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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 still not clear whether iron deposition is an epiphenomenon or a mediator of disease processes. In this review, the role of iron in the pathophysiology of MS will be summarized. In addition, the importance of conventional and advanced magnetic resonance imaging techniques in the characterization of brain iron deposition in MS will be reviewed. Although there is currently not enough evidence to support clinical use of iron chelation in MS, an overview of studies of iron chelation or antioxidant therapies will be also provided.
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Iron and multiple sclerosis
James M. Stankiewicz, Mohit Neema, Antonia Ceccarelli
Department of Neurology, Brigham and Womens Hospital, Harvard Medical School, Partners Multiple Sclerosis Center, Brookline, MA, USA
article info
Article history:
Received 20 November 2013
Received in revised form 28 February 2014
Accepted 14 March 2014
Available online 15 May 2014
Multiple sclerosis
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 still not clear whether iron deposition is an epiphe-
nomenon or a mediator of disease processes. In this review, the role of iron in the pathophysiology of
MS will be summarized. In addition, the importance of conventional and advanced magnetic reso-
nance imaging techniques in the characterization of brain iron deposition in MS will be reviewed.
Although there is currently not enough evidence to support clinical use of iron chelation in MS, an
overview of studies of iron chelation or antioxidant therapies will be also provided.
Ó2014 Elsevier Inc. All rights reserved.
1. Introduction
Iron 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 inammation, or dysregulation
of iron transport proteins because of inammation (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 ultraehigh-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 irons 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 repre-
sent 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 pathophys-
iology of MS. Recent data from key original reports regarding the
role of conventional and advanced MRI techniques in the assess-
ment 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.
2. Iron metabolism
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
deciency at birth can impair normal cognitive development. Iron
deciency 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).
*Corresponding author at: Department of Neurology, Brigham and Womens
Hospital, Harvard Medical School, Partners Multiple Sclerosis Center, 1 Brookline
Place, Brookline, MA 02445, USA. Tel.: þ1 6177326118; fax: þ1 6177326540.
E-mail address: (A. Ceccarelli).
Contents lists available at ScienceDirect
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Neurobiology of Aging 35 (2014) S51eS58
3. Iron trafcking in the body
3.1. Entry through the gut
Iron is absorbed via the gut, most often in the duodenum
through the crypts of Lieberkühn. For iron to enter the blood-
stream, 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 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. 2).
3.2. Cellular iron transport and homeostasis
Transferrin receptor (TfR) and Tf mediate cellular uptake. Tf
and TfR have a high binding afnity for one another. These binding
complexes are taken up by cells via clathrin-coated pits. After
acidication 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).
4. Iron trafcking and distribution in the brain
4.1. Brain iron transit
Iron intake in the brain is also rigorously regulated and interacts
withothermetalssuchascopper(Skjørringe et al., 2012). It can enter
the brain through the blood-brain barrier and blood-cerebrospinal
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 uid
through the subarachnoid space (Benarroch, 2009)(Fig. 3).
4.2. Normal cellular and structural distribution of iron in the brain
Starting at low levels at birth, brain iron concentration increases
rapidly over the rst 2 decades of life and then rises more slowly
thereafter (Hallgren and Sourander, 1958). Oligodendrocytes and
astrocytes acquire solely noneTf-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
Fig. 1. Dietary iron (1e2 mg per day) is absorbed by cells of the duodenum before being exported into plas ma where it binds to transferrin (Tf). Tf-bound iron is delivered to
tissues and cel ls (primarily to reticuloc ytes) where it is incorporated in hemoglobin. Old erythrocytes (red blood cells) are phagocytosed by macrophages, which degrade
hemoglobin and recycle iron back into plasma (2 0e30 mg per day) where it again binds Tf. If iron is absorbed or released into the plasma at a higher level than the iron-binding
capacity of Tf , then the excess noneTf-bound iron is deposited in paren chymal tissues (such as the liver). Reprinted from De Domenico et al. (20 08) with permission from the
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58S52
concentrations of iron are found in the globus pallidus, caudate
nucleus, putamen, dentate nucleus, red nucleus, and substantia
nigra (Aoki et al., 1989).
5. Imaging brain iron deposition in multiple sclerosis
MRI is a powerful tool to detect and quantify brain iron
deposition in vivo. Among all the brains 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 inuence
the MRI signal because of their low concentration (Haacke et al.,
2005; Schenck and Zimmermann, 2004). Brain iron accumula-
tion 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 quan-
titative MRI techniques have been developed and employed in
detection and quantication of iron in the brain. The use of high-
eld (3 T) and ultraehigh-eld (>3 T) MRI has further facilitated
the detection of brain iron in both GM and WM. In the following
Fig. 2. Ferric iron, Fe(III), in the diet is converted toferrous iron, Fe(II),bya 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.
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58 S53
sections, the role of iron in the pathophysiology of MS and its link
to neuroinammation, neurodegeneration, and clinical status is
5.1. GM iron deposition
A common 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 et al., 2006a, 2006b;
Ceccarelli et al., 2009, 2010, 2011; Drayer et al., 1987a, 1987b;
Neema et al., 2007, 2009; Tjoa et al., 2005; Zhang et al., 2007,
2010). Although iron has emerged as a surrogate marker for
neurodegeneration in MS, it still remains unclear whether iron
deposition is simply an epiphenomenon resulting from brain
tissue degeneration or if it directly contributes to brain damage
in MS.
Recent T2 intensity studies involving early and milder forms
of MS (Ceccarelli et al., 2009, 2010, 2011) have begun to bridge
gaps in knowledge regarding the role of iron deposition in the
pathophysiology of the disease. In patients with clinically
isolated syndrome (CIS), lower T2 intensity in the caudate nu-
cleus was found compared with healthy controls (Ceccarelli et al.,
2010). In patients with established MS, T2 hypointensity best
predicted disability progression over time and was a better
marker of disability than other measures such as whole brain
atrophy and T2-lesion volume (Neema et al., 2009). In contrast,
in CIS patients, T2 hypointensity of deep GM was not associated
with subsequent evolution to clinically denite MS (Ceccarelli
et al., 2010). Further evidence that iron could accumulate early
in the disease course has been provided by studies in pediatric
MS patients (Ceccarelli et al., 2011). Like 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. The transferrin receptor 1 (TfR1) in the luminal membrane of brain endothelial cells binds ferric iron (Fe
loaded Tf and internalizes this complex in endosomes, where Fe
is reduced to ferrous iron (Fe
). Ferrous iron may be transported to the cytosol by the endosomal divalent metal
transporter 1 (DMT1) and then exported into the extracellular uid by action of ferroportin. An alternative hypothesis (not shown) is that the Tf-TfR1 receptor complex may be
transported from the luminal to the abluminal surface followed by iron release. Ceruloplasmin, expressed in astrocyte end-foot processes, oxidizes newly released Fe
to Fe
which binds to Tf. Tf is the main source of iron for neurons. Fe
may also bind to adenosine triphosphate (ATP) or citrate released from astrocytes and be transported in the form of
nonetransferrin-bound iron (NTBI), which is the source of iron to oligodendrocytes and astrocytes. Oligodendrocytes synthesize Tf, which may have a role in intracellular iron
transport along their processes. In the cytosol, the storage protein ferritin sequesters and reduces levels of free iron. Mitoferrin (not shown) transports iron into the mitochondria,
where the chaperone frataxin facilitates the biosynthesis of iron-sulfur (Fe/S) clusters. Reprinted from Benarroch (2009) with permission from the publisher.
