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Ferric iron, Fe(III), in the diet is converted to ferrous iron, Fe(II), by a ferroreductase duodenal cytochrome b that is located on the apical surface of enterocytes of the duodenal mucosa. Fe(II) is then transported into enterocytes through the divalent metal transporter (DMT1). Fe(II) in enterocytes can be incorporated into the cytosolic iron-storage molecule ferritin or can be transported across the basolateral surface of enterocytes into the plasma by ferroportin. Fe(II) is subsequently converted to Fe(III) by a membrane-associated ferroxidase, hephaestin. Reprinted from De Domenico et al. (2008) with permission from the publisher. 

Ferric iron, Fe(III), in the diet is converted to ferrous iron, Fe(II), by a ferroreductase duodenal cytochrome b that is located on the apical surface of enterocytes of the duodenal mucosa. Fe(II) is then transported into enterocytes through the divalent metal transporter (DMT1). Fe(II) in enterocytes can be incorporated into the cytosolic iron-storage molecule ferritin or can be transported across the basolateral surface of enterocytes into the plasma by ferroportin. Fe(II) is subsequently converted to Fe(III) by a membrane-associated ferroxidase, hephaestin. Reprinted from De Domenico et al. (2008) with permission from the publisher. 

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Iron is essential for normal cellular functioning of the central nervous system. Abnormalities in iron metabolism may lead to neuronal death and abnormal iron deposition in the brain. Several studies have suggested a link between brain iron deposition in normal aging and chronic neurologic diseases, including multiple sclerosis (MS). In MS, it is s...

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... al., 2008). Export from the basolateral side of the enterocyte involves fer- roportin and hephaestin. Hepcidin and hemochromatosis protein 2 are thought to interact to determine how much iron is admitted to the bloodstream via a feedback loop ( Pantopoulos et al., 2012). In the bloodstream, iron circulates in the blood bound to trans- ferrin (Tf) (Fig. ...
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... CIS, selective T2 hypo- intensity was found in the caudate nucleus of pediatric MS patients with a sparing of other deep GM structures (Ceccarelli et al., 2011). Furthermore, despite their favorable clinical course and the lower overall brain tissue damage, similar T2 intensity was found in benign MS patients compared with secondary progressive MS patients (Ceccarelli et al., 2009). Taken together, Fig. 3. Overview of iron homeostasis in the central nervous system. ...
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... is critical for normal brain functioning. However, aberrant iron metabolism and abnormal iron deposition in the brain are associated with many neurologic disorders including multiple sclerosis (MS) (Stankiewicz and Brass, 2009). Several possible causes of abnormal iron deposition in MS have been postulated including blood-brain barrier dysfunction, decreased iron clearance because of axonal dysfunction and in fl ammation, or dysregulation of iron transport proteins because of in fl ammation (Stankiewicz et al., 2007). Abnormal iron homeostasis may contribute to the neurodegeneration seen in MS. Magnetic resonance imaging (MRI) studies have shown that excessive iron accumulates in the gray matter (GM) of MS patients, mainly in the basal ganglia. Recently, the use of advanced MRI techniques and ultra e high- fi eld MRI has aided characterization of iron deposits in both the GM and white matter (WM) of patients with MS. However, further MRI optimization will enhance our understanding of iron ’ s role in MS pathophysiology. Combined histopathologic MRI studies have begun to elucidate the role of iron deposition in MS pathology. More investigation in MS is required to clarify whether either chelation or antioxidant treatments represent a viable therapeutic alternative. In this article, we will provide an overview of research related to the normal iron homeostasis and role of iron in the pathophysiology of MS. Recent data from key original reports regarding the role of conventional and advanced MRI techniques in the assessment of iron deposition in MS will be explored. We will also focus on the most relevant therapeutic intervention studies with respect to both animal and human models that have added to the current understanding of iron toxicity in MS. The maintenance of proper iron concentrations in the body is vital to optimal functioning. Iron is involved in many crucial processes including myelin production, oxygen transport, glucose metabolism, synthesis of neurotransmitters, and DNA replication (Pinero and Connor, 2000). It