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REVIEW ARTICLE
Iron metabolism and its detection through MRI in parkinsonian
disorders: a systematic review
Sara Pietracupa
1
&Antonio Martin-Bastida
2
&Paola Piccini
2
Received: 10 April 2017 /Accepted: 22 August 2017
#Springer-Verlag Italia S.r.l. 2017
Abstract Iron deposition in the brain normally increase
with age, but its accumulation in certain regions is ob-
served in a number of neurodegenerative diseases in-
cluding Parkinson’s disease (PD) and other parkinson-
isms. Whether iron overload leads to dopaminergic neu-
ronal death in the SN of PD patients or is instead sim-
ply a by-product of the neurodegenerative progression is
still yet to be ascertained. Magnetic resonance imaging
(MRI) is a non-invasive method to assess brain iron
content in PD patients. In PD, accurate radiologic visu-
alization of basal ganglia is required. Deep gray matter
nuclei are well presented in T2- and T2*-weighted im-
ages. T2*-weighted gradient-echo (GRE) is widely used
to assess calcifications and also for iron detection. On
the other hand, new methods specifically designed for
detecting iron-induced susceptibility differences can be
further improved by sequences like susceptibility-
weighted imaging (SWI). In the present review, we
aim to summarize the available data on brain iron de-
position in PD.
Keywords Parkinsonian disorders .Parkinson’sdisease .
Iron .Magnetic resonance imaging
Introduction
Iron accumulates in the brain in healthy aging; however, its
accumulation in specific regions is observed in neurodegener-
ative diseases including Parkinson’s disease (PD) [1]. Specific
areas of the brain, such as globus pallidus (GB), substantia
nigra (SN), dentate nucleus (DN), and motor cortex (MC),
show increased mineralization in healthy brain. Neurons store
iron in the form of ferritin, which exists as light (L) and heavy
(H) chains. The iron redox couple mediates the transfer of
single electrons through the reversible oxidation/reduction re-
actions of Fe(II) and Fe(III). The biological redox potential,
electronic spin state as well as the reactivity of iron, is deter-
mined by the nature of the ligand to which the species are
bound. Iron configuration dictates whether an iron-based bio-
molecule is responsible for reactions involving oxygen trans-
port and storage, electron transfer, or oxidation/reduction of
other molecules [2]. Reactions involving iron in the body are
predominately redox-based, hydrolytic, or involve polynucle-
ar complex formation [3]. This is especially important for the
brain, where some of the highest concentrations of iron in the
body are maintained [4].
It has been hypothesized by a number of studies that nigral
mineralization may be a surrogate biomarker of PD. Mutations
in proteins involved in neuronal iron homeostasis have been
linked with PD, including transferrin (Tf) [5], iron regulatory
protein2(IRP2)[6], ferritin (Ft) [7], and divalent metal trans-
porter 1 (DMT1) [8]. In experimental animal models, direct
injection of iron in SN causes dopaminergic neurodegeneration
[9]. In addition, feeding neonatal mice with iron can trigger
parkinsonism and nigral degeneration [10].
Neurodegenerative disorders characterized by brain iron ac-
cumulation, like aceruloplasminemia [11,12],
neuroferritinopathy [13,14], and neurodegeneration with brain
iron accumulation (NBIA) [15] present parkinsonian symptoms.
*Sara Pietracupa
sara.pietracupa@uniroma1.it
1
IRCSS Neuromed, Pozzilli, Italy
2
Centre for Neuroinflammation and Neurodegeneration, Department
of Medicine, Imperial College London, London, UK
Neurol Sci
DOI 10.1007/s10072-017-3099-y
Loss-of-function mutations of IRPs show similar iron ac-
cumulation observed in idiopathic PD. Conversely, modula-
tion of iron content shows beneficial effects on PD animal
models. PD toxin model, 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-
OHDA) cause SN iron accumulation in mice. These PD
models show reduction of dopaminergic degeneration in SN
and increased striatal dopamine turnover after administration
of iron chelators [16–18]. Iron-mediated toxicity in these
models can also be ameliorated by genetic or pharmacologi-
cally restoring Ft [16] and Cp [19].