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58S54
these ndings suggest that brain iron accumulation occurs early
in the disease course and increases with disease duration. Few
studies have looked at the effect of treatment on brain T2 signal
change (Bermel et al., 2005; Pawate et al., 2012). A recent
longitudinal year long pilot study of natalizumab treatment of
MS patients (Pawate et al., 2012) showed a treatment effect on
limiting progression of T2 hypointensity in GM, suggesting that
impeding the inammatory cascade could lead to decreased iron
deposition in the brain.
Although T2 intensity studies have provided important clues
regarding iron accumulation in the brain of MS patients, the
effects of various other confounding factors, such as water con-
tent, make the T2 intensity method a nonspecic indicator for
estimating iron levels (Neema et al., 2007). Because of their
increased sensitivity to iron-related susceptibility changes, new
advanced quantitative MRI techniques, and related postprocessing
analysis, combined with the use of high-eld and ultraehigh-eld
strength MRI, are currently being employed to further dene the
role of iron in MS (Bagnato et al., 2013; Ge et al., 2007; Habib et al.,
2012; Hagemeier et al., 2012a, 2013a, 2013b; Hammond et al.,
2008; Khalil et al., 2009, 2011a, 2011b; Lebel et al., 2012; Pitt
et al., 2010; Ropele et al., 2011; Rumzan et al., 2013; Walsh
et al., 2014; Zivadinov et al., 2012). To date, most of these MRI
studies have signicantly improved the detection of abnormal
iron deposition in cortical and deep GM and conrmed its clinical
relevance in MS (Bagnato et al., 2013; Ge et al., 2007; Habib et al.,
2012; Hagemeier et al., 2012a, 2013a, 2013b; Hammond et al.,
2008; Khalil et al., 2009, 2011a, 2011b; Lebel et al., 2012; Pitt
et al., 2010; Ropele et al., 2011; Rumzan et al., 2013; Walsh
et al., 2014; Zivadinov et al., 2012). Interestingly, using 7-T MRI
and quantitative magnetic susceptibility mapping (Al-Radaideh
et al., 2013), iron deposition in several deep GM areas, including
the caudate, putamen, pallidus, and pulvinar nucleus, has been
shown in CIS patients, further supporting and extending previous
ndings (Ceccarelli et al., 2010). Recently, a study using
susceptibility-weighted ltered phase imaging found that GM
iron-related changes may precede GM atrophy in CIS patients
suggesting that abnormal iron deposition may be an early surro-
gate of the disease (Hagemeier et al., 2012a).
Although the measures of GM iron deposition hold promise as
clinically relevant biomarkers, more work is necessary before these
techniques nd use in clinical practice to inform care for individual
5.2. WM iron deposition
Pathologic studies have shown that iron accumulation in the
WM is mainly present at the level of MS lesions (Craelius et al.,
1982; Hametner et al., 2013) and near the veins (Adams, 1988).
However, MRI detection of iron deposition in the WM is still
challenging because of the confounding effect on the MRI signals
of edema, inammation, gliosis, and myelin content (Langkammer
et al., 2010; Neema et al., 2007; Walsh et al., 2013; Yao et al.,
2012). The application of multimodal approach of advanced
iron-sensitive MRI techniques, such as phase imaging, R2*, and
ultraehigh-eld scanners, has enhanced the current understand-
ing of WM iron deposition in MS. In particular, with the use of
phase imaging, it is possible to visualize phase hypointense WM
lesions that are likely high in iron content and often missed by
conventional MRI sequences (Eissa et al., 2009; Haacke et al.,
2009; Hagemeier et al., 2012b; Hammond et al., 2008). Various
phase hypointense WM MS lesion patterns have also been iden-
tied such as nodular, ring, and scattered shapes, suggesting that
iron deposition could be inside or at the edge of phase WM le-
sions in MS (Eissa et al., 2009; Haacke et al., 2009; Hagemeier
et al., 2012b). Such phase WM lesions have also been observed
even at the earliest clinical stages of MS (Hagemeier et al., 2012b).
Although the interplay between various cellular structures is
thought to be responsible for the diverse hypointense patterns in
the WM lesions (Bagnato et al., 2011; Bian et al., 2013; Mehta
et al., 2013), the mechanisms behind these have yet to be eluci-
dated. In addition, a reliable MRI method to characterize the
presence of iron in WM is currently unavailable (Walsh et al.,
2013; Yao et al., 2012). Future combined histopathologic-
multimodal MRI studies will shed light on the mechanisms un-
derlying iron-related MRI changes seen in WM, which in turn may
provide insights into understanding the link between WM dam-
age and clinical status.
Fig. 4. T2 hypointensity in multiple sclerosis (MS): T2-weighted fast spin-echo axial magnetic resonance imaging scans obtained at 1.5 Tof a healthy control (A) in the fth decade
and an age-matched patient with relapsing-remitting MS (B). In the patient with MS, note bilateral hypointensity of various deep gray matter areas, including the thalamus,
lentiform nucleus, and caudate compared with the healthy control. This T2 hypointensity most likely represents pathologic iron deposition. The patient also has brain atrophy.
Reprinted from Neema et al. (2012) with permission from the publisher.
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58 S55
6. Iron toxicity
Bound iron is considered safe,but free iron is more likely to
exchange electrons with nearby molecules and produce free radi-
cals. Normal metabolic processes in the mitochondria form
hydrogen peroxide as the result of molecular reduction of oxygen.
Hydrogen peroxide alone is not particularly toxic, but in the pres-
ence of free iron (Fe2þ), a free radical (OH) is formed when free
iron donates an electron to hydrogen peroxide via the Fenton
reaction. This free radical can interact with oxygen and other
molecules in the brain to form more free radicals propagating a
deleterious positive feedback loop. Hydroxyl radicals can attack
proteins, deoxynucleic acids, and lipid membranes. This process can
disrupt cellular integrity and function eventually leading to cell
apoptosis (Halliwell, 2006). Oxidative stress has been implicated in
the pathogenesis of MS, potentially contributing to both demye-
lination and axonal damage (Gilgun-Sherki et al., 2004).
7. Protection from iron-mediated damage
7.1. Endogenous protection
Experimental work suggests that the body has natural processes
in place to stem potentially damaging free-radical formation. Both
glutathione and vitamin E have been implicated as protective.
Glutathione in a reduced state interacts with hydrogen peroxide
and other organic peroxides to yield an oxidized form of gluta-
thione, water, and alcohol. Removal of hydrogen peroxide leaves
less potential for interaction with free iron and less subsequent
production of hydroxyl radicals. Cells able to survive potentially to
toxic iron show increased glutathione production (Aguirre et al.,
2006). A form of vitamin E (alpha-tocopherol) can act as an anti-
oxidant by donating a proton to reactive oxygen species, thus
making them more stable and less reactive (Crichton et al., 2002).
Experimental work nds that cerebellar granule cell cultures and
hippocampal neurons treated with iron in the presence of either
alpha-tocopherol or an analogue were better preserved (de Jesus
Ferreira et al., 2005; Van der Worp et al., 1999).
7.2. Exogenous protection
Because iron may contribute to the pathogenesis of MS, human
and animal investigations have been performed to ascertain
whether binding iron (chelation) or reducing iron associated free-
radical damage (antioxidants) might represent viable treatment
7.2.1. Chelation
Iron chelators may attenuate free-radical toxicity by binding
circulating free iron and preventing this iron from participating in
redox reactions. Iron chelation therapy has been tried in the
experimental autoimmune model of MS with some success. A study
conducted in experimental autoimmune encephalomyelitis (EAE)
induced by spinal cord homogenates showed a response to des-
ferrioxamine (Bowern et al., 1984). Two other studies investigated
desferrioxamine in a myelin basic protein-induced EAE model.
