The impact of brain iron accumulation on cognition: A systematic review

Abstract

Iron is involved in many processes in the brain including, myelin generation, mitochondrial function, synthesis of ATP and DNA and the cycling of neurotransmitters. Disruption of normal iron homeostasis can result in iron accumulation in the brain, which in turn can partake in interactions which amplify oxidative damage. The development of MRI techniques for quantifying brain iron has allowed for the characterisation of the impact that brain iron has on cognition and neurodegeneration. This review uses a systematic approach to collate and evaluate the current literature which explores the relationship between brain iron and cognition. The following databases were searched in keeping with a predetermined inclusion criterion: Embase Ovid, PubMed and PsychInfo (from inception to 31 st March 2020). The included studies were assessed for study characteristics and quality and their results were extracted and summarised. This review identified 41 human studies of varying design, which statistically assessed the relationship between brain iron and cognition. The most consistently reported interactions were in the Caudate nuclei, where increasing iron correlated poorer memory and general cognitive performance in adulthood. There were also consistent reports of a correlation between increased Hippocampal and Thalamic iron and poorer memory performance, as well as, between iron in the Putamen and Globus Pallidus and general cognition. We conclude that there is consistent evidence that brain iron is detrimental to cognitive health, however, more longitudinal studies will be required to fully understand this relationship and to determine whether iron occurs as a primary cause or secondary effect of cognitive decline.

Association between serum iron concentrations and cognitive impairment in older adults aged 60 years and older: A dose-response analysis of National Health and Nutrition Examination Survey

“…The study by Gao et al also showed that serum iron concentrations were only positively correlated with brain iron in the right hippocampus and were not correlated with brain iron other regions of interest [ 37 ]. A recent review summarized that iron accumulated heterogeneously across brain regions, and Caudate nuclei, Hippocampus and Thalamus were the regions where iron was most frequently reported to correlate with memory performance, while iron deposition in the putamen was correlate to poorer general cognition [ 7 ]. These findings suggested that abnormal iron status might have different effects on various brain regions.…”

Contributions of HFE polymorphisms to brain and blood iron load, and their links to cognitive and motor function in healthy adults

“…A further aim of the present study was to investigate the relationships between brain iron, cognition and motor function, with the hypothesis that such relationships may differ according to HFE genotype. Based on growing evidence that higher iron load is generally deleterious to cognitive performance in older adults 6,27 and that C282Y/H63D is associated with disturbed iron metabolism leading to iron overload, the expectation that higher iron in the HFE ‐pos group would be related to lower performance was reasonable. On the other hand, the limited literature on this topic has provided mixed findings, with some beneficial effects observed in HFE ‐pos individuals.…”

“…For the analyses, we focused on the basal ganglia (caudate, putamen, pallidum) because iron accumulates most in these regions, and they are relevant for cognitive performance 2,6,27 . In addition, we added an average measure of cortical iron, which includes all cortical regions of the cerebrum as segmented by Freesurfer, from which we excluded the medial temporal lobe, where artifacts were detected notably in the parahippocampal gyrus.…”

“…Finally, we explored relationships between brain iron, blood markers of iron, and cognitive/motor performance encompassing five domains (working memory, executive function, episodic memory, perceptual speed, motor speed). Given the detrimental effects of brain iron overload on cognition, 1,6,27 we expected that high iron load would be more strongly associated with worse performance in the HFE ‐pos than in the HFE ‐neg group. However, given the counterintuitive results reported above, 25 we could not rule out an alternative hypothesis, with a negative association between iron and cognition in the HFE ‐neg group, but not in HFE ‐pos group.…”

Senescent Microglia: The Key to the Ageing Brain?

“…A hallmark of senescent or dystrophic microglia in the ageing brain is the accumulation of iron [ 55 , 167 , 168 , 169 ], with documented negative impacts on cognition. The accumulation of iron is noted in regions that are particularly vulnerable to pathology in Parkinson’s Disease (PD) [ 170 ], with iron loaded, dystrophic microglia being found associated with Lewy Bodies.…”