The reason why iron accumulates in PD could be explained
by a number of iron-related proteins that are altered in PD. Ft
levels have been found to be decreased in postmortem PD
brains [20]; moreover, loss of iron storage capacity leads to
increased free unbound iron being more available for oxida-
tive reactions. Iron accumulation in PD might be caused by
increased neuronal iron import. DMT1 has been shown to be
elevated in the SN of postmortem PD brains [21]. This could
promote iron import, but the levels of transferrin receptor 1
(TfR1), which is required for DMT1-mediated iron import
were found unchanged when corrected for neuronal loss
[22–24]. On the other hand, increased iron deposition might
also be attributed to reduced iron export. Although ceruloplas-
min (Cp) levels have been shown to beunaltered in PD brains,
however its activity is reduced in SN, which could narrow iron
efflux [19].
Furthermore, tau protein can play a role in iron accumula-
tion in PD [25]. A selective reduction oftau found in SN ofPD
patients may also contribute to iron accumulation by
preventing APP-mediated iron export [26].
Theroleofneuromalanin(NM)inironchelationhas
been recently proposed, NM binds iron in two different
high and low affinity sites. Most of the iron is bound to
high affinity sites, but under iron overload conditions, the
high affinity sites of NM are saturated, and iron binds to
the low affinity sites [27,28]. In the latter sites, iron is
sequesteredinthereactiveformandcouldplayadelete-
rious effect by promoting redox reactions when NM is
released to extraneuronal matrix. Therefore, the binding
of iron could have a protective role under physiological
conditions, but a toxic gain of function may manifest
when iron overload is present in the brain [29].
Neurotoxic interactions between iron and dopamine have
been recently proposed to explain degeneration of the SN
in PD [30]. Moreover, specific T1-weighted magnetic res-
onance imaging (MRI) sequence has been demonstrated
to detect NM signal changes to accurately discriminate
PD patients from controls. Nevertheless, the relationship
between iron accumulation and NM using multimodal im-
aging techniques has not found clear results [31].
Recent developments in MRI make it now possible to ex-
amine brain iron content in PD patients. Imaging studies have
shown increased iron accumulation at early stages of PD even
before symptom onset [32–34]. The SN iron accumulation in
PD patients, shown by MRI, correlates with disease severity
[35,36] and duration. In this review, we will focus on the MRI
methods used for iron detection in PD. The Medline database
on PubMed was searched for relevant papers (last accessed on
the March 2017) using the following queries: BBrain iron
deposition^and BParkinson’s disease^or BParkinsonism.^
We only considered in this review MRI studies, excluding
metabolic studies.
MRI methods to study iron accumulation
T2-weighted spin echo (SE) and fluid attenuation inversion
recovery (FLAIR) are the standard MRI protocol in neuro-
degenerative diseases showing hyperintensity in areas of
white matter (WM) lesions [37].FLAIRisusedtomaxi-
mize the detectability of lesions attenuating the signal gen-
erated by cerebrospinal fluid (CSF) [38]. Furthermore, SE-
based sequences have recently been modified with sam-
pling perfection with application optimized contrasts
(SPACE) using different flip-angle evolution [39,40].
This technique is a T2-weighted three-dimensional turbo
SE sequence with long echo time (TE) that enables fast
high-resolution three-dimensional images [39,40]. T2*-
weighted-GRE is also useful for detecting microbleeds
and calcifications [38]. Deep gray matter nuclei are well
presented in T2- and T2*-weighted images; however,
methods specifically designed for detecting iron-induced
susceptibility differences can be further improved by se-
quences like susceptibility-weighted imaging (SWI).
