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• W3109297122 abstract "HomeRadiologyVol. 298, No. 2 PreviousNext Reviews and CommentaryFree AccessEditorialIron Accumulation, Not β-Amyloid or Brain Volumes, Is Linked to Cognition in Older Patients Who Are NondementedGloria C. Chiang Gloria C. Chiang Author AffiliationsFrom the Department of Radiology, Division of Neuroradiology, NewYork-Presbyterian/Weill Cornell Medical Center, 525 E 68th St, Starr Pavilion, Box 141, New York, NY 10065.Address correspondence to the author (e-mail: [email protected]).Gloria C. Chiang Published Online:Nov 24 2020https://doi.org/10.1148/radiol.2020204157MoreSectionsPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In See also the article by Chen et al in this issue.Gloria Chiang, MD, is an associate professor in the neuroradiology division of the Department of Radiology at NewYork-Presbyterian/Weill Cornell Medical College Hospital. Her research focuses on using quantitative MRI and PET techniques to diagnose, monitor, and elucidate the pathophysiology of neurodegenerative diseases more effectively. Dr Chiang is the principal investigator on an National Institutes of Health (NIH) grant and has served on an NIH study section.Download as PowerPointOpen in Image Viewer Alzheimer disease (AD) remains the most common cause of dementia and is a devastating diagnosis for individuals and caregivers alike. Researchers and clinical trials have largely focused on β-amyloid plaques, one of the pathologic indicators of AD that is commonly implicated as the inciting factor for neurodegeneration. The 2018 National Institute on Aging–Alzheimer’s Association Research Framework built on this “amyloid hypothesis” by proposing the ATN system for classifying disease stages on the basis of the presence or absence of cerebral β-amyloid deposition, pathologic τ, and neurodegeneration (1). However, 10%–40% of cognitively normal older individuals have evidence of cerebral β-amyloid deposition but no symptoms (2), which suggests that β-amyloid alone may not be sufficient for the development of AD.Postmortem studies have shown evidence for iron imbalance and accumulation in AD brain tissue compared with healthy control brain tissue (3), with iron colocalizing with β-amyloid plaques and neurofibrillary tangles. These β-amyloid plaques can bind ferric iron and reduce it to the redox-active form, ferrous iron, which reacts with hydrogen peroxide to generate hydroxyl radicals, leading to oxidative damage (4,5). Studies in animal models of AD have reported that iron chelation of these β-amyloid plaques can abolish these interactions, reducing downstream oxidative stress and neurofibrillary tangle formation (4–6). Therefore, iron may have a synergistic role with β-amyloid in inciting key pathophysiologic processes leading to AD.By using advanced imaging techniques, authors of recent studies have investigated whether altered iron levels can be detected in vivo in patients with AD. Indeed, studies have reported higher levels of brain iron in cortical and subcortical regions in those with AD compared with healthy control patients (7). One study also found that higher baseline hippocampal iron levels predicted accelerated longitudinal decline in episodic memory, executive dysfunction, and attention in individuals with evidence of cerebral β-amyloid deposition (8). These studies further suggest that iron accumulation may have a significant role in AD pathogenesis.In this issue of Radiology, Chen et al (9) investigated the relationship between brain iron levels and cognition in a nondemented cohort. By using the Biomarkers for Older Controls at Risk for Dementia, or BIOCARD, study, they retrospectively analyzed imaging and neuropsychologic data from 150 nondemented older participants (mean age, 69 years), 121 of whom were cognitively normal and 29 of whom had cognitive symptoms but did not meet criteria for mild cognitive impairment. All participants had undergone 3.0-T MRI that included quantitative susceptibility mapping, a contrast-free technique used to quantify tissue iron concentration. The majority (97 of 150; 65%) of participants also underwent PET with the amyloid tracer Pittsburgh compound B to assess for cerebral β-amyloid deposition.Twelve regions of interest were segmented to quantify regional iron levels and volumes: the frontal, parietal, temporal, and occipital cortex; mesial temporal structures, including the entorhinal cortex, hippocampus, and amygdala; the cingulate; and the basal ganglia. Biologic parametric mapping was used to explore voxel-based correlations among iron, β-amyloid, and cognitive scores. Twelve neuropsychologic tests were used to assess four cognitive domains—verbal episodic memory, executive function, visuospatial processing, and language—as well as global cognition.Major strengths of this study