{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T14:12:41Z","timestamp":1791727961139,"version":"4.3.4"},"reference-count":202,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,4,6]],"date-time":"2023-04-06T00:00:00Z","timestamp":1680739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health (Ricerca Corrente)","award":["PTC-19-602325 (RS)"],"award-info":[{"award-number":["PTC-19-602325 (RS)"]}]},{"name":"Alzheimer\u2019s Association Part the Cloud: Translational Research Funding for Alzheimer\u2019s Disease (PTC)","award":["PTC-19-602325 (RS)"],"award-info":[{"award-number":["PTC-19-602325 (RS)"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dysfunction of the complex cerebral networks underlying wakefulness and awareness is responsible for Disorders of Consciousness (DoC). Traumatic Brain Injury (TBI) is a common cause of DoC, and it is responsible for a multi-dimensional pathological cascade that affects the proper functioning of the brainstem and brain consciousness pathways. Iron (Fe), Zinc (Zn), and Copper (Cu) have a role in the neurophysiology of both the ascending reticular activating system, a multi-neurotransmitter network located in the brainstem that is crucial for consciousness, and several brain regions. We aimed to summarize the role of these essential metals in TBI and its possible link with consciousness alterations. We found that TBI alters many neuronal molecular mechanisms involving essential metals, causing neurodegeneration, neural apoptosis, synaptic dysfunction, oxidative stress, and inflammation. This final pattern resembles that described for Alzheimer\u2019s disease (AD) and other neurological and psychiatric diseases. Furthermore, we found that amantadine, zolpidem, and transcranial direct current stimulation (tDCS)\u2014the most used treatments for DoC recovery\u2014seem to have an effect on essential metals-related pathways and that Zn might be a promising new therapeutic approach. This review summarizes the neurophysiology of essential metals in the brain structures of consciousness and focuses on the mechanisms underlying their imbalance following TBI, suggesting their possible role in DoC. The scenario supports further studies aimed at getting a deeper insight into metals\u2019 role in DoC, in order to evaluate metal-based drugs, such as metal complexes and metal chelating agents, as potential therapeutic options.<\/jats:p>","DOI":"10.3390\/ijms24076867","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T04:08:03Z","timestamp":1680840483000},"page":"6867","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Imbalance of Essential Metals in Traumatic Brain Injury and Its Possible Link with Disorders of Consciousness"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5624-1140","authenticated-orcid":false,"given":"Rosanna","family":"Squitti","sequence":"first","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina, Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Reale","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Neuroriabilitazione ad Alta Intensit\u00e0 Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0256-3766","authenticated-orcid":false,"given":"Vincenzo","family":"Tondolo","sequence":"additional","affiliation":[{"name":"Digestive and Colorectal Surgery, Fatebenefratelli Isola Tiberina, Gemelli Isola, 00186 Rome, Italy"},{"name":"Digestive Surgery Unit, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0581-2318","authenticated-orcid":false,"given":"Daniela","family":"Crescenti","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6162-252X","authenticated-orcid":false,"given":"Sonia","family":"Bellini","sequence":"additional","affiliation":[{"name":"Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Moci","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Neuroriabilitazione ad Alta Intensit\u00e0 Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pietro","family":"Caliandro","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Neurologia, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Padua","sequence":"additional","affiliation":[{"name":"Fondazione Policlinico Universitario A. Gemelli IRCCS, UOC Neuroriabilitazione ad Alta Intensit\u00e0 Largo Agostino Gemelli 8, 00168 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Rongioletti","sequence":"additional","affiliation":[{"name":"Department of Laboratory Science, Research and Development Division, Fatebenefratelli Isola Tiberina, Gemelli Isola, 00186 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1126\/science.272.5259.225","article-title":"Arousal: Revisiting the reticular activating system","volume":"272","author":"Steriade","year":"1996","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41582-020-00428-x","article-title":"Recovery from disorders of consciousness: Mechanisms, prognosis and emerging therapies","volume":"17","author":"Edlow","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.nicl.2015.11.004","article-title":"Relationship between the anterior forebrain mesocircuit and the default mode network in the structural bases of disorders of consciousness","volume":"10","author":"Lant","year":"2016","journal-title":"Neuroimage Clin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/s41583-019-0212-7","article-title":"The brain\u2019s default network: Updated anatomy, physiology and evolving insights","volume":"20","author":"Buckner","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2349","DOI":"10.1523\/JNEUROSCI.5587-06.2007","article-title":"Dissociable intrinsic connectivity networks for salience processing and executive control","volume":"27","author":"Seeley","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/nrneurol.2013.279","article-title":"Disorders of consciousness after acquired brain injury: The state of the science","volume":"10","author":"Giacino","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.3171\/2017.10.JNS17352","article-title":"Estimating the global incidence of traumatic brain injury","volume":"130","author":"Dewan","year":"2019","journal-title":"J. Neurosurg."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"29","DOI":"10.4037\/aacnacc2021331","article-title":"Traumatic Brain Injury Update","volume":"32","author":"Scarboro","year":"2021","journal-title":"AACN Adv. Crit. Care"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.tins.2016.03.002","article-title":"Traumatic Axonal Injury: Mechanisms and Translational Opportunities","volume":"39","author":"Hill","year":"2016","journal-title":"Trends Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"556","DOI":"10.3171\/2009.9.JNS09626","article-title":"Prevalence and impact of diffuse axonal injury in patients with moderate and severe head injury: A cohort study of early magnetic resonance imaging findings and 1-year outcome","volume":"113","author":"Skandsen","year":"2010","journal-title":"J. Neurosurg."