SWI is a novel high-resolution MRI modality which
[41–43] requires a different from traditional spin-density,
T1, or T2 imaging recalled echo pulse sequence to acquire
images. The use of long TE allows for phase development
between the excitation pulse and data acquisition that is
sufficient for the differentiation of susceptibility variations
[41]. Due to its sensitivity, this method exploits the sus-
ceptibility differences between tissues and uses the phase
image to detect these [42–44]. The magnitude and phase
data are combined to produce an enhanced contrast mag-
nitude image that is exquisitely sensitive to venous blood,
hemorrhage, and iron deposition. Furthermore,
susceptibility-weighted-angiography (SWAN) is useful to
precisely delineate small blood vessels, microbleeds, iron,
and calcium deposits. SWAN is innately less affected by
the chemical shift compared to SWI with significantly
enhanced susceptibility information. Finally, quantitative
susceptibility mapping (QSM) provides a novel contrast
mechanism in MRI [45] converting the phase shifts to
localize magnetic susceptibility.
Neurol Sci
Brain iron deposition in PD
In 1986, Drayer et al. [46] assessed for the first time the differ-
ences in T2 relaxation times in basal ganglia and SN in six
patients diagnosed with multi system atrophy (MSA) and pro-
gressive sopranuclear palsy (PSP) and 14 healthy controls
(HC). Authors found decreased T2 relaxation times in the pu-
tamen (PUT), and less prominent decreased in the caudate nu-
cleus (CN) and lateral pars compacta of the SN in the MSA and
PSP population compared with HC. Conversely, other authors
[47], studied postmortem brains of five subjects: four dying of
non-neurological conditions and one subject with PD by means
of T2-weighted images, showing no differences in iron distri-
bution in the basal ganglia between both study groups. Antonini
et al. [48] evaluated T2 relaxation times in 30 PD patients and
33 HC using a 1.5 T MRI. When compared to HC, PD patients
showed decreased T2 values in CN, putamen (PUT), and SN;
however, no clinical correlations were found with the afore-
mentioned regional increased iron accumulations.
In the last decade, several studies have focused their inter-
estinevaluatingironoverloadinPDpatients(Table1).
Increased evidence using SWI techniques confirm that parkin-
sonian patients show increased iron accumulation in deep
braingraynucleiwhencomparedtoHC[49–52,55,59,60].
Several works [57,62] also demonstrated increased phase
values in the SN of PD positively correlating with UPDRS
motor scores (UPDRS III) [49] and Hoehn and Yahr (H&Y)
stage [55]aswellasadifferentironaccumulationinclinical
laterality [53]. In particular, Zhang et al. [49] investigated a
population of 42 PD patients and 30 HC analyzing SN and
basal ganglia. PD patients showed an increased deposition in
SN, PUT, and red nucleus (RN) bilaterally when compared to
HC. In addition, SN phase radians correlated with UPDRS III
of the most affected side. On the other hand, Wu and col-
leagues [55] demonstrated elevated iron deposition in PUT,
CN, RN, GP, and SN of 54 PD patients (18 PD patients with
HY < 1.5 and 36 PS patients with HY > 1.5) compared to 40
HC. The phase values of the GB and the SN showed negative
correlations with the HY stage. According to other data [50],
the regional phase values of 25 PD patients can reveal the
differences between PD patients with symmetric and
lateralized PD, even though the study included only a small
number of PD patients and HC. By contrast, other authors [59,
] found increased nigral mineralization in PD patients when
compared to HC; however, no correlations with motor sever-
ity as assessed with UPDRS III and disease stage were found.
