Acknowledgement
The authors thank Hee Jin Kim, MD, PhD, from Hanyang University, Chung-Hwan Kang, RT, Ha-young Kim, BS, Suji Kim, RN, from Konkuk University Medical Center for their support in the patient recruitment, imaging data acquisition and management of this study.
References
- Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L. The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 2014;13:1045-1060 https://doi.org/10.1016/S1474-4422(14)70117-6
- Aquino D, Bizzi A, Grisoli M, Garavaglia B, Bruzzone MG, Nardocci N, et al. Age-related iron deposition in the basal ganglia: quantitative analysis in healthy subjects. Radiology 2009;252:165-172 https://doi.org/10.1148/radiol.2522081399
- Buijs M, Doan NT, van Rooden S, Versluis MJ, van Lew B, Milles J, et al. In vivo assessment of iron content of the cerebral cortex in healthy aging using 7-tesla T2*-weighted phase imaging. Neurobiol Aging 2017;53:20-26 https://doi.org/10.1016/j.neurobiolaging.2016.09.005
- Lane DJR, Ayton S, Bush AI. Iron and Alzheimer's disease: an update on emerging mechanisms. J Alzheimers Dis 2018;64(S1):S379-S395 https://doi.org/10.3233/JAD-179944
- McCarthy RC, Sosa JC, Gardeck AM, Baez AS, Lee CH, Wessling-Resnick M. Inflammation-induced iron transport and metabolism by brain microglia. J Biol Chem 2018;293:7853-7863 https://doi.org/10.1074/jbc.RA118.001949
- Ropele S, Wattjes MP, Langkammer C, Kilsdonk ID, Graaf WL, Frederiksen JL, et al. Multicenter R2* mapping in the healthy brain. Magn Reson Med 2014;71:1103-1107 https://doi.org/10.1002/mrm.24772
- Moon Y, Han SH, Moon WJ. Patterns of brain iron accumulation in vascular dementia and Alzheimer's dementia using quantitative susceptibility mapping imaging. J Alzheimers Dis 2016;51:737-745 https://doi.org/10.3233/JAD-151037
- Cogswell PM, Wiste HJ, Senjem ML, Gunter JL, Weigand SD, Schwarz CG, et al. Associations of quantitative susceptibility mapping with Alzheimer's disease clinical and imaging markers. Neuroimage 2021;224:117433
- Yim Y, Choi JD, Cho JH, Moon Y, Han SH, Moon WJ. Magnetic susceptibility in the deep gray matter may be modulated by apolipoprotein E4 and age with regional predilections: a quantitative susceptibility mapping study. Neuroradiology 2022;64:1331-1342 https://doi.org/10.1007/s00234-021-02859-9
- van Duijn S, Bulk M, van Duinen SG, Nabuurs RJA, van Buchem MA, van der Weerd L, et al. Cortical iron reflects severity of Alzheimer's disease. J Alzheimers Dis 2017;60:1533-1545 https://doi.org/10.3233/JAD-161143
- Spotorno N, Acosta-Cabronero J, Stomrud E, Lampinen B, Strandberg OT, van Westen D, et al. Relationship between cortical iron and tau aggregation in Alzheimer's disease. Brain 2020;143:1341-1349 https://doi.org/10.1093/brain/awaa089
- Damulina A, Pirpamer L, Soellradl M, Sackl M, Tinauer C, Hofer E, et al. Cross-sectional and longitudinal assessment of brain iron level in Alzheimer disease using 3-T MRI. Radiology 2020;296:619-626 https://doi.org/10.1148/radiol.2020192541
- Ayton S, Fazlollahi A, Bourgeat P, Raniga P, Ng A, Lim YY, et al. Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline. Brain 2017;140:2112-2119 https://doi.org/10.1093/brain/awx137
- Ayton S, Wang Y, Diouf I, Schneider JA, Brockman J, Morris MC, et al. Brain iron is associated with accelerated cognitive decline in people with Alzheimer pathology. Mol Psychiatry 2020;25:2932-2941 https://doi.org/10.1038/s41380-019-0375-7
