Figures
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 31st 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.
Citation: Spence H, McNeil CJ, Waiter GD (2020) The impact of brain iron accumulation on cognition: A systematic review. PLoS ONE 15(10): e0240697. https://doi.org/10.1371/journal.pone.0240697
Editor: Efthimios M. C. Skoulakis, Biomedical Sciences Research Center Alexander Fleming, GREECE
Received: July 2, 2020; Accepted: October 1, 2020; Published: October 15, 2020
Copyright: © 2020 Spence et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its supporting information files.
Funding: Principal Grant Holder: GW Funder: The Roland Sutton Academic Trust https://www.abdn.ac.uk/ims/research/abic/roland-sutton-academic-trust-1427.php Sponsers only provided financial support.
Competing interests: The authors have declared that no competing interests exist.
Introduction
Iron has many biological roles including the cycling of neurotransmitters, enzyme and mitochondrial function, ATP and DNA synthesis and myelin generation [1–4]. In the healthy human adult brain, the total concentration of iron is around 0–200μg per gram of tissue, typically being lower in the White Matter (WM) and cortical Grey Matter (GM) (<60 μg per gram) [2]. 90% of brain iron is stored in ferritin with only 0.05% of brain iron being present in the labile iron pool [5]. In healthy aging, iron accumulates heterogeneously in specific regions of the brain, bound mainly to ferritin and neuromelanin [6] and largely located in the deep GM nuclei [7–10]. There is a rapid increase in iron accumulation (different depending on brain region) from birth up until around 20 years old, at which point the accumulation rate slows in some regions, reaching a plateau in middle age and increasing again after 60 years old [1, 7]. Due to this relationship with age, brain iron has been the focus of many studies finding associations between regional brain iron levels and age-related cognitive decline, as well as several neurodegenerative diseases [4, 6].
Several theories as to the role of brain iron in cognitive decline have been suggested. Many of these mechanisms revolve around the ability of iron to induce oxidative stress via Fenton’s reaction [11]. During Fenton’s reaction, excess iron reacts with reactive oxygen species (ROS), such as hydrogen peroxide to produce highly reactive OH˙ radicals which can in turn induce iron release from mitochondrial iron-sulphur cluster proteins and iron storage proteins. Released iron can then undergo Fenton’s reaction, amplifying ROS generation [6, 12]. When ROS and free radicals generated via Fenton’s reaction exceed the antioxidant capacity of brain cells, oxidative stress is induced leading to loss of DNA integrity, lipid peroxidation, mitochondrial dysfunction, protein misfolding and ultimately neuronal cell death. This oxidative stress is thought to be exacerbated by the induction of neuroinflammation. Upregulation of HO-1 in glia is also thought to contribute to neurodegeneration as prolonged action may be involved in iron sequestration, intracellular stress and mitochondrial insufficiency [6, 13–15]. Another potential mechanism by which brain iron levels could influence cognitive decline/neurodegeneration is Ferroptosis. This is an iron-dependent necrosis mechanism which is characterised by shrunken mitochondria with increased density and outer membrane rupture [16].
In terms of the mechanism by which iron accumulates, it has been shown in several studies that participants with Parkinson’s disease (PD) have an increased permeability of the blood brain barrier (BBB) and upregulation of iron transporters such as Lactotransferrin [5, 12, 17]. This would allow for the increased uptake of iron into the brain and may account for the increase of iron accumulation in the brain in neurodegenerative disease. Furthermore, in diseases such as Alzheimer’s disease (AD), PD and prion disease, iron is shown to associate with protein aggregates and in the case of Amyloid beta, it is thought that iron plays a role in the toxicity of these protein aggregates [18–20]. Although these theories have been proposed, the full extent of the role of iron in cognitive decline and neurodegeneration remains unclear.