is, therefore, unsurprising that iron de fi ciency at birth can impair normal cognitive development. Iron de fi ciency later in life may lead to cognitive impairment, attentional problems, or restless leg syndrome (Beard, 2003). Conversely, too much iron can also cause neurologic disease. Neuroferritinopathy, a disorder of movement characterized by extrapyramidal symptoms, is thought to be because of a mutation in ferritin light chain gene 1 resulting in ferritin and iron accumulation in the brain (Mancuso et al., 2005). Normally, elimination of iron from the body is fairly consistent and occurs from either bleeding or shedding of cells from the skin or gut. Consequently, iron concentration in the body is regulated by control of iron intake from food (Fig. 1). Iron is absorbed via the gut, most often in the duodenum through the crypts of Lieberkühn. For iron to enter the bloodstream, it must pass through the gut cells. On the intestinal luminal side, mechanisms involving ferrireductase duodenal cytochrome b activity and divalent metal transporter 1 (DMT1) are involved in entry into the enterocyte (De Domenico et al., 2008). Export from the basolateral side of the enterocyte involves ferroportin and hephaestin. Hepcidin and hemochromatosis protein 2 are thought to interact to determine how much iron is admitted to the bloodstream via a feedback loop (Pantopoulos et al., 2012). In the bloodstream, iron circulates in the blood bound to transferrin (Tf) (Fig. 2). Transferrin receptor (TfR) and Tf mediate cellular uptake. Tf and TfR have a high binding af fi nity for one another. These binding complexes are taken up by cells via clathrin-coated pits. After acidi fi cation in the endosome, iron is released from Tf and is exported into the cytoplasm by DMT1 (De Domenico et al., 2008). Dissociated Tf and TfR are exported back to the cell surface, and Tf reenters the bloodstream (Dautry-Varsat et al., 1983). Regulation of cellular iron levels are achieved through feedback loops involving iron-response proteins and iron-response elements that are involved in translation of ferritin, TfR, and other regularly proteins. Further details can be found in an excellent review by Rouault (2006a). Iron intake in the brain is also rigorously regulated and interacts with other metals such as copper (Skjørringe et al., 2012). It can enter the brain through the blood-brain barrier and blood-cerebrospinal fl uid barrier, which exists between the blood and the choroid plexus (Skjørringe et al., 2012). Most commonly, iron-bound Tf in the blood is captured by TfR found on brain endothelial cells, and this complex is then endocytosed. Once iron has crossed into the central nervous system, it is released from Tf into the interstitium (Benarroch, 2009). Brain iron homeostasis is tightly regulated, and this balance is achieved in a similar way to peripheral control of intracellular iron (Rouault and Cooperman, 2006b). Currently, the mechanisms for iron egress from the brain are poorly understood. Brain iron is likely reabsorbed back into the bloodstream via the cerebrospinal fl uid through the subarachnoid space (Benarroch, 2009) (Fig. 3). Starting at low levels at birth, brain iron concentration increases rapidly over the fi rst 2 decades of life and then rises more slowly thereafter (Hallgren and Sourander, 1958). Oligodendrocytes and astrocytes acquire solely non e Tf-bound iron, whereas neurons have both TfRs and DMT1 (Moos et al., 2007). Although monocytes and macrophages contain iron to promote free radicals as part of respiratory burst activity, brain microglia rarely contain iron. Iron can also be stored in the central nervous system bound not only to stable ferritin but also to more reactive substances like neuro- melanin and hemosiderin. In the normal brain, the highest concentrations of iron are found in the globus pallidus, caudate nucleus, putamen, dentate nucleus, red nucleus, and substantia nigra (Aoki et al., 1989). MRI is a powerful tool to detect and quantify brain iron deposition in vivo. Among all the brain ’ s essential metals, brain iron concentrations are normally high enough to affect the MRI signal (Stankiewicz et al., 2007). Iron can be found as heme iron, such as in hemoglobin, or non-heme iron. Unlike heme iron, failure to achieve homeostasis of non-heme iron metabolism has been associated with neurodegeneration (Madsen and Gitlin, 2007). Although MRI is not able to accurately differentiate between heme iron and non-heme iron in vivo, it is suggested that ferritin and hemosiderin are the only types of non-heme iron responsible for MRI signal changes (Haacke et al., 2005; Schenck and Zimmermann, 2004). Other non-heme iron forms, such as the free liable iron pool or Tf-bound iron, do not seem to in fl uence the MRI signal because of their low