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1097\/00075198-200204000-00002","article-title":"Inflammatory response in acute traumatic brain injury: A double-edged sword","volume":"8","author":"Rancan","year":"2002","journal-title":"Curr. Opin. Crit. Care"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1093\/brain\/awaa321","article-title":"The synapse in traumatic brain injury","volume":"144","author":"Jamjoom","year":"2021","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"587197","DOI":"10.3389\/fnins.2021.587197","article-title":"Iron Metabolism Disorders for Cognitive Dysfunction after Mild Traumatic Brain Injury","volume":"15","author":"Huang","year":"2021","journal-title":"Front. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1038\/nm.2507","article-title":"Ischemia and reperfusion--from mechanism to translation","volume":"17","author":"Eltzschig","year":"2011","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.ebiom.2018.01.021","article-title":"Traumatic Brain Injury and Alzheimer\u2019s Disease: The Cerebrovascular Link","volume":"28","author":"Wisniewski","year":"2018","journal-title":"EBioMedicine"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1101\/SQB.1987.052.01.054","article-title":"Zinc fingers: A novel protein fold for nucleic acid recognition","volume":"52","author":"Klug","year":"1987","journal-title":"Cold Spring Harb. Symp. Quant. Biol."},{"key":"ref_17","unstructured":"Lippard, S., and Berg, J. (1994). Principles of Bioinorganic Chemistry, University Science Books."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1002\/j.1460-2075.1994.tb06541.x","article-title":"Evolution of cytochrome oxidase, an enzyme older than atmospheric oxygen","volume":"13","author":"Castresana","year":"1994","journal-title":"EMBO J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.jtemb.2012.04.004","article-title":"Discovery of human zinc deficiency: 50 years later","volume":"26","author":"Prasad","year":"2012","journal-title":"J. Trace Elem. Med. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1097\/MOG.0b013e328321b395","article-title":"Zinc deficiency","volume":"25","author":"Tuerk","year":"2009","journal-title":"Curr. Opin. Gastroenterol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.bbrc.2009.01.074","article-title":"The ligand environment of zinc stored in vesicles","volume":"380","author":"Wellenreuther","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1007\/s00018-014-1617-0","article-title":"Current understanding of ZIP and ZnT zinc transporters in human health and diseases","volume":"71","author":"Kambe","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1146\/annurev-nutr-080508-141119","article-title":"Functional significance of zinc-related signaling pathways in immune cells","volume":"29","author":"Haase","year":"2009","journal-title":"Annu. Rev. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1079\/PNS19890050","article-title":"Clinical and nutritional aspects of changes in acute-phase proteins during inflammation","volume":"48","author":"Fleck","year":"1989","journal-title":"Proc. Nutr. Soc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1089\/108729100750018290","article-title":"Physiology, immunology, and disease transmission in human breast milk","volume":"14","author":"Georgeson","year":"2000","journal-title":"AIDS Patient Care STDS"},{"key":"ref_26","unstructured":"Thomas, L. (2023, February 20). Trace Elements. Laboratory Investigation of Trace Elements. Essential Trace Elements. Zinc. In Clinical Laboratory Diagnostics. Available online: https:\/\/www.labor-und-diagnose.de\/."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"6843","DOI":"10.1073\/pnas.0502257102","article-title":"Interleukin-6 regulates the zinc transporter Zip14 in liver and contributes to the hypozincemia of the acute-phase response","volume":"102","author":"Liuzzi","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","unstructured":"Cousins, R.J. (1996). Acute Phase Reactants, Ziegler."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1357","DOI":"10.1016\/j.clnu.2022.02.015","article-title":"ESPEN micronutrient guideline","volume":"41","author":"Berger","year":"2022","journal-title":"Clin. Nutr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.bbrc.2004.07.102","article-title":"Interleukin-6 regulates hepatic transporters during acute-phase response","volume":"322","author":"Siewert","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1096\/fasebj.2.13.2458983","article-title":"Tissue-specific regulation of zinc metabolism and metallothionein genes by interleukin 1","volume":"2","author":"Cousins","year":"1988","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5844","DOI":"10.1523\/JNEUROSCI.14-10-05844.1994","article-title":"Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles","volume":"14","author":"Masters","year":"1994","journal-title":"J. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Pal, A., Cerchiaro, G., Rani, I., Ventriglia, M., Rongioletti, M., Longobardi, A., and Squitti, R. (2022). Iron in Alzheimer\u2019s Disease: From Physiology to Disease Disabilities. Biomolecules, 12.","DOI":"10.3390\/biom12091248"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1986","DOI":"10.1056\/NEJM199912233412607","article-title":"Disorders of iron metabolism","volume":"341","author":"Andrews","year":"1999","journal-title":"N. Engl. J. Med."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1258\/000456303763046021","article-title":"Wilson\u2019s disease: The importance of measuring serum caeruloplasmin non-immunologically","volume":"40","author":"Walshe","year":"2003","journal-title":"Ann. Clin. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.brainres.2008.10.056","article-title":"Copper transport to the brain by the blood-brain barrier and blood-CSF barrier","volume":"1248","author":"Choi","year":"2009","journal-title":"Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.neubiorev.2015.01.018","article-title":"Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response","volume":"51","author":"Andrews","year":"2015","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0301-0511(96)05222-2","article-title":"Arousal systems and attentional processes","volume":"45","author":"Robbins","year":"1997","journal-title":"Biol. Psychol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"110770","DOI":"10.1016\/j.jinorgbio.2019.110770","article-title":"Potential role of serotonin as a biological reductant associated with copper transportation","volume":"199","author":"Saito","year":"2019","journal-title":"J. Inorg. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1007\/s00775-019-01737-3","article-title":"Copper and the brain noradrenergic system","volume":"24","author":"Lutsenko","year":"2019","journal-title":"J. Biol. Inorg. Chem."},{"key":"ref_41","unstructured":"Hoogenraad, T. (2001). Wilson Disease, Intermed Medical Publishers."