Although iron status measurement has been possible for many years, the emergence of novel techniques in magnetic resonance imaging have allowed for the specific, non-invasive measurement of brain iron. Techniques such as Susceptibility Weighted Imaging (SWI), R2* relaxation time and Quantitative Susceptibility Mapping (QSM) make use of the magnetic properties of iron in order to map the spatial distribution of iron in the brain from magnitude and phase images [21]. QSM is considered the most sensitive and specific technique for measuring iron in the brain non-invasively [22] and the ability of QSM to accurately measure brain iron has been validated in several post-mortem studies [23, 24]. It is hoped that such measures of brain iron will allow for further elucidation of the brain iron accumulation patterns and their relationship with cognitive decline and neurodegeneration.
This review will discuss the relationships between brain iron and cognition elucidated in human studies across a wide age range; in healthy adults as well as, in individuals with diseases including PD, AD, Type 2 Diabetes Mellitus with cognitive impairment, mild cognitive impairment (MCI) and Multiple Sclerosis (MS). We aim to present the current understanding of regional brain iron accumulation patterns and their relation to cognitive performance outcomes, in order to gain a greater understanding of the potential mechanisms underlying this iron-cognition relationship. We hypothesise that age-related regional increase in brain iron levels will correlate with impairment of specific regional cognitive function.
Methods
The PRISMA statement recommendations for systematic review were followed in this systematic review in order to provide high quality reporting [25, 26].
Information sources and eligibility criteria
A systematic electronic search strategy was generated at the start of this study. Electronic searching was carried out on 31st March 2020 using the following electronic databases: Embase Ovid (1974–31 March 2020), PubMed (Inception– 31 March 2020) and Psych Info (1806–31 March 2020). Studies were assessed for adherence to pre-determined inclusion/exclusion criteria detailed below.
Inclusion criteria
Studies were included in this review if they reported on the following:
- Human Studies measuring Brain iron level AND cognition
- Statistical comparison of brain iron and cognitive performance
- Published in English Language AND the full text was available
Exclusion criteria
Studies were excluded from this review if they were:
- Animal studies
- Measuring only systemic iron status (no measure of brain specific iron levels)
- Single case studies, Reviews, protocols editorials or conference abstract
- Studies investigating effects of maternal iron on offspring cognition
Search strategy
The full search strategies used for this review are detailed in Table 1.
Study selection
All studies found in the electronic search were assessed for their eligibility for inclusion in this review by Holly Spence. Studies were included if they met all the inclusion criteria and included studies had their referenced papers reviewed for eligibility for inclusion. The included studies ultimately consisted of published articles and theses only.
Synthesis of results
The following study characteristics were extracted from each study for assessment of study quality and study comparison: Number of participants; participant gender ratio; participant average age; type of study design; measures of cognition used; measures of brain iron used; statistical methods used. Results which were statistically significant (p<0.05) were extracted and summarised from each study.
Quality assessment
Each study which satisfied the inclusion and exclusion criteria was assessed for quality via a 10-point based system using the following 10 criteria: (1) Does the study have a clearly defined research objective? (2) Does the study adequately describe the inclusion/exclusion criteria? (3) Is the sample size adequate? (4) Does the study report on the population parameters/demographics? (5) Does the study report detail on appropriate assessment of Cognition? (6) Does the study report detail of the assessment of iron? (7) Does the study provide an appropriate control group? (8) Does the study apply the appropriate statistical analyses? (9) Does the study adequately report the strength of results? (10) Do the authors report on the limitations of their study?
Results
Study selection
The electronic search of Embase Ovid, PubMed and PsychInfo yielded 643 citations in total. After duplicates were removed, 411 studies remained for screening. Once these studies were screened, 141 non-human studies were excluded, 4 papers were excluded due to being unavailable in English and 106 reviews, editorials and conference abstracts were removed. In total 6 studies were excluded due to being single case studies, 60 were excluded for not measuring brain iron and 6 were excluded for not measuring cognition. Finally, 24 studies did not assess statistically the relationship between iron and cognition and so were excluded, as well as 3 studies which measured only the effects of maternal iron on offspring cognition. A total of 28 studies remained for reference screening. After references were reviewed, a further 13 eligible studies were obtained. A total of 41 studies were therefore included in this review. The full details of the study selection process are outlined in Fig 1.