- Yoon J, Gong E, Chatnuntawech I, Bilgic B, Lee J, Jung W, et al. Quantitative susceptibility mapping using deep neural network: QSMnet. Neuroimage 2018;179:199-206 https://doi.org/10.1016/j.neuroimage.2018.06.030
- Jung W, Yoon J, Ji S, Choi JY, Kim JM, Nam Y, et al. Exploring linearity of deep neural network trained QSM: QSMnet. Neuroimage 2020;211:116619
- Yang J, Lee S, Moon Y, Lee J, Moon WJ. Relationship between cortical iron and diabetes mellitus in older adults with cognitive complaints: a quantitative susceptibility map study. Investig Magn Reson Imaging 2023;27:84-92 https://doi.org/10.13104/imri.2023.0002
- Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56:303-308 https://doi.org/10.1001/archneur.56.3.303
- McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:263-269 https://doi.org/10.1016/j.jalz.2011.03.005
- Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7:270-279 https://doi.org/10.1016/j.jalz.2011.03.008
- Moon Y, Lim C, Kim Y, Moon WJ. Sex-related differences in regional blood-brain barrier integrity in non-demented elderly subjects. Int J Mol Sci 2021;22:2860
- Park M, Moon WJ, Moon Y, Choi JW, Han SH, Wang Y. Region-specific susceptibility change in cognitively impaired patients with diabetes mellitus. PLoS One 2018;13:e0205797
- Wardlaw JM, Smith EE, Biessels GJ, Cordonnier C, Fazekas F, Frayne R, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol 2013;12:822-838 https://doi.org/10.1016/S1474-4422(13)70124-8
- Klein A, Tourville J. 101 labeled brain images and a consistent human cortical labeling protocol. Front Neurosci 2012;6:171
- Nordenskjold R, Malmberg F, Larsson EM, Simmons A, Ahlstrom H, Johansson L, et al. Intracranial volume normalization methods: considerations when investigating gender differences in regional brain volume. Psychiatry Res 2015;231:227-235 https://doi.org/10.1016/j.pscychresns.2014.11.011
- Smith SM. Fast robust automated brain extraction. Hum Brain Mapp 2002;17:143-155 https://doi.org/10.1002/hbm.10062
- Li W, Wu B, Liu C. Quantitative susceptibility mapping of human brain reflects spatial variation in tissue composition. Neuroimage 2011;55:1645-1656 https://doi.org/10.1016/j.neuroimage.2010.11.088
- Wu B, Li W, Avram AV, Gho SM, Liu C. Fast and tissue-optimized mapping of magnetic susceptibility and T2* with multi-echo and multi-shot spirals. Neuroimage 2012;59:297-305 https://doi.org/10.1016/j.neuroimage.2011.07.019
- Kim HG, Park S, Rhee HY, Lee KM, Ryu CW, Rhee SJ, et al. Quantitative susceptibility mapping to evaluate the early stage of Alzheimer's disease. Neuroimage Clin 2017;16:429-438 https://doi.org/10.1016/j.nicl.2017.08.019
- van Rooden S, Versluis MJ, Liem MK, Milles J, Maier AB, Oleksik AM, et al. Cortical phase changes in Alzheimer's disease at 7T MRI: a novel imaging marker. Alzheimers Dement 2014;10:e19-e26 https://doi.org/10.1016/j.jalz.2013.02.002
- Thal DR, Rub U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002;58:1791-1800 https://doi.org/10.1212/WNL.58.12.1791
- Thal DR, Beach TG, Zanette M, Lilja J, Heurling K, Chakrabarty A, et al. Estimation of amyloid distribution by [18F]flutemetamol PET predicts the neuropathological phase of amyloid β-protein deposition. Acta Neuropathol 2018;136:557-567 https://doi.org/10.1007/s00401-018-1897-9
