Impact of brain and blood iron on glial density in aging, and relations to cognition: evidence from a 5-year longitudinal multimodal MRI-PET study.

Human aging is characterized by low-grade neuroinflammation, contributing to brain deterioration. However, the mechanisms underlying age-related neuroinflammation remain poorly understood. It is well documented that iron accumulates in the aging brain. While iron is essential for various biological functions, excessive iron load and accumulation in older age may potentially trigger neuroinflammation and cognitive decline. We investigate whether iron load and accumulation in the brain may serve as a mechanism underlying neuroinflammation and cognitive decline, and whether blood-based markers of iron metabolism could be indicators of subsequent neuroinflammation. Thirty-nine cognitively healthy participants (19 female, aged 50-81 years) underwent blood sampling, cognitive testing, magnetic resonance imaging for brain iron quantification using quantitative susceptibility mapping (QSM), and [11C]PBR28 positron emission tomography (PET) to quantify TSPO (Translocator Protein) binding and glial density, a marker of neuroinflammation. A composite score of ferritin, transferrin and transferrin receptors reflected peripheral blood iron load. Serum hepcidin at baseline was also investigated, due to its potential role in inflammation, together with high-sensitivity C-Reactive Protein as a general marker of inflammation. Changes in brain and blood iron levels over a period of 2.7 and 5.3 years, respectively, were measured prior to PET assessment. Results revealed that higher region-specific brain iron accumulation was associated with subsequent higher TSPO density in caudate and thalamus. Higher baseline iron load and accumulation in thalamus were associated with steeper decline in working memory, perceptual and motor speed. TSPO binding was not associated with cognitive performance. Further, higher baseline serum hepcidin (and, at trend, systemic iron load) predicted higher subsequent global grey matter TSPO binding. Our findings suggest that higher local subcortical iron accumulation contributes to low-grade neuroinflammation in middle-aged and older adults, but only brain iron accounts for cognitive and motor decline, indicating that low-grade neuroinflammation may partly constitute an adaptive response to the deleterious effects of iron overload on neurocognitive processes. Higher levels of systemic iron load and serum hepcidin may further constitute early markers of higher global TSPO binding.