Ana M. Daugherty

Bart Larsen

Nadja Schröder

Frontiers in Human Neuroscience

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TYPE EditorialPUBLISHED 27 April 2023DOI 10.3389/fnhum.2023.1198276OPEN ACCESSEDITED AND REVIEWED BYJe rey Liddell,The University of Melbourne, Australia*CORRESPONDENCEAna M. Daughertyana.daugherty@wayne.eduRECEIVED 31 March 2023ACCEPTED 13 April 2023PUBLISHED 27 April 2023CITATIONDaugherty AM, Larsen B and Schröder N (2023)Editorial: The impacts of iron accumulation oncognitive impairments.Front. Hum. Neurosci. 17:1198276.doi: 10.3389/fnhum.2023.1198276COPYRIGHT© 2023 Daugherty, Larsen and Schröder. This isan open-access article distributed under theterms of the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and that theoriginal publication in this journal is cited, inaccordance with accepted academic practice.No use, distribution or reproduction ispermitted which does not comply with theseterms.Editorial: The impacts of ironaccumulation on cognitiveimpairmentsAna M. Daugherty1,2*, Bart Larsen3 and Nadja Schröder41Department of Psychology and Institute of Gerontology, Wayne State University, Detroit, MI,United States, 2Michigan Alzheimer’s Disease Research Center, Ann Arbor, MI, United States,3Department of Psychiatry, Penn/CHOP Lifespan Brain Institute, University of Pennsylvania, Philadelphia,PA, United States, 4Department of Physiology, Instituto de Ciências Básicas da Saúde, UniversidadeFederal do Rio Grande do Sul, Porto Alegre, RS, BrazilKEYWORDSaging, dementia - Alzheimer’s disease, ferroptosis, serum biomarker, imaging biomarkersEditorial on the Research TopicThe impacts of iron accumulation on cognitive impairmentsIron is an essential micronutrient in the human diet that is absorbed and allocatedthroughout the body to support basic metabolic processes. Physiological iron can beclassified by its function in the body: heme iron is a component of hem-containingproteins, such as hemoglobin for oxygen transport and cytochromes that are involvedin mitochondrial energy production, and non-heme iron is stored in cells to supportmitochondrial energy production and as cofactor for enzyme activity. In the nervoussystem, non-heme iron participates in myelination processes, neurotransmitter synthesisand receptor expression—the fundamental neural substrates of cognitive function. Whereas,large stores of non-heme iron are thought to support cognitive development in earlylife, iron dyshomeostasis and accumulation in aging and related disease coincides withincident neurodegeneration and functional loss. This set of observations has inspired a fieldof study to investigate the involvement of brain iron accumulation in the pathogenesisof neurodegenerative disorders and as a potential biomarker of risk for neural andcognitive declines.Abnormal non-heme iron accumulation in brain tissue in aging and related diseasehas been suggested for over a century, with first observations beginning in the 1850–80’s(Foley et al., 2022). Nearly a century later, the free radical theory of aging posited iron as anessential redox agent that is abundant in human tissue and precipitates oxidative stress, withpotential downstream degenerative effects (Harman, 1956). Yet, up until recently, exploringthe association of iron with neurodegeneration had been limited to post-mortem tissueassay. New pre-clinical models and clinical measurement has advanced experimental andin vivo observational studies that are necessary to validate use of iron as a biomarker ofneural and cognitive decline. In particular, studies of cognition and function in relation toiron homeostasis across the life course are rare and this remains a critical gap for clinicaltranslation. This themed issue includes summary review articles on iron dyshomeostasispotentially driving neurodegeneration, and empirical studies applying in vivomeasurementto predict dementia and age-related cognitive decline.Frontiers inHumanNeuroscience 01 frontiersin.orgDaugherty et al. 10.3389/fnhum.2023.1198276Cumulative evidence indicates that iron accumulates inbrain regions during typical aging and, to a greater extent,with the progression of neurodegenerative diseases, such asAlzheimer’s and Parkinson’s diseases. What remains unclear isif iron precipitates pathology or is a coincident biomarker ofneurodegeneration. Wang et al. provide a scoping review articleof iron dyshomeostasis that reciprocally interacts with multiplepathways of neurodegeneration, including glial activation andneuroinflammation, oxidative stress, and neuronal loss. Buildingfrom a strong pre-clinical evidence base, Wang et al. further linkiron dyshomeostasis with amyloid β and hyperphosphorylated tauaccumulation that are hallmark pathology of Alzheimer’s disease.Ferroptosis—a unique form of cell death that is the result of iron-driven accumulation of lipid peroxides—may be a linchpin inAlzheimer’s disease pathogenesis. They review areas for furtherstudy, including several promising routes of treatment to test acausal