Dose-dependent impairment of brain functional and microstructural connectivity during leukaemia chemotherapy

'Chemobrain' language symptoms are commonly reported by adults receiving intensive chemotherapy for acute myeloid leukaemia (AML), but real-time detection eludes clinical imaging modalities. We performed a prospective, observational, longitudinal cohort study employing serial comprehensive neurocognitive assessment and brain functional MRI (fMRI) in 20 adults receiving intensive chemotherapy for newly diagnosed AML. At chemotherapy completion, fMRI demonstrated significantly reduced functional connectivity between the salience (anterior cingulate cortex [ACC]) and the left language (inferior frontal gyrus [IFG] and posterior superior temporal gyrus [pSTG]) networks (p = 0.008), supported by significant decreases in white matter fibre density in the corpus callosum (p = 0.009) and in the tract connecting the ACC and left IFG (p = 0.037). Increasing cytarabine dose significantly correlated with decreasing ACC-IFG connectivity (R² = 0.51, p = 0.021). Correlative analyses identified significant associations between worse brain imaging findings (language region connectivity and volume); worse verbal fluency scores; and increasing treatment intensity (cytarabine dose, transfusions and serum ferritin) (R² > 0.5, p < 0.05). Taken together, this study provides novel evidence that AML chemotherapy induces measurable alterations in brain microstructure and functional connectivity, particularly affecting salience and language networks, and suggests a dose-dependent effect with escalating cytarabine and transfusion exposure.