Willenborg et al. (1988) found no response if the desferrioxamine
was administered in a preclinical phase, whereas Pedchenko and
LeVine (1999) found that if the desferrioxamine was administered
later, during a time of clinical symptoms, it effectively attenuates
the disease. The short half-life of desferrioxamine, potential critical
window for effect, or other free-radical scavenging effects outside
iron binding might account for the discrepant studies. Pedchenko
and Levine (1999) also reported that dexrazoxane, another iron
chelator similar to desferrioxamine but with a longer half-life also
attenuated the course of EAE, but its effect was less robust than that
seen with desferrioxamine. Also, rats given dexrazoxane in
conjunction with mitoxantrone experienced more improvement on
clinical indices than rats treated solely with mitoxantrone
(Weilbach et al., 2004).
Only 1 human trial using desferrioxamine has been conducted in
a small group of secondary progressive MS patients (Lynch et al.,
2000). Nine patients received up to 8 courses of desferrioxamine,
and although the drug was well tolerated, little effect was seen on
disability. Specically, a single patient improved, 3 patients were
unchanged, and 5 patients worsened. These disappointing results
call into question whether treatment with desferrioxamine (or iron
chelation more generally) could be an effective treatment strategy
for MS. It is worth noting, however, that this trial was small and that
the enrolled patients had more advanced disease. Patients with
higher disability typically have been refractory to treatment in MS
drug trials.
It is clear that iron deposition occurs in MS and that iron
chelation can work in the EAE model. It remains to be seen, how-
ever, whether chelation therapy can be a successful treatment
strategy in MS.
7.2.2. Antioxidants
Antioxidants might help counteract irons role in disease by
protecting the body from oxidative stresses. A study of MS plaques
revealed decreased levels of antioxidants and increased free-radical
activity (Langemann et al., 1992). MS patients also exhibit increased
levels of oxidative stress markers compared with normal controls,
with correlation seen between disability and higher levels of
oxidative stress markers (Oliveira et al., 2012).
Many antioxidants have been suggested to be neuroprotective
through reduction of free-radical formation including vitamin A,
vitamin C, vitamin E, coenzyme Q10, green tea extract, nitric oxide,
selegiline (monoamine oxidase inhibitor with antioxidant proper-
ties), and Ginkgo biloba.
A full accounting of antioxidants that have been successful in
attenuating the EAE model of MS is outside the scope of this review,
but many have succeeded. Commonly recognized antioxidants that
work on an EAE model include vitamin A (Massacesi et al., 1987),
vitamin C (Spitsin et al., 2002), lipoic acid (Marracci et al., 2002),
resveratrol (Shindler et al., 2010), blueberries (Xin et al., 2012),
green tea (Aktas et al., 2004), and curcumin (Xie et al., 2009).
Although these antioxidants can show an effect in animals, it is not
always clear that this effect is because of reduction of free radicals.
For example, experimental work with green tea extract demon-
strates that this compound affects T cells (Wang et al., 2012). It is
also worth noting that some antioxidants such as idebenone have
failed to provide a benecial effect in the EAE model (Fiebiger et al.,
Few human trials of antioxidants have been performed. Perhaps,
the most visible drug with potential antioxidant effect in the MS
space is the recently Food and Drug Administrationeapproved
dimethyl fumarate. Although argument remains about how the
drug is having its treatment effect on MS, experiments suggest that
the drug works on a free-radical scavenging pathway (Nrf2) and has
antioxidant effects (Linker et al., 2011). Another drug, inosine, has
been trialed in 2 separate MS cohorts. This precursor drug is
metabolized to the antioxidant uric acid. Although successful in an
EAE model, inosine has shown mixed results in relapsing-remitting
MS patients. Gonsette et al. (2010) did not show a benet from the
drug. Markowitz et al. (2009) found that MS patients with higher
serum urate levels did benet from inosine compared with their
pretreatment state. Renal calculi were seen in both the Gonsette
(3.8%) and Markowitz (25%) trials. Double-blind placebo-controlled
studies with increased enrollment and longer observation periods
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58S56
are needed before conclusions about long-term efcacy and safety
of antioxidants can be made.
8. Conclusions
We have reviewed the physiology of iron metabolism and the
role of abnormal brain iron deposition in MS. We have seen that
although iron is vital for normal neuronal processes, abnormal iron
accumulation may cause neurodegeneration through lipid peroxi-
dation and cell death in the brain. Human MRI studies reported an
association between abnormal brain iron deposition and clinical
dysfunction in MS patients. It remains to be elucidated whether
iron deposition is a marker or mediator of the destructive cascade in
MS. Future studies incorporating newer pulse sequences, multi-
modal MRI in conjunction with histopathologic assessments, and
novel postprocessing techniques should shed light on mechanisms
responsible for abnormal iron deposition and on its role in the
pathogenesis of MS. Animal models of MS have shown a neuro-
protective effect by either iron chelation or antioxidants; however,
in MS patients, the effectiveness of these pharmacologic modi-
cation is still debatable and requires further investigation.
Disclosure statement
None of the authors have a conicts of interest.
Adams, C.W., 1988. Perivascular iron deposition and other vascular damage in
multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 51, 260e265.
Aguirre, P., Mena, N., Tapia, V., Rojas, A., Arrendondo, N., Núñez, M.T., 2006. Anti-
oxidant responses of cortex neurons to iron loading. Biol. Res. 39, 103e104 .
Aktas, O., Prozorovski, T., Smorodchenko, A., Savaskan, N.E., Lauster, R.,
Kloetzel, P.M., Infante-Duarte, C., Brocke, S., Zipp, E., 2004. Green tea
epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts
neuroprotection in autoimmune encephalomyelitis. J. Immunol. 173,
Al-Radaideh, A.M., Wharton, S.J., Lim, S.Y., Tench, C.R., Morgan, P.S., Bowtell, R.W.,
Constantinescu, C.S., Gowland, P.A., 2013. Increased iron accumulation occurs in
the earliest stages of demyelinating disease: an ultra-high eld susceptibility
mapping study in clinically isolated syndrome. Mult. Scler. 19, 896e903.
Aoki, S., Okada, Y., Nishimura, K., Barkovich, A.J., Kjos, B.O., Brasch, R.C., Norman, D.,
1989. Normal deposition of brain iron in childhood and adolescence: MRI
imaging at 1.5T. Radiology 172, 381e385.
Bagnato, F., Hametner, S., Welch, E.B., 2013. Visualizing iron in multiple sclerosis.
Magn. Reson. Imaging 31, 376e384.
Bagnato, F., Hametner, S., Yao, B., van Gelderen, P., Merkle, H., Cantor, F.K.,
Lassmann, H., Duyn, J.H., 2011. Tracking iron in multiple sclerosis: a combined
imaging and histopathological study at 7 Tesla. Brain 134, 3602e3615.
Bakshi, R., Benedict, R.H., Bermel, R.A., Caruthers, S.D., Puli, S.R., Tjoa, C.W.,
Fabiano, A.J., Jacobs, L., 2002. T2 hypointensity in the deep gray matter of pa-
tients with multiple sclerosis: a quantitative magnetic resonance imaging study.
Arch. Neurol. 59, 62e68.
Bakshi, R., Dmochowski, J., Shaikh, Z.A., Jacobs, L., 2001. Gray matter T2 hypo-
intensity is related to plaques and atrophy in the brains of multiple sclerosis
patients. J. Neurol. Sci. 185, 19e26.
Bakshi, R., Shaikh, Z.A., Janardhan, V., 200 0. MRI T2 shortening (black T2)in
multiple sclerosis: frequency, location, and clinical correlation. Neuroreport 11,
Beard, J., 2003. Iron deciency alters brain development and functioning. J. Nutr.
133, 1468Se1472S .
Benarroch, E.E., 2009. Brain iron homeostasis and neurodegenerative disease.
Neurology 72, 1436e1440 .