Study characteristics
Study characteristics were collated and are presented in Tables 2 and 3; with Table 2 presenting details on overall study design and Table 3 presenting details on participants and study groups
Quality assessment
All included studies were assessed for quality using a 10-point-based scoring system and each score was converted to a % Quality Score (QS). The quality scores for all studies can be seen in Table 4. 26 of the 41 assessed studies were of high quality (QS>90%), 14 were of very good quality (QS of 80%-90%) and 1 study was of good quality (QS of 70%-80%).
Summary of results
The key findings relating to the brain iron-cognition relationship were extracted from each study in this review and are summarised in Table 5. 11 of the reviewed papers showed a significant relationship between whole brain iron concentration and measures of cognition (including memory, general intelligence, visual performance, processing speed, social cognition and BOLD modulation). Every other study reviewed reported significant associations between iron levels in specific brain regions and individual measures of cognition, as presented in Fig 2.
Figure presents number of studies reporting significant association (p<0.05) between regional iron and cognition measures. *Pallidum had associations between regional iron and memory in one study [30] but had association in all cognitive measures except memory in a second study [42].
Discussion
Summary of evidence
This review analysed human studies in which brain iron and cognition were measured and their relationship assessed statistically. Many of studies assessed reported a significant relationship between total brain iron and general cognitive performance and many links between regional iron levels and specific measures of cognition were also reported. Memory function was the most frequently reported cognitive measure to be correlated with brain iron, however, this was the most frequently assessed cognitive outcome. Regions where iron was most frequently reported to correlate with memory performance were the Caudate nuclei, Hippocampus and Thalamus. All other regions were also associated with memory in at least one study except for the Globus Pallidus where regional iron had no reported associations with memory. The associations between the caudate, hippocampus and thalamus iron and memory are somewhat unsurprising as each of these regions are known to be involved in different facets of memory function [67–69] and so it is plausible that disruption of these circuits via iron accumulation would confer memory dysfunction. The efficacy of interactions between the caudate and hippocampus in memory function has been associated with availability of dopamine receptors [70, 71], which has in turn been proposed as having a potential role in iron accumulation [72]. Studies have suggested that iron and dopamine can interact to induce oxidative stress and neurodegeneration by forming a toxic couple [72]. Animal studies have also demonstrated that iron deficient mice and rats show decreased dopamine transporter and receptor levels and general dopaminergic dysfunction [73, 74]. This suggests that with an increase iron, there could be an increase in dopamine receptors and transporters, enhancing toxic coupling between iron and dopamine and thus increasing neurodegeneration in dopamine rich regions, however, this requires further investigation.
Furthermore, higher iron levels in the caudate nuclei were also consistently reported to correlate to poorer general cognitive performance. However, the putamen had the most reported associations with general cognition, with the Globus Pallidus and the Substantia Nigra also being associated with general cognition in more than one study. The putamen has roles in many different neurological functions such as, sensory and motor information processing, learning and language [75–77]. This could explain the consistency of reports that iron accumulation here is associated with poorer general cognitive performance, further suggesting that iron accumulation causes atrophy which leads to a localised disruption of function.
Although assessed in less of the studies reviewed, there were associations between reduced motor function and increased striatal iron content, as well as, increased iron in the Putamen and increased disability scores, such as, Dementia rating scale, Extended disability status score and the UPDRS-III for rating of Parkinson’s pathology. Due to its many neurological roles and connections, atrophy in the Putamen is known to be involved in pathology of several diseases such as, Parkinson’s disease, Multiple Sclerosis and Dementia with Lewy Bodies [78–81]. The striatum consists of the caudate and putamen and is crucial for connections to the basal ganglia which is heavily involved in motor control [82]. These associations therefore suggest that iron accumulation is capable of either causing atrophy or is accompanied by atrophy, which in turn causes regional damage that can interfere with circuitry in the brain. This is in line with the findings of several of the included studies that increases in regional brain iron were strongly associated with regional volume decrease [34, 35, 49, 54], suggesting that brain iron increase is correlated with atrophy.
