Brain iron deposition mediates cognitive impairment in COPD: A possible imaging marker linking systemic inflammation to neurodegeneration

Background Cognitive impairment is a relatively prevalent comorbidity in chronic obstructive pulmonary disease (COPD), yet its neuropathological mechanism remains poorly understood.Methods We enrolled 48 stable COPD patients, categorized into cognitively normal (CogN, n = 22) and impaired (Cog, n = 26) groups based on Montreal Cognitive Assessment (MoCA) scores, along with 34 matched healthy controls. All participants underwent 3T MRI with quantitative susceptibility mapping (QSM) to quantify regional brain iron content. Group comparisons of whole-brain and region-of-interest susceptibility were performed. Mediation analysis was then used to test whether specific brain iron deposition mediates the relationship of both COPD status and peripheral inflammatory markers with cognitive performance.Results Cog patients showed increased total iron in the right cerebellum crus I, while CogN patients exhibited higher paramagnetic susceptibility (χpara) in the left orbitofrontal cortex (OFC), right precentral gyrus, and right brainstem. χpara in the left OFC and right brainstem were positively correlated with total MoCA, abstraction, and orientation scores. Mediation analysis demonstrated that χpara of the left OFC mediated the effects of both COPD status and systemic neutrophil counts on impaired abstraction. Additionally, right brainstem χpara mediated the relationship between COPD and deficits in orientation.Conclusions COPD patients with cognitive impairment exhibited distinct patterns of brain iron deposition. Importantly, deposition in several key regions served as a potential mediator, linking both COPD and systemic inflammation to specific cognitive deficits. These preliminary findings suggest a possible association between brain iron accumulation and cognitive impairment in COPD, offering candidate neuroimaging markers for early identification.