Bermel, R.A., Puli, S.R., Rudick, R.A., Weinstock-Guttman, B., Fisher, E.,
Munschauer 3rd, F.E., Bakshi, R., 2005. Prediction of longitudinal brain atrophy
in multiple sclerosis by gray matter magnetic resonance imaging T2 hypo-
intensity. Arch. Neurol. 62, 1371e13 76.
Bian, W., Harter, K., Hammond-Rosenbluth, K.E., Lupo, J.M., Xu, D., Kelley, D.A.,
Vigneron, D.B., Nelson, S.J., Pelletier, D., 2013. A serial in vivo 7T magnetic
resonance phase imaging study of white matter lesions in multiple sclerosis.
Mult. Scler. 19, 69e75.
Bowern, N., Ramshaw, I., Clark, I., Doherty, P., 1984. Inhibition of autoimmune
neuropathological process by treatment with an iron chelating agent. J. Exp.
Med. 160, 1532e1543.
Brass, S.D., Benedict, R.H., Weinstock-Guttman, B., Munschauer, F., Bakshi, R., 2006a.
Cognitive impairment is associated with subcortical magnetic resonance
imaging grey matter T2 hypointensity in multiple sclerosis. Mult. Scler. 12,
Brass, S.D., Chen, N.K., Mulkern, R.V., Bakshi, R., 2006b. Magnetic resonance imaging
of iron deposition in neurological disorders. Top Magn. Reson. Imaging 17,
Ceccarelli, A., Filippi, M., Neema, M., Arora, A., Valsasina, P., Rocca, M.A., Healy, B.C.,
Bakshi, R., 2009. T2 hypointensity in the deep gray matter of patients with
benign multiple sclerosis. Mult. Scler. 15, 678e686.
Ceccarelli, A., Rocca, M.A., Neema, M., Martinelli, V., Arora, A., Tauhid, S., Ghezzi, A.,
Comi, G., Bakshi, R., Filippi, M., 2010. Deep gray matter T2 hypointensity is
present in patients with clinically isolated syndromes suggestive of multiple
sclerosis. Mult. Scler. 16, 39e44.
Ceccarelli, A., Rocca, M.A., Perego, E., Moiola, L., Ghezzi, A., Martinelli, V., Comi, G.,
Filippi, M., 2011. Deep grey matter T2 hypo-intensity in patients with paediatric
multiple sclerosis. Mult. Scler. 17, 702e707.
Craelius, W., Migdal, M.W., Luessenhop, C.P., Sugar, A., Mihalakis, I., 1982. Iron
deposits surrounding multiple sclerosis plaques. Arch. Pathol. Lab. Med. 106,
Crichton, R.R., Wilmet, S., Legssyer, R., Ward, R.J., 2002. Molecular and cellular
mechanisms of iron homeostasis and toxicity in mammalian cells. J. Inorg.
Biochem. 91, 9e18.
Dautry-Varsat, A., Ciechanover, A., Lodish, H.F., 1983. pH and the recycling of
transferrin during receptor-mediated endocytosis. Proc. Natl. Acad. Sci. U.S.A 80,
De Domenico, I., McVey Ward, D., Kaplan, J., 2008. Regulation of iron acquisition and
storage: consequences for iron-linked disorders. Nat. Rev. Mol. Cell Biol. 9,
de Jesus Ferreira, M.C., Crouzin, N., Barbanel, G., Cohen-Solal, C., Récasens, M.,
Vignes, M., Guiramand, J., 2005. A transient treatment of hippocampal neurons
with alpha-tocopherol induces a long-lasting protection against oxidative
damage via a genomic action. Free Radic. Biol. Med. 39, 1009e1020.
Drayer, B., Burger, P., Hurwitz, B., Dawson, D., Cain, J., 1987a. Reduced signal
intensity on MR images of thalamus and putamen in multiple sclerosis:
increased iron content? AJR Am. J. Roentgenol. 149, 357e363.
Drayer, B.P., Burger, P., Hurwitz, B., Dawson, D., Cain, J., Leong, J., Herfkens, R.,
Johnson, G.A., 1987b. Magnetic resonance imaging in multiple sclerosis:
decreased signal in thalamus and putamen. Ann. Neurol. 22, 546e550.
Eissa, A., Lebel, R.M., Korzan, J.R., Zavodni, A.E., Warren, K.G., Catz, I., Emery, D.J.,
Wilman, A.H., 2009. Detecting lesions in multiple sclerosis at 4.7 tesla using
phase susceptibility-weighting and T2-weighting. J. Magn. Reson. Imaging 30,
Fiebiger, S.M., Bros, H., Grobosch, T., Janssen, A., Chanvillard, C., Paul, F., Dörr, J.,
Millward, J.M., Infante-Duarte, C., 2013. The antioxidant idebenone fails to
prevent or attenuate chronic experimental autoimmune encephalomyelitis in
the mouse. J. Neuroimmunol. 262, 66e71.
Ge, Y., Jensen, J.H., Lu, H., Helpern, J.A., Miles, L., Inglese, M., Babb, J.S., Herbert, J.,
Grossman, R.I., 2007. Quantitative assessment of iron accumulation in the deep
gray matter of multiple sclerosis by magnetic eld correlation imaging. AJNR
Am. J. Neuroradiol. 28, 1639e164 4.
Gilgun-Sherki, Y., Melamed, E., Offen, D., 2004. The role of oxidative stress in the
pathogenesis of multiple sclerosis: the need for effective antioxidant therapy.
J. Neurol. 251, 261e268.
Gonsette, R.E., Sindic, C., Dhooghe, M.B., De Deyn, P.P., Medaer, R., Michotte, A.,
Seeldrayers, P., Guillaume, D., 2010. Neuroprotection in multiple sclerosis: the
Association of Inosine and Interferon ASIIMS study group. Boosting endogenous
beta in relapsing- remitting Multiple Sclerosis (ASIIMS) trial. Mult. Scler. 16,
Haacke, E.M., Cheng, N.Y., House, M.J., Liu, Q., Neelavalli, J., Ogg, R.J., Khan, A.,
Ayaz, M., Kirsch, W., Obenaus, A., 2005. Imaging iron stores in the brain using
magnetic resonance imaging. Magn. Reson. Imaging 23, 1e25.
Haacke, E.M., Makki, M., Ge, Y., Maheshwari, M., Sehgal, V., Hu, J., Selvan, M., Wu, Z.,
Latif, Z., Xuan, Y., Khan, O., Garbern, J., Grossman, R.I., 2009. Characterizing iron
deposition in multiple sclerosis lesions using susceptibility weighted imaging.
J. Magn. Reson. Imaging 29, 537e544.
Habib, C.A., Liu, M., Bawany, N., Garbern, J., Krumbein, I., Mentzel, H.J.,
Reichenbach, J., Magnano, C., Zivadinov, R., Haacke, E.M., 2012. Assessing
abnormal iron content in the deep gray matter of patients with multiple
sclerosis versus healthy controls. AJNR Am. J. Neuroradiol. 33, 252e258.
Hagemeier, J., Heininen-Brown, M., Poloni, G.U., Bergsland, N., Magnano, C.R.,
Durfee, J., Kennedy, C., Carl, E., Weinstock-Guttman, B., Dwyer, M.G.,
Zivadinov, R., 2012b. Iron deposition in multiple sclerosis lesions measured by
susceptibility-weighted imaging ltered phase: a case control study. J. Magn.
Reson. Imaging 36, 73e83.
Hagemeier, J., Weinstock-Guttman, B., Bergsland, N., Heininen-Brown, M., Carl, E.,
Kennedy, C., Magnano, C., Hojnacki, D., Dwyer, M.G., Zivadinov, R., 2012a. Iron
deposition on SWI-ltered phase in the subcortical deep gray matter of patients
with clinically isolated syndrome may precede structure-specic atrophy. AJNR
Am. J. Neuroradiol. 33, 1596e1601.
