Diffusion MRI Markers of Symptom Interference and Survival in Head and Neck Cancer Survivors

Background: Diffusion MRI (dMRI) provides sensitive markers of brain microstructure and glymphatic function. The interplay between brain microstructure and glymphatic function in shaping long-term survivorship outcomes remains unclear. We examined associations of dMRI markers with survival and symptom interference in long-term head and neck (HN) cancer survivors and tested whether glymphatic function modified these associations. Methods: dMRI data from 135 long-term HN cancer survivors were analyzed. Radial diffusivity (RD) and fractional anisotropy (FA) were quantified across 76 gray matter regions and 45 white matter tracts. Glymphatic function was indirectly estimated using diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index. Survival status was determined through clinical follow-up, and symptom interference was assessed using the MD Anderson Symptom Inventory. Stepwise regression identified microstructural measures associated with survival and symptom interference, followed by moderation analyses testing the role of DTI-ALPS. Results: Reduced RD in the left medial orbitofrontal cortex (MOFC), higher FA in the left and lower FA in the right entorhinal cortex, and higher FA in the right extreme capsule were associated with longer survival (p < 0.0006, corrected for multiple comparisons). Lower RD in the left uncinate fasciculus (UF) and superior temporal cortex (STC) and lower FA in the right caudal anterior cingulate cortex (CACC) were associated with lower symptom interference (p < 0.0006, corrected for multiple comparisons). Higher DTI-ALPS strengthened the association between preserved MOFC microstructure and longer survival (β = -1.95, p < 0.001) and moderated the associations of microstructure in the UF (βs > 4.08, p < 0.001), STC (β = 5.82, p < 0.001), and CACC (β = 16.47, p < 0.001) with symptom interference. Conclusions: dMRI markers of brain microstructure and glymphatic function are associated with long-term outcomes in HN cancer survivors. These findings support a region-specific resilience framework and highlight the potential of dMRI-based biomarkers for characterizing brain health in cancer survivorship.