Comment on “Diagnostic Potential of Macromolecular Proton Fraction Mapping Combined with Quantitative Susceptibility Mapping as a Subcortical Biomarker for Parkinson’s Disease” by Fujiwara et al.

To the Editor, I read with great interest the recent article by Fujiwara et al. 1 describing the integration of macromolecular proton fraction (MPF) mapping with quantitative susceptibility mapping (QSM) as a composite subcortical biomarker for Parkinson's disease (PD).The authors should be commended for exploring this innovative multiparametric approach.However, we wish to highlight several aspects that merit further consideration before these findings can be generalized.First, the study cohort (20 PD patients and 9 controls) is relatively small, and no power calculation was presented.Given the high interindividual variability in both MPF and QSM metrics, the limited sample size may overestimate diagnostic separation.Larger, multicenter cohorts would be necessary to validate reproducibility and normative thresholds.Second, while MPF and QSM individually capture complementary tissue microstructure and iron load, 2,3 the physiological interpretation of their combined alterations remains ambiguous.The observed correlations could reflect non-specific iron and myelin interactions rather than diseasespecific pathology.Clarifying the biological basis, possibly through phantom validation or histopathologic correlation, would strengthen the mechanistic inference.4 Third, the study lacks discussion on cross-vendor and field-strength harmonization.Both MPF and QSM are highly sensitive to sequence parameters and reconstruction pipelines, so without inter-scanner reproducibility testing, clinical translation remains uncertain.Providing raw data ranges or coefficients of variation would enhance transparency and comparability. 2 Finally, it would be valuable to contextualize these results against existing PD imaging biomarkers such as neuromelanin-sensitive MRI and diffusion tensor metrics.5 Demonstrating additive diagnostic value beyond established techniques could reinforce the clinical impact of this combined approach.I appreciate the authors' contribution and hope these suggestions encourage further standardization and validation efforts to advance quantitative MRI biomarkers in Parkinson's disease.