concentration (Haacke et al., 2005; Schenck and Zimmermann, 2004). Brain iron accumulation shortens the longitudinal (T1) and transverse (T2) relaxation times of the mobile protons in the brain resulting in signal loss or hypointensity on T2-weighted images (T2 hypointensity) and hyperintensity on T1-weighted images (T1 hyperintensity). Building on these principles, several pulse sequences and quantitative MRI techniques have been developed and employed in detection and quanti fi cation of iron in the brain. The use of high- fi eld (3 T) and ultra e high- fi eld ( > 3 T) MRI has further facilitated the detection of brain iron in both GM and WM. In the following sections, the role of iron in the pathophysiology of MS and its link to neuroin fl ammation, neurodegeneration, and clinical status is described. A common fi nding in patients with MS on spin-echo T2-weighted clinical MRI scans is diffuse hypointensity of the cortical and deep GM areas (e.g., the red nucleus, thalamus, dentate nucleus, lentiform nucleus, caudate, and rolandic cortex) versus age-matched normal controls (Fig. 4). T2 hypointensity in GM has been shown to be associated with brain atrophy, disability progression, and cognitive impairment in patients with MS (Bakshi et al., 2000, 2001, 2002; Bermel et al., 2005; Brass et al., 2006a, 2006b; Ceccarelli et al., 2009, 2010, 2011; Drayer et al., 1987a, 1987b; Neema et al., 2007, 2009, 2012; Tjoa et al., 2005; Zhang et al., 2007, 2010). T2 hypointensity, as a sign of excessive GM iron deposition, has been shown to be present in all MS subtypes (Bakshi et al., 2000, 2001, 2002; Bermel et al., 2005; Brass ...

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... Iron is essential in the normal functioning of the CNS and is highly enriched within myelinating oligodendrocytes [166][167][168]. Iron concentrations increase within the brain parenchyma during normal aging, but this is accelerated in PwMS and is more pronounced in those with progressive disease courses [169,170]. ...
... Analysis of MS tissue by MRI demonstrates that there is increased iron concentrations at the macroscopic level, specifically in the deep grey matter structures [167,171,173]; these are the same structures that display atrophy even early in PwMS [32]. Following demyelination there is a shift in the distribution of iron; iron is increased in microglia and macrophages in areas surrounding plaques [174], but reduced within lesions [148,175,176] and the NAWM of PwMS [177][178][179]. ...
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There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing–remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood. The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood–brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.
... With ongoing disease progression, a combination of these histopathological changes might counterbalance the T1-RT alterations leading to a reduced effect on T1 values. Of note, iron accumulation, which can be excessive in the GM of patients with MS, correlates negatively with T1-RT and can have a significant impact on mean T1-RT in the cortex and thalami in patients with longer disease duration (35). However, the literature is inconsistent regarding iron accumulation in the thalamus (31,36,37). ...
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Background: Cortical and thalamic pathologies have been associated with cognitive impairment in patients with multiple sclerosis (MS). Objective: We aimed to quantify cortical and thalamic damage in patients with MS using a high-resolution T1 mapping technique and to evaluate the association of these changes with clinical and cognitive impairment. Methods: The study group consisted of 49 patients with mainly relapsing-remitting MS and 17 age-matched healthy controls who received 3T MRIs including a T1 mapping sequence (MP2RAGE). Mean T1 relaxation times (T1-RT) in the cortex and thalami were compared between patients with MS and healthy controls. Additionally, correlation analysis was performed to assess the relationship between MRI parameters and clinical and cognitive disability. Results: Patients with MS had significantly decreased normalized brain, gray matter, and white matter volumes, as well as increased T1-RT in the normal-appearing white matter, compared to healthy controls ( p < 0.001). Partial correlation analysis with age, sex, and disease duration as covariates revealed correlations for T1-RT in the cortex ( r = −0.33, p < 0.05), and thalami (right thalamus: r = −0.37, left thalamus: r = −0.50, both p < 0.05) with working memory and information processing speed, as measured by the Symbol-Digit Modalities Test. Conclusion: T1-RT in the cortex and thalamus correlate with information processing speed in patients with MS.