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3233\/JAD-201556","article-title":"Copper Imbalance in Alzheimer\u2019s Disease and Its Link with the Amyloid Hypothesis: Towards a Combined Clinical, Chemical, and Genetic Etiology","volume":"83","author":"Squitti","year":"2021","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"533","DOI":"10.2174\/1567205018666211022085755","article-title":"Non-Ceruloplasmin Copper as a Stratification Biomarker of Alzheimer\u2019s Disease Patients: How to Measure and Use It","volume":"18","author":"Squitti","year":"2021","journal-title":"Curr. Alzheimer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"297","DOI":"10.3389\/fncel.2017.00297","article-title":"Zinc as a Neuromodulator in the Central Nervous System with a Focus on the Olfactory Bulb","volume":"11","author":"Blakemore","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/0301-0082(94)90082-5","article-title":"Modulation of inhibitory and excitatory amino acid receptor ion channels by zinc","volume":"42","author":"Smart","year":"1994","journal-title":"Prog. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1471S","DOI":"10.1093\/jn\/130.5.1471S","article-title":"Importance of zinc in the central nervous system: The zinc-containing neuron","volume":"130","author":"Frederickson","year":"2000","journal-title":"J. Nutr."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.neuroscience.2008.01.061","article-title":"Zinc at glutamatergic synapses","volume":"158","author":"Paoletti","year":"2009","journal-title":"Neuroscience"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1515\/revneuro-2019-0052","article-title":"Role of zinc and copper ions in the pathogenetic mechanisms of traumatic brain injury and Alzheimer\u2019s disease","volume":"31","author":"Isaev","year":"2020","journal-title":"Rev. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1113\/jphysiol.2002.020172","article-title":"Zn2+ currents are mediated by calcium-permeable AMPA\/kainate channels in cultured murine hippocampal neurones","volume":"543","author":"Jia","year":"2002","journal-title":"J. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1716","DOI":"10.1073\/pnas.96.4.1716","article-title":"Elimination of zinc from synaptic vesicles in the intact mouse brain by disruption of the ZnT3 gene","volume":"96","author":"Cole","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/S0006-8993(99)02095-8","article-title":"Evidence that synaptically-released zinc contributes to neuronal injury after traumatic brain injury","volume":"852","author":"Suh","year":"2000","journal-title":"Brain Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.brainres.2006.09.094","article-title":"Injured Fluoro-Jade-positive hippocampal neurons contain high levels of zinc after traumatic brain injury","volume":"1127","author":"Hellmich","year":"2007","journal-title":"Brain Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2164","DOI":"10.1523\/JNEUROSCI.08-06-02164.1988","article-title":"Zinc alters excitatory amino acid neurotoxicity on cortical neurons","volume":"8","author":"Koh","year":"1988","journal-title":"J. Neurosci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/j.neuroscience.2021.01.010","article-title":"The Function and Regulation of Zinc in the Brain","volume":"457","author":"Krall","year":"2021","journal-title":"Neuroscience"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Levenson, C.W. (2020). Zinc and Traumatic Brain Injury: From Chelation to Supplementation. Med. Sci., 8.","DOI":"10.3390\/medsci8030036"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"24373","DOI":"10.1074\/jbc.M611376200","article-title":"Zinc irreversibly damages major enzymes of energy production and antioxidant defense prior to mitochondrial permeability transition","volume":"282","author":"Gazaryan","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"47524","DOI":"10.1074\/jbc.M108834200","article-title":"Zn2+ induces permeability transition pore opening and release of pro-apoptotic peptides from neuronal mitochondria","volume":"276","author":"Jiang","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1039\/C5MT00234F","article-title":"A time-course analysis of changes in cerebral metal levels following a controlled cortical impact","volume":"8","author":"Portbury","year":"2016","journal-title":"Metallomics"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"9903","DOI":"10.1523\/JNEUROSCI.1713-04.2004","article-title":"Late calcium EDTA rescues hippocampal CA1 neurons from global ischemia-induced death","volume":"24","author":"Calderone","year":"2004","journal-title":"J. Neurosci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.neulet.2008.05.068","article-title":"Chelation of neurotoxic zinc levels does not improve neurobehavioral outcome after traumatic brain injury","volume":"440","author":"Hellmich","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Doering, P., Stoltenberg, M., Penkowa, M., Rungby, J., Larsen, A., and Danscher, G. (2010). Chemical blocking of zinc ions in CNS increases neuronal damage following traumatic brain injury (TBI) in mice. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0010131"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1007\/s10072-012-1214-7","article-title":"Increased expression of ferritin in cerebral cortex after human traumatic brain injury","volume":"34","author":"Liu","year":"2013","journal-title":"Neurol. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.3174\/ajnr.A2637","article-title":"Brain iron quantification in mild traumatic brain injury: A magnetic field correlation study","volume":"32","author":"Raz","year":"2011","journal-title":"AJNR Am. J. Neuroradiol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"392","DOI":"10.2174\/1570159X14666151230110058","article-title":"Molecular, Cellular and Clinical Aspects of Intracerebral Hemorrhage: Are the Enemies within?","volume":"14","author":"Righy","year":"2016","journal-title":"Curr. Neuropharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1007\/s00018-013-1509-8","article-title":"Iron deposits in the chronically inflamed central nervous system and contributes to neurodegeneration","volume":"71","author":"Andersen","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2995","DOI":"10.1111\/jcmm.14206","article-title":"Role of mitochondrial calcium uniporter-mediated Ca2+ and iron accumulation in traumatic brain injury","volume":"23","author":"Zhang","year":"2019","journal-title":"J. Cell. Mol. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/S0891-5849(03)00109-6","article-title":"Intralysosomal iron: A major determinant of oxidant-induced cell death","volume":"34","author":"Yu","year":"2003","journal-title":"Free Radic. Biol. