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

总结 轴突损伤发生在多发性硬化的早期，被认为是进行性硬化的病理基础。 残疾。轴突缺失与急性和慢性脱髓鞘的时空动态关系尚不清楚 特征性的并且可能在患者之间、病变类型之间以及在正常外观的白色物质内变化 （NAWM）。随着靶向髓鞘再生的有希望的疗法的出现， 需要对轴突病理学有更高的特异性，以提高我们对MS疾病进展的理解。 MS组织的组织学分析已经证实了病变内轴突密度的显著降低， NAWM伴随着轴突结构的一系列形态学改变，包括 卵形、肿胀、变薄和横切。我们已经证明了轴突肿胀的影像学相关性， 使用高梯度扩散MRI（利用300 mT/m梯度）的MS患者胼胝体丢失 用于轴突结构的体内显微镜评估的Connectome扫描仪上的强度。 我们的目标是通过纵向研究来验证这些横断面成像结果， 与组织病理学进行系统比较，以更好地了解空间和时间 MS中轴突变性的演变以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， 高梯度扩散MRI显示轴突体积增大，密度降低， 整个大脑的形态学变化反映了进行性轴突功能障碍， 临床残疾我们将进行纵向成像研究，以确定 脱髓鞘和进行性轴突结构病理在MS病变和NAWM整个脑。 我们将评估脱髓鞘和轴突损伤对进行性脊髓损伤的发展的相对影响。 身体残疾和认知功能障碍的MS.在与克利夫兰诊所的研究人员合作，我们 将校准和完善MS病变和NAWM中轴突直径和密度的弥散MRI测量， 来自死后MS脑组织中的组织病理学的轴突直径和密度测量。 尸检样本中轴突缺失的普遍性，以及缺乏轴突缺失的可靠生物标志物， 存活患者的死亡，加强了对轴突变性的有效成像相关性的需要， 使我们能够在真实的时间内追踪轴突结构的变化，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 病理学观察轴突直径的变化。这项研究产生的数据将推动我们的 了解轴索损伤在MS发病机制中的作用，促进临床 可用于轴突结构病理学的体内成像标记物，以帮助患者选择和评估 MS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.