Damage to the hippocampus in obstructive sleep apnea: a link no longer missing.
Damage to the hippocampus in obstructive sleep apnea: a link no longer missing.
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阻塞性睡眠呼吸暂停对海马体的损害：不再缺失的一个环节。
作者：
Macey,PaulM
欧文和他的同事们的发现为证实阻塞性睡眠呼吸暂停（OSA）患者的海马体脑损伤提供了完整的证据。在直接检查OSA患者的大脑之前，间接证据如认知和情绪症状[2]提示高级脑功能[3]被破坏。具体来说，记忆受损和高度抑郁症状在OSA中很常见[4-6]，这两种功能都与海马体密切相关[7,8]。间歇性缺氧是OSA的一个特征，动物模型显示海马神经元死亡[9,10]，这与OSA损害海马的理论一致。最早对OSA患者大脑进行的直接测量包括磁共振波谱（MRS），这些测量显示白质中n -乙酰天冬氨酸水平较低，与较低的代谢活性和可能的损伤相一致[11,12]。早期的磁共振成像（MRI）研究包括标准的视觉评估，发现OSA与亚临床病理（但不是主要病理[14]），特别是白质高强度（WMH）[14]之间存在一定的联系。这种高信号之所以如此命名，是因为它们在一些MRI扫描中表现为白质中的亮“点”，主要反映血管损伤，与正常衰老和高血压有关[15,16]。OSA中WMH的数量超过了正常的衰老，但鉴于OSA与高血压b[17]之间的重叠，尚不清楚这种脑部病理是否是睡眠障碍所特有的。在90年代末和21世纪初的这些研究之后，新的方法允许对MRI指标进行统计分析，从而导致了多项评估OSA患者大脑结构和功能的研究。（在PubMed上搜索“阻塞性睡眠呼吸暂停脑MRI”，会出现几十个这样的结果。）最近，我们的团队使用较新的MRS技术来测量特定大脑区域的多种化学物质的浓度，包括脑岛bbb中较低的γ-氨基丁酸，以及多个区域中较高的肌醇（可能表明神经胶质激活）和谷氨酸（可能反映高兴奋或可能的兴奋毒性）[18 - 21]。总的来说，这些MRI结果与osa相关的大脑结构变化是一致的，包括海马的特异性改变[22,23]，或周围组织（海马旁回[24]，颞叶皮层[25,26]）的变化，这些变化也可能反映了海马的缺陷。换句话说，在过去30年的文献中，海马损伤的迹象包括表明功能障碍的症状、间歇性缺氧的动物模型和许多神经影像学研究。欧文的发现现在增加了一个缺失的环节，直接测量人类OSA患者的海马病理。这种伤害的性质是什么，它是可以预防的还是可逆的？欧文研究的病理结果显示髓磷脂厚度减少和损失，而在体内的人体研究显示出混合效应，我们最近的研究结果表明，在海马体的不同子区中，体积增加和减少的组合。持续气道正压通气（CPAP）治疗OSA可使症状和海马结构部分正常化。CPAP脑缺陷的可逆性表明，OSA的结构变化并非都是永久性的，这表明存在一些适应性或病理性变化，而不是神经元死亡。然而，考虑到欧文的研究发现人体组织萎缩，以及间歇性缺氧动物模型中的细胞凋亡，我们似乎有理由认为神经元受到了一些永久性损伤。欧文的研究也…
The findings by Owen and colleagues [1] complete a circle of evidence confirming brain injury in the hippocampus in people with obstructive sleep apnea (OSA). Before direct examination of the brain in OSA, circumstantial evidence such as cognitive and mood symptoms [2] suggested disrupted higher brain function [3]. Specifically, impaired memory and high levels of depressive symptoms are common in OSA [4–6], and both functions are strongly associated with the hippocampus [7, 8]. Animal models of intermittent hypoxia, one characteristic of OSA, showed neuronal death in the hippocampus [9, 10], consistent with the theory that OSA damages the hippocampus. The earliest direct measurements in the brain of OSA patients involved magnetic resonance spectroscopy (MRS), and these showed lower levels of N-acetylaspartate in white matter, consistent with lower metabolic activity and possible damage [11, 12]. Early magnetic resonance imaging (MRI) studies consisted of standard visual assessments, and some association was found between OSA and subclinical pathology (but not major pathology [13]), specifically white matter hyperintensities (WMH)[14]. Such hyperintensities, so named because they appear on some MRI scans as bright “spots” in white matter, reflect mostly vascular damage and are associated with normal aging as well as hypertension [15, 16]. The amount of WMH in OSA is beyond normal aging, but given the overlap between OSA and hypertension [17], it is not clear whether this brain pathology is specific to the sleep disorder. After these studies in the late 90s and early 2000s, new methodology allowed statistical analyses of MRI metrics, leading to multiple studies assessing brain structure and function in OSA.(A PubMed search for “obstructive sleep apnea brain MRI” will bring up dozens of these.) More recently, our group has used newer MRS techniques to measure concentrations of multiple chemicals in specific brain regions, including lower γ-aminobutyric acid in the insula [18], and higher myo-inositol (possibly indicative of glial activation) and glutamate (likely reflecting high excitation or possibly excitotoxicity) in multiple areas [18–21]. When considered in their totality, these MRI findings are consistent with OSA-related structural changes in the brain, including specific alterations in the hippocampus [22, 23], or changes in surrounding tissue (parahippocampal gyrus [24], temporal cortex [25, 26]) that may also reflect hippocampal deficits. In other words, signs of hippocampal damage in the literature of the past 30 years include symptoms indicating dysfunction, animal models of intermittent hypoxia, and many neuroimaging studies. The Owen’s findings now add a missing link, direct measures of hippocampal pathology in human OSA patients.What is the nature of this injury, and is it preventable or reversible? While the pathology findings in the Owen’s study show a reduction in thickness and loss of myelin, in vivo human studies show mixed effects, with our recent findings indicating a combination of volume increases and decreases across different subfields of the hippocampus [27]. Treatment of OSA with continuous positive airway pressure (CPAP) can partially normalize both symptoms and hippocampal structure [23]. Reversibility of brain deficits with CPAP suggests that structural changes seen in OSA are not all permanent, which points to some adaptive or pathological changes short of neuronal death. However, given the Owen’s findings of atrophy in human tissue, and apoptosis in animal models of intermittent hypoxia, it seems reasonable to assume there is some permanent damage to neurons. The Owen’s study also …