBB功能改变与（通过弥散加权pCASL数据评估）和岛叶、海马、额叶和小脑结构完整性（如MD所示）; [和4）在探索性目的中，在持续气道正压通气治疗3个月和9个月时检查OSA亚组中的BBB完整性，并与治疗前反应和对照进行比较]。 总之，OSA受试者在控制自主神经、认知和呼吸功能的部位显示出脑损伤。OSA中这种脑损伤的一个潜在原因可能是BBB功能的变化，[这在OSA中以前没有报道过]。我们的初步研究表明，血脑屏障功能改变，这种改变与自主神经，认知和呼吸控制部位的脑损伤有关。这项研究的信息有可能揭示导致OSA脑损伤的过程。因此，它对通过修复BBB功能来鉴定OSA的有效治疗具有重要意义，如在其他[急性（例如，中风、创伤性脑损伤和多发性硬化症）和慢性（例如，阿尔茨海默病、慢性低灌注、皮质发育不良和自身免疫性脑脊髓炎）发病条件]，这可能会显着改善发病率、死亡率和生活质量。 患者人群。