The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with in situ postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.

进行性多发性硬化症 (PMS) 中导致神经功能障碍的致病机制尚不清楚。骨髓皮质 MS (MCMS) 中与脑白质 (WM) 脱髓鞘无关的皮质神经元丢失以及对具有广泛皮质萎缩和与复发活动无关的残疾进展 (PIRA) 的 MS 患者的识别支持了除脑 WM 脱髓鞘之外的致病机制。在死后 MCMS 大脑中研究了有髓鞘 T2 病变的三维分布和潜在病理学。来自先前表征的 MCMS（10 例）和典型 MS (TMS) 病例（12 例）的死后脑切片与原位死后 T2 高信号和 T1 低信号共同记录。 T1 强度阈值用于建立区分 MCMS 和 TMS 的分类器。该分类器在 36 个未表征的死后大脑中进行了验证，并应用于参加 SPRINT-MS 的 255 名活着的 PMS 参与者的基线 MRI。死后 MCMS 大脑中的有髓鞘 T2 高信号具有连续的脑室周围分布，在侧脑室枕极处扩展，观察到有髓鞘轴突变性的表面梯度。 MRI 分类器区分病理证实的死后 MCMS 和 TMS 病例的准确度为 94%。对于 SPRINT-MS 患者，MRI 分类器识别出 78% 为 TMS，10% 为 MCMS，12% 为少量脑 T1 和 T2 强度。在 SPRINT-MS 中，MCMS 和 TMS 队列中扩大的残疾状态量表和脑萎缩测量结果相似。 22% 的活着的 PMS 患者中很少有脑 WM 脱髓鞘，这引发了关于脑 WM 脱髓鞘在所有 MS 患者残疾进展中的主要作用的问题，并且对 MS 患者的临床管理和 PMS 的临床试验结果具有影响。室周有髓纤维变性为多发性硬化症神经变性的表面梯度提供了额外的支持。