Neuroinflammation is an important pathogenic mechanism in many neurodegenerative diseases, including those caused by frontotemporal lobar degeneration. Post-mortem and in vivo imaging studies have shown brain inflammation early in these conditions, proportional to symptom severity and rate of progression. However, evidence for corresponding blood markers of inflammation and their relationships to central inflammation and clinical outcome are limited. There is a pressing need for such scalable, accessible and mechanistically relevant blood markers because these will reduce the time, risk and costs of experimental medicine trials. We therefore assessed inflammatory patterns of serum cytokines from 214 patients with clinical syndromes associated with frontotemporal lobar degeneration in comparison to healthy controls, including their correlation with brain regional microglial activation and disease progression. Serum assays used the MesoScale Discovery V-Plex-Human Cytokine 36 plex panel plus five additional cytokine assays. A subgroup of patients underwent 11C-PK11195 mitochondrial translocator protein PET imaging, as an index of microglial activation. A principal component analysis was used to reduce the dimensionality of cytokine data, excluding cytokines that were undetectable in >50% of participants. Frequentist and Bayesian analyses were performed on the principal components to compare each patient cohort with controls and test for associations with central inflammation, neurodegeneration-related plasma markers and survival. The first component identified by the principal component analysis (explaining 21.5% variance) was strongly loaded by pro-inflammatory cytokines, including TNF-α, TNF-R1, M-CSF, IL-17A, IL-12, IP-10 and IL-6. Individual scores of the component showed significant differences between each patient cohort and controls. The degree to which a patient expressed this peripheral inflammatory profile at baseline was correlated negatively with survival (higher inflammation, shorter survival), even when correcting for baseline clinical severity. Higher pro-inflammatory profile scores were associated with higher microglial activation in frontal and brainstem regions, as quantified with 11C-PK11195 mitochondrial translocator protein PET. A permutation-based canonical correlation analysis confirmed the association between the same cytokine-derived pattern and central inflammation across brain regions in a fully data-based manner. This data-driven approach identified a pro-inflammatory profile across the frontotemporal lobar degeneration clinical spectrum, which is associated with central neuroinflammation and worse clinical outcome. Blood-based markers of inflammation could increase the scalability and access to neuroinflammatory assessment of people with dementia, to facilitate clinical trials and experimental medicine studies.

中文翻译：

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血液炎症与额颞叶变性的神经炎症和生存率有关


神经炎症是许多神经退行性疾病的重要致病机制，包括额颞叶变性引起的疾病。尸检和体内影像学研究表明，在这些情况下，早期会出现脑部炎症，与症状的严重程度和进展速度成正比。然而，关于炎症的相应血液标志物及其与中枢炎症和临床结局的关系的证据是有限的。迫切需要这种可扩展、可访问且机械相关的血液标志物，因为这将减少实验性医学试验的时间、风险和成本。因此，我们与健康对照相比评估了 214 名患有额颞叶变性相关临床综合征的患者血清细胞因子的炎症模式，包括它们与大脑区域小胶质细胞活化和疾病进展的相关性。血清检测使用 MesoScale Discovery V-Plex-人细胞因子 36 重检测组合加上 5 种其他细胞因子检测。一组患者接受了 11C-PK11195 线粒体转运蛋白 PET 成像，作为小胶质细胞活化的指标。主成分分析用于降低细胞因子数据的维度，排除在 >50% 的参与者中检测不到的细胞因子。对主成分进行频率分析和贝叶斯分析，将每个患者队列与对照组进行比较，并检测与中枢炎症、神经退行性变相关血浆标志物和生存率的关联。主成分分析确定的第一个成分 （解释 21.5% 的方差） 是促炎细胞因子的强烈负载，包括 TNF-α 、 TNF-R1 、 M-CSF 、 IL-17A 、 IL-12 、 IP-10 和 IL-6。 该组件的个体评分显示每个患者队列和对照组之间存在显着差异。患者在基线时表达这种外周炎症特征的程度与生存率 （较高的炎症、较短的生存期） 呈负相关，即使在校正基线临床严重程度时也是如此。较高的促炎谱评分与额叶和脑干区域的较高小胶质细胞激活相关，如 11C-PK11195 线粒体转运蛋白 PET 所量化的那样。基于排列的经典相关分析以完全基于数据的方式证实了相同的细胞因子衍生模式与跨大脑区域的中枢炎症之间的关联。这种数据驱动的方法确定了额颞叶变性临床谱中的促炎特征，这与中枢神经炎症和较差的临床结果有关。基于血液的炎症标志物可以增加痴呆患者神经炎症评估的可扩展性和可及性，以促进临床试验和实验医学研究。