Sensitivity of Quantitative Susceptibility Mapping for Clinical Research in Deep Gray Matter

Quantitative susceptibility mapping (QSM) is an advanced MRI technique for assessing iron, calcium, and myelin tissue levels based on magnetic susceptibility. QSM consists of multiple processing steps, with various choices for each step. While QSM is increasingly applied in neurodegenerative disease research, its reproducibility and sensitivity in detecting susceptibility changes across groups or over time, which underpin the interpretation of clinical outcomes, have not been thoroughly quantified. This study aimed to evaluate how choices in background field removal (BFR), dipole inversion algorithms, and anatomical referencing impact the detection of changes in deep gray matter susceptibility. We used aging-related changes in brain iron, established in earlier foundational studies, as a surrogate model to test the sensitivity and reproducibility of 378 different QSM pipelines toward the detection of longitudinal susceptibility changes in a clinical setting. We used 10-year follow-up data and scan-rescan data of healthy adults scanned at 3T. Our results demonstrated high variability in the sensitivity of QSM pipelines toward detecting susceptibility changes. While most pipelines detected the same over-time changes, the choice of the BFR algorithm and the referencing strategy influenced reproducibility error and sensitivity substantially. Notably, pipelines using RESHARP with AMP-PE, HEIDI, or LSQR inversion showed the highest overall sensitivity. The findings suggest a strong impact of algorithmic choices in QSM processing on the ability to detect physiological changes in the brain. Careful consideration should be given to the pipeline configuration for reliable clinical outcomes.