Hagemeier, J., Weinstock-Guttman, B., Heininen-Brown, M., Poloni, G.U.,
Bergsland, N., Schirda, C., Magnano, C.R., Kennedy, C., Carl, E., Dwyer, M.G.,
Minagar, A., Zivadinov, R., 2013a. Gray matter SWI-ltered phase and atrophy
are linked to disability in MS. Front. Biosci. (Elite Ed) 5, 525e532.
Hagemeier, J., Yeh, E.A., Brown, M.H., Bergsland, N., Dwyer, M.G., Carl, E., Weinstock-
Guttman, B., Zivadinov, R., 2013b. Iron content of the pulvinar nucleus of the
thalamus is increased in adolescent multiple sclerosis. Mult. Scler. 19, 567e576.
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58 S57
Hallgren, B., Sourander, P., 1958. The effect of age on the non-haemin iron in the
human brain. J. Neurochem. 3, 41e45.
Halliwell, B., 2006. Oxidative stress and neurodegeneration: where are we now?
J. Neurochem. 97, 1634e1658.
Hametner, S., Wimmer, I., Haider, L., Pfeifenbring, S., Brück, W., Lassmann, H., 2013.
Iron and neurodegeneration in the multiple sclerosis brain. Ann. Neurol. 74,
Hammond, K.E., Metcalf, M., Carvajal, L., Okuda, D.T., Srinivasan, R., Vigneron, D.,
Nelson, S.J., Pelletier, D., 2008. Quantitative in vivo magnetic resonance imaging of
multiple sclerosis at 7 Tesla with sensitivity to iron. Ann. Neurol. 64, 707e713.
Khalil, M., Enzinger, C., Langkammer, C., Tscherner, M., Wallner-Blazek, M.,
Jehna, M., Ropele, S., Fuchs, S., Fazekas, F., 2009. Quantitative assessment of
brain iron by R(2)* relaxometry in patients with clinically isolated syndrome
and relapsing-remitting multiple sclerosis. Mult. Scler. 15, 1048e1054.
Khalil, M., Langkammer, C., Ropele, S., Petrovic, K., Wallner-Blazek, M., Loitfelder, M.,
Jehna, M., Bachmaier, G., Schmidt, R., Enzinger, C., Fuchs, S., Fazekas, F., 2011a.
Determinants of brain iron in multiple sclerosis: a quantitative 3T MRI study.
Neurology 77, 1691e1697.
Khalil, M., Teunissen, C., Langkammer, C., 2011b. Iron and neurodegeneration in
multiple sclerosis. Mult. Scler. Int. 2011, 606807.
Langemann, H., Kabiersch, A., Newcombe, J., 1992. Measurement of low-molecular-
weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white
matter from patients with multiple sclerosis. Eur. Neurol. 32, 248e252.
Langkammer, C., Krebs, N., Goessler, W., Scheurer, E., Ebner, F., Yen, K., Fazekas, F.,
Ropele, S., 2010. Quantitative MR imaging of brain iron: a postmortem valida-
tion study. Radiology 257, 455e462.
Lebel, R.M., Eissa, A., Seres, P., Blevins, G., Wilman, A.H., 2012. Quantitative high-eld
imaging of sub-cortical gray matter in multiple sclerosis. Mult. Scler.18, 433e441.
Linker, R.A., Lee, D.H., Ryan, S., van Dam, A.M., Conrad, R., Bista, P., Zeng, W.,
Hronowsky, X., Buko, A., Chollate, S., Ellrichmann, G., Brück, W., Dawson, K.,
Goelz, S., Wiese, S., Scannevin, R.H., Lukashev, M., Gold, R., 2011. Fumaric acid
esters exert neuroprotective effects in neuroinammation via activation of the
Nrf2 antioxidant pathway. Brain 134, 678e692.
Lynch, S.G., Fonseca, T., Levine, S.M., 2000. A multiple course trial of desferriox-
amine in chronic progressive multiple sclerosis. Cell Mol. Biol. 46, 865e869.
Madsen, E., Gitlin, J.D., 2007. Copper and iron disorders of the brain. Annu. Rev.
Neurosci. 30, 317e337.
Mancuso, M., Davidzon, G., Kurlan, R.M., Tawil, R., Bonilla, E., Di Mauro, S.,
Powers, J.M., 2005. Hereditary ferritinopathy: a novel mutation, its cellular
pathology, and pathogenetic insights. J. Neuropathol. Exp. Neurol. 64, 280e294.
Markowitz, C.E., Spitsin, S., Zimmerman, V., Jacobs, D., Udupa, J.K., Hooper, D.C.,
Koprowski, H., 2009. The treatment of multiple sclerosis with inosine. J. Altern.
Complement. Med. 15, 619e625.
Marracci, G.H., Jones, R.E., McKeon, G.P., Bourdette, D.N., 2002. Alpha lipoic acid
inhibits T cell migration into the spinal cord and suppresses and treats exper-
imental autoimmune encephalomyelitis. J. Neuroimmunol. 13, 104e114.
Massacesi, L., Abbamondi, A.L., Giorgi, C., Sarlo, F., Lolli, F., Amaducci, L., 1987.
Suppression of experimental allergic encephalomyelitis by retinoic acid.
J. Neurol. Sci. 80, 55e64.
Mehta, V., Pei, W., Yang, G., Li, S., Swamy, E., Boster, A., Schmalbrock, P., Pitt, D., 2013.
Iron is a sensitive biomarker for inammation in multiple sclerosis lesions. PLoS
One 8, e57573.
Moos, T., Rosengren Nielsen, T., Skjorringe, T., Morgan, E.H., 2007. Iron trafcking
inside the brain. J. Neurochem. 103, 1730e1740 .
Neema, M., Arora, A., Healy, B.C., Guss, Z.D., Brass, S.D., Duan, Y., Buckle, G.J.,
Glanz, B.I., Stazzone, L., Khoury, S.J., Weiner, H.L., Guttmann, C.R., Bakshi, R.,
2009. Deep gray matter involvement on brain MRI scans is associated with
clinical progression in multiple sclerosis. J. Neuroimaging 19, 3e8.
Neema, M., Ceccarelli, A., Jackson, J., Bakshi, R., 2012. Magnetic resonance imaging in
multiple sclerosis. In: Weiner, H., Stankiewicz, J. (Eds.), Multiple Sclerosis:
Diagnosis and Therapy. Wiley-Blackwell, West Sussex, England, pp. 136e162.
Neema, M., Stankiewicz, J., Arora, A., Dandamudi, V.S., Batt, C.E., Guss, Z.D.,
Al-Sabbagh, A., Bakshi, R., 2007. T1- and T2-based MRI measures of diffuse gray
matter and white matter damage in patients with multiple sclerosis.
J. Neuroimaging 17, 16Se21S.
Oliveira, S.R., Kallaur, A.P., Simão, A.N., Morimoto, H.K., Lopes, J., Panis, C.,
Petenucci, D.L., da Silva, E., Cecchini, R., Kaimen-Maciel, D.R., Reiche, E.M., 2012.
Oxidative stress in multiple sclerosis patients in clinical remission: association
with the expanded disability status scale. J. Neurol. Sci. 321, 49e53.
Pantopoulos, K., Porwal, S.K., Tartakoff, A., Devireddy, L., 2012. Mechanisms of
mammalian iron homeostasis. Biochemistry 51, 5705e5724.
Pawate, S., Wang, L., Song, Y., Sriram, S., 2012. Analysis of T2 intensity by magnetic
resonance imaging of deep gray matter nuclei in multiple sclerosis patients:
effect of immunomodulatory therapies. J. Neuroimaging 22, 137e144.