... The normal human body loses about 1-2 mg of iron every day [36,43]. Iron in the body is mainly excreted from intestinal mucosa, skin cells, sweat and urine [4,30,44]. ...
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Iron is an essential trace metal for almost all organisms, including human; however, oxidative stress can easily be caused when iron is in excess, producing toxicity to the human body due to its capability to be both an electron donor and an electron acceptor. Although there is a strict regulation mechanism for iron homeostasis in the human body and brain, it is usually inevitably disturbed by genetic and environmental factors, or disordered with aging, which leads to iron metabolism diseases, including many neurodegenerative diseases such as Alzheimer’s disease (AD). AD is one of the most common degenerative diseases of the central nervous system (CNS) threatening human health. However, the precise pathogenesis of AD is still unclear, which seriously restricts the design of interventions and treatment drugs based on the pathogenesis of AD. Many studies have observed abnormal iron accumulation in different regions of the AD brain, resulting in cognitive, memory, motor and other nerve damages. Understanding the metabolic balance mechanism of iron in the brain is crucial for the treatment of AD, which would provide new cures for the disease. This paper reviews the recent progress in the relationship between iron and AD from the aspects of iron absorption in intestinal cells, storage and regulation of iron in cells and organs, especially for the regulation of iron homeostasis in the human brain and prospects the future directions for AD treatments.
... A unique minor cluster of microglia (designated iMG) exhibited high expression of genes related to metal homeostasis (Ftl1, Fth1, and Atox1), and a large number of ribosomal component genes ( Table 1). This signature is reminiscent of an embryonic-like "primitive" microglial state identified as a minor population existing in the developing postnatal brain (50), but may also may a reflect response to dysregulated CNS iron homeostasis, a hallmark of EAE and MS lesions (51). In line with this notion, iMG also expressed high levels of Cd52 and Tyrobp, associated with DAM-like states (44,48), suggesting that these cells are also activated by the neuroinflammatory state in EAE. ...
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Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system, representing the leading cause of non-traumatic neurologic disease in young adults. This disease is three times more common in women, yet more severe in men, but the mechanisms underlying these sex differences remain largely unknown. MS is initiated by autoreactive T helper cells, but CNS-resident and CNS-infiltrating myeloid cells are the key proximal effector cells regulating disease pathology. We have previously shown that genetic ablation of p38α MAP kinase broadly in the myeloid lineage is protective in the autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), but only in females, and not males. To precisely define the mechanisms responsible, we used multiple genetic approaches and bone marrow chimeras to ablate p38α in microglial cells, peripheral myeloid cells, or both. Deletion of p38α in both cell types recapitulated the previous sex difference, with reduced EAE severity in females. Unexpectedly, deletion of p38α in the periphery was protective in both sexes. In contrast, deletion of p38α in microglia exacerbated EAE in males only, revealing opposing roles of p38α in microglia vs. periphery. Bulk transcriptional profiling revealed that p38α regulated the expression of distinct gene modules in male vs. female microglia. Single-cell transcriptional analysis of WT and p38α-deficient microglia isolated from the inflamed CNS revealed a diversity of complex microglial states, connected by distinct convergent transcriptional trajectories. In males, microglial p38α deficiency resulted in enhanced transition from homeostatic to disease-associated microglial states, with the downregulation of regulatory genes such as Atf3, Rgs1, Socs3, and Btg2, and increased expression of inflammatory genes such as Cd74, Trem2, and MHC class I and II genes. In females, the effect of p38α deficiency was divergent, exhibiting a unique transcriptional profile that included an upregulation of tissue protective genes, and a small subset of inflammatory genes that were also upregulated in males. Taken together, these results reveal a p38α-dependent sex-specific molecular pathway in microglia that is protective in CNS autoimmunity in males, suggesting that autoimmunity in males and females is driven by distinct cellular and molecular pathways, thus suggesting design of future sex-specific therapeutic approaches.
