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Life sciences · Preprint
arXiv · October 27, 2026
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Macromolecular pool fraction (MPF) is a quantitative imaging biomarker sensitive to myelin integrity and other changes in tissue macromolecular content, but specialized acquisitions and reconstruction methods limit its use in large-scale studies. We present a physics-guided, self-supervised deep learning framework for retrospectively estimating MPF directly from conventional clinical brain MRI ($T_1$-weighted, $T_2$-weighted, and fluid-attenuated inversion recovery [FLAIR]) without paired quantitative reference scans. The framework embeds an analytical two-pool magnetization transfer signal model that related sequence-averaged radiofrequency transmit power to apparent longitudinal relaxation. To accommodate heterogeneous clinical protocols, the network conditions intermediate features on acquisition parameters via adaptive instance normalization. It was trained and evaluated on a multisite, multivendor, multiprotocol dataset of 7,705 MRI sessions (3 T). Across 1,237 test sessions, mean MPF was $0.182 \pm 0.007$ in white matter and $0.144 \pm 0.009$ in gray matter, with limited variation across vendor-by-protocol groups (between-group coefficient of variation: 2.65% and 5.63%, respectively). In 70 sessions with demyelinating-disease labels, MPF was 35.6% lower in segmented lesions than in normal-appearing white matter. MPF maps from two different clinical protocols acquired in a healthy volunteer showed a mean voxel-wise absolute percentage difference of 7.7% and a concordance correlation coefficient of $0.888$, indicating good cross-protocol consistency. These results suggest that magnetization transfer-informed self-supervised learning enables stable MPF mapping from conventional clinical MRI, providing a scalable approach to investigate demyelinating pathology in both existing imaging archives and prospectively acquired conventional clinical scans without dedicated qMT acquisitions.