Pedchenko, T.V., LeVine, S.M., 1999. Desferrioxamine suppresses experimental
allergic encephalomyelitis induced by MBP in SJL mice. J. Neuroimmunol. 84,
188 e197.
Pinero, D., Connor, J., 2000. Iron in the brain: an important contributor in normal
and diseased states. Neuroscientist 6, 435e453.
Pitt, D., Boster, A., Pei, W., Wohleb, E., Jasne, A., Zachariah, C.R., Rammohan, K.,
Knopp, M.V., Schmalbrock, P., 2010. Imaging cortical lesions in multiple sclerosis
with ultra-high-eld magnetic resonance imaging. Arch. Neurol. 67, 812e818.
Ropele, S., de Graaf, W., Khalil, M., Wattjes, M.P., Langkammer, C., Rocca, M.A.,
Rovira, A., Palace, J., Barkhof, F., Filippi, M., Fazekas, F., 2011. MRI assessment of
iron deposition in multiple sclerosis. J. Magn. Reson. Imaging 34, 13e21.
Rouault, T.A., 2006a. The role of iron regulatory proteins in mammalian iron
homeostasis and disease. Nat. Chem. Biol. 2, 406e414.
Rouault, T.A., Cooperman, S., 2006b. Brain iron metabolism. Semin. Pediatr. Neurol.
13, 14 2e148.
Rumzan, R., Wang, J.J., Zeng, C., Chen, X., Li, Y., Luo, T., Lv, F., Wang, Z.P., Hou, H.,
Huang, F., 2013. Iron deposition in the precentral grey matter in patients with
multiple sclerosis: a quantitative study using susceptibility-weighted imaging.
Eur. J. Radiol. 82, e95ee99.
Schenck, J.F., Zimmerman, E.A., 2004. High-eld magnetic resonance imaging of
brain iron: birth of a biomarker? NMR Biomed. 17, 433e445.
Shindler, K.S., Ventura, E., Dutt, M., Elliott, P., Fitzgerald, D.C., Rostami, A., 2010. Oral
resveratrol reduces neuronal damage in a model of multiple sclerosis.
J. Neuroophthalmol. 30, 328e339.
Skjørringe, T., Møller, L.B., Moos, T., 2012. Impairment of interrelated iron- and
copper homeostatic mechanisms in brain contributes to the pathogenesis of
neurodegenerative disorders. Front. Pharmacol. 3, 169.
Spitsin, S.V., Scott, G.S., Mikheeva, T., Zborek, A., Kean, R.B., Brimer, C.M.,
Koprowski, H., Hooper, D.C., 2002. Comparison of uric acid and ascorbic acid in
protection against EAE. Free Radic. Biol. Med. 33, 1363e1371.
Stankiewicz, J., Panter, S.S., Neema, M., Arora, A., Batt, C.E., Bakshi, R., 2007. Iron in
chronic brain disorders: imaging and neurotherapeutic implications. Neuro-
therapeutics 4, 371e386.
Stankiewicz, J.M., Brass, S.D., 2009. Role of iron in neurotoxicity: a cause for concern
in the elderly? Curr. Opin. Clin. Nutr. Metab. Care 12, 22e29.
Tjoa, C.W., Benedict, R.H., Weinstock-Guttman, B., Fabiano, A.J., Bakshi, R., 2005. MRI
T2 hypointensity of the dentate nucleus is related to ambulatory impairment in
multiple sclerosis. J. Neurol. Sci. 234, 17e24.
Van der Worp, H.B., Thomas, C.E., Kappelle, L.J., Hoffman, W.P., de Wildt, D.J.,
Bär, P.R., 1999. Inhibition of iron-dependent and ischemia-induced brain
damage by the alpha tocopherol analo gue MDL74,722. Exp. Neurol. 155,
103 e108.
Walsh, A.J., Blevins, G., Lebel, R.M., Seres, P., Emery, D.J., Wilman, A.H., 2014.
Longitudinal MR imaging of iron in multiple sclerosis: an imaging marker of
disease. Radiology 270, 186e196.
Walsh, A.J., Lebel, R.M., Eissa, A., Blevins, G., Catz, I., Lu, J.Q., Resch, L., Johnson, E.S.,
Emery, D.J., Warren, K.G., Wilman, A.H., 2013. Multiple sclerosis: validation of
MR imaging for quantication and detection of iron. Radiology 267, 531e542.
Wang, J., Ren, Z., Xu, Y., Xiao, S., Meydani, S.N., Wu, D., 2012. Epigallocatechin-
3-gallate ameliorates experimental autoimmune encephalomyelitis by altering
balance among CD4þT-cell subsets. Am. J. Pathol. 180, 221e234.
Weilbach, F.X., Chan, A., Toyka, K.V., Gold, R., 2004. The cardioprotector dexrazoxane
augments therapeutic efcacy of mitoxantrone in experimental autoimmune
encephalomyelitis. Clin. Exp. Immunol. 135, 49e55.
Willenborg, D.O., Bowern, N.A., Danta, G., Doherty, P.C., 1988. Inhibition of allergic
encephalomyelitis by the iron chelating agent desferrioxamine: differential
effect depending on type of sensitizing encephalitogen. J. Neuroimmunol. 17,
127e135 .
Xie, L., Li, X.K., Funeshima-Fuji, N., Kimura, H., Matsumoto, Y., Isaka, Y., Takahara, S.,
2009. Amelioration of experimental autoimmune encephalomyelitis by curcu-
min treatment through inhibition of IL-17 production. Int. Immunopharmacol.
9, 575e581.
Xin, J., Feinstein, D.L., Hejna, M.J., Lorens, S.A., McGuire, S.O., 2012. Benecial effects
of blueberries in experimental autoimmune encephalomyelitis. J. Agric. Food
Chem. 60, 5743e5748.
Yao, B., Bagnato, F., Matsuura, E., Merkle, H., van Gelderen, P., Cantor, F.K., Duyn, J.H.,
2012. Chronic multiple sclerosis lesions: characterization with high-eld-
strength MR imaging. Radiology 262, 206e215.
Zhang, Y., Metz, L.M., Yong, V.W., Mitchell, J.R., 2010. 3T deep gray matter T2
hypointensity correlates with disability over time in stable relapsing-remitting
multiple sclerosis: a 3-year pilot study. J. Neurol. Sci. 297, 76e81.
Zhang, Y., Zabad, R., Wei, X., Metz, L., Hill, M., Mitchell, J., 2007. Deep grey matter
"black T2" on 3 tesla magnetic resonance imaging correlates with disability in
multiple sclerosis. Mult. Scler. 13, 880e883.
Zivadinov, R., Hein inen-Brown, M., Schirda, C.V., Poloni, G .U., Bergsland, N.,
Weinstock-Guttman, B., Dwyer, M.G., 2012. Abnorm al subcortical deep-gray
matter susceptibility-weighted imaging ltered phase measurements in
patients with multiple sclero sis: a case-control study. Neuroimage 59,
J.M. Stankiewicz et al. / Neurobiology of Aging 35 (2014) S51eS58S58
... However, excess iron that is not properly sequestered (e.g. as cytosolic ferritin) can have deleterious effects through the formation of reactive oxygen species ( Dixon and Stockwell, 2014 ). A variety of factors can alter the iron homeostasis in the brain including healthy aging ( Daugherty and Raz, 2013 ;Hallgren and Sourander, 1958 ;Li et al., 2021 ), behavioral factors such as body mass index (BMI) and cigarette smoking ( Li et al., 2021 ), as well as neurological disorders including Parkinson's disease and multiple sclerosis (MS) ( Acosta-Cabronero et al., 2017 ;Stankiewicz et al., 2014 ). ...