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1487","DOI":"10.1080\/15548627.2016.1190072","article-title":"Iron overload causes endolysosomal deficits modulated by NAADP-regulated 2-pore channels and RAB7A","volume":"12","author":"Fernandez","year":"2016","journal-title":"Autophagy"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"19657","DOI":"10.3390\/ijms160819657","article-title":"The Incremental Induction of Neuroprotective Properties by Multiple Therapeutic Strategies for Primary and Secondary Neural Injury","volume":"16","author":"Lee","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"21970","DOI":"10.1038\/srep21970","article-title":"A combination of serum iron, ferritin and transferrin predicts outcome in patients with intracerebral hemorrhage","volume":"6","author":"Yang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1177\/1535370218773055","article-title":"The loss of copper is associated with the increase in copper metabolism MURR domain 1 in ischemic hearts of mice","volume":"243","author":"Li","year":"2018","journal-title":"Exp. Biol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1177\/1535370220969844","article-title":"COMMD1 upregulation is involved in copper efflux from ischemic hearts","volume":"246","author":"Li","year":"2021","journal-title":"Exp. Biol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1016\/j.expneurol.2007.06.018","article-title":"Multiple proteins implicated in neurodegenerative diseases accumulate in axons after brain trauma in humans","volume":"208","author":"Uryu","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Tamagno, E., Guglielmotto, M., Vasciaveo, V., and Tabaton, M. (2021). Oxidative Stress and Beta Amyloid in Alzheimer\u2019s Disease. Which Comes First: The Chicken or the Egg?. Antioxidants, 10.","DOI":"10.3390\/antiox10091479"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"5481","DOI":"10.1038\/s41380-021-01249-0","article-title":"The Amyloid-beta Pathway in Alzheimer\u2019s Disease","volume":"26","author":"Hampel","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/34910","article-title":"Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein","volume":"391","author":"Saftig","year":"1998","journal-title":"Nature"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1126\/science.286.5440.735","article-title":"Beta-secretase cleavage of Alzheimer\u2019s amyloid precursor protein by the transmembrane aspartic protease BACE","volume":"286","author":"Vassar","year":"1999","journal-title":"Science"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S0014-5793(00)02076-7","article-title":"Regulation of APP cleavage by alpha-, beta- and gamma-secretases","volume":"483","author":"Nunan","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5690","DOI":"10.1073\/pnas.97.11.5690","article-title":"In search of gamma-secretase: Presenilin at the cutting edge","volume":"97","author":"Selkoe","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1126\/science.1064638","article-title":"A portrait of Alzheimer secretases--new features and familiar faces","volume":"293","author":"Esler","year":"2001","journal-title":"Science"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1136\/jnnp.57.4.419","article-title":"Beta amyloid protein deposition in the brain after severe head injury: Implications for the pathogenesis of Alzheimer\u2019s disease","volume":"57","author":"Roberts","year":"1994","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1072","DOI":"10.3171\/jns.2003.98.5.1072","article-title":"Amyloid beta accumulation in axons after traumatic brain injury in humans","volume":"98","author":"Smith","year":"2003","journal-title":"J. Neurosurg."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1016\/j.neuron.2013.10.008","article-title":"The pathobiology of vascular dementia","volume":"80","author":"Iadecola","year":"2013","journal-title":"Neuron"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s10571-015-0308-1","article-title":"Microvascular Dysfunction and Cognitive Impairment","volume":"36","author":"Faraci","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1161\/CIRCULATIONAHA.117.027448","article-title":"Cerebral Perfusion and the Risk of Dementia: A Population-Based Study","volume":"136","author":"Wolters","year":"2017","journal-title":"Circulation"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"117253","DOI":"10.1016\/j.jns.2020.117253","article-title":"Role of mitochondrial dysfunction, oxidative stress and autophagy in progression of Alzheimer\u2019s disease","volume":"421","author":"Bhatia","year":"2021","journal-title":"J. Neurol. Sci."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1089\/ars.2011.4173","article-title":"Mitochondrion-derived reactive oxygen species lead to enhanced amyloid beta formation","volume":"16","author":"Leuner","year":"2012","journal-title":"Antioxid. Redox Signal."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0022-510X(98)00092-6","article-title":"Copper, iron and zinc in Alzheimer\u2019s disease senile plaques","volume":"158","author":"Lovell","year":"1998","journal-title":"J. Neurol. Sci."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"726954","DOI":"10.1155\/2013\/726954","article-title":"Metal dyshomeostasis and inflammation in Alzheimer\u2019s and Parkinson\u2019s diseases: Possible impact of environmental exposures","volume":"2013","author":"Myhre","year":"2013","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Squitti, R., Ventriglia, M., Simonelli, I., Bonvicini, C., Costa, A., Perini, G., Binetti, G., Benussi, L., Ghidoni, R., and Koch, G. (2021). Copper Imbalance in Alzheimer\u2019s Disease: Meta-Analysis of Serum, Plasma, and Brain Specimens, and Replication Study Evaluating ATP7B Gene Variants. Biomolecules, 11.","DOI":"10.3390\/biom11070960"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1186\/1742-2094-9-179","article-title":"Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: A microarray study","volume":"9","author":"Cribbs","year":"2012","journal-title":"J. Neuroinflamm."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1007\/s12035-014-8657-1","article-title":"Body fluid cytokine levels in mild cognitive impairment and Alzheimer\u2019s disease: A comparative overview","volume":"50","author":"Brosseron","year":"2014","journal-title":"Mol. Neurobiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1155\/2006\/276239","article-title":"Microglia activation in the brain as inflammatory biomarker of Alzheimer\u2019s disease neuropathology and clinical dementia","volume":"22","author":"Xiang","year":"2006","journal-title":"Dis. Markers"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"322","DOI":"10.3389\/fncel.2015.00322","article-title":"Implications of glial nitric oxide in neurodegenerative diseases","volume":"9","author":"Yuste","year":"2015","journal-title":"Front. Cell. Neurosci."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1523\/JNEUROSCI.21-04-01179.2001","article-title":"\u03b2-Amyloid stimulation of microglia and monocytes results in TNF\u03b1-dependent expression of inducible nitric oxide synthase and neuronal apoptosis","volume":"21","author":"Combs","year":"2001","journal-title":"J. Neurosci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1212\/WNL.45.2.397","article-title":"Cuban optic neuropathy","volume":"45","author":"Newman","year":"1995","journal-title":"Neurology"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1046\/j.1471-4159.1999.0720741.x","article-title":"Quantification of axonal damage in traumatic brain injury: Affinity purification and characterization of cerebrospinal fluid tau proteins","volume":"72","author":"Zemlan","year":"1999","journal-title":"J. Neurochem."