Maxwell Dain L, Orian Jacqueline M
Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, School of Agriculture, Biomedicine and Environment, La Trobe University, Bundoora, VIC, Australia.
Department of Anatomy and Neuroscience, The University of Melbourne, Parkville, VIC, Australia.
J Cent Nerv Syst Dis. 2023 Nov 6;15:11795735231211508. doi: 10.1177/11795735231211508. eCollection 2023.
Recent decades have witnessed significant progress in understanding mechanisms driving neurodegeneration and disease progression in multiple sclerosis (MS), but with a focus on the cerebrum. In contrast, there have been limited studies of cerebellar disease, despite the common occurrence of cerebellar symptoms in this disorder. These rare studies, however, highlight the early cerebellar involvement in disease development and an association between the early occurrence of cerebellar lesions and risk of worse prognosis. In parallel developments, it has become evident that far from being a region specialized in movement control, the cerebellum plays a crucial role in cognitive function, via circuitry connecting the cerebellum to association areas of the cerebrum. This complexity, coupled with challenges in imaging of the cerebellum have been major obstacles in the appreciation of the spatio-temporal evolution of cerebellar damage in MS and correlation with disability and progression. MS studies based on animal models have relied on an induced neuroinflammatory disease known as experimental autoimmune encephalomyelitis (EAE), in rodents and non-human primates (NHP). EAE has played a critical role in elucidating mechanisms underpinning tissue damage and been validated for the generation of proof-of-concept for cerebellar pathological processes relevant to MS. Additionally, rodent and NHP studies have formed the cornerstone of current knowledge of functional anatomy and cognitive processes. Here, we propose that improved insight into consequences of cerebellar damage in MS at the functional, cellular and molecular levels would be gained by more extensive characterization of EAE cerebellar pathology combined with the power of experimental paradigms in the field of cognition. Such combinatorial approaches would lead to improved potential for the development of MS sensitive markers and evaluation of candidate therapeutics.
近几十年来，在理解多发性硬化症（MS）中驱动神经退行性变和疾病进展的机制方面取得了重大进展，但重点是大脑。相比之下，尽管小脑症状在这种疾病中很常见，但对小脑疾病的研究却很有限。然而，这些为数不多的研究强调了小脑在疾病发展早期就受到影响，以及小脑病变的早期出现与预后较差风险之间的关联。与此同时，越来越明显的是，小脑远非一个专门负责运动控制的区域，它通过连接小脑与大脑联合区域的神经回路，在认知功能中发挥着关键作用。这种复杂性，再加上小脑成像方面的挑战，一直是理解MS中小脑损伤的时空演变以及与残疾和疾病进展相关性的主要障碍。基于动物模型的MS研究依赖于一种在啮齿动物和非人类灵长类动物（NHP）中诱发的神经炎症性疾病，即实验性自身免疫性脑脊髓炎（EAE）。EAE在阐明组织损伤的潜在机制方面发挥了关键作用，并已被验证可用于生成与MS相关的小脑病理过程的概念验证。此外，啮齿动物和NHP研究构成了当前功能解剖学和认知过程知识的基石。在此，我们提出，通过更广泛地表征EAE小脑病理学，并结合认知领域实验范式的力量，可以在功能、细胞和分子水平上更好地洞察MS中小脑损伤的后果。这种组合方法将提高开发MS敏感标志物和评估候选治疗方法的潜力。