... In MS, increased iron concentrations have been reported in the putamen, caudate, and other deep gray matter (DGM) regions and decreased concentrations have been noted in the thalamus ( Khalil et al., 2015 ;Stankiewicz et al., 2014 ;Walsh et al., 2013 ). Increased iron has also been noted in the Rolandic cortex, although at a lower frequency than for DGM iron changes ( Bakshi et al., 2000 ). ...
... Iron is also know to concentrate at the rim of chronically active WM lesions within microglia ( Gillen et al., 2018 ) whereas post mortem studies suggested that iron is depleted from normally-appearing WM ( Hametner et al., 2013 ). These iron alterations may be caused by a variety of different cellular or biochemical mechanisms, such as altered iron transport across the blood-brain barrier, inflammatory activity, or iron depletion from glial syncytium (decreased concentration) Stankiewicz et al., 2014 ). ...
Brain iron homeostasis is necessary for healthy brain function. MRI and histological studies have shown altered brain iron levels in the brains of patients with multiple sclerosis (MS), particularly in the deep gray matter (DGM). Previous studies were able to only partially separate iron-modifying effects because of incomplete knowledge of iron-modifying processes and influencing factors. It is therefore unclear to what extent and at which stages of the disease different processes contribute to brain iron changes. We postulate that spatially covarying magnetic susceptibility networks determined with Independent Component Analysis (ICA) reflect, and allow for the study of, independent processes regulating iron levels. We applied ICA to quantitative susceptibility maps for 170 individuals aged 9 to 81 years without neurological disease (“Healthy Aging” (HA) cohort), and for a cohort of 120 patients with MS and 120 age- and sex-matched healthy controls (HC; together the “MS/HC” cohort). Two DGM-associated “susceptibility networks” identified in the HA cohort (the Dorsal Striatum and Globus Pallidus Interna Networks) were highly internally reproducible (i.e. “robust”) across multiple ICA repetitions on cohort subsets. DGM areas overlapping both robust networks had higher susceptibility levels than DGM areas overlapping only a single robust network, suggesting that these networks were caused by independent processes of increasing iron concentration. Because MS is thought to accelerate brain aging, we hypothesized that associations between age and the two robust DGM-associated networks would be enhanced in patients with MS. However, only one of these networks was altered in patients with MS, and it had a null age association in patients with MS rather than a stronger association. Further analysis of the MS/HC cohort revealed three additional disease-related networks (the Pulvinar, Mesencephalon, and Caudate Networks) that were differentially altered between patients with MS and HCs and between MS subtypes. Exploratory regression analyses of the disease-related networks revealed differential associations with disease duration and T2 lesion volume. Finally, analysis of ROI-based disease effects in the MS/HC cohort revealed an effect of disease status only in the putamen ROI and exploratory regression analysis did not show associations between the caudate and pulvinar ROIs and disease duration or T2 lesion volume, showing the ICA-based approach was more sensitive to disease effects. These results suggest that the ICA network framework increases sensitivity for studying patterns of brain iron change, opening a new avenue for understanding brain iron physiology under normal and disease conditions.
... 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]. ...
Full-text available
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.
... Finally, MS (Stankiewicz et al., 2014) and migraine (Dominguez et al., 2019;Kruit et al., 2009) share the characteristic of iron deposition in deep grey matter. ...
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Background: Migraine headache simultaneously presents with early symptoms among most
... 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.
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This review is a condensed summary of representative articles addressing the sex/gender bias in multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). The strong effects of sex on the incidence and possibly also the activity and progression of these disorders should be implemented in the evaluation of any phase of clinical research and also in treatment choice consideration in clinical practice and evaluation of MRI parameters. Some relationships between clinical variables and gender still remain elusive but with further understanding of sex/gender-related differences, we should be able to provide appropriate patient-centered care and research.
Iron released from oligodendrocytes during demyelination or derived from haemoglobin breakdown products is believed to amplify oxidative tissue injury in multiple sclerosis (MS). However, the pathophysiological significance of iron-containing haemoglobin breakdown products themselves is rarely considered in the context of MS and their cellular specificity and mode of action remain unclear. Using myelinating cell cultures, we now report the cytotoxic potential of hemin (ferriprotoporphyrin IX chloride), a major degradation product of haemoglobin, is 25-fold greater than equimolar concentrations of free iron in myelinating cultures; a model that reproduces the complex multicellular environment of the CNS. At low micro molar concentrations (3.3 - 10 μM) we observed hemin preferentially binds to myelin and axons to initiate a complex detrimental response that results in targeted demyelination and axonal loss but spares neuronal cell bodies, astrocytes and the majority of oligodendroglia. Demyelination and axonal loss in this context are executed by a combination of mechanisms that include iron-dependent peroxidation by reactive oxygen species (ROS) and ferroptosis. These effects are microglial-independent, do not require any initiating inflammatory insult and represent a direct effect that compromises the structural integrity of myelinated axons in the CNS. Our data identify hemin-mediated demyelination and axonal loss as a novel mechanism by which intracerebral degradation of haemoglobin may contribute to lesion development in MS.
Objective To quantify iron deposits in the basal ganglia and to evaluate its relation to age, sex, body mass index and brain laterality. Methods Prospective observational study. Data were collected from the patients’ electronic medical records. The concentration of iron deposits in the brain was assessed using whole-brain MRI at 3.0 Tesla. Results 138 participants were selected, 69.6% were female and the mean age was 47 ± 19 years. The κ coefficient was very strong (k = 0.92, p < 0.001). Age showed a moderate correlation between iron deposits in the caudate and putamen nuclei, on both right and left sides. In overall and right-handed individuals, a significantly higher iron concentration was observed on the left side for the caudate nucleus, putamen, thalamus, globus pallidus, and centrum semiovale, and for left-handed individuals, it was also observed in the left side-for the putamen and centrum semiovale. A weak correlation was shown between body mass index and left and right substantia nigra, left caudate nuclei, left putamen and right globus pallidus. Conclusion Our results showed a significantly higher iron deposit on the left side in most brain regions. In addition, the body mass index may also be related to iron overload, especially in the caudate nucleus. Advances in knowledge Brain iron deposits may be normal, owing to aging, or be pathological, such as neurodegeneration. Thus, it is important to know how much is expected of iron deposition in the brain of healthy populations.
Thiophenols are chemical species with multiple desirable biological properties, including their primary and secondary antioxidant capacity. In this work, the repairing antioxidant activity of eight different thiophenols has been investigated for damaged leucine and tryptophane. The investigation was carried out employing quantum mechanical and transition state methods to calculate the thermodynamic and kinetic data of the reactions involved, while simulating the biological conditions at physiological pH and aqueous and lipidic medium. The analysis of the atomic charges and the spin densities at each of the points on the potential energy surface was the tool that allowed the elucidation of the reaction mechanisms through which thiophenols repair the oxidative damage caused to the amino acids leucine and tryptophan. It was found that thiophenols can repair leucine via a hydrogen atom transfer mechanism in a manner which is similar to the one used by glutathione to repair the carbon‐centered radicals of guanosine. In addition, thiophenols can also restore tryptophane, a nitrogen‐centered radical, via proton‐coupled electron transfer and single electron transfer mechanisms. Moreover, both processes occur at close to diffusion‐controlled rates.