role of iron in Alzheimer’s disease.This future direction of study underscores the need for ironmeasurement techniques that can be correlated with changes inbrain health and cognitive function, or that are sensitive to targetedintervention. Tran et al. review modern methods, including exvivo assay, peripheral measurement, and in vivo imaging that canprobe the intersection of iron dyshomeostasis and Alzheimer’sdisease pathogenesis. The multiple methods have been validatedwith correlations to disease pathology, cognitive decline or diseasesymptom progression, but each offer different perspective on thefunction of iron. Biofluid measurement of iron-related proteinsand metabolites in cerebrospinal fluid, blood serum and saliva canestimate systemic iron dyshomeostasis, whereas in vivo magneticresonance imaging provides brain region estimates of iron forspecific cognitive vulnerability. They conclude there is insufficientevidence at this time to support iron dyshomeostasis as a causeof neurodegeneration in aging and related disease; however,its colocalization with neural pathology and correlation withfunctional impairment further bolster use of iron measurements asa biomarker for risk of cognitive decline.The empirical papers in this themed issue further underscorethis application. Ficiarà et al. apply machine learning profiles todemonstrate the value of biofluid iron as an additional biomarkerintegrated into the amyloid/tau/neurodegeneration frameworkof Alzheimer’s disease diagnosis. As described in the includedreview articles, the accumulation and action of amyloid β,hyperphosphorylated tau and downstream neurodegeneration allact in concert with iron dyshomeostasis. Ficiarà et al. report that theaddition of cerebrospinal fluid and serum iron measures improveidentification of persons with dementia of the Alzheimer’s typeand mild cognitive impairment relative to control. This suggestsbiofluid markers of iron dyshomeostasis that are feasible in clinicalsettings may aid early detection and intervention for Alzheimer’sdisease risk. The sensitivity of iron measures to pre-clinicalcognitive decline is further shown by Gustavsson et al. With in vivoquantitative susceptibility mapping, they find iron accumulationin the dorsolateral prefrontal cortex in healthy adults (ages 20–79years at baseline) predicted greater decline in workingmemory overapproximately 3 years. Intriguingly, the Val158Met polymorphismof the Cetechol-O-methyltransferase (COMT) gene modified therate of iron accumulation among older adults in the sample: Valhomozygotes, who presumably had lower endogenous dopamine,had greater iron accumulation in the dorsolateral prefrontal cortexand striatum as compared to Met carriers. Non-heme iron isinvolved in dopamine synthesis, and the novel work of Gustavssonet al. suggests that genetic predisposition for low endogenousdopamine may exacerbate iron accumulation in catecholaminergicregions that support age-sensitive working memory functions.This themed issue provides a framework for future study intothe application of iron as a biomarker of risk for neural andcognitive decline. Contained within is summary evidence fromover 150 years of study, modernized methods, and avenues toprobe the intersection of iron dyshomeostasis with other plausiblemechanisms of cognitive impairment and neurodegeneration.Building from this set of papers, the field may one dayanswer the fundamental question: what is the role of iron incognitive decline?Author contributionsAD, BL, and NS contributed to the writing and revisionof this editorial, accompanying the curated, and edited themedissue. All authors contributed to the article and approved thesubmitted version.FundingThe editors’ time was supported in part by funding from theNational Institutes of Health (grant numbers 2R01-AG011230 andP30-AG072931 to AD and K99-MH127293 to BL), the NationalCouncil for Scientific Technological Development (CNPq; grantnumbers 403154/2021-9 and 305656/2019-8 to NS), and theNational Institute of Science and Technology for TranslationalMedicine (INCT-TM grant number 465458/2014-9 to NS).Conflict of interestThe authors declare that the research was conducted in theabsence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteed orendorsed by the publisher.Frontiers inHumanNeuroscience 02 frontiersin.orgDaugherty et al. 10.3389/fnhum.2023.1198276ReferencesFoley, P. B., Hare, D. J., and Double, K. L. (2022). A brief history of brain ironaccumulation in Parkinson disease and related disorders. J. Neural. Transm. 129,505–520. doi: 10.1007/s00702-022-02505-5Harman, D. (1956). Aging: a theory based on free radical andradiation chemistry. J. Gerontol. 11, 298–300. doi: 10.1093/geronj/11.3.298Frontiers inHumanNeuroscience 03 frontiersin.org

Editorial: The impacts of iron accumulation on cognitive impairments

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Editorial: The impacts of iron accumulation on cognitive impairments

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