Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine, and PET, Rigshospitalet, Copenhagen, Denmark.
Clinical Neurosciences, Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
Ann Neurol. 2018 May;83(5):902-914. doi: 10.1002/ana.25219. Epub 2018 May 11.
To investigate whether blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of suboptimal treatment response in relapsing-remitting multiple sclerosis (RRMS).
Thirty-five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE-MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant K , a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 years of treatment.
Subjects with loss of NEDA status at 2 years had a 51% higher mean K in normal-appearing white matter (NAWM) measured after 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02-0.09, p = 0.002). K in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70-0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%.
Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts suboptimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here. Ann Neurol 2018;83:902-914.
研究通过动态对比增强磁共振成像（DCE-MRI）测量的血脑屏障（BBB）通透性是否能早期发现复发缓解型多发性硬化症（RRMS）患者的治疗反应欠佳。
35 例 RRMS 患者在开始接受芬戈莫德或那他珠单抗治疗前（这两种药物的作用机制均为减少淋巴细胞向中枢神经系统内浸润），于 3T 磁共振扫描仪上进行 DCE-MRI 扫描，分别于治疗前、治疗后 3 个月和 6 个月时进行扫描。我们使用 Patlak 模型计算了摄取常数 K，这是 BBB 通透性的一个衡量指标。治疗 2 年后失去无疾病活动证据（NEDA）状态被定义为治疗反应欠佳。
2 年后失去 NEDA 状态的患者，在治疗 6 个月后，正常表现的白质（NAWM）中的平均 K 值比保持 NEDA 状态的患者高 51%（平均差值=0.06ml/100g/min，95%置信区间[CI]为 0.02-0.09，p=0.002）。6 个月时的 NAWM K 值是 2 年后失去 NEDA 状态的一个很好的预测指标（曲线下面积=0.84，95%CI 为 0.70-0.99，p=0.003），K 值大于 0.136ml/100/g/min 时，2 年后治疗反应欠佳的优势比为 12.4，敏感性为 73%，特异性为 82%。
我们的研究结果表明，DCE-MRI 测量的 BBB 通透性能够可靠地预测治疗反应欠佳，是 BBB 健康状况的替代标志物。我们发现了一个疾病活动的预测阈值，这与之前报道的临床孤立综合征和此处研究的 RRMS 非常相似。Ann Neurol 2018;83:902-914。