... In a previous study, ironstorage indicators did not differ between MS patients with and without RLS. 6 Since inflammation and neurodegeneration in MS have been documented to be affected by aberrant iron metabolism and deposition 41 , iron involvement in MS-related RLS pathogenesis should be further investigated. The exclusion of patients with an EDSS ≥7 and the relatively low median EDSS in our group of MS patients limits the generalizability of our results. ...
Article
Study objectives: To carry out an analysis of leg movement activity during sleep in a polysomnography (PSG) dataset of patients with multiple sclerosis (MS), in comparison to idiopathic restless legs syndrome (iRLS) and healthy controls. Methods: In this cross-sectional, observational, instrumental study, fifty-seven patients (males/females: 11/46; mean age 46.2±10.2 years) with a diagnosis of MS underwent a telephone interview assessing the five standard diagnostic criteria for RLS and PSG. Sleep architecture and leg movement activity (LMA) during sleep were subsequently compared: 1) 40 MS patients without RLS (MS-RLS) vs. 28 healthy controls; 2) 17 MS patients with RLS (MS+RLS) vs. 35 patients with iRLS; 3) MS+RLS vs. MS-RLS. Results: MS-RLS and MS+RLS presented increased sleep latency, percentage of sleep stage N1, and reduced total sleep time compared to healthy controls and iRLS, respectively. The periodic limb movements during sleep (PLMS) index (PLMSI) was higher in MS-RLS than in healthy controls (p = 0.035) and lower in MS+RLS compared to iRLS (p = 0.024). PLMS in MS+RLS were less periodic, less often bilateral and with shorter single movements, compared to the typical PLMS in iRLS. Conclusions: MS is a risk factor for RLS, PLMS, and for a lower sleep quality in comparison to healthy patients. PLMS in MS+RLS are fewer and shorter if compared to iRLS. Our results suggest a dissociation between motor (PLMS) and sensory symptoms (RLS sensory component) in RLS secondary to MS, with possible treatment implications.
... The exact cause of low T2 signal intensity within the lesions remained unclear. As our lesions were induced by the injection of a chemical toxin, the decreased signal could be due to the following factors: mechanical damage, the impact of degraded myelin (debris), and an iron susceptibility effect associated with the myelin-forming cells and inflammatory cells [44]. Given the purpose of the current study, degraded myelin was not evaluated (eriochrome cyanine detects only healthy myelin). ...
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Myelin plays a critical role in the pathogenesis of neurological disorders but is difficult to characterize in vivo using standard analysis methods. Our goal was to develop a novel analytical framework for estimating myelin content using T2-weighted magnetic resonance imaging (MRI) based on a de- and re-myelination model of multiple sclerosis. We examined 18 mice with lysolecithin induced demyelination and spontaneous remyelination in the ventral white matter of thoracic spinal cord. Cohorts of 6 mice underwent 9.4T MRI at days 7 (peak demyelination), 14 (ongoing recovery), and 28 (near complete recovery), as well as histological analysis of myelin and the associated cellularity at corresponding timepoints. Our MRI framework took an unsupervised learning approach, including tissue segmentation using a Gaussian Markov random field (GMRF), and myelin and cellularity feature estimation based on the Mahalanobis distance. For comparison, we also investigated 2 regression-based supervised learning approaches, one using our GMRF results, and another using a freely available generalized additive model (GAM). Results showed that GMRF segmentation was 73.2% accurate, and our unsupervised learning method achieved a correlation coefficient of 0.67 (top quartile: 0.78) with histological myelin, similar to 0.70 (top quartile: 0.78) obtained using supervised analyses. Further, the area under the receiver operator characteristic curve of our unsupervised myelin feature (0.883, 95% CI: 0.874–0.891) was significantly better than any of the supervised models in detecting white matter myelin as compared to histology. Collectively, metric learning using standard MRI may prove to be a new alternative method for estimating myelin content, which ultimately can improve our disease monitoring ability in a clinical setting.
