Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy.
Biomarker-based risk prediction for the onset of neuroinflammation in X-linked adrenoleukodystrophy.
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DOI：
10.1016/j.ebiom.2023.104781
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发表时间：
2023-10
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影响因子：
11.1
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x -连锁肾上腺脑白质营养不良（X-ALD）是高度可变的，从缓慢进展的肾上腺髓神经病变到严重的脑脱髓鞘和炎症（脑ALD， CALD），影响儿童期发病高峰的男性。目前还缺乏整合基于血液的生物标志物来指示CALD发病的风险模型，从而无法进行及时干预。因此，我们评估了血液生物标志物以及目前的神经影像学预测因子对CALD早期检测的预后价值。我们使用Simoa®和Luminex®技术在一个回顾性的男性CALD风险评估队列中测量了血液生物标志物，该队列包括134名X-ALD患者和66名对照组，以及一个表型盲法验证组（25名4-13岁的X-ALD男孩）。在指示轴突损伤、星形胶质细胞/小胶质细胞激活或免疫细胞募集的25个生物标志物中，神经丝轻链（NfL）对儿童/青少年CALD的早期指征具有最高的预后价值。在评估队列中测定的血浆NfL截止水平为8.33 pg/mL，在验证组中正确区分CALD的准确率为96% [95% CI: 80-100]。多变量logistic回归模型显示，与健康对照组相比，将NfL与GFAP或细胞因子/趋化因子（IL-15、IL-12p40、CXCL8、CCL11、CCL22和IL-4）联合使用在CALD中显著升高，对检测神经炎症没有额外的益处。一些细胞因子/趋化因子仅在儿童/青少年CALD中升高，而在无症状的X-ALD儿童中已经上调（IL-15、IL-12p40和CCL7）。在成人中，NfL水平可以区分CALD，但低于具有相似（MRI）病变严重程度的儿童/青少年CALD患者。血液GFAP不能区分CALD和非炎性X-ALD。基于生物标志物的风险预测，通过ROC分析确定血浆NfL临界值为8.33 pg/mL，表明儿童X-ALD患者发生CALD具有高敏感性和特异性。在无症状的X-ALD男孩中，特定的促炎细胞因子/趋化因子谱可能表明一种与CALD峰值发病一致的启动的、内在的炎症状态。成人与儿童CALD患者生物标志物水平的年龄相关差异在预测成人CALD的发病和进展时值得谨慎。需要进一步的评估来评估NfL临界值对CALD发病风险预后的临床应用。， .
X-linked adrenoleukodystrophy (X-ALD) is highly variable, ranging from slowly progressive adrenomyeloneuropathy to severe brain demyelination and inflammation (cerebral ALD, CALD) affecting males with childhood peak onset. Risk models integrating blood-based biomarkers to indicate CALD onset, enabling timely interventions, are lacking. Therefore, we evaluated the prognostic value of blood biomarkers in addition to current neuroimaging predictors for early detection of CALD. We measured blood biomarkers in a retrospective, male CALD risk-assessment cohort consisting of 134 X-ALD patients and 66 controls and in a phenotype-blinded validation set (25 X-ALD boys, 4–13 years) using Simoa®and Luminex® technologies. Among 25 biomarkers indicating axonal damage, astrocye/microglia activation, or immune-cell recruitment, neurofilament light chain (NfL) had the highest prognostic value for early indication of childhood/adolescent CALD. A plasma NfL cut-off level of 8.33 pg/mL, determined in the assessment cohort, correctly discriminated CALD with an accuracy of 96% [95% CI: 80–100] in the validation group. Multivariable logistic regression models revealed that combining NfL with GFAP or cytokines/chemokines (IL-15, IL-12p40, CXCL8, CCL11, CCL22, and IL-4) that were significantly elevated in CALD vs healthy controls had no additional benefit for detecting neuroinflammation. Some cytokines/chemokines were elevated only in childhood/adolescent CALD and already upregulated in asymptomatic X-ALD children (IL-15, IL-12p40, and CCL7). In adults, NfL levels distinguished CALD but were lower than in childhood/adolescent CALD patients with similar (MRI) lesion severity. Blood GFAP did not differentiate CALD from non-inflammatory X-ALD. Biomarker-based risk prediction with a plasma NfL cut-off value of 8.33 pg/mL, determined by ROC analysis, indicates CALD onset with high sensitivity and specificity in childhood X-ALD patients. A specific pro-inflammatory cytokine/chemokine profile in asymptomatic X-ALD boys may indicate a primed, immanent inflammatory state aligning with peak onset of CALD. Age-related differences in biomarker levels in adult vs childhood CALD patients warrants caution in predicting onset and progression of CALD in adults. Further evaluations are needed to assess clinical utility of the NfL cut-off for risk prognosis of CALD onset. , .