JNNP:去甲肾上腺素能治疗阿尔茨海默病的认知和神经精神反应,系统回顾和荟萃分析

2022-08-07 网络 网络

神经递质去甲肾上腺素(NA),也称为去甲肾上腺素,对唤醒和许多认知过程,包括注意力、学习、记忆、执行和抑制控制至关重要。主要由源自去甲肾上腺素能神经元合成和释放4整个大脑的弥漫性投射作用于三种主要的肾

神经递质去甲肾上腺素(NA),也称为去甲肾上腺素,对唤醒和许多认知过程,包括注意力、学习、记忆、执行和抑制控制至关重要。主要由源自去甲肾上腺素能神经元合成和释放4整个大脑的弥漫性投射作用于三种主要的肾上腺受体(AR)类别:α1、α2和β。通常,刺激α1-AR和β-ARs可增强神经传递和可塑性,而突触前α2-ARs可自动抑制NA释放。除了神经传递外,NA还调节小胶质细胞监测和突触毒性。阿尔茨海默病的tau病理学进展可能始于蓝斑LC,在LC中,神经元丢失发生在疾病的早期。使用对神经黑色素敏感的MRI进行的体内研究表明,与健康老年人相比,阿尔茨海默病患者的LC变性。去甲肾上腺素能系统在注意、记忆和执行功能中的作用使得LC去甲肾上腺素能够细胞的丧失与阿尔茨海默痴呆症直接相关。LC-NA系统也与阿尔茨海默病的行为和神经精神症状有关。鉴于阿尔茨海默病LC-NA系统的早期变化,它是治疗认知和行为功能障碍的潜在靶点。

一系列药物通过去甲肾上腺素能途径发挥作用。NA的突触可用性通过抑制再摄取和降解而增加,而受体可以直接被刺激/阻断。临床上使用的许多药物抑制钠的再摄取,阻止突触清除。16例包括选择性去甲肾上腺素能再摄取抑制剂(NRI)和选择性较差的5-羟色胺-去甲肾上腺素再摄取抑制剂,称为抗抑郁药,但也用于焦虑、疼痛和神经病变。已确立的注意力缺陷多动障碍治疗方法,包括哌醋甲酯和阿托莫西汀,通过这种机制发挥作用。莫达非尼是一种兴奋剂,部分通过抑制钠再摄取发挥作用。去甲肾上腺素能治疗神经退行性疾病的临床试验是几十年前首次进行的。然而,在一系列小型研究未能提供令人信服的证据证明阿尔茨海默病的治疗效果后,人们的兴趣减弱了。最近,随着在体内检测该系统的新工具和新的药物选择,对早期LC-NA参与阿尔茨海默病的认识有所增加。

因此,本研究对阿尔茨海默病中主要具有去甲肾上腺素能作用的药物进行了系统回顾和荟萃分析。此处包含的药物在其作用中并非纯粹的去甲肾上腺素能,但在所用剂量下,这可能是其主要机制评估了去甲肾上腺素能药物在阿尔茨海默病认知和行为方面的治疗效果。本文发表在《神经病学,神经外科学和精神病学杂志》上()。

搜索了MEDLINE、Embase和临床资料。用于满足所有标准的研究:(1)研究人群定义为阿尔茨海默病、轻度认知障碍(MCI)、帕金森病(PD)、路易体痴呆、额颞痴呆(FTD)或进行性核上麻痹的患者;(2) 比较增加NA水平或作用于三种受体类别之一的药物与安慰剂的前瞻性临床试验,以及(3)报告认知、神经精神或行为结果的研究。列出了完整的搜索词和纳入/排除标准。未包括正在进行的去甲肾上腺素能药物临床试验。专注于一个慢性疗程药物作用的前瞻性临床试验,不包括单剂量研究。虽然单剂量实验研究对于理解药物的作用机制很有价值,特别是当与辅助神经生理学或神经影像学一起进行时,但它们并不能说明慢性治疗的临床疗效。

研究流程

除非有明显的去甲肾上腺素能作用的证据,否则具有跨多种神经递质系统活性的药物不包括在内。因此被排除在外的药物有奥氮平和曲唑酮;虽然它们具有轻微的去甲肾上腺素能作用,但与多巴胺能和5-羟色胺能作用相比,这些作用具有次要意义。考虑到前者对NA的相对选择性,32种单胺氧化酶A型抑制剂包括在内,而B型抑制剂不包括在内。去甲肾上腺素能系统参与L-3,4-二羟基苯丙氨酸的作用不强。认知结果包括对筛选测试和特定认知领域(注意力、情景言语记忆、情景视觉记忆、执行功能和工作记忆、语义记忆和视觉空间能力)的“整体认知”测量。行为和神经精神症状的全球测量;包括焦虑和冷漠。纳入了客观的观察指标,包括基于照料者的评估,但不包括要求患者报告其症状(例如抑郁或焦虑)的自评结果。

去甲肾上腺素(NA)通过突触的释放、三种受体亚型的作用以及通过去甲肾上腺素转运体(NET)的再摄取

四名评审员(MCBD、MdG、BG和IO)独立筛选标题和摘要。然后,在决定是否纳入之前,评审员之间讨论了可能符合条件的研究。每个领域的结果指标是根据其在纳入研究中的使用频率确定的层次结构选择的。例如,对于整体认知结果测量,在七项阿尔茨海默病研究中使用了迷你精神状态检查(MMSE),因此纳入了这些研究的分析。两项阿尔茨海默病研究采用了阿尔茨海默症评估量表认知子量表(ADAS-Cog),报告了整体认知的测量结果,因此分析中包括了这项研究的结果。对于冷漠,四项阿尔茨海默病研究使用了冷漠评估量表(AES),并在可用的情况下提取。下一个最常见的冷漠指数是神经精神病学冷漠量表(NPI-A),而一项研究使用了额叶系统行为量表(FrSBe-A)。对于认知子领域结果指标的选择,优先考虑最常用的指标,然后从其余研究中选择被认为最相似的指标

去甲肾上腺素能药物在认知上的森林图 

纳入了19项随机对照试验(1811名患者),其中6项质量“良好”,7项“一般”,6项“较差”。对其中10项研究(1300名患者)进行的荟萃分析表明,去甲肾上腺素能药物对整体认知有显著的小的积极影响,使用迷你精神状态检查或阿尔茨海默病评估量表认知子量表(标准化平均差分:0.14,95%)进行测量 CI:0.03至0.25,p=0.01;I2=0%)。在注意力测量方面未发现显著影响(SMD:0.01,95%) CI:−0.17-0.19,p=0.91;I2=0)。荟萃分析包括8项试验(425名患者),并检测到去甲肾上腺素能药物的大量积极作用(SMD:0.45,95%) CI:0.16至0.73,p=0.002;I2=58%)。在剔除异常值以解释研究的异质性后,这种积极影响仍然存在。

重新调整现有去甲肾上腺素能药物的用途最有可能为阿尔茨海默病的一般认知和冷漠提供有效的治疗。然而,在设计未来的临床试验之前,应该考虑几个因素。这包括针对适当的患者亚组,了解单个药物的剂量效应及其与其他治疗的相互作用,以最小化风险并最大限度地提高治疗效果。

David MCBDel Giovane MLiu KY, et al Cognitive and neuropsychiatric effects of noradrenergic treatment in Alzheimer’s disease: systematic review and meta-analysis

 

 

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    2022-12-02 venlin
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