... In its simplest mechanism, iron chelation therapy sequesters and clears the labile iron pool, thus counteracting oxidative damage resulting from pathologic iron accumulation [18,43,67,70]. As discussed in further detail below and elsewhere, this mechanism has direct relevance to a number of neurological disorders including AD, PD, progressive supranuclear palsy (PSP) [71], ischemic stroke, and intracranial hemorrhage, where iron dyshomeostasis-disruption of the iron balance leading to iron accumulation and consequent toxicity-is a known potential contributor to disease pathogenesis and neuronal injury [12,41,42,68,[72][73][74]. Although current evidence strongly suggests that iron overload is associated with oxidative stress and injury in these states, it is unlikely that reversal of iron accumulation alone will reverse the underlying disease processes. ...
... Alternatively, its mechanisms promoting synaptic function, glucose metabolism, or cerebrovascular function may play a role and merit further investigation. In multiple sclerosis, brain iron is found to accumulate independently of inflammation and is increasingly thought to contribute to pathogenesis [74]. DFO was found to suppress inflammatory damage in animal models [80,122] and was tolerated in early clinical studies of this disease [123,124]. ...
Article
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Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine (DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer’s disease (AD), Parkinson’s disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.
... Brain iron levels are known to be disturbed in multiple sclerosis (MS) (Filippi et al., 2019;Hagemeier, Geurts, & Zivadinov, 2012;Zecca, Youdim, Riederer, Connor, & Crichton, 2004). Most studies reported increased iron concentrations in the deep gray matter (DGM) (Stankiewicz, Neema, & Ceccarelli, 2014) and around plaques (Craelius, Migdal, Luessenhop, Sugar, & Mihalakis, 1982), and reduced iron concentrations within lesions (Haider et al., 2014;Kutzelnigg et al., 2005;Laule et al., 2013;Yao et al., 2012;Yao et al., 2014), in the normal-appearing white matter (WM) (Hametner et al., 2013;Paling et al., 2012;Popescu et al., 2017;Yu et al., 2018), and in the thalamus Burgetova et al., 2017;Khalil et al., 2015;Louapre et al., 2017;Pontillo et al., 2019;Schweser et al., 2018;Uddin, Lebel, Seres, Blevins, & Wilman, 2016;Zivadinov et al., 2018). The literature considers findings of increased regionaverage iron concentrations as evidence for iron influx Ndayisaba, Kaindlstorfer, & Wenning, 2019;Williams, Buchheit, Berman, & LeVine, 2012), whereas it is less clear how to interpret reduced iron concentrations. ...
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Increased brain iron concentration is often reported concurrently with disease development in multiple sclerosis (MS) and other neurodegenerative diseases. However, it is unclear whether the higher iron concentration in patients stems from an influx of iron into the tissue or a relative reduction in tissue compartments without much iron. By taking into account structural volume, we investigated tissue iron content in the deep gray matter (DGM) over 2 years, and compared findings to previously reported changes in iron concentration. 120 MS patients and 40 age‐ and sex‐matched healthy controls were included. Clinical testing and MRI were performed both at baseline and after 2 years. Overall, iron content was calculated from structural MRI and quantitative susceptibility mapping in the thalamus, caudate, putamen, and globus pallidus. MS patients had significantly lower iron content than controls in the thalamus, with progressive MS patients demonstrating lower iron content than relapsing–remitting patients. Over 2 years, iron content decreased in the DGM of patients with MS, while it tended to increase or remain stable among controls. In the thalamus, decreasing iron content over 2 years was associated with disability progression. Our study showed that temporally increasing magnetic susceptibility in MS should not be considered as evidence for iron influx because it may be explained, at least partially, by disease‐related atrophy. Declining DGM iron content suggests that, contrary to the current understanding, iron is being removed from the DGM in patients with MS.
