Longitudinal effects of comorbidities on brain structure and cognition in older breast cancer survivors

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BACKGROUND: Neural substrates of cancer-related cognitive impairment (CRCI) remain poorly understood, especially in older adults facing aging-related cognitive decline and comorbid chronic conditions. METHODS: Breast cancer survivors aged ≥60 years (n = 64) and non-cancer controls (n = 62) completed structural MRI and neuropsychological testing and self-reported cognition and health information at pretreatment baseline and 12- and 24-month follow-ups. Regional gray matter volume and brain age were evaluated using FreeSurfer and brainageR. Longitudinal linear mixed models tested effects of group, time, and group-by-time interactions on volume. Secondary analyses examined relationships between group, comorbidities, age, gray matter volume, and cognition. RESULTS: Survivors exhibited frontal (p = 0.025, q = 0.058), thalamic (p = 0.008, q = 0.052), and limbic (p = 0.015, q = 0.052) gray matter decline relative to controls over 24 months, with smaller effects in parietal (p = 0.055, q = 0.097) and temporal (p = 0.091, q = 0.127) regions. Survivors showed average yearly frontal and thalamic volume loss at twice the rate of controls (p < 0.05). Survivors with a high comorbidity burden (≥3 comorbidities) exhibited the lowest frontal gray matter volume at all timepoints. A trend-level group-by-time interaction for brain age (p = 0.093) suggested accelerated brain aging in survivors. Survivors failed to show practice effects in the attention, processing speed, and executive functioning neuropsychological domain, whereas controls improved significantly over time (group-by-time interaction p = 0.030). CONCLUSIONS: Older breast cancer survivors tended to demonstrate gray matter decline and accelerated brain aging throughout the first two years of survivorship, with comorbidity burden amplifying frontal vulnerability. Findings highlight the need for longitudinal cognitive monitoring and targeted intervention, particularly for older survivors with high comorbidity burden.

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