Glymphatic, Structural, and Cognitive Changes During Breast Cancer Chemotherapy: A Longitudinal MRI Study

The glymphatic system maintains brain homeostasis through cerebrospinal fluid transport and waste clearance. Its potential involvement in chemotherapy-related cognitive impairment remains largely unexplored due to limited in vivo evidence. In this prospective longitudinal study, 126 female breast cancer patients underwent multiparametric brain MRI and neuropsychological assessments at three time points: baseline (bc1), after the first cycle of neoadjuvant chemotherapy (bc2), and upon completion of neoadjuvant chemotherapy (bc3). Glymphatic function was assessed using four MRI-derived metrics: choroid plexus (CP) volume, perivascular space (PVS) volume fraction, free water (FW), and Diffusion Tensor Imaging-Along the Perivascular Space (DTI-ALPS) index. Brain tissue segmentation was conducted to quantify the volume fractions of gray matter (GM) in cortex and subcortex, white matter (WM), and cerebrospinal fluid (CSF) relative to intracranial volume. Neuropsychological assessments included the Self-Rating Anxiety Scale (SAS), the Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog), and a battery of objective cognitive tests. Longitudinal changes and interrelationships were analyzed using linear mixed-effects models, correlation analyses, and cross-lagged panel analysis. During chemotherapy, CP volume increased (p < 0.001), while PVS volume fraction decreased (p = 0.003); no significant changes were found in FW or DTI-ALPS. GM volumes in both cortex and subcortex declined (both p = 0.02). SAS scores increased (p = 0.02), and FACT-Cog scores decreased (p < 0.001), with no significant changes in objective test scores. From bc2 to bc3, increases in CP volume were negatively correlated with reductions in PVS volume fraction (r = -0.40, p < 0.001). From bc1 to bc3, reductions in PVS volume fraction were associated with decreases in both cortical GM volumes (r = 0.32, p < 0.001). At bc2, cortical GM atrophy was correlated with increased SAS scores (r = -0.30, p = 0.002). Cross-lagged panel analysis showed that CP enlargement at bc2 preceded PVS volume fraction reduction at bc3 (β = -1.66, p = 0.007). During neoadjuvant chemotherapy, breast cancer patients exhibited a unique pattern of glymphatic system alterations, suggesting its potential as an imaging marker of treatment-related brain changes.