Toward a validated in vivo imaging marker of axonal damage predictive of progressive disability in multiple sclerosis

摘要 轴突损伤发生在多发性硬化症的早期，被认为是进行性疾病的病理基础 残疾。与急性和慢性脱髓鞘有关的轴突丢失的时空动力学不是很好。 在患者、病变类型和外观正常的白质内具有特征性且可能不同。 (NAWM)。随着以髓鞘再生为靶点的有前景的治疗方法的出现，非侵入性成像标记物 需要对轴突病理有更高的特异性，以提高我们对MS疾病进展的理解。 多发性硬化症组织的组织病理学分析证实，病变内轴突密度显著降低， NAWM伴有一系列轴突结构的形态改变，包括 卵形、肿胀、变薄和横切。我们已经证明了轴突肿胀和 利用300mT/m梯度的高梯度弥散磁共振成像显示多发性硬化症患者的胼胝体丢失 Connectome扫描仪用于体内轴突结构显微评估的优势。 我们的目标是通过纵向调查和 与组织病理学的系统比较，以更好地了解空间和时间 多发性硬化轴突变性的演变及影响疾病进展的致病因素。我们 假设慢性脱髓鞘导致轴突肿胀和最终脱落，可以检测到 高梯度弥散成像增加轴突大小，降低轴突密度，轴突程度 整个大脑的形态变化反映了进行性轴突功能障碍，表现为进行性 临床残疾。我们将进行一项纵向成像研究，以确定 MS病变和全脑NAWM的脱髓鞘和进行性轴突结构病理改变。 我们将评估脱髓鞘和轴突损伤对进行性脑脊髓炎发展的相对影响。 多发性硬化症的身体残疾和认知功能障碍与克利夫兰诊所的研究人员合作，我们 将校准和改进MS病变和NAWM中轴突直径和密度的弥散磁共振测量 尸检多发性硬化症脑组织轴突直径和密度的组织病理学测量。 尸检标本中轴突缺失的发生率，以及缺乏可靠的轴突生物标志物 在活着的患者中丢失，加强了对轴突变性的有效成像关联的需要，该成像关联将 使我们能够实时跟踪轴突结构的变化，而不是在尸检标本的末期。 绘制MS患者轴突直径分布的高梯度dMRI技术将使我们能够证实 病理观察轴突直径的变化。这项研究产生的数据将推动我们的 认识轴突损伤在MS发病机制中的作用并促进临床的发展 可用轴突结构病理活体成像标记物帮助患者选择和评估 MS患者神经保护治疗试验中的治疗反应

SUMMARY Axonal damage occurs early in multiple sclerosis and is considered the pathologic substrate of progressive disability. The spatiotemporal dynamics of axonal loss in relation to acute and chronic demyelination are not well characterized and likely vary between patients, lesion types, and within the normal-appearing white matter (NAWM). With the emergence of promising therapies targeting remyelination, noninvasive imaging markers with greater specificity to axonal pathology are needed to improve our understanding of disease progression in MS. Histopathological analyses of MS tissue have confirmed significant reductions in axon density within lesions and NAWM accompanied by a range of morphological alterations in axonal structure, including the appearance of ovoids, swelling, thinning, and transection. We have demonstrated the imaging correlates of axonal swelling and loss in the corpus callosum of MS patients using high-gradient diffusion MRI, leveraging the 300 mT/m gradient strengths on the Connectome scanner for the in vivo microscopic assessment of axonal structure. Our goal is to validate these cross-sectional imaging findings through longitudinal investigation and systematic comparison against histopathology to gain a better understanding of the spatial and temporal evolution of axonal degeneration in MS and the pathogenic factors influencing disease progression. We hypothesize that chronic demyelination leads to axonal swelling and eventual dropout that can be detected as increased axonal size and decreased density by high-gradient diffusion MRI, and that the degree of axonal morphologic change throughout the brain reflects progressive axonal dysfunction and manifests as progressive clinical disability. We will pursue a longitudinal imaging study to determine the relationship between demyelination and progressive axonal structural pathology in MS lesions and NAWM throughout the whole brain. We will evaluate the relative influence of demyelination and axonal damage on the development of progressive physical disability and cognitive dysfunction in MS. In collaboration with investigators at the Cleveland Clinic, we will calibrate and refine diffusion MRI measures of axon diameter and density in MS lesions and NAWM against axon diameter and density measurements from histopathology in postmortem MS brain tissue. The prevalence of axonal loss in postmortem samples, and the absence of a reliable biomarker for axonal loss in living patients, reinforces the need for a validated imaging correlate of axonal degeneration that would allow us to track changes in axonal structure in real time rather than at their end stage on autopsy specimens. High-gradient dMRI techniques that map axon diameter distributions in MS patients will enable us to corroborate the changes in axon diameter observed on pathology. The data generated from this study will advance our understanding of the role of axonal damage in the pathogensis of MS and facilitate the development of clinically usable in vivo imaging markers of axonal structural pathology to aid in patient selection and assessment of treatment response in trials of neuroprotective therapies in MS.