A translational MRI approach to validate acute axonal damage detection as an early event in multiple sclerosis.
A translational MRI approach to validate acute axonal damage detection as an early event in multiple sclerosis.
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DOI：
10.7554/elife.79169
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发表时间：
2024-01-09
期刊：
影响因子：
7.7
通讯作者：
De Santis S
中科院分区：
文献类型：
--
作者：
Cerdán Cerdá A;Toschi N;Treaba CA;Barletta V;Herranz E;Mehndiratta A;Gomez-Sanchez JA;Mainero C;De Santis S
轴索变性是多发性硬化症的中心病理特征，与不可逆转的临床残疾密切相关。目前在活体内检测轴突损伤的非侵入性方法在其特异性和临床适用性方面存在局限性，并且缺乏适当的验证。我们的目标是验证一种MRI框架，该框架基于对存在轴突病理的大鼠扩散信号(AxCaliber)的多间隔建模，通过注射破坏轴突神经末梢的神经毒素来实现。然后，我们应用相同的MRI方案来绘制多发性硬化症复发缓解期患者和年龄匹配的健康对照组的大脑轴突完整性图。AxCaliber对大鼠的急性轴突损伤很敏感，靶束上的平均轴突直径显著增加，这与神经丝染色有关。电子显微镜证实平均轴突直径增大与急性轴突病理有关。在患有多发性硬化症的人类中，我们发现在大多数看起来正常的白质区域，平均轴突口径弥漫性增加，优先影响病程较短的患者。我们的结果表明，基于MRI的轴突直径标记物是一种敏感和特异的成像生物标记物，它将非侵入性成像与潜在的生物底物进行对比，揭示了多发性硬化症的全身性轴突损害是一种早期事件。
Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.
影响因子：
4.3
作者：
Barakovic, Muhamed;Pizzolato, Marco;Tax, Chantal M. W.;Rudrapatna, Umesh;Magon, Stefano;Dyrby, Tim B.;Granziera, Cristina;Thiran, Jean-Philippe;Jones, Derek K.;Canales-Rodriguez, Erick J.
通讯作者：
Canales-Rodriguez, Erick J.