include the richness of the data set and large sample size, allowing the authors to investigate associations among iron, β-amyloid, and cognitive scores in four ways. Multiple linear regressions were applied to (a) the entire cohort of 150 nondemented participants, (b) the subgroup that had amyloid PET imaging to adjust for the presence of β-amyloid (n = 97), (c) the subgroup that had negative amyloid PET scans (n = 75), and (d) the subgroup that was cognitively normal with no symptoms (n = 121). These sensitivity analyses allow the reader to conjecture how the relationship between iron and β-amyloid may change in these different scenarios.The first major finding of the study was the strong negative association between hippocampal iron levels and episodic memory, which held true in all subgroup sensitivity analyses. Because the hippocampus is considered an early site for the development of AD pathology and has a key role in memory, it is not surprising that higher levels of iron in this region would be associated with lower memory scores. This also corroborates findings from a previous study (8) that found hippocampal iron levels to be predictive of longitudinal decline in episodic memory among individuals positive for β-amyloid. However, in the study by Chen et al (9), the association between hippocampal iron and memory remained significant, even after adjustment for the presence of cerebral β-amyloid, which suggests that iron may impact memory through processes that are independent of β-amyloid. Iron-mediated oxidative stress and ferroptosis, a type of iron-dependent programmed cell death, could be possibilities.Second, hippocampal iron levels were associated with global cognitive and executive function scores, but the associations were largely driven by the β-amyloid negative group. It is possible that, once significant cerebral β-amyloid has accumulated, the patient is already further along in AD pathogenesis and other disease processes may influence cognition more than hippocampal iron, such as τ or metabolic deficits.Beyond the hippocampus, iron appeared most closely associated with cognitive function in the β-amyloid negative group, with frontal, parietal, temporal, mesial temporal, and basal ganglia iron levels all showing significant associations with cognition. Altered iron homeostasis may thus be most meaningful to study in the earliest stage of disease, before there is significant cerebral β-amyloid deposition. One could even speculate as to whether iron plays a role in β-amyloid plaque formation. Therapeutic trials targeted to iron in this stage could ascertain whether β-amyloid deposition can be delayed or even prevented.The voxel-based analyses of iron, β-amyloid, and cognition raise other important questions. Specifically, there were nine clusters in which iron levels were negatively correlated with β-amyloid, two of which were associated with global cognition, and only three clusters in which they were positively correlated. Preclinical and postmortem studies suggest that iron and β-amyloid colocalize and act synergistically to effect downstream AD pathogenesis (4,5). However, these analyses suggest that iron and β-amyloid may arise independently and in spatially distinct areas. Whether iron accumulates in a stereotypical fashion, like β-amyloid and τ, warrants further research. Importantly, cerebral β-amyloid levels at PET and regional brain volumes derived from MRI, our standard methods of assessing AD pathology, were not associated with cognition.A few limitations of this study warrant discussion. First, this was a cross-sectional study that used the presence or absence of cerebral β-amyloid and cognitive symptoms to assess the relationship between iron and cognition in nondemented individuals. Because iron was most closely linked to cognition in the β-amyloid– negative group, it would be important to follow these participants longitudinally to see if they subsequently develop β-amyloid plaques, or whether the iron predicts non-AD forms of cognitive decline. Could these participants have higher iron levels and subtle cognitive deficits from subclinical ischemic or traumatic events, rather than AD?Another limitation is the lack of a τ biomarker in these analyses. Iron has been reported to interact with neurofibrillary tangles in preclinical studies (5). Could the relationship between hippocampal iron levels and episodic memory be mediated by the presence of neurofibrillary tangles, which are known to accumulate early in the hippocampus on the basis of Braak staging?Finally, should iron be included in the proposed ATN classification system, particularly early in the disease course, perhaps even earlier than the presence of β-amyloid? Interestingly, iron chelation in patients with AD was attempted previously. A study from 1991 reported that intramuscular administration