Kalman Bernadette, Leist Thomas P
SLRHC Columbia University, Department of Neurology, Multiple Sclerosis Research Center, New York, NY 10019, USA.
Neuromolecular Med. 2003;3(3):147-58. doi: 10.1385/NMM:3:3:147.
Neurodegeneration is the main pathological correlate of accumulating disability in progressive stages of Multiple Sclerosis (MS), but both histologic and imaging studies detect significant tissue loss even in early disease. These observations raise the question as to whether neurodegeneration in MS is a primary mechanism or whether it develops secondary to inflammation and demyelination. Recent data suggest that the atrophy of brain and cord is directly linked to inflammation and may partly be independent of demyelination. Released products of both residential and infiltrating immune cells can induce ultrastructural changes and celldeath by multiple mechanism. We propose that the inflammation-induced tissue response is controlled by genetic variations and to some extent involves a mitochondrion-driven mechanism in MS, similar to that described in the final pathway of other neurodegenerative disorders. Current therapeutic strategies primarily target the immune system which results in a successful down-regulation of plaque formation and of relapse rate. However, measures of clinical disability best correlate with the degree of neurodegeneration rather than with the volume of plaques, and these immune-modulating regimens may only incompletely affect the accumulating tissue loss. Considering the need for additional therapeutic strategies, we emphasize the degenerative components, and review a mitochondrial mechanism of tissue loss potentially involved in the process of MS.
神经退行性变是多发性硬化症（MS）进展期残疾累积的主要病理相关因素，但组织学和影像学研究均发现，即使在疾病早期也存在明显的组织损失。这些观察结果引发了一个问题，即MS中的神经退行性变是一种原发性机制，还是继发于炎症和脱髓鞘。最近的数据表明，脑和脊髓的萎缩与炎症直接相关，并且可能部分独立于脱髓鞘。驻留和浸润免疫细胞释放的产物可通过多种机制诱导超微结构变化和细胞死亡。我们提出，炎症诱导的组织反应受基因变异控制，并且在某种程度上涉及MS中的线粒体驱动机制，类似于其他神经退行性疾病最终途径中所描述的机制。目前的治疗策略主要针对免疫系统，这导致斑块形成和复发率成功下调。然而，临床残疾的测量指标与神经退行性变程度的相关性最佳，而不是与斑块体积相关，并且这些免疫调节方案可能只能不完全影响累积的组织损失。考虑到需要额外的治疗策略，我们强调退行性成分，并综述了MS过程中可能涉及的组织损失的线粒体机制。