In the study by Pechkam et al. [61], the authors addressed the
lack of significant correlations to the small number of PD
patients studied (18 patients). Previous results also suggest a
positive correlation between phase shifts values in SN and
serum ceruloplasmin levels in PD patients [52]in45PDpa-
tients (25 with decreased ceruloplasmin levels and 20 with
normal serum ceruplasmin levels and 45 HC). The original
finding in this study that PD patients with reduced ceruloplas-
min levels showed decreased nigral phase values when com-
pared with HC whilst PD patients with normal ceruloplasmin
levels demonstrated no changes in phase values when com-
pared with HC, suggests a role in iron deposition mediated by
ceruloplasmin levels. In a recent cross-sectional study [62], of
70 non-demented PD using high-pass filtered phase imaging,
PD patients showed higher levels of iron in SN, GP, and PUT
in PD patients compared to HC. Further correlations with
nigral mineralization were found with motor severity as
assessed with UPDRS III in off-medicated state and
bradykinesia-rigidity subscores. Moreover, when PD groups
were subdivided according to UPDRS-III score, iron mineral-
ization appears to be stratified according to disease motor
severity, confirming the idea that patients with a more severe
disease show a greater iron accumulation.
Other authors, Schwarz et al. (2014) [57], investigated the
usefulness of nigrosome-1 detection using SWI. Their sample
was divided as follows: a prospective case control study in 19
subjects (10 PD, 9 HC) and a retrospective cross-sectional
study in 95 consecutive patients (9 PD, 81 non-PD, 5 non-
Tabl e 1 Overview of studies using T2, T2*, SWI, and QSM sequence
in Parkinson’s disease and other parkinsonisms
MR sequence HC PD
Drayer et al., [46] T2 GE 14 6 MSA
6PSP
Brooks et al., [47]T2 61PD
Antonini, [48]T2GE3330
Zhang et al. [49]T2GE
SWI
30 42
Grabner et al. [50]T1
SWI
525
Zhang et al. [51]T1
SWI
26 40
Jin et al. [52]T1
SWI
45 45
Wang et al. [53]T1IR
T1 FSE
T2 FLAIR
T2*ESWAN
14 20
Ulla et al. [54]T1
GRE
26 27
Wu et al. [55]T1
T2
SWI
54 40
Barbosa et al. [56]T1
R2 and R2 *
30 20
Schwarz et al. [57] SWI 90 19
He et al. [58] QSM 35 44
Guan et al. [59] QSM 40 60
Hopes et al. [60]T1
T2*
20 70
Peckham et al. [61] SWI 16 18
Martin Bastida et al. [62] SWI 20 70
Neurol Sci
diagnostic studies exclude). Two independent raters classified
subjects into PD and non-PD assessing the presence or ab-
sence of nigrosome-1. Almost 90% of participants were cor-
rectly classified, demonstrating a high sensitivity of the cur-
rent imaging sequence.
ESWAN sequences are also useful in detecting iron accu-
mulation. Wang et al. (2013) [53] demonstrated the presence
of smaller main MPV in the SN of PD patients as well as
negative correlation between the extent of reduction and se-
verity of motor symptoms, in a population of 20 PD patients
with different disease stages and 14 HC.
Recent works have been focused on evaluating the util-
ity of quantitative magnetic resonance (QMR) [56,58 and
59]. In a recent study (60) including 60 PD patients and 30
HC and comparing R2, R2* with quantitative susceptibil-
ity mapping (QSM), authors found QSM more accurate in
detecting iron accumulation. Further increased iron accu-
mulation measured with QSM in SN of PD patients but
also a spread in other structures such as RN and GP in
patients with a more advanced disease were found [59].
In addition, authors demonstrated positive correlation be-
tween QSM values and disease duration and UPDRS III in
a large number of subjects including 60 PD patients (45
withHY>2.5and15withHY>3)and40HC[58].
Finally, two longitudinal studies evaluated so far brain
iron overload in PD patients by means of R2* over a period
of 3 and 2 years, respectively [54,60]. In the first longitu-
dinal study [54], authors evaluated 26 PD patients and 26
HC by a first MRI whereas 14 PD patients and 18 HC
3 years after by a second MRI, whilst the second longitu-
dinal study included 70 PD patients in the cross-sectional
arm and 35 PD patients and 20 HC in the follow-up [60]. In
both studies, authors found significant changes in nigral
R2*valuesincomparisonwith HC which correlated with
changes in disease severity in the SN.
