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（海马和额叶皮层）和呼吸（小脑）功能的区域出现脑损伤。 OSA 这些区域的结构性缺陷与发病率、死亡率增加和生活质量下降相关的症状相关。然而，导致 OSA 这些部位脑损伤的潜在过程尚不清楚。 [OSA 中血脑屏障 (BBB) 功能的改变]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，OSA 中尚未发表有关 BBB 变化的报告，也没有与这种情况下 BBB 功能和脑损伤之间的任何关系相关的报告。使用非侵入性磁共振成像 (MRI) 程序，我们的初步研究首次显示 OSA 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 测量值）进行评估） 完整性）在岛叶、海马、额叶和小脑区域，[以及情感和认知 OSA 控制方面的变化]。然而，[这项试点研究中的样本量不允许我们控制显着的协变量，例如年龄、性别、体重指数 (BMI) 和血压]。因此，具体的[目标是：] 1) 比较未经治疗的中度至重度 OSA 与年龄、性别、[BMI 匹配] 对照之间的 BBB 状态（根据弥散加权 pCASL 计算）； 2) 比较 OSA 与年龄、性别和 [BMI 匹配] 对照之间 [岛叶、海马、额叶皮质和小脑，以及情感和认知功能] 的脑损伤（由 MD 评估）； 3) 检查 OSA 受试者 BBB 功能改变（通过弥散加权 pCASL 数据评估）与岛叶、海马、额叶和小脑结构完整性（如 MD 所示）之间的关系； [4) 作为探索性目标，在连续气道正压治疗 3 个月和 9 个月时检查 OSA 子集的 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、认知和呼吸功能的部位表现出脑损伤。 OSA 中这种脑损伤的一个潜在原因可能是 BBB 功能的变化，[此前在 OSA 中尚未报道过]。我们的初步研究表明，血脑屏障功能发生了改变，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，它对于通过修复 BBB 功能来确定 OSA 的有效治疗方法具有重要意义，如用于其他[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]，这可以显着改善发病率， 该地区的死亡率和生活质量 患者群体。