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Objective Iron may contribute to the pathogenesis and progression of multiple sclerosis (MS) due to its accumulation in the human brain with age. Our study focused on nonheme iron distribution and the expression of the iron-related proteins ferritin, hephaestin, and ceruloplasmin in relation to oxidative damage in the brain tissue of 33 MS and 30 control cases. Methods We performed (1) whole-genome microarrays including 4 MS and 3 control cases to analyze the expression of iron-related genes, (2) nonheme iron histochemistry, (3) immunohistochemistry for proteins of iron metabolism, and (4) quantitative analysis by digital densitometry and cell counting in regions representing different stages of lesion maturation. ResultsWe found an age-related increase of iron in the white matter of controls as well as in patients with short disease duration. In chronic MS, however, there was a significant decrease of iron in the normal-appearing white matter (NAWM) corresponding with disease duration, when corrected for age. This decrease of iron in oligodendrocytes and myelin was associated with an upregulation of iron-exporting ferroxidases. In active MS lesions, iron was apparently released from dying oligodendrocytes, resulting in extracellular accumulation of iron and uptake into microglia and macrophages. Iron-containing microglia showed signs of cell degeneration. At lesion edges and within centers of lesions, iron accumulated in astrocytes and axons. InterpretationIron decreases in the NAWM of MS patients with increasing disease duration. Cellular degeneration in MS lesions leads to waves of iron liberation, which may propagate neurodegeneration together with inflammatory oxidative burst. Ann Neurol 2013;74:848-861
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Iron is essential for normal neurological function because of its role in oxidative metabolism and because it is a cofactor in the synthesis of neurotransmitters and myelin. In the past several years, there has been increased attention to the importance of oxidative stress in the central nervous system. Iron is the most important inducer of reactive oxygen species, therefore, the relation of iron to neurodegenerative processes is more appreciated today than it was a few years ago. Nevertheless, despite this increased attention and awareness, our knowledge of iron metabolism in the brain at the cellular and molecular levels is still limited. Iron is distributed in a heterogeneous fashion among the different regions and cells of the brain. This regional and cellular heterogeneity is preserved across many species. Brain iron concentrations are not static; they increase with age and in many diseases and decrease when iron is deficient in the diet. In infants and children, insufficient iron in the diet is associated with decreased brain iron and with changes in behavior and cognitive functioning. Abnormal iron accumulation in the diseased brain areas and, in some cases, alterations in iron-related proteins have been reported in many neurodegenerative diseases, including Hallervorden-Spatz syndrome, Alzheimer’s disease, Parkinson’s disease, and Friedreich’s ataxia. There is strong evidence for iron-mediated oxidative damage as a primary contributor to cell death in these disorders. Demyelinating diseases, such as multiple sclerosis, especially warrant study in relation to iron availability. Myelin synthesis and maintenance have a high iron requirement, thus, oligodendrocytes must have a relatively high and constant supply of iron. However, the high oxygen utilization, high density of lipids, and high iron content of white matter all combine to increase the risk of oxidative damage. We review here the current knowledge of the normal metabolism of iron in the brain and the suspected role of iron in neuropathology.
Conference Paper
Iron deficiency anemia in early life is related to altered behavioral and neural development. Studies in human infants suggest that this is an irreversible effect that may be related to changes in chemistry of neurotransmitters, organization and morphology of neuronal networks, and neurobiology of myelination. The acquisition of iron by the brain is an age-related and brain-region-dependent process with tightly controlled rates of movement of iron across the blood-brain barrier. Dopamine receptors and transporters are altered as are behaviors related to this neurotransmitter. The growing body of evidence suggests that brain iron deficiency in early life has multiple consequences in neurochemistry and neurobiology.
Magnetic resonance imaging (MRI) of the brain and spinal cord has become a routine tool for the diagnosis and monitoring of multiple sclerosis (MS) and has emerged as a key supportive outcome measure in clinical trials. Conventional MRI lesion and atrophy measures are particularly useful for assessing macroscopic damage but lack sensitivity and specificity to the underlying MS pathology. They also show relatively weak relationships to clinical status such as predictive strength for clinical change. Advanced MR techniques, such as diffusion, magnetization transfer imaging, relaxometry, and MR spectroscopy are relatively more specific and sensitive to the underlying pathology. These measures have provided unique insights into the pathophysiology of MS and may help resolve the dissociation between clinical and conventional MRI findings. This chapter summarizes the importance and role of MRI in the characterization of MS-related brain and spinal cord tissue damage.
Magnetic resonance imaging (MRI) has become the primary technique with which neurologists support the diagnosis of multiple sclerosis (MS), and with which researchers monitor disease evolution in both natural history studies and treatment trials. This review summarises the contribution of brain and spinal cord MRI to the diagnosis of MS, illustrating the appearance of MS pathology on the most common MRI sequences. We also discuss the differences in MRI findings between the clinical types of MS and the development of newer non-conventional sequences. THE CONTRIBUTION OF MRI TO THE DIAGNOSIS OF MS The first application of MRI in MS was described in 1981. Since then, MRI of MS has rapidly evolved and new acquisition techniques, characterised by increased sensitivity and specificity with respect to pathology, have been developed. MRI is now an important paraclinical tool for the diagnosis of MS because it allows detection of MS lesions in vivo throughout
Purpose: To investigate the relationship between magnetic resonance (MR) imaging markers of iron content and disease severity in patients with multiple sclerosis (MS) over a 2-year period. Materials and methods: This prospective study was approved by the local ethics committee, and written informed consent was obtained from all participants. Seventeen patients with MS and 17 control subjects were examined twice, 2 years apart, by using phase imaging and transverse relaxation (R2*) mapping at 4.7 T. Quantitative differences in iron content in deep gray matter between patients and control subjects were evaluated with repeated-measures multivariate analysis of variance separately for R2* mapping and phase imaging. Multiple regression analysis was used to evaluate correlations of MR imaging measures, both 2-year-difference and single-time measurements, to baseline disease severity. Results: R2* mapping using 2-year-difference measurements had the highest correlation to disease severity (r = 0.905, P < .001) compared with R2* mapping using single-time measurements (r = 0.560, P = .019) and phase imaging by using either single-time (r = 0.539, P = .026) or 2-year-difference (r = 0.644, P = .005) measurements. Significant increases in R2* occur during 2 years in the substantia nigra (P < .001) and globus pallidus (P = .035), which are both predictors of disease in regression analysis, in patients compared with control subjects. There were group differences in the substantia nigra, globus pallidus, pulvinar thalamus, thalamus, and caudate nucleus, compared with control subjects with R2* mapping (P < .05), and group differences in the caudate nucleus and pulvinar thalamus, compared with control subjects with phase imaging (P < .05). Conclusion: There are significant changes in deep gray matter iron content in MS during 2 years measured with MR imaging, changes that are strongly related to physical disability. Longitudinal measurements may produce a higher correlation to disease severity compared with single-time measurements because baseline iron content of deep gray matter is variable among subjects.
Anti-inflammatory drugs are effective on relapses, but neuroprotective agents to prevent disability are still unavailable. Uric acid has neuroprotective effects in experimental models including encephalomyelitis and appears to be involved in multiple sclerosis. Oral administration of inosine, a precursor of uric acid, increases serum uric acid levels and is well tolerated. Our objective was to test the possibility that a combination therapy associating an anti-inflammatory drug (interferon beta) and an endogenous neuroprotective molecule (uric acid) would be more effective than interferon beta alone on the accumulation of disability. Patients with relapsing-remitting multiple sclerosis on interferon beta for at least 6 months were randomized to interferon beta + inosine or interferon beta + placebo for 2 years. The dose of inosine was adjusted to maintain serum uric acid levels in the range of asymptomatic hyperuricaemia (<or=10 mg/dl). The primary end points were percentage of patients with progression of disability and time to sustained progression (Kaplan-Meier analysis). The combination of interferon beta and inosine was safe and well tolerated but did not provide any additional benefit on accumulation of disability compared with interferon beta alone. We conclude that endogenous neuroprotective mechanisms recently identified in multiple sclerosis are complex and uric acid does not reflect the entire story.