- Collij LE, Heeman F, Salvado G, Ingala S, Altomare D, de Wilde A, et al. Multitracer model for staging cortical amyloid deposition using PET imaging. Neurology 2020;95:e1538-e1553 https://doi.org/10.1212/WNL.0000000000010256
- Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del Tredici K. Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 2006;112:389-404 https://doi.org/10.1007/s00401-006-0127-z
- Greicius MD, Srivastava G, Reiss AL, Menon V. Default-mode network activity distinguishes Alzheimer's disease from healthy aging: evidence from functional MRI. Proc Natl Acad Sci U S A 2004;101:4637-4642 https://doi.org/10.1073/pnas.0308627101
- He X, Qin W, Liu Y, Zhang X, Duan Y, Song J, et al. Abnormal salience network in normal aging and in amnestic mild cognitive impairment and Alzheimer's disease. Hum Brain Mapp 2014;35:3446-3464 https://doi.org/10.1002/hbm.22414
- Rosenberg PB, Nowrangi MA, Lyketsos CG. Neuropsychiatric symptoms in Alzheimer's disease: what might be associated brain circuits? Mol Aspects Med 2015;43-44:25-37 https://doi.org/10.1016/j.mam.2015.05.005
- Moon Y, Moon WJ, Kim H, Han SH. Regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in Alzheimer's disease patients. Eur Neurol 2014;71:223-229 https://doi.org/10.1159/000356343
- You SC, Walsh CM, Chiodo LA, Ketelle R, Miller BL, Kramer JH. Neuropsychiatric symptoms predict functional status in Alzheimer's disease. J Alzheimers Dis 2015;48:863-869 https://doi.org/10.3233/JAD-150018
- Sun W, Ueno D, Narumoto J. Brain neural underpinnings of interoception and decision-making in Alzheimer's disease: a narrative review. Front Neurosci 2022;16:946136
- Kumar A, Fontana IC, Nordberg A. Reactive astrogliosis: a friend or foe in the pathogenesis of Alzheimer's disease. J Neurochem 2023;164:309-324 https://doi.org/10.1111/jnc.15565
- Marutle A, Gillberg PG, Bergfors A, Yu W, Ni R, Nennesmo I, et al. (3)H-deprenyl and (3)H-PIB autoradiography show different laminar distributions of astroglia and fibrillar β-amyloid in Alzheimer brain. J Neuroinflammation 2013;10:90
- van Bergen JMG, Li X, Quevenco FC, Gietl AF, Treyer V, Meyer R, et al. Simultaneous quantitative susceptibility mapping and flutemetamol-PET suggests local correlation of iron and β-amyloid as an indicator of cognitive performance at high age. Neuroimage 2018;174:308-316 https://doi.org/10.1016/j.neuroimage.2018.03.021
- Bulk M, van der Weerd L, Breimer W, Lebedev N, Webb A, Goeman JJ, et al. Quantitative comparison of different iron forms in the temporal cortex of Alzheimer patients and control subjects. Sci Rep 2018;8:6898
- Gong NJ, Dibb R, Bulk M, van der Weerd L, Liu C. Imaging beta amyloid aggregation and iron accumulation in Alzheimer's disease using quantitative susceptibility mapping MRI. Neuroimage 2019;191:176-185 https://doi.org/10.1016/j.neuroimage.2019.02.019
- McIntosh A, Mela V, Harty C, Minogue AM, Costello DA, Kerskens C, et al. Iron accumulation in microglia triggers a cascade of events that leads to altered metabolism and compromised function in APP/PS1 mice. Brain Pathol 2019;29:606-621 https://doi.org/10.1111/bpa.12704
- Joseph-Mathurin N, Dorieux O, Trouche SG, Boutajangout A, Kraska A, Fontes P, et al. Amyloid beta immunization worsens iron deposits in the choroid plexus and cerebral microbleeds. Neurobiol Aging 2013;34:2613-2622 https://doi.org/10.1016/j.neurobiolaging.2013.05.013