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1111\/bpa.12248","article-title":"The neuropathology of chronic traumatic encephalopathy","volume":"25","author":"McKee","year":"2015","journal-title":"Brain Pathol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.expneurol.2012.01.013","article-title":"Axonal pathology in traumatic brain injury","volume":"246","author":"Johnson","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.neubiorev.2016.05.009","article-title":"Blood biomarkers for brain injury: What are we measuring?","volume":"68","author":"Kawata","year":"2016","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_101","doi-asserted-by":"crossref","unstructured":"Bartolome, F., Carro, E., and Alquezar, C. (2022). Oxidative Stress in Tauopathies: From Cause to Therapy. Antioxidants, 11.","DOI":"10.3390\/antiox11081421"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"617588","DOI":"10.3389\/fnagi.2021.617588","article-title":"Mitochondrial Dysfunction and Oxidative Stress in Alzheimer\u2019s Disease","volume":"13","author":"Misrani","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"163","DOI":"10.3389\/fnins.2018.00163","article-title":"The Association of Tau with Mitochondrial Dysfunction in Alzheimer\u2019s Disease","volume":"12","author":"Cheng","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1161\/CIRCRESAHA.116.309927","article-title":"Untangling Neurons with Endothelial Nitric Oxide","volume":"119","author":"Iadecola","year":"2016","journal-title":"Circ. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40478-020-00924-7","article-title":"Biological links between traumatic brain injury and Parkinson\u2019s disease","volume":"8","author":"Delic","year":"2020","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Chiesa, R. (2015). The elusive role of the prion protein and the mechanism of toxicity in prion disease. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1004745"},{"key":"ref_107","first-page":"8042","article-title":"Cellular prion protein (PrP(C)) and its role in stress responses","volume":"8","author":"Zeng","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1051\/vetres:2007048","article-title":"Physiological role of the cellular prion protein","volume":"39","author":"Arnaud","year":"2008","journal-title":"Vet. Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/s40478-017-0435-7","article-title":"Tau phosphorylation induced by severe closed head traumatic brain injury is linked to the cellular prion protein","volume":"5","author":"Rubenstein","year":"2017","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1007\/s11011-014-9550-3","article-title":"Ablation of matrix metalloproteinase-9 gene decreases cerebrovascular permeability and fibrinogen deposition post traumatic brain injury in mice","volume":"30","author":"Muradashvili","year":"2015","journal-title":"Metab. Brain Dis."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1089\/neu.2014.3471","article-title":"Primary blast-induced traumatic brain injury in rats leads to increased prion protein in plasma: A potential biomarker for blast-induced traumatic brain injury","volume":"32","author":"Pham","year":"2015","journal-title":"J. Neurotrauma"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"17415","DOI":"10.1074\/jbc.M115.643577","article-title":"Prion-Protein-interacting Amyloid-beta Oligomers of High Molecular Weight Are Tightly Correlated with Memory Impairment in Multiple Alzheimer Mouse Models","volume":"290","author":"Kostylev","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s004010100405","article-title":"Marked increase of neuronal prion protein immunoreactivity in Alzheimer\u2019s disease and human prion diseases","volume":"101","author":"Voigtlander","year":"2001","journal-title":"Acta Neuropathol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/nature07761","article-title":"Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers","volume":"457","author":"Lauren","year":"2009","journal-title":"Nature"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1016\/j.bbrc.2016.09.062","article-title":"Cellular prion protein as a receptor for amyloid-beta oligomers in Alzheimer\u2019s disease","volume":"483","author":"Salazar","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"16857","DOI":"10.1523\/JNEUROSCI.1858-12.2012","article-title":"The complex PrP(c)-Fyn couples human oligomeric Abeta with pathological tau changes in Alzheimer\u2019s disease","volume":"32","author":"Larson","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1097\/00005053-195308000-00001","article-title":"Alzheimer\u2019s disease; A clinico-pathologic analysis of twenty-three cases with a theory on pathogenesis","volume":"118","author":"Goodman","year":"1953","journal-title":"J. Nerv. Ment. Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1111\/j.1471-4159.1960.tb13369.x","article-title":"The non-haemin iron in the cerebral cortex in Alzheimer\u2019s disease","volume":"5","author":"Hallgren","year":"1960","journal-title":"J. Neurochem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/0140-6736(91)92978-B","article-title":"Intramuscular desferrioxamine in patients with Alzheimer\u2019s disease","volume":"337","author":"Dalton","year":"1991","journal-title":"Lancet"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1021\/acs.molpharmaceut.0c00474","article-title":"Challenges and Opportunities of Deferoxamine Delivery for Treatment of Alzheimer\u2019s Disease, Parkinson\u2019s Disease, and Intracerebral Hemorrhage","volume":"18","author":"Farr","year":"2021","journal-title":"Mol. Pharm."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/jnr.490310111","article-title":"A histochemical study of iron, transferrin, and ferritin in Alzheimer\u2019s diseased brains","volume":"31","author":"Connor","year":"1992","journal-title":"J. Neurosci. Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1002\/jnr.490310214","article-title":"Regional distribution of iron and iron-regulatory proteins in the brain in aging and Alzheimer\u2019s disease","volume":"31","author":"Connor","year":"1992","journal-title":"J. Neurosci. Res."