Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer's disease.
Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer's disease.
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DOI：
10.1093/brain/awab094
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发表时间：
2021-07-28
期刊：
影响因子：
--
通讯作者：
Miners JS
中科院分区：
文献类型：
--
作者：
Asby D;Boche D;Allan S;Love S;Miners JS
见Huuskonen等人。(DOI：)获取本文的科学评论。全身性感染会加重阿尔茨海默病。在这项尸检研究中，Asby等人。提供证据表明，它通过提高大脑中多种细胞因子的水平，并通过加剧阿尔茨海默病的脑低灌流和血管渗漏来实现这一点，而不依赖于不溶性淀粉样蛋白-β42的水平。我们研究了阿尔茨海默病和血管性痴呆患者(n = 75例)、血管性痴呆患者(n = 22例)和年龄匹配的对照组(n = 46例)颞叶上皮质(Brodmann区22区)感染对脑细胞因子水平和脑血管功能的影响。采用中尺度发现复合分析法检测脑组织细胞因子水平，用酶联免疫吸附试验检测脑血管功能指标。多种脑细胞因子在阿尔茨海默病和血管性痴呆中升高：IL-15和IL-17A在终末期阿尔茨海默病(Braak TangleV-VI期)最高，而IL-2、IL-5、IL12p40和IL-16在中期Braak Tangle病III-IV期最高。多种细胞因子(IL-1β、IL-6、肿瘤坏死因子-α、IL-8和IL-15)在阿尔茨海默病合并全身感染时进一步升高。脑低灌注--表现为MAG：PLP1降低和血管内皮生长因子-A(VEGF)增加--和血脑屏障泄漏(表现为纤维蛋白原水平升高)，在阿尔茨海默病和血管性痴呆患者中加剧，在有全身感染的非痴呆症对照组中也是如此。淀粉样蛋白-β42水平与感染无关，也与脑细胞因子水平无关。在对照组，随着干扰素-γ、IL-2、IL-4、IL-6、IL-10、IL-12p70、IL-13和肿瘤坏死因子-α(肿瘤坏死因子-α)的升高，皮质血流灌注下降，但这些关系随着阿尔茨海默病的进展和感染(甚至在Braak 0-II期大脑中)而消失。阿尔茨海默病患者周细胞标志物皮质血小板衍生生长因子受体-β(PDGFR-β)水平降低，内皮素-1(EDN1)水平升高，与淀粉样蛋白-β水平和疾病进展有关，仅受全身感染的轻微影响。我们的发现表明，系统性感染改变了脑细胞因子水平，加剧了与阿尔茨海默病和血管性痴呆相关的脑低灌流和血脑屏障疏松，独立于不溶性淀粉样蛋白-β的水平，并强调系统性感染是痴呆症的重要贡献者，需要在老年人群中及早识别和治疗。
See Huuskonen et al. (doi:) for a scientific commentary on this article. Systemic infection exacerbates Alzheimer’s disease. In this postmortem study, Asby et al. provide evidence that it does so by raising the levels of multiple cytokines in the brain and by exacerbating cerebral hypoperfusion and vascular leakage in Alzheimer’s disease, independently of the level of insoluble amyloid-β42. We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer’s disease patients (n = 75), vascular dementia patients (n = 22) and age-matched control subjects (n = 46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer’s disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V–VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III–IV disease. Several cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-15) were further raised in Alzheimer’s disease with systemic infection. Cerebral hypoperfusion—indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)—and blood–brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer’s disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-β42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-γ, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-α (TNF-α) but these relationships were lost with progression of Alzheimer’s disease, and with infection (even in Braak stage 0–II brains). Cortical platelet-derived growth factor receptor-β (PDGFRβ), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer’s disease; these were related to amyloid-β level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood–brain barrier leakiness associated with Alzheimer’s disease and vascular dementia, independently of the level of insoluble amyloid-β, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.