Plank Julia R, Pardej Sara K, Raman Mira M, McNab Jennifer, Green Tamar
Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University, 1520 Page Mill Road, Palo Alto, CA 94304, USA.
Department of Radiology, Stanford University, Stanford, CA, USA.
medRxiv. 2025 Sep 18:2025.09.16.25335916. doi: 10.1101/2025.09.16.25335916.
Myelin may represent a modifiable treatment target in neurodevelopmental disorders, however, a reliable tool for assessment of myelin alterations in clinical settings is needed. Prior work shows commonly acquired T1-weighted (T1w) and T2-weighted (T2w) scans can be transformed into ratio maps and subsequently provide a reasonable estimate of cortical myelin content. We investigated T1w/T2w ratios for measuring cortical myelin in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway.
In this prospective study, 112 children (86 RASopathies, 26 typical developing (TD), aged 6-17 years) completed T1w and T2w MRI scans and NIH Toolbox cognitive assessments. Parent-rated mobility and strength impact scores were also acquired. T1w/T2w ratio maps were calculated at three levels of the cortex in FreeSurfer, and average values were extracted from 68 regions-of-interest (ROIs) at each level across the brain and from eight subcortical ROIs. Group differences were assessed using analyses of covariance, including a false discovery rate adjustment for multiple comparisons. As an exploratory analysis, differences in cognitive scores and parent-rated health were assessed across quartiles of whole-brain T1w/T2w ratios.
Widespread decreases in T1w/T2w ratios were found in the RASopathies group, suggesting decreased cortical myelin content. Of the T1w/T2w ratios sampled along the midline, 63 of 68 cortical ROIs were significantly reduced in RASopathies ( <.050). Of the subcortical ROIs, only the T1w/T2w ratio in the accumbens was significantly reduced in RASopathies compared to TD (Cohen's =0.520, =.024). Exploratory quartile analyses across the whole sample indicated significant effects of T1w/T2w ratio quartile on mobility (=.002) and strength impact ratings (<.001), such that subjects in higher T1w/T2w ratio quartiles had better physical health ratings.
These results support the utility of T1w/T2w ratio mapping as a sensitive tool for detecting cortical myelin alterations in genetically defined neurodevelopmental disorders. Exploratory analyses suggest a relationship between cortical myelin content and physical mobility and stamina. Future work should explore the clinical relevance of these findings for cognitive and functional outcomes and assess their potential as biomarkers for targeted therapeutic interventions.
髓磷脂可能是神经发育障碍中一个可改变的治疗靶点，然而，临床环境中评估髓磷脂改变的可靠工具是必要的。先前的研究表明，常见的T1加权（T1w）和T2加权（T2w）扫描可以转换为比率图，并随后对皮质髓磷脂含量提供合理估计。我们研究了T1w/T2w比率在测量RAS-MAPK信号通路神经发育障碍儿童皮质髓磷脂中的作用。
在这项前瞻性研究中，112名儿童（86名患有RAS病，26名发育正常（TD），年龄6至17岁）完成了T1w和T2w MRI扫描以及美国国立卫生研究院工具箱认知评估。还获取了家长评定的运动和力量影响评分。在FreeSurfer中计算皮质三个层面的T1w/T2w比率图，并从全脑每个层面的68个感兴趣区域（ROI）以及八个皮质下ROI中提取平均值。使用协方差分析评估组间差异，包括对多重比较进行错误发现率调整。作为探索性分析，在全脑T1w/T2w比率的四分位数中评估认知分数和家长评定健康状况的差异。
在RAS病组中发现T1w/T2w比率普遍降低，表明皮质髓磷脂含量减少。在沿中线采样的T1w/T2w比率中，RAS病组68个皮质ROI中的63个显著降低（P<.050）。在皮质下ROI中，与TD组相比，RAS病组仅伏隔核中的T1w/T2w比率显著降低（Cohen's d =0.520，P =.024）。对整个样本进行的探索性四分位数分析表明，T1w/T2w比率四分位数对运动能力（P =.002）和力量影响评分（P<.001）有显著影响，即T1w/T2w比率四分位数较高的受试者身体健康评分较好。
这些结果支持T1w/T2w比率映射作为检测基因定义的神经发育障碍中皮质髓磷脂改变的敏感工具的实用性。探索性分析表明皮质髓磷脂含量与身体运动能力和耐力之间存在关联。未来的工作应探索这些发现对认知和功能结果的临床相关性，并评估它们作为靶向治疗干预生物标志物的潜力。