... Some studies have shown a loss of iron from normal appearing white matter (WM), while others have reported an increase in iron concentration in the deep gray matter (GM). [7][8][9][10][11][12] Due to its high sensitivity to iron, in-vivo magnetic resonance imaging (MRI), especially using T 2 *-weighted sequences, is ideally suited to investigate the role of iron in pathophysiology. However, there is an enormous gap between in-vivo imaging (mm scale) and pathology (sub-m scale), which needs to be bridged to better understand the pathological correlates of MRI signal changes. ...
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Purpose To perform magnetic resonance microscopy (MRM) on human cortex and a cortical lesion as well as the adjacent normal appearing white matter. To shed light on the origins of MRI contrast by comparison with histochemical and immunostaining. Methods 3D MRM at a nominal isotropic resolution of 15 and 18 μm was performed on 2 blocks of tissue from the brain of a 77-year-old man who had MS for 47 years. One block contained normal appearing cortical gray matter (CN block) and adjacent normal appearing white matter (NAWM), and the other also included a cortical lesion (CL block). Postmortem ex-vivo MRI was performed at 11.7T using a custom solenoid coil and T2*-weighted 3D GRE sequence. Histochemical and immunostaining were done after paraffin embedding for iron, myelin, oligodendrocytes, neurons, blood vessels, macrophages and microglia, and astrocytes. Results MRM could identify individual iron-laden oligodendrocytes with high sensitivity (70% decrease in signal compared to surrounding) in CN and CL blocks, as well as some iron-laden activated macrophages and microglia. Iron-deficient oligodendrocytes seemed to cause relative increase in MRI signal within the cortical lesion. High concentration of myelin in the white matter was primarily responsible for its hypointense appearance relative to the cortex, however, signal variations within NAWM could be attributed to changes in density of iron-laden oligodendrocytes. Conclusion Changes in iron accumulation within cells gave rise to imaging contrast seen between cortical lesions and normal cortex, as well as the patchy signal in NAWM. Densely packed myelin and collagen deposition also contributed to MRM signal changes. Even though we studied only one block each from normal appearing and cortical lesions, such studies can help better understand the origins of histopathological and microstructural correlates of MRI signal changes in multiple sclerosis and contextualize the interpretation of lower-resolution in vivo MRI scans.
... The highest iron levels, up to 250 mg/kg tissue, are found in deep gray matter structures (Krebs et al., 2014). A disturbed iron metabolism has been linked to a variety of neurological disorders (Pinero and Connor, 2000;Ward et al., 2014), such as Alzheimer's disease (AD) (Quintana et al., 2006;Schenck et al., 2006), multiple sclerosis (MS) (Hametner et al., 2013;Stankiewicz et al., 2014) or Parkinson's disease (PD) (Martin et al., 2008;Sofic et al., 1988). ...
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A variety of Magnetic Resonance Imaging (MRI) techniques are known to be sensitive to brain iron content. In principle, iron sensitive MRI techniques are based on local magnetic field variations caused by iron particles in tissue. The purpose of this study was to investigate the sensitivity of MR relaxation and magnetization transfer parameters to changes in iron oxidation state compared to changes in iron concentration. Therefore, quantitative MRI parameters including R1, R2, R2∗, quantitative susceptibility maps (QSM) and magnetization transfer ratio (MTR) of post mortem human brain tissue were acquired prior and after chemical iron reduction to change the iron oxidation state and chemical iron extraction to decrease the total iron concentration. All assessed parameters were shown to be sensitive to changes in iron concentration whereas only R2, R2∗ and QSM were also sensitive to changes in iron oxidation state. Mass spectrometry confirmed that iron accumulated in the extraction solution but not in the reduction solution. R2∗ and QSM are often used as markers for iron content. Changes in these parameters do not necessarily reflect variations in iron content but may also be a result of changes in the iron's oxygenation state from ferric towards more ferrous iron or vice versa.