RESUMEN

Iron is necessary for many neurobiological mechanisms, but its overaccumulation can be harmful. Factors triggering age-related brain iron accumulation remain largely unknown and longitudinal data are insufficient. We examined associations between brain iron load and accumulation and, blood markers of iron metabolism, cardiovascular health, lifestyle factors (smoking, alcohol use, physical activity, diet), and ApoE status using longitudinal data from the IronAge study (n = 208, age = 20-79, mean follow-up time = 2.75 years). Iron in cortex and basal ganglia was estimated with magnetic resonance imaging using quantitative susceptibility mapping (QSM). Our results showed that (1) higher peripheral iron levels (i.e., composite score of blood iron markers) were related to greater iron load in the basal ganglia; (2) healthier diet was related to higher iron levels in the cortex and basal ganglia, although for the latter the association was significant only in younger adults (age = 20-39); (3) worsening cardiovascular health was related to increased iron accumulation; (4) younger ApoE ε4 carriers accumulated more iron in basal ganglia than younger non-carriers. Our results demonstrate that modifiable factors, including lifestyle, cardiovascular, and physiological ones, are linked to age-related brain iron content and accumulation, contributing novel information on potential targets for interventions in preventing brain iron-overload.

RESUMEN

Brain iron overload and decreased integrity of the dopaminergic system have been independently reported as brain substrates of cognitive decline in aging. Dopamine (DA), and iron are co-localized in high concentrations in the striatum and prefrontal cortex (PFC), but follow opposing age-related trajectories across the lifespan. DA contributes to cellular iron homeostasis and the activation of D1-like DA receptors (D1DR) alleviates oxidative stress-induced inflammatory responses, suggesting a mutual interaction between these two fundamental components. Still, a direct in-vivo study testing the iron-D1DR relationship and their interactions on brain function and cognition across the lifespan is rare. Using PET and MRI data from the DyNAMiC study (n=180, age=20-79, %50 female), we showed that elevated iron content was related to lower D1DRs in DLPFC, but not in striatum, suggesting that dopamine-rich regions are less susceptible to elevated iron. Critically, older individuals with elevated iron and lower D1DR exhibited less frontoparietal activations during the most demanding task, which in turn was related to poorer working-memory performance. Together, our findings suggest that the combination of elevated iron load and reduced D1DR contribute to disturbed PFC-related circuits in older age, and thus may be targeted as two modifiable factors for future intervention.

Asunto(s)

Dopamina , Memoria a Corto Plazo , Femenino , Adulto , Humanos , Adulto Joven , Persona de Mediana Edad , Anciano , Dopamina/fisiología , Memoria a Corto Plazo/fisiología , Longevidad , Hierro , Receptores de Dopamina D1/metabolismo , Corteza Prefrontal/fisiología , Trastornos de la Memoria

RESUMEN

Ageing is associated with excessive free brain iron, which may induce oxidative stress and neuroinflammation, likely causing cognitive deficits. Lack of dopamine may be a factor behind the increase of iron with advancing age, as it has an important role in cellular iron homoeostasis. We investigated the effect of COMT Val 158 Met (rs4680), a polymorphism crucial for dopamine degradation and proxy for endogenous dopamine, on iron accumulation and working memory in a longitudinal lifespan sample (n = 208, age 20-79 at baseline, mean follow-up time = 2.75 years) using structural equation modelling. Approximation of iron content was assessed using quantitative susceptibility mapping in striatum and dorsolateral prefrontal cortex (DLPFC). Iron accumulated in both striatum and DLPFC during the follow-up period. Greater iron accumulation in DLPFC was associated with more deleterious change in working memory. Older (age 50-79) Val homozygotes (with presumably lower endogenous dopamine) accumulated more iron than older Met carriers in both striatum and DLPFC, no such differences were observed among younger adults (age 20-49). In conclusion, individual differences in genetic predisposition related to low dopamine levels increase iron accumulation, which in turn may trigger deleterious change in working memory. Future studies are needed to better understand how dopamine may modulate iron accumulation across the human lifespan.