Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.
Plasma inflammation for predicting phenotypic conversion and clinical progression of autosomal dominant frontotemporal lobar degeneration.
复制标题
DOI：
10.1136/jnnp-2022-330866
复制
发表时间：
2023-07
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
检测全身炎症标志物可能会改善临床预后，并有助于确定常染色体显性遗传额颞叶变性(FTLD)患者的治疗途径。我们检测了致病变异携带者(MAPT、C9orf72、GRN)和加入ARTFL-LEFFTDS纵向额颞叶变性联盟的非携带者家族成员的血浆IL-6、肿瘤坏死因子α和YKL-40浓度。我们评估了基线血浆炎症与临床和神经影像变化率(标准化(Z)结果的线性混合效应模型)之间的关系。我们使用曲线下面积分析比较了临床正常的无症状携带者(“无症状转化者”)和有症状的携带者(“无症状转化者”)之间的炎症反应。并与血浆神经丝轻链(NFL)的判别准确率进行比较。我们研究了394名参与者(非携带者=143人，C9orf72=117人，GRN=62人，MAPT=72人)。MAPT患者肿瘤坏死因子α水平越高，功能下降越快(B=0.12(0.0 2，0.2 2，p=0.0 2))，颞叶萎缩越明显。在C9orf72患者中，肿瘤坏死因子α升高与较快的功能下降(B=0.09(0.03，0.16)，p=0.006)和认知功能下降(B=−0.16(−0.22，−0.10，p<；0.001)相关，而IL-6升高与较快的功能下降(B=0.12(0.03，0.21)，p=0.01)相关。无症状转换组的肿瘤坏死因子α水平高于无转换组(β=0.29(0.09，0.48)，p=0.004)，与单纯血浆NFL相比，差异有统计学意义(ΔR2=0.16，p=0.007；NFL：OR=1.4(1.0 3，1.9)，p=0.03；肿瘤坏死因子α：OR=7.7(1.7，31.7)，p=0.007)。全身性促炎蛋白检测，尤其是肿瘤坏死因子α检测，可以改善常染色体显性遗传性FTLD致病变异携带者的临床预后，这些携带者尚未表现出严重的损害。将肿瘤坏死因子α与神经功能障碍标志物(如神经营养不良)相结合，可以优化对无症状致病变异携带者即将出现的症状转换的检测，并可能有助于个性化治疗方法。
Measuring systemic inflammatory markers may improve clinical prognosis and help identify targetable pathways for treatment in patients with autosomal dominant forms of frontotemporal lobar degeneration (FTLD). We measured plasma concentrations of IL-6, TNFα and YKL-40 in pathogenic variant carriers (MAPT, C9orf72, GRN) and non-carrier family members enrolled in the ARTFL-LEFFTDS Longitudinal Frontotemporal Lobar Degeneration consortium. We evaluated associations between baseline plasma inflammation and rate of clinical and neuroimaging changes (linear mixed effects models with standardised (z) outcomes). We compared inflammation between asymptomatic carriers who remained clinically normal (‘asymptomatic non-converters’) and those who became symptomatic (‘asymptomatic converters’) using area under the curve analyses. Discrimination accuracy was compared with that of plasma neurofilament light chain (NfL). We studied 394 participants (non-carriers=143, C9orf72=117, GRN=62, MAPT=72). In MAPT, higher TNFα was associated with faster functional decline (B=0.12 (0.02, 0.22), p=0.02) and temporal lobe atrophy. In C9orf72, higher TNFα was associated with faster functional decline (B=0.09 (0.03, 0.16), p=0.006) and cognitive decline (B=−0.16 (−0.22, −0.10), p<0.001), while higher IL-6 was associated with faster functional decline (B=0.12 (0.03, 0.21), p=0.01). TNFα was higher in asymptomatic converters than non-converters (β=0.29 (0.09, 0.48), p=0.004) and improved discriminability compared with plasma NfL alone (ΔR2=0.16, p=0.007; NfL: OR=1.4 (1.03, 1.9), p=0.03; TNFα: OR=7.7 (1.7, 31.7), p=0.007). Systemic proinflammatory protein measurement, particularly TNFα, may improve clinical prognosis in autosomal dominant FTLD pathogenic variant carriers who are not yet exhibiting severe impairment. Integrating TNFα with markers of neuronal dysfunction like NfL could optimise detection of impending symptom conversion in asymptomatic pathogenic variant carriers and may help personalise therapeutic approaches.
登录
查看更多内容
影响因子：
3.3
作者：
Ntymenou S;Tsantzali I;Kalamatianos T;Voumvourakis KI;Kapaki E;Tsivgoulis G;Stranjalis G;Paraskevas GP
通讯作者：
Paraskevas GP
影响因子：
5.3
作者：
Rojas JC;Karydas A;Bang J;Tsai RM;Blennow K;Liman V;Kramer JH;Rosen H;Miller BL;Zetterberg H;Boxer AL
通讯作者：
Boxer AL
影响因子：
9.9
作者：
Rojas JC;Wang P;Staffaroni AM;Heller C;Cobigo Y;Wolf A;Goh SM;Ljubenkov PA;Heuer HW;Fong JC;Taylor JB;Veras E;Song L;Jeromin A;Hanlon D;Yu L;Khinikar A;Sivasankaran R;Kieloch A;Valentin MA;Karydas AM;Mitic LL;Pearlman R;Kornak J;Kramer JH;Miller BL;Kantarci K;Knopman DS;Graff-Radford N;Petrucelli L;Rademakers R;Irwin DJ;Grossman M;Ramos EM;Coppola G;Mendez MF;Bordelon Y;Dickerson BC;Ghoshal N;Huey ED;Mackenzie IR;Appleby BS;Domoto-Reilly K;Hsiung GR;Toga AW;Weintraub S;Kaufer DI;Kerwin D;Litvan I;Onyike CU;Pantelyat A;Roberson ED;Tartaglia MC;Foroud T;Chen W;Czerkowicz J;Graham DL;van Swieten JC;Borroni B;Sanchez-Valle R;Moreno F;Laforce R;Graff C;Synofzik M;Galimberti D;Rowe JB;Masellis M;Finger E;Vandenberghe R;de Mendonça A;Tagliavini F;Santana I;Ducharme S;Butler CR;Gerhard A;Levin J;Danek A;Otto M;Sorbi S;Cash DM;Convery RS;Bocchetta M;Foiani M;Greaves CV;Peakman G;Russell L;Swift I;Todd E;Rohrer JD;Boeve BF;Rosen HJ;Boxer AL;ALLFTD and GENFI consortia
通讯作者：
ALLFTD and GENFI consortia
影响因子：
9.9
作者：
Rohrer, J. D.;Guerreiro, R.;Rossor, M. N.
通讯作者：
Rossor, M. N.
影响因子：
64.8
作者：
Burberry, Aaron;Wells, Michael F.;Eggan, Kevin
通讯作者：
Eggan, Kevin