Discussion
In the last decade, a great number of studies evaluated iron
overload in parkinsonian disorders and other neurodegenera-
tive diseases. So far, there is accordance between authors that
iron is a promising biomarker for diagnosis in PD and other
parkinsonisms. However, the present studies present some
limitations. First of all, most of them are retrospective studies,
to our knowledge, only two longitudinal studies confirmed so
far, that iron overload increases as the disease progresses [54,
60]. Secondly, there is still lack of agreement between authors
on which is the most accurate sequence to study iron deposi-
tion. Indeed, a recent meta-analysis which compared postmor-
tem results with iron deposition detected by using MRI [63]
demonstrated that both R2* and SWI have some limitations in
evaluating iron deposition. This meta-analysis confirmed an
increased iron accumulation in SN and PUT as assessed by
R2*, SWI, and postmortem studies. On the other hand, whilst
both SWI and R2* indicated an increase in iron levels in the
RN, postmortem samples failed to find a correlation between
disease severity and iron deposition in RN. A number of con-
founding factors can influence imaging results. Calcifications,
microbleeds, and myelinated fibers can disrupt the iron signals
in both R* and SWI. These difficulties may be overcome
applying QSM sequences as previous studies already con-
firmed [53,56,57].
NM loss may be another confounding factor able to
reduce iron signals since in normal conditions it stores
big quantity of iron in the brain. A recent study [31]inves-
tigated the relationship between iron content in the SN and
neuromelanin signal changes combining T1 neuromelanin-
sensitive MRI sequence and T2* relaxometry. In this study,
iron content in the SN of PD patients did not show any
significant correlation with neuromelanin MRI signal
changes, which may indicate that neuromelanin reduction
and iron accumulation derive from different pathogenetic
mechanisms. MRI techniques sensitive to both NM chang-
es and iron accumulation have been hypothesize to be po-
tential surrogate biomarkers of PD [54,60,62,64–69]Ina
recent study [69], 43 PD patients (13 late stage PD, 12 de
novo PD patients, 10 PD patients with a 2–5-year disease
duration, and 10 HS) were studied with NM MRI-sensi-
tive. Authors were able to identify a significant NM deple-
tion parallel with disease progression between PD patients
in an early stage of disease and groups of PD patients
belonging to more advanced disease stages. Moreover, oth-
er authors already found significant correlations between
NM loss and disease stage and severity [66]. On the other
hand, previous studies confirmed the role of iron as a
promising diagnostic biomarker in PD, finding an in-
creased iron accumulation in the SN correlating with dis-
ease duration and motor impairment [62]aswellasareli-
able marker of disease progression [54,60].
The use of iron sensitive MRI sequences may also be of
therapeutic interest. Iron chelators, such as deferiprone,
showed a disease-modifying effect in animal models of
PD [70]. So far, two randomized clinical trial with this
drug have been conducted in PD patients, showing mild
reductions in motor severity after 6–12 months of treat-
ment associated with iron removal in SN, CN, and DN
[71]. In the future, action of iron chelation and other drugs
can be followed with MRI as well as iron overload over
disease progression.
Conclusions
A number of studies have demonstrated that iron plays a role
in PD. Moreover, topographic distribution of iron could help
Neurol Sci
in some cases of parkinsonism in early stage differential diag-
nosis, even tough it is not clear if the increase in iron content in
PD is a pathogenetic or epiphenomenic event related to dopa-
minergic neurodegeneration. So far a limitation of previous
studies is that almost all of them have included only a rela-
tively small number of subjects. Larger studies are necessary
to confirm that iron can be considered as a novel biomarker in
PD and a new therapeutic target.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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