Disability independent of cerebral white matter demyelination in progressive multiple sclerosis

IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Acta Neuropathologica Pub Date : 2024-08-31 DOI:10.1007/s00401-024-02796-w
Vikas Singh, Yufan Zheng, Daniel Ontaneda, Kedar R Mahajan, Jameson Holloman, Robert J Fox, Kunio Nakamura, Bruce D Trapp
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Abstract

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.

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进行性多发性硬化症患者的残疾与脑白质脱髓鞘无关
人们对导致进行性多发性硬化症(PMS)神经系统残疾的致病机制知之甚少。脊髓皮质多发性硬化症(MCMS)中独立于大脑白质(WM)脱髓鞘的皮质神经元缺失,以及具有广泛皮质萎缩和独立于复发活动(PIRA)的残疾进展的多发性硬化症患者的鉴定,都支持大脑WM脱髓鞘以外的致病机制。研究人员对多发性硬化症死后大脑中髓鞘化 T2 病变的三维分布和潜在病理进行了调查。对先前定性的 MCMS(10 例)和典型 MS(TMS)病例(12 例)的死后脑切片与原位死后 T2 高密度和 T1 低密度进行了共同登记。利用 T1 强度阈值建立了区分 MCMS 和 TMS 的分类器。该分类器在 36 个未定性的死后大脑中进行了验证,并应用于参加 SPRINT-MS 的 255 名在世 PMS 患者的基线 MRI。MCMS死后大脑中的髓质T2高密度呈连续的脑室周围分布,并在侧脑室枕极扩展,在该处观察到髓质轴突变性的由表及里梯度。核磁共振成像分类器能区分经病理证实的尸检MCMS和TMS病例,准确率高达94%。对于 SPRINT-MS 患者,核磁共振成像分类器将 78% 识别为 TMS,10% 识别为 MCMS,12% 识别为大脑 T1 和 T2 强度不足。在 SPRINT-MS 中,MCMS 和 TMS 组群的扩展残疾状况量表和脑萎缩测量结果相似。22%的在世多发性硬化症患者存在大脑WM脱髓鞘现象,这让人怀疑大脑WM脱髓鞘在所有多发性硬化症患者的残疾进展中是否起主要作用,并对多发性硬化症患者的临床管理和多发性硬化症的临床试验结果产生了影响。脑室周围髓鞘纤维变性为多发性硬化症神经退行性变的表里梯度提供了更多支持。
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来源期刊
Acta Neuropathologica
Acta Neuropathologica 医学-病理学
CiteScore
23.70
自引率
3.90%
发文量
118
审稿时长
4-8 weeks
期刊介绍: Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.
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