From the Departments of Physical Therapy (A.M.B., R.J.W., W.T.T., S.C.F., D.J.L., C.R.S., H.A., K.V.), Statistics (M.J.D., S.C.), Pharmacology and Therapeutics (H.L.S.), and Physiology and Functional Genomics (G.A.W.), University of Florida, Gainesville; Departments of Pediatrics and Neurology (E.L.F., G.T., D.-J.W.) and Advanced Imaging Research Center (W.D.R.), Oregon Health & Science University, Portland; and Children's Hospital of Philadelphia (A.T.H.), PA.
Neurology. 2020 Mar 3;94(9):e897-e909. doi: 10.1212/WNL.0000000000009012. Epub 2020 Feb 5.
To investigate the potential of lower extremity magnetic resonance (MR) biomarkers to serve as endpoints in clinical trials of therapeutics for Duchenne muscular dystrophy (DMD) by characterizing the longitudinal progression of MR biomarkers over 48 months and assessing their relationship to changes in ambulatory clinical function.
One hundred sixty participants with DMD were enrolled in this longitudinal, natural history study and underwent MR data acquisition of the lower extremity muscles to determine muscle fat fraction (FF) and MRI T biomarkers of disease progression. In addition, 4 tests of ambulatory function were performed. Participants returned for follow-up data collection at 12, 24, 36, and 48 months.
Longitudinal analysis of the MR biomarkers revealed that vastus lateralis FF, vastus lateralis MRI T, and biceps femoris long head MRI T biomarkers were the fastest progressing biomarkers over time in this primarily ambulatory cohort. Biomarker values tended to demonstrate a nonlinear, sigmoidal trajectory over time. The lower extremity biomarkers predicted functional performance 12 and 24 months later, and the magnitude of change in an MR biomarker over time was related to the magnitude of change in function. Vastus lateralis FF, soleus FF, vastus lateralis MRI T, and biceps femoris long head MRI T were the strongest predictors of future loss of function, including loss of ambulation.
This study supports the strong relationship between lower extremity MR biomarkers and measures of clinical function, as well as the ability of MR biomarkers, particularly those from proximal muscles, to predict future ambulatory function and important clinical milestones.
NCT01484678.
通过描述下肢磁共振（MR）生物标志物在 48 个月内的纵向进展，并评估其与步行临床功能变化的关系，来探讨其作为杜氏肌营养不良症（DMD）治疗药物临床试验终点的潜力。
本纵向、自然史研究纳入了 160 名 DMD 患者，他们接受了下肢肌肉的 MR 数据采集，以确定肌肉脂肪分数（FF）和疾病进展的 MRI T 生物标志物。此外，还进行了 4 项步行功能测试。参与者在 12、24、36 和 48 个月时返回进行随访数据采集。
MR 生物标志物的纵向分析显示，在这个主要为步行的队列中，股外侧肌 FF、股外侧肌 MRI T 和股二头肌长头 MRI T 生物标志物是随时间推移进展最快的生物标志物。生物标志物值随时间呈非线性、类正弦轨迹变化。下肢生物标志物可预测 12 个月和 24 个月后的功能表现，且随时间变化的生物标志物的变化幅度与功能变化幅度相关。股外侧肌 FF、比目鱼肌 FF、股外侧肌 MRI T 和股二头肌长头 MRI T 是预测未来功能丧失（包括丧失步行能力）的最强生物标志物。
本研究支持下肢 MR 生物标志物与临床功能测量之间的密切关系，以及 MR 生物标志物（尤其是来自近端肌肉的生物标志物）预测未来步行功能和重要临床里程碑的能力。
临床试验.gov 标识符：NCT01484678。
