Plank Julia R, Gozdas Elveda, Bruno Jennifer, McGhee Chloe A, Wu Hua, Raman Mira M, Saggar Manish, Green Tamar
Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, 1520 Page Mill Road, Palo Alto, CA 94304, USA.
Center for Cognitive and Neurobiological Imaging, Stanford University, Stanford, CA 94305, USA.
medRxiv. 2025 Feb 26:2025.02.25.25322881. doi: 10.1101/2025.02.25.25322881.
Evidence suggests pathological roles of myelination in neurodevelopmental disorders, but our understanding is limited. We investigated quantitative T1 mapping (QT1) as a clinically feasible tool for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).
We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 measures of myelin content included the macromolecular tissue volume (MTV) in white matter and R1 (1/T1 relaxation) of the cortex. For white matter, we assessed between-groups differences across 39 tracts. For cortical R1, we used principal components analysis to reduce dimensionality and capture myelination patterns across 360 regions. A multivariate ANOVA assessed differences across principal components. Finally, a support vector machine (SVM) identified the most discriminative features between TD and RASopathies.
Thirty-four of 39 tracts were higher in MTV in RASopathies relative to TD ( <.05), indicating widespread elevation in myelination. Our MANOVA revealed a group effect on cortical R1 (=.002, =.028), suggesting cortical myelination differences between-groups. SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between-groups.
We found widespread elevated myelin in white matter tracts and region-dependent patterns of cortical myelination in children with RASopathies. QT1 enabled us to leverage preclinical models showing oligodendrocyte dysfunction to uncover the myelination pattern in the developing human brain. Using QT1, myelin represents a promising treatment target that can be identified and monitored in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.
有证据表明髓鞘形成在神经发育障碍中具有病理作用，但我们对此的了解有限。我们研究了定量T1映射（QT1）作为一种临床可行的工具，用于测量患有RAS-MAPK信号通路神经发育障碍（RAS病）儿童的髓鞘形成情况。
我们收集了72名儿童（49名患有RAS病，23名发育正常（TD））的QT1、扩散加权和结构MRI扫描数据。髓鞘含量的QT1测量指标包括白质中的大分子组织体积（MTV）和皮质的R1（1/T1弛豫）。对于白质，我们评估了39条纤维束之间的组间差异。对于皮质R1，我们使用主成分分析来降维和捕捉360个区域的髓鞘形成模式。多变量方差分析评估主成分之间的差异。最后，支持向量机（SVM）确定了TD组和RAS病组之间最具区分性的特征。
相对于TD组，RAS病组39条纤维束中有34条的MTV更高（P<.05），表明髓鞘形成普遍增加。我们的多变量方差分析显示组间对皮质R1有影响（F =.002，ηp2 =.028），表明组间皮质髓鞘形成存在差异。SVM的准确率为87%，并确定认知和皮质R1特征是组间最具区分性的特征。
我们发现患有RAS病的儿童白质纤维束中髓鞘广泛增加，且皮质髓鞘形成存在区域依赖性模式。QT1使我们能够利用显示少突胶质细胞功能障碍的临床前模型，揭示发育中人类大脑的髓鞘形成模式。使用QT1，髓鞘代表了一个有前景的治疗靶点，可在神经发育障碍中进行识别和监测，为推进当前治疗策略提供了巨大潜力。