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"9866","DOI":"10.1073\/pnas.94.18.9866","article-title":"Iron accumulation in Alzheimer disease is a source of redox-generated free radicals","volume":"94","author":"Smith","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1046\/j.1471-4159.2000.0740270.x","article-title":"In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer\u2019s disease: A central role for bound transition metals","volume":"74","author":"Sayre","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"7609","DOI":"10.1021\/bi990438f","article-title":"The A beta peptide of Alzheimer\u2019s disease directly produces hydrogen peroxide through metal ion reduction","volume":"38","author":"Huang","year":"1999","journal-title":"Biochemistry"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1046\/j.1471-4159.2002.t01-1-01061.x","article-title":"Iron (III) induces aggregation of hyperphosphorylated tau and its reduction to iron (II) reverses the aggregation: Implications in the formation of neurofibrillary tangles of Alzheimer\u2019s disease","volume":"82","author":"Yamamoto","year":"2002","journal-title":"J. Neurochem."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.neuroimage.2019.02.019","article-title":"Imaging beta amyloid aggregation and iron accumulation in Alzheimer\u2019s disease using quantitative susceptibility mapping MRI","volume":"191","author":"Gong","year":"2019","journal-title":"Neuroimage"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"11782","DOI":"10.1039\/C7NR06794A","article-title":"Nanoscale synchrotron X-ray speciation of iron and calcium compounds in amyloid plaque cores from Alzheimer\u2019s disease subjects","volume":"10","author":"Everett","year":"2018","journal-title":"Nanoscale"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1046\/j.1471-4159.1995.64010307.x","article-title":"Iron levels modulate alpha-secretase cleavage of amyloid precursor protein","volume":"64","author":"Bodovitz","year":"1995","journal-title":"J. Neurochem."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/aps.2017.113","article-title":"Iron dysregulates APP processing accompanying with sAPP\u03b1 cellular retention and \u03b2-secretase inhibition in rat cortical neurons","volume":"39","author":"Chen","year":"2018","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1007\/s00401-009-0497-0","article-title":"Formation of amyloid-beta oligomers in brain vascular smooth muscle cells transiently exposed to iron-induced oxidative stress","volume":"117","author":"Frackowiak","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"493","DOI":"10.3233\/JAD-180802","article-title":"Understanding the Amyloid Hypothesis in Alzheimer\u2019s Disease","volume":"68","author":"Paroni","year":"2019","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"45518","DOI":"10.1074\/jbc.M207435200","article-title":"An iron-responsive element type II in the 5\u2032-untranslated region of the Alzheimer\u2019s amyloid precursor protein transcript","volume":"277","author":"Rogers","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"4202","DOI":"10.1074\/jbc.RA118.005142","article-title":"Fluorescence resonance energy transfer links membrane ferroportin, hephaestin but not ferroportin, amyloid precursor protein complex with iron efflux","volume":"294","author":"Dlouhy","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nm.2613","article-title":"Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export","volume":"18","author":"Lei","year":"2012","journal-title":"Nat. Med."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1097\/00001756-199309000-00015","article-title":"Increased frequency of the transferrin C2 subtype in Alzheimer\u2019s disease","volume":"4","author":"Carstens","year":"1993","journal-title":"Neuroreport"},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1159\/000068480","article-title":"Interaction of the H63D mutation in the hemochromatosis gene with the apolipoprotein E epsilon 4 allele modulates age at onset of Alzheimer\u2019s disease","volume":"15","author":"Combarros","year":"2003","journal-title":"Dement. Geriatr. Cogn. Disord."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3233\/JAD-2008-14107","article-title":"Involvement of ApoE E4 and H63D in sporadic Alzheimer\u2019s disease in a folate-supplemented Ontario population","volume":"14","author":"Percy","year":"2008","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1136\/jmg.2003.015552","article-title":"Synergy between the C2 allele of transferrin and the C282Y allele of the haemochromatosis gene (HFE) as risk factors for developing Alzheimer\u2019s disease","volume":"41","author":"Robson","year":"2004","journal-title":"J. Med. Genet."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.neurobiolaging.2003.06.008","article-title":"Evaluation of HFE (hemochromatosis) mutations as genetic modifiers in sporadic AD and MCI","volume":"25","author":"Berlin","year":"2004","journal-title":"Neurobiol. Aging"},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1016\/S0197-4580(01)00219-6","article-title":"The hemochromatosis gene affects the age of onset of sporadic Alzheimer\u2019s disease","volume":"22","author":"Sampietro","year":"2001","journal-title":"Neurobiol. Aging"},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1002\/ajmg.b.10069","article-title":"Association of HFE mutations with neurodegeneration and oxidative stress in Alzheimer\u2019s disease and correlation with APOE","volume":"119B","author":"Pulliam","year":"2003","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_144","doi-asserted-by":"crossref","first-page":"142.e9","DOI":"10.1016\/j.neurobiolaging.2020.01.013","article-title":"Failure to detect synergy between variants in transferrin and hemochromatosis and Alzheimer\u2019s disease in large cohort","volume":"89","author":"Vance","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"6760","DOI":"10.1038\/ncomms7760","article-title":"Ferritin levels in the cerebrospinal fluid predict Alzheimer\u2019s disease outcomes and are regulated by APOE","volume":"6","author":"Ayton","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1001\/jamaneurol.2016.4406","article-title":"Association of Cerebrospinal Fluid Ferritin Level with Preclinical Cognitive Decline in APOE-epsilon4 Carriers","volume":"74","author":"Ayton","year":"2017","journal-title":"JAMA Neurol."},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.nbd.2018.12.010","article-title":"Cerebrospinal fluid ferritin levels predict brain hypometabolism in people with underlying beta-amyloid pathology","volume":"124","author":"Diouf","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_148","doi-asserted-by":"crossref","first-page":"104810","DOI":"10.1016\/j.nbd.2020.104810","article-title":"Cerebrospinal fluid ceruloplasmin levels predict cognitive decline and brain atrophy in people with underlying beta-amyloid pathology","volume":"139","author":"Diouf","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1136\/jnnp-2017-316551","article-title":"Evidence that iron accelerates Alzheimer\u2019s pathology: A CSF biomarker study","volume":"89","author":"Ayton","year":"2018","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1093\/brain\/awx137","article-title":"Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline","volume":"140","author":"Ayton","year":"2017","journal-title":"Brain"},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1148\/radiol.2020192541","article-title":"Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRI","volume":"296","author":"Damulina","year":"2020","journal-title":"Radiology"},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1002\/alz.12282","article-title":"Regional brain iron associated with deterioration in Alzheimer\u2019s disease: A large cohort study and theoretical significance","volume":"17","author":"Ayton","year":"2021","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"2252","DOI":"10.1021\/ar400293h","article-title":"Metal ions and intrinsically disordered proteins and peptides: From Cu\/Zn amyloid-beta to general principles","volume":"47","author":"Faller","year":"2014","journal-title":"Acc. Chem. Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"4165","DOI":"10.1021\/acs.biochem.8b00572","article-title":"The Human Amyloid Precursor Protein Binds Copper Ions Dominated by a Picomolar-Affinity Site in the Helix-Rich E2 Domain","volume":"57","author":"Young","year":"2018","journal-title":"Biochemistry"},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.redox.2017.10.014","article-title":"Oxidative stress and the amyloid beta peptide in Alzheimer\u2019s disease","volume":"14","author":"Cheignon","year":"2018","journal-title":"Redox Biol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.neurobiolaging.2019.04.001","article-title":"A quantitative model of human neurodegenerative diseases involving protein aggregation","volume":"80","author":"Kepp","year":"2019","journal-title":"Neurobiol. Aging"},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.ccr.2019.06.018","article-title":"Copper imbalance in Alzheimer\u2019s disease: Convergence of the chemistry and the clinic","volume":"397","author":"Kepp","year":"2019","journal-title":"Coord. Chem. Rev."},{"key":"ref_159","first-page":"797","article-title":"Psychiatric disorders and traumatic brain injury","volume":"4","author":"Schwarzbold","year":"2008","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1176\/jnp.6.4.358","article-title":"Frontal-subcortical circuits and neuropsychiatric disorders","volume":"6","author":"Mega","year":"1994","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_161","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1176\/appi.neuropsych.18040093","article-title":"Epidemiology and Natural History of Psychiatric Disorders After TBI","volume":"30","author":"Ponsford","year":"2018","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1097\/00001199-199808000-00003","article-title":"Axis I psychopathology in individuals with traumatic brain injury","volume":"13","author":"Hibbard","year":"1998","journal-title":"J. Head Trauma Rehabil."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"634","DOI":"10.3389\/fpsyg.2017.00634","article-title":"Depression in Men and Women One Year Following Traumatic Brain Injury (TBI): A TBI Model Systems Study","volume":"8","author":"Lavoie","year":"2017","journal-title":"Front. Psychol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1176\/appi.neuropsych.17090180","article-title":"Traumatic Brain Injury and Posttraumatic Stress Disorder: Conceptual, Diagnostic, and Therapeutic Considerations in the Context of Co-Occurrence","volume":"30","author":"Vasterling","year":"2018","journal-title":"J. Neuropsychiatry Clin. Neurosci."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1097\/00001199-200511000-00001","article-title":"Pathophysiologic aspects of major depression following traumatic brain injury","volume":"20","author":"Jorge","year":"2005","journal-title":"J. Head Trauma Rehabil."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3171\/jns.1992.76.1.0119","article-title":"Central and peripheral biogenic amine effects of brain missile wounding and increased intracranial pressure","volume":"76","author":"Soblosky","year":"1992","journal-title":"J. Neurosurg."},{"key":"ref_167","doi-asserted-by":"crossref","unstructured":"Mukandala, G., Tynan, R., Lanigan, S., and O\u2019Connor, J.J. (2016). The Effects of Hypoxia and Inflammation on Synaptic Signaling in the CNS. Brain Sci., 6.","DOI":"10.3390\/brainsci6010006"},{"key":"ref_168","first-page":"269","article-title":"Trace element studies on Karachi population. Part IV: Blood copper, zinc, magnesium and lead levels in psychiatric patients with depression, mental retardation and seizure disorders","volume":"39","author":"Manser","year":"1989","journal-title":"J. Pak. Med. Assoc."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s12011-016-0720-5","article-title":"Study of the Serum Copper Levels in Patients with Major Depressive Disorder","volume":"174","author":"Styczen","year":"2016","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/j.pharep.2015.10.006","article-title":"The role of glutamatergic, GABA-ergic, and cholinergic receptors in depression and antidepressant-like effect","volume":"68","author":"Pytka","year":"2016","journal-title":"Pharmacol. Rep."},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.pharep.2014.09.009","article-title":"Essential elements in depression and anxiety. Part II","volume":"67","author":"Mlyniec","year":"2015","journal-title":"Pharmacol. Rep."},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"1558","DOI":"10.1016\/S1734-1140(13)71517-2","article-title":"Oxidative stress markers in affective disorders","volume":"65","author":"Siwek","year":"2013","journal-title":"Pharmacol. Rep."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"864753","DOI":"10.4061\/2011\/864753","article-title":"Copper Inhibits NMDA Receptor-Independent LTP and Modulates the Paired-Pulse Ratio after LTP in Mouse Hippocampal Slices","volume":"2011","author":"Smith","year":"2011","journal-title":"Int. J. Alzheimer\u2019s Dis."},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/j.1471-4159.2011.07417.x","article-title":"Biphasic effects of copper on neurotransmission in rat hippocampal neurons","volume":"119","author":"Peters","year":"2011","journal-title":"J. Neurochem."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.pnpbp.2010.02.010","article-title":"The role of zinc in neurodegenerative inflammatory pathways in depression","volume":"35","author":"Szewczyk","year":"2011","journal-title":"Prog. Neuro-Psychopharmacol. Biol. Psychiatry"},{"key":"ref_176","doi-asserted-by":"crossref","unstructured":"Rafalo, A., Sowa-Kucma, M., Pochwat, B., Nowak, G., and Szewczyk, B. (2016). Zinc Deficiency and Depression, IntechOpen.","DOI":"10.5772\/63210"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1002\/jnr.10600","article-title":"Release of glutamate and GABA in the hippocampus under zinc deficiency","volume":"72","author":"Takeda","year":"2003","journal-title":"J. Neurosci. Res."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.neuint.2006.06.005","article-title":"Impairment of GABAergic neurotransmitter system in the amygdala of young rats after 4-week zinc deprivation","volume":"49","author":"Takeda","year":"2006","journal-title":"Neurochem. Int."