背景:炎症已被认为是神经变性的关键角色,包括额颞叶痴呆(FTD)。一些关于零星FTD的研究导致不确定的结果,而缺乏对遗传FTD的大量研究。这项研究的目的是确定细胞因子和趋化因子血浆循环水平在一个大队列的遗传FTD,在GeNetic额颞叶痴呆倡议(GENFI)内收集。
方法:采用中尺度技术对434份血浆样本中30种炎性因子水平进行分析,包括94个症状突变携带者[(SMC);15个在微管相关蛋白Tau(MAPT)中突变,在颗粒蛋白前体(GRN)中34个,在9号染色体开放阅读框(C9ORF)中45个],168例症状前突变携带者(PMC;34MAPT,70GRN和64C9ORF72)和173非载波控制(NC)]。
结果:MAPT和GRNSMC与NC相比,以下细胞因子显着上调(P<0.05):肿瘤坏死因子(TNF)α,白细胞介素(IL)-7、IL-15、IL-16、IL-17A。此外,仅在GRNSMC中,其他因素上调,包括:IL-1β,IL-6,IL-10,IL-12/IL-23p40,eotaxin,eotaxin-3,干扰素γ诱导蛋白(IP-10),单核细胞趋化蛋白(MCP)4.相反,与NC相比,SMC中IL-1α水平降低。在PMC中也发现了这种细胞因子的水平显着降低,与突变类型无关。在SMC,未发现病程与细胞因子和趋化因子水平之间存在相关性.考虑到NFL和GFAP水平,正如预期的那样,与NC相比,SMC显着增加。即使通过突变基因对有症状的患者进行分层,这些平均值的差异仍然显着(P<0.0001)。相反,考虑到NFL的水平,GFAP,和改变的炎症分子,没有出现显著的相关性。
结论:我们发现炎症蛋白在MAPT和GRNSMC中上调,仅在GRN中改变了一些特定的因素,而C9ORF72携带者未见变化.值得注意的是,SMC和PMC中只有IL-1α水平降低,与因果突变的类型无关,提示在疾病的临床前阶段发生的常见修饰。
BACKGROUND: Inflammation has been proposed as a crucial player in neurodegeneration, including Frontotemporal Dementia (FTD). A few studies on sporadic FTD lead to inconclusive results, whereas large studies on genetic FTD are lacking. The aim of this study is to determine cytokine and chemokine plasma circulating levels in a large cohort of genetic FTD, collected within the GENetic Frontotemporal dementia Initiative (GENFI).
METHODS: Mesoscale technology was used to analyse levels of 30 inflammatory factors in 434 plasma samples, including 94 Symptomatic Mutation carriers [(SMC); 15 with mutations in Microtubule Associated Protein Tau (MAPT) 34 in Progranulin (GRN) and 45 in Chromosome 9 Open Reading Frame (C9ORF)72], 168 Presymptomatic Mutation Carriers (PMC; 34 MAPT, 70 GRN and 64 C9ORF72) and 173 Non-carrier Controls (NC)].
RESULTS: The following cytokines were significantly upregulated (P<0.05) in MAPT and GRN SMC versus NC: Tumor Necrosis Factor (TNF)α, Interleukin (IL)-7, IL-15, IL-16, IL-17A. Moreover, only in GRN SMC, additional factors were upregulated, including: IL-1β, IL-6, IL-10, IL-12/IL-23p40, eotaxin, eotaxin-3, Interferon γ-induced Protein (IP-10), Monocyte Chemotactic Protein (MCP)4. On the contrary, IL-1α levels were decreased in SMC compared with NC. Significantly decreased levels of this cytokine were also found in PMC, independent of the type of mutation. In SMC, no correlations between disease duration and cytokine and chemokine levels were found. Considering NfL and GFAP levels, as expected, significant increases were observed in SMC as compared to NC. These differences in mean values remain significant even when stratifying symptomatic patients by the mutated gene (P<0.0001). Considering instead the levels of NfL, GFAP, and the altered inflammatory molecules, no significant correlations emerged.
CONCLUSIONS: We showed that inflammatory proteins are upregulated in MAPT and GRN SMC, with some specific factors altered in GRN only, whereas no changes were seen in C9ORF72 carriers. Notably, only IL-1α levels were decreased in both SMC and PMC, independent of the type of causal mutation, suggesting common modifications occurring in the preclinical phase of the disease.