Whilst not evaluated in the included studies, differences in iron status have been observed between sexes particularly during development. Larsen et al. observed these differences in their 2020 study, which determined that male brain iron levels plateau at an earlier age than in females in some brain regions. Due to this later plateau during development females generally begin adulthood with higher brain iron levels than men. However, at older age, females are shown to have generally lower iron stores in some brain regions than males, potentially due to menstruation [83–85]. Female brain iron deficit mediated by menstruation would however, be highly variable, dependent on the characteristics of an individuals’ menstruation (i.e. menstruation pattern, heaviness of blood loss etc.) [83]. This may put females at a lower risk of brain iron-mediated cognitive impairment, however the effects of sex-mediated brain iron on cognition have not been extensively studied.
All studies included in this review controlled for sex during their analyses. Fifteen of the included studies assessed sex-mediated brain iron differences statistically; 1 study found that while temporal iron levels did not significantly differ between men and women, cerebellar iron was significantly higher in males compared to females [27]; 1 studies found significantly higher hippocampal iron in men compared to women [28]; 1 study found that regional brain iron in women plateaus later than in men during development [1] and the remaining 12 studies observed no significant difference in brain iron in any assessed region between males and females [29, 31, 34–36, 38, 42, 44, 47, 51, 54, 63].
Although primarily focusing on the associations between brain iron and cognition, some of the papers reviewed did provide insight into potential mechanisms for this relationship. It has been previously reported that iron in the brain tends to localise to protein aggregates and some studies have shown that iron plays a role in the toxicity of some of these aggregates [86–89]. In fact, when amyloid β (Aβ) is complexed with iron it can induce ROS via Fenton’s reaction leading to oxidative stress and activation of the Bcl-2 apoptotic pathway [18, 19]. Iron has also been shown to localise with protein aggregates such as tau and amyloid beta in animal models for AD and PD [88, 90, 91]. Several of the studies included in this review reported that iron was localised to Aβ plaques and neurofibrillary tangles [27, 58]. A study by Ayton et al. [27], included in this review, found that brain iron level mediated 17% of the effect of Neurofibrillary tangles on cognitive performance. This, taken with the afore mentioned literature, suggests that iron could amplify neurodegenerative processes such as protein misfolding, rather than being a primary cause or effect of disease.
Limitations
Whilst this article was able to provide a comprehensive review of the literature investigating the relationship between brain iron and cognition, there were several limitations to this study. Firstly, there was a wide variety of methods for measuring both brain iron and cognition and this must be considered when comparing the included studies. Secondly, although a thorough search of the literature was conducted, it is possible that relevant studies were missed and thus not included. Furthermore, all included studies were published articles or theses and thus there is an element of publication bias in this review that must be considered. Additionally, some of the studies included in this review had relatively small sample sizes which may reduce the power of some of the conclusions made. The participants all bar one of the studies in this review were adults and so the findings cannot be applied to children or adolescents. Finally, the potential mechanisms by which iron accumulation in the brain could cause cognitive dysfunction were not assessed in this review and remain unclear.
Conclusions
To conclude, this review has investigated the effects of brain iron on aspects of cognition. There is consistent evidence in the studies reviewed that in adulthood, an increase in brain iron had a detrimental effect on cognitive ability. However, it seems that iron accumulates heterogeneously across brain regions and when only some regions have high iron, their specific function can be impaired. In this way, increased iron in the Caudate nuclei, Hippocampus and Thalamus is consistently reported to correlate to poorer memory performance; whereas, increased iron in the putamen was more consistently reported to correlate to poorer general cognition. These findings strongly suggest an effect of brain iron on cognition and this relationship should therefore be investigated further. Going forward, it is important to determine whether iron is a primary cause of brain atrophy or whether brain iron accumulation is a secondary effect of brain atrophy. Regardless of the mechanisms underlying the relationship between brain iron and cognition, MRI techniques for quantifying brain iron therefore show promise as a potential non-invasive biomarker for age-related cognitive decline.
Acknowledgments
The authors would like to thank the Roland Sutton Academic Trust for their financial support.
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