From Translational Imaging in Neurology (ThINk) Basel, Department of Biomedical Engineering, Faculty of Medicine (A. Cagol, L.M.-G., S.L., C.T., M.B., R.G., P.-J.L., M.W., E.R., E.-W.R., Ö.Y., L.K., C. Granziera), Neurologic Clinic and Policlinic, MS Center and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) (A. Cagol, L.M.-G., C.T., M.B., R.G., P.-J.L., M.W., E.R.,O.Y., J.O., J.L., M.D.S., B.F.-B., T.D., D.L., L.K., J.K., C. Granziera), Department of Clinical Research (P.B., S.A.S.), Division of Radiological Physics, Department of Radiology (M.W.), and Division of Diagnostic and Interventional Neuroradiology, Clinic for Radiology and Nuclear Medicine (J.M.L.), University Hospital Basel, University of Basel, Switzerland; Translational Neuroradiology Section (C.T), National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD; Medical Image Analysis Center (MIAC) and Quantitative Biomedical Imaging Group (qbig), Department of Biomedical Engineering (E.R., P.C.C.), University Basel; Departments of Neurology (S.M., J.V.) and Radiology (J.W.), Cantonal Hospital St. Gallen; Departments of Neurology (L.A., O.F.) and Radiology (L.R.), Cantonal Hospital Aarau; Departments of Neurology (G.D., C.Z., C.G.) and Neuroradiology (E.P.), Neurocenter of Southern Switzerland, Lugano; Departments of Neurology, Inselspital (A. Chan, A.S.), and Diagnostic and Interventional Neuroradiology, Inselspital (F.W.) Bern University Hospital and University of Bern; Departments of Clinical Neurosciences, Division of Neurology (C.P., R.A.D.P.), and Radiology (R.A.D.P.) Lausanne University Hospital and University of Lausanne; Department of Clinical Neurosciences, Division of Neurology (C.B., P.H.L.), and Radiology (M.I.V.) Geneva University Hospitals and Faculty of Medicine; Faculty of Biomedical Sciences (C.Z.), Università della Svizzera Italiana, Lugano, Switzerland; Institute of Experimental Neurology, Division of Neuroscience (M.A.); Vita-Salute San Raffaele University and Hospital, Milan, Italy.
Neurology. 2024 Jan 9;102(1):e207768. doi: 10.1212/WNL.0000000000207768. Epub 2023 Dec 13.
Progression independent of relapse activity (PIRA) is a crucial determinant of overall disability accumulation in multiple sclerosis (MS). Accelerated brain atrophy has been shown in patients experiencing PIRA. In this study, we assessed the relation between PIRA and neurodegenerative processes reflected by (1) longitudinal spinal cord atrophy and (2) brain paramagnetic rim lesions (PRLs). Besides, the same relationship was investigated in progressive MS (PMS). Last, we explored the value of cross-sectional brain and spinal cord volumetric measurements in predicting PIRA.
From an ongoing multicentric cohort study, we selected patients with MS with (1) availability of a susceptibility-based MRI scan and (2) regular clinical and conventional MRI follow-up in the 4 years before the susceptibility-based MRI. Comparisons in spinal cord atrophy rates (explored with linear mixed-effect models) and PRL count (explored with negative binomial regression models) were performed between: (1) relapsing-remitting (RRMS) and PMS phenotypes and (2) patients experiencing PIRA and patients without confirmed disability accumulation (CDA) during follow-up (both considering the entire cohort and the subgroup of patients with RRMS). Associations between baseline MRI volumetric measurements and time to PIRA were explored with multivariable Cox regression analyses.
In total, 445 patients with MS (64.9% female; mean [SD] age at baseline 45.0 [11.4] years; 11.2% with PMS) were enrolled. Compared with patients with RRMS, those with PMS had accelerated cervical cord atrophy (mean difference in annual percentage volume change [MD-APC] -1.41; = 0.004) and higher PRL load (incidence rate ratio [IRR] 1.93; = 0.005). Increased spinal cord atrophy (MD-APC -1.39; = 0.0008) and PRL burden (IRR 1.95; = 0.0008) were measured in patients with PIRA compared with patients without CDA; such differences were also confirmed when restricting the analysis to patients with RRMS. Baseline volumetric measurements of the cervical cord, whole brain, and cerebral cortex significantly predicted time to PIRA (all ≤ 0.002).
Our results show that PIRA is associated with both increased spinal cord atrophy and PRL burden, and this association is evident also in patients with RRMS. These findings further point to the need to develop targeted treatment strategies for PIRA to prevent irreversible neuroaxonal loss and optimize long-term outcomes of patients with MS.
与复发活动无关的进展（PIRA）是多发性硬化症（MS）中总体残疾累积的关键决定因素。已有研究表明，经历 PIRA 的患者存在脑萎缩加速。本研究通过（1）纵向脊髓萎缩和（2）脑顺磁性边缘病变（PRLs）评估了 PIRA 与神经退行性过程之间的关系。此外，我们还在进展性 MS（PMS）中探讨了同样的关系。最后，我们探讨了横断面脑和脊髓容积测量值在预测 PIRA 中的价值。
从一项正在进行的多中心队列研究中，我们选择了具有以下特征的 MS 患者：（1）存在基于敏感性的 MRI 扫描，以及（2）在基于敏感性的 MRI 前 4 年内有定期的临床和常规 MRI 随访。通过线性混合效应模型比较脊髓萎缩率（RRMS 和 PMS 表型之间）和 PRL 计数（负二项回归模型），通过多变量 Cox 回归分析比较基线 MRI 容积测量值与 PIRA 之间的关系。
共纳入 445 名 MS 患者（64.9%为女性；基线时平均[SD]年龄为 45.0[11.4]岁；11.2%为 PMS）。与 RRMS 患者相比，PMS 患者颈髓萎缩加速（年百分比体积变化平均差值[MD-APC]-1.41； = 0.004），PRL 负荷更高（发病率比[IRR]1.93； = 0.005）。与无残疾累积（CDA）的患者相比，经历 PIRA 的患者脊髓萎缩增加（MD-APC-1.39； = 0.0008），PRL 负担加重（IRR 1.95； = 0.0008）；当将分析限制在 RRMS 患者时，也得到了相同的结果。颈髓、全脑和大脑皮质的基线容积测量值显著预测 PIRA 发生时间（所有 P≤0.002）。
本研究结果表明，PIRA 与脊髓萎缩增加和 PRL 负担增加有关，RRMS 患者中也存在这种关联。这些发现进一步表明，需要制定针对 PIRA 的靶向治疗策略，以防止不可逆的神经轴突丢失，优化 MS 患者的长期结局。
