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The T1-Weighted/T2-Weighted Ratio as an In Vivo Proxy for Reduced Intracortical Myelin Content in Youth With
Julia R Plank1, Sara K Pardej1, Mira M Raman1
1Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California.
Background:
Myelin may represent a modifiable treatment target in neurodevelopmental disorders, but accessible in vivo tools for assessing myelin alterations in clinical settings are limited. The T1-weighted/T2-weighted (T1w/T2w) ratio, derived from standard magnetic resonance imaging (MRI), offers a proxy for cortical myelin and may aid in detecting abnormalities. Leveraging a genetics-first approach, we tested whether youth with RASopathies, neurodevelopmental disorders caused by RAS-MAPK (mitogen-activated protein kinase) variants, show differences in cortical myelin measured using T1w/T2w ratios compared with typically developing (TD) peers.
Methods:
In this prospective study, 112 youth (86 with RASopathies, 26 TD; ages 6-17 years) completed T1w and T2w MRI scans and NIH Toolbox cognitive assessments; parent-rated mobility and strength impact scores were also collected. T1w/T2w ratios were calculated at cortical depths in FreeSurfer, and average values were extracted from 68 regions of interest (ROIs). Group differences were assessed using analysis of covariance with false discovery rate (FDR) correction. Correlations between regional T1w/T2w ratios and mobility, strength, and cognitive scores were examined.
Results:
Widespread decreases in T1w/T2w ratios were found in the RASopathies group compared with the TD group. Among ratios sampled at mid-depth, 63 of 68 cortical ROIs were reduced in individuals with RASopathies (pFDR < .050). An analysis controlling for the global mean T1w/T2w ratio identified 6 ROIs with reductions beyond the global cortical effect (pFDR < .050). Higher ratios were associated with better strength impact (ps = .001-.005) and mobility (ps = .023-.045) but not cognitive scores (ps = .059-.716).
Conclusions:
The T1w/T2w ratio may serve as a sensitive tool for detecting microstructural alterations in genetically defined neurodevelopmental disorders. Future work is needed to clarify the biological underpinnings and clinical relevance of T1w/T2w ratios for cognitive and functional outcomes.