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.bbr.2015.03.064","article-title":"Antidepressant activity of fluoxetine in the zinc deficiency model in rats involves the NMDA receptor complex","volume":"287","author":"Doboszewska","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1126\/science.1222939","article-title":"Synaptic dysfunction in depression: Potential therapeutic targets","volume":"338","author":"Duman","year":"2012","journal-title":"Science"},{"key":"ref_181","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4137\/NMI.S6349","article-title":"Decreased zinc and increased copper in individuals with anxiety","volume":"4","author":"Russo","year":"2011","journal-title":"Nutr. Metab. Insights"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.3945\/jn.109.106369","article-title":"Zinc deficiency affects DNA damage, oxidative stress, antioxidant defenses, and DNA repair in rats","volume":"139","author":"Song","year":"2009","journal-title":"J. Nutr."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"16770","DOI":"10.1073\/pnas.222679399","article-title":"Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line","volume":"99","author":"Ho","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"632","DOI":"10.3389\/fnins.2018.00632","article-title":"Iron and Alzheimer\u2019s Disease: From Pathogenesis to Therapeutic Implications","volume":"12","author":"Liu","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1016\/j.jnutbio.2014.07.003","article-title":"Iron and mechanisms of emotional behavior","volume":"25","author":"Kim","year":"2014","journal-title":"J. Nutr. Biochem."},{"key":"ref_186","doi-asserted-by":"crossref","unstructured":"Chen, M.H., Su, T.P., Chen, Y.S., Hsu, J.W., Huang, K.L., Chang, W.H., Chen, T.J., and Bai, Y.M. (2013). Association between psychiatric disorders and iron deficiency anemia among children and adolescents: A nationwide population-based study. BMC Psychiatry, 13.","DOI":"10.1186\/1471-244X-13-161"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"456","DOI":"10.29271\/jcpsp.2018.06.456","article-title":"Relation between Depressive Disorder and Iron Deficiency Anemia among Adults Reporting to a Secondary Healthcare Facility: A Hospital-Based Case Control Study","volume":"28","author":"Shafi","year":"2018","journal-title":"J. Coll. Physicians Surg. Pak."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1102609","article-title":"Placebo-controlled trial of amantadine for severe traumatic brain injury","volume":"366","author":"Giacino","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0006-8993(02)02961-X","article-title":"Hypersensitivity of dopamine transmission in the rat striatum after treatment with the NMDA receptor antagonist amantadine","volume":"949","author":"Peeters","year":"2002","journal-title":"Brain Res."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"3703","DOI":"10.1007\/s12035-022-02814-6","article-title":"Amantadine Attenuated Hypoxia-Induced Mitochondrial Oxidative Neurotoxicity, Apoptosis, and Inflammation via the Inhibition of TRPM2 and TRPV4 Channels","volume":"59","author":"Ocal","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1038\/sj.mp.4001759","article-title":"Fine mapping of a susceptibility locus for bipolar and genetically related unipolar affective disorders, to a region containing the C21ORF29 and TRPM2 genes on chromosome 21q22.3","volume":"11","author":"McQuillin","year":"2006","journal-title":"Mol. Psychiatry"},{"key":"ref_192","doi-asserted-by":"crossref","unstructured":"Yu, P., Cai, X., Liang, Y., Wang, M., and Yang, W. (2020). Roles of NAD(+) and Its Metabolites Regulated Calcium Channels in Cancer. Molecules, 25.","DOI":"10.3390\/molecules25204826"},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1097\/PHM.0000000000000069","article-title":"Zolpidem and restoration of consciousness","volume":"93","author":"Whyte","year":"2014","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.neuropharm.2008.07.004","article-title":"Post-hypoxic changes in rat cortical neuron GABA A receptor function require L-type voltage-gated calcium channel activation","volume":"56","author":"Wang","year":"2009","journal-title":"Neuropharmacology"},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1212\/WNL.0000000000000260","article-title":"tDCS in patients with disorders of consciousness: Sham-controlled randomized double-blind study","volume":"82","author":"Thibaut","year":"2014","journal-title":"Neurology"},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1016\/j.brs.2017.08.007","article-title":"Repeated transcranial direct current stimulation improves cognitive dysfunction and synaptic plasticity deficit in the prefrontal cortex of streptozotocin-induced diabetic rats","volume":"10","author":"Wu","year":"2017","journal-title":"Brain Stimul."},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1039\/C7MT00329C","article-title":"Combined brain Fe, Cu, Zn and neurometabolite analysis\u2014A new methodology for unraveling the efficacy of transcranial direct current stimulation (tDCS) in appetite control","volume":"10","author":"Ziomber","year":"2018","journal-title":"Metallomics"},{"key":"ref_198","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.expneurol.2016.02.017","article-title":"Effect of zinc supplementation on neuronal precursor proliferation in the rat hippocampus after traumatic brain injury","volume":"279","author":"Cope","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1016\/j.physbeh.2011.06.007","article-title":"Zinc supplementation provides behavioral resiliency in a rat model of traumatic brain injury","volume":"104","author":"Cope","year":"2011","journal-title":"Physiol. Behav."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3171\/jns.1986.64.2.0224","article-title":"Serum and urine zinc response in head-injured patients","volume":"64","author":"McClain","year":"1986","journal-title":"J. Neurosurg."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1089\/neu.1996.13.25","article-title":"Zinc supplementation is associated with improved neurologic recovery rate and visceral protein levels of patients with severe closed head injury","volume":"13","author":"Young","year":"1996","journal-title":"J. Neurotrauma"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/19390211.2017.1304486","article-title":"Impact of Zinc Supplementation on the Clinical Outcomes of Patients with Severe Head Trauma: A Double-Blind Randomized Clinical Trial","volume":"15","author":"Khazdouz","year":"2018","journal-title":"J. Diet. Suppl."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6867\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:11:35Z","timestamp":1760123495000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/7\/6867"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,6]]},"references-count":202,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijms24076867"],"URL":"https:\/\/doi.org\/10.3390\/ijms24076867","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,6]]}}}