of deferoxamine slowed the rate of decline in daily living skills in patients with AD during a period of 24 months (10). With current imaging techniques allowing for in vivo quantification of brain iron, β-amyloid, τ, and neurodegeneration, the effects of such iron chelation therapy on AD pathology could be more specifically monitored.Because there is a potential antiamyloid therapy on the horizon, the amyloid hypothesis of AD appears to be validated. However, numerous concomitant disease processes may contribute to AD pathogenesis, including iron accumulation, and these deserve further investigation. It is possible that the most effective treatment of AD will depend on a combination of therapies, particularly if they target processes that precede the appearance of β-amyloid plaques.Disclosures of Conflicts of Interest: G.C.C. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: disclosed money to author’s institution for grant from National Institutes of Health; disclosed publishing royalties form Relias Media. Other relationships: disclosed no relevant relationships.G.C.C. supported by the National Institute on Aging of the National Institutes of Health under award number R01AG068398. The content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health.References1. Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018;14(4):535–562. Crossref, Medline, Google Scholar2. Jansen WJ, Ossenkoppele R, Knol DL, et al. Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA 2015;313(19):1924–1938. Crossref, Medline, Google Scholar3. Tao Y, Wang Y, Rogers JT, Wang F. Perturbed iron distribution in Alzheimer’s disease serum, cerebrospinal fluid, and selected brain regions: a systematic review and meta-analysis. J Alzheimers Dis 2014;42(2):679–690. Crossref, Medline, Google Scholar4. Smith MA, Harris PL, Sayre LM, Perry G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc Natl Acad Sci U S A 1997;94(18):9866–9868. Crossref, Medline, Google Scholar5. Sayre LM, Perry G, Harris PLR, Liu Y, Schubert KA, Smith MA. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: a central role for bound transition metals. J Neurochem 2000;74(1):270–279. Crossref, Medline, Google Scholar6. Guo C, Wang P, Zhong ML, et al. Deferoxamine inhibits iron induced hippocampal tau phosphorylation in the Alzheimer transgenic mouse brain. Neurochem Int 2013;62(2):165–172. Crossref, Medline, Google Scholar7. Kim HG, Park S, Rhee HY, et al. Quantitative susceptibility mapping to evaluate the early stage of Alzheimer’s disease. Neuroimage Clin 2017;16:429–438. Crossref, Medline, Google Scholar8. Ayton S, Fazlollahi A, Bourgeat P, et al. Cerebral quantitative susceptibility mapping predicts amyloid-β-related cognitive decline. Brain 2017;140(8):2112–2119. Crossref, Medline, Google Scholar9. Chen L, Soldan A, Oishi K, et al. Quantitative susceptibility mapping of brain iron and β-amyloid in MRI and PET relating to cognitive performance in cognitively normal older adults. Radiology 2021;298:353–362. Link, Google Scholar10. Crapper McLachlan DR, Dalton AJ, Kruck TP, et al. Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 1991;337(8753):1304–1308. Crossref, Medline, Google ScholarArticle HistoryReceived: Oct 28 2020Revision requested: Nov 3 2020Revision received: Nov 3 2020Accepted: Nov 5 2020Published online: Nov 24 2020Published in print: Feb 2021 FiguresReferencesRelatedDetailsAccompanying This ArticleQuantitative Susceptibility Mapping of Brain Iron and β-Amyloid in MRI and PET Relating to Cognitive Performance in Cognitively Normal Older AdultsNov 24 2020RadiologyRecommended Articles Quantitative Susceptibility Mapping of Brain Iron and β-Amyloid in MRI and PET Relating to Cognitive Performance in Cognitively Normal Older AdultsRadiology2020Volume: 298Issue: 2pp. 353-362Cross-sectional and Longitudinal Assessment of Brain Iron Level in Alzheimer Disease Using 3-T MRIRadiology2020Volume: 296Issue: 3pp. 619-626Molecular Imaging Approaches in DementiaRadiology2021Volume: 298Issue: 3pp. 517-530Imaging Aspects of the HippocampusRadioGraphics2022Volume: 42Issue: 3pp. 822-840Multimodality Imaging of Dementia: Clinical Importance and Role of Integrated Anatomic and Molecular ImagingRadioGraphics2020Volume: 40Issue: 1pp. 200-222See More RSNA Education Exhibits 3D Stereotactic Surface Projection of 18F-FDG Brain PET Improves Diagnosis of Neurological DisordersDigital Posters2019The Role of MRI in the Diagnosis of Neurodegeneration and Dementia: Patterns of Brain Atrophy by Visual Rating ScalesDigital Posters2019Cerebral Β Amyloid Related DisordersDigital Posters2021 RSNA Case Collection NeuroferritinopathyRSNA Case Collection2021Semantic dementiaRSNA Case Collection2020Fahr's SyndromeRSNA Case Collection2021 Vol. 298, No. 2 Metrics Altmetric Score PDF download" @default.
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