Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming.
Transcriptomic signatures of psychomotor slowing in peripheral blood of depressed patients: evidence for immunometabolic reprogramming.
复制标题
DOI：
10.1038/s41380-021-01258-z
复制
发表时间：
2021-12
影响因子：
11
通讯作者：
Felger JC
中科院分区：
文献类型：
--
作者：
Bekhbat M;Goldsmith DR;Woolwine BJ;Haroon E;Miller AH;Felger JC
炎症影响基底神经节运动回路，并与精神运动发育迟缓相关，精神运动发育迟缓是重度抑郁症（MD）的一个关键症状。我们先前报道了循环蛋白质炎症生物标志物与精神发育迟缓之间的相关性，通过神经心理学测试探测MD患者的精神发育速度。为了发现外周血免疫细胞中与精神病减缓相关的新的转录特征，在88名医学稳定的、未用药的、非卧床的MD患者的主要队列中分析了微阵列数据。结果在第二组57例难治性抑郁症（TRD）患者中得到证实和扩展，在抗炎治疗前和治疗后分别使用肿瘤坏死因子拮抗剂英夫利昔单抗和安慰剂。反映纯运动和认知运动处理速度的综合得分分别与每个队列中的403和266个基因转录本线性相关（|R|>0.30，p<0.01），其富含细胞因子信号传导和糖酵解相关途径（p<0.05）。在初级队列中的无监督聚类揭示了两个精神发育迟缓相关基因共表达模块，其富集了干扰素、白细胞介素-6、有氧糖酵解和氧化磷酸化途径（p<0.05，q<0.1）。转录本主要来源于单核细胞、浆细胞样树突细胞和自然杀伤细胞（p <0.05）。在高血浆C反应蛋白浓度（> 5 mg/L）的英夫利昔单抗治疗TRD患者中，两种富含氧化应激和线粒体降解的差异共表达模块与精神反应时间的改善相关（p<0.05）。这些结果表明，外周血免疫细胞中的炎症信号传导和相关的代谢重编程与抑郁症的全身炎症有关，并可能影响相关的脑回路，以促进精神活动减缓。
Inflammation impacts basal ganglia motor circuitry in association with psychomotor retardation, a key symptom of major depression (MD). We previously reported associations between circulating protein inflammatory biomarkers and psychomotor slowing as measured by neuropsychological tests probing psychomotor speed in patients with MD. To discover novel transcriptional signatures in peripheral blood immune cells related to psychomotor slowing, microarray data were analyzed in a primary cohort of 88 medically-stable, unmedicated, ambulatory MD patients. Results were confirmed and extended in a second cohort of 57 patients with treatment resistant depression (TRD) before and after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab versus placebo. Composite scores reflecting pure motor and cognitive-motor processing speed were linearly associated with 403 and 266 gene transcripts in each cohort, respectively (|R|>0.30, p<0.01), that were enriched for cytokine signaling and glycolysis-related pathways (p<0.05). Unsupervised clustering in the primary cohort revealed two psychomotor slowing-associated gene co-expression modules that were enriched for interferon, interleukin-6, aerobic glycolysis, and oxidative phosphorylation pathways (p<0.05, q<0.1). Transcripts were predominantly derived from monocytes, plasmacytoid dendritic cells, and natural killer cells (p’s<0.05). In infliximab-treated TRD patients with high plasma C-reactive protein concentrations (>5mg/L), two differential co-expression modules enriched for oxidative stress and mitochondrial degradation were associated with improvements in psychomotor reaction time (p<0.05). These results indicate that inflammatory signaling and associated metabolic reprogramming in peripheral blood immune cells are associated with systemic inflammation in depression and may affect relevant brain circuits to promote psychomotor slowing.
登录
查看更多内容
影响因子：
6.9
作者：
Felger, J. C.;Cole, S. W.;Pace, T. W. W.;Hu, F.;Woolwine, B. J.;Doho, G. H.;Raison, C. L.;Miller, A. H.
通讯作者：
Miller, A. H.
影响因子：
11
作者：
Felger JC;Haroon E;Patel TA;Goldsmith DR;Wommack EC;Woolwine BJ;Le NA;Feinberg R;Tansey MG;Miller AH
通讯作者：
Miller AH
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
10.6
作者：
Dowlati, Yekta;Herrmann, Nathan;Lanctot, Krista L.
通讯作者：
Lanctot, Krista L.
影响因子：
3.7
作者：
Frenois, Francois;Moreau, Maite;Castanon, Nathalie
通讯作者：
Castanon, Nathalie