Systemic inflammation and white matter free water jointly explain chemotherapy-related cognitive decline in breast...

Chemotherapy-related cognitive impairment (CRCI) is frequently reported in breast cancer survivors and shows marked interindividual variability. Whether this variability reflects early white matter vulnerability linked to poorer cognitive outcomes remains unclear.

In this longitudinal study, 188 breast cancer patients and 36 healthy controls were assessed across three chemotherapy stages. Patients were classified according to the presence (n = 82) or absence (n = 106) of subjective cognitive decline based on longitudinal change in self-reported cognitive function. Diffusion MRI was used to derive free water fraction (FWF) and free water corrected fractional anisotropy (FAt) in white matter tracts. Longitudinal trajectories of FWF and FAt were evaluated across the three groups, and associations between these metrics with peripheral inflammatory markers and cognitive measures were examined. A mediation framework was applied to assess whether systemic inflammation and white matter alterations jointly contributed to chemotherapy-related cognitive decline.

Patients with subjective cognitive decline showed a significant increase in FWF in the superior corona radiata (SCR), whereas no comparable change was observed in patients with stable subjective cognition or in healthy controls. Higher SCR FWF was associated with higher levels of systemic inflammation and poorer cognitive performance. In contrast, no significant longitudinal differences were detected in FAt across groups. Serial mediation analyses indicated that chemotherapy-related cognitive decline was indirectly mediated by systemic inflammation and subsequent increases in SCR FWF.

These findings support an inflammation-white matter-cognition pathway underlying CRCI and highlight white matter free water as a potential imaging marker of neuroinflammatory vulnerability.