Iron deposition of the deep grey matter in patients with multiple sclerosis and neuromyelitis optica: A control quantitative study by 3D-enhanced susceptibility-weighted angiography (ESWAN)

doi:10.1016/j.ejrad.2012.01.003

European Journal of Radiology

Volume 81, Issue 4, April 2012, Pages e633-e639

https://doi.org/10.1016/j.ejrad.2012.01.003 Get rights and content

Abstract

Purpose

Previous studies have detected abnormal iron deposition in the deep grey matter (DGM) of multiple sclerosis (MS). The regional specificity of the DGM iron deposition in neuromyelitis optica (NMO) is still unclear. We compared the differences in the DGM iron concentration between MS and NMO patients.

Methods

We enrolled 42 relapsing–remitting MS (RRMS) patients, 42 NMO patients and 42 healthy controls undergoing brain conventional MRI and three-dimensional (3D)-enhanced T₂*-weighted angiography (ESWAN) sequences. We obtained the mean phase values (MPVs) for ESWAN-filtered phase images. An analysis of covariance (ANCOVA) was used to compare MPVs among three groups. The correlations of MPVs changes with disease duration and expanded disability status scale (EDSS) were analyzed.

Results

The RRMS patients had higher DGM iron concentration than did the NMO and control groups, but only the bilateral substantia nigra (SN) showed a significant statistical difference among three groups (p < 0.05). In the RRMS group, the iron concentration in the bilateral head of the caudate nucleus (HCN) (left: p < 0.0001; right: p = 0.0134) and the dentate nucleus (DN) (p < 0.05 for both) were correlated with disease duration. In the NMO group, no correlation was found between the DGM iron concentration and disease duration (p > 0.05). Furthermore, no correlations were found between the DGM iron concentration and EDSS (p > 0.05).

Conclusions

We confirm the iron concentration in the DGM iron content of MS patients is more than NMO patients and healthy controls in the same age range. Furthermore, the disease duration was found to be a significant contributor to patients with MS.

Introduction

Iron is essential for normal neuronal metabolism and plays a key role in physiological processes, such as oxygen transport, neurotransmitter synthesis, electron transfer, mitochondrial energy generation and myelination [1]. Iron is stored in the brain as ferritin, which contains excess iron atoms not immediately engaged in metabolic activities under normal conditions. With age, iron is deposited in some regions of the brain, predominantly in the basal ganglia. An increased rate of iron deposition has also been observed in certain chronic neurological disorders. Recent reports have documented the role of iron in the pathogenesis of diseases, such as multiple sclerosis (MS) [2], [3], Parkinson's disease [4] and several other disorders.

Brain iron has been quantified in vivo using the following MRI methods: relaxation time mapping, magnetic field correlation imaging, direct saturation imaging, and susceptibility-weighted imaging (SWI) [5]. SWI is a novel MRI technique that takes advantage of the magnetic susceptibility differences of various tissues and these differences can be differentiated in high-pass filtered SWI phase images. 3D-enhanced T₂*-weighted angiography (ESWAN) combines a unique 3D T₂*-based multi-echo acquisition with a special reconstruction algorithm and has significant advantages over the conventional SWI method, including an enhanced susceptibility sensitivity, a high spatial resolution, a high signal noise ratio and a reduced chemical shift artefact [6]. Iron is a paramagnetic element with different magnetic susceptibilities to the surrounding parenchyma, and it changes the local magnetic field in the presence of an externally applied magnetic field, thereby changing the phase value of regions where iron is present [7]. Iron concentration can be quantified by measuring the mean phase values (MPVs) of different brain structures.

MS and neuromyelitis optica (NMO) are common inflammatory demyelinating diseases of the central nervous system (CNS). The nosological position of NMO was unknown until the discovery of NMO-IgG [8], suggesting that NMO is different from MS and has a fundamentally different aetiology. The cause and pathogenesis of MS and NMO are still unclear, but differences in pathology, neuroimaging and the response to some immunotherapies highlight the dissimilarity between MS and NMO.

Several studies have reported that MS patients have abnormal iron deposition in the deep grey matter (DGM) [3]. To our knowledge, no studies have investigated abnormal DGM iron concentration in NMO patients or the correlation between the DGM iron concentration and the clinic progresses in MS and NMO patients. Therefore, our study had two main objectives based on the use of ESWAN: (1) to quantify iron concentration and compare iron concentration in the DGM of MS and NMO patients, and (2) to detect the correlation of the DGM iron deposition with the disease duration and expanded disability status scale (EDSS) in these two diseases.

Section snippets

Subjects

We studied 42 patients with clinically diagnosed relapsing–remitting MS (RRMS) and 42 sex and age-matched patients with NMO. These two groups were further divided into two age subgroups: one group with patients in the age ranged from 20 to 39 years and the other group with patients in the age ranged from 40 to 59 years. RRMS diagnoses were made according to the revised McDonald criteria, and NMO diagnoses were based on the recently revised Wingerchuk's diagnostic criteria, which include absolute

Results

The MPVs in the HCN, GP, PUT, THA, SN and RN structures of the 42 volunteers were 1977 ± 40.87, 1912 ± 39.25, 1925 ± 24.39, 2027 ± 6.73, 1921 ± 25.33 and 1916 ± 42.1 radius, respectively. Compared with previously published regional iron concentration in the post-mortem brains of healthy adults by Hallgren and Sourander [10], which were 9.28, 21.30, 13.32, 4.76, 18.64 and 19.48 mg per 100 g of wet weight, respectively, we observed a negative correlation between the MPVs of the ROIs and the post-mortem brain

Discussion

In our study, abnormal brain iron deposition in the DGM of MS patients was quantified using ESWAN as indicated by MRI [3] results and histopathologic studies [2] while this phenomenon was not observed in NMO patients. Additionally, disease duration was positively correlated with the iron concentration measured in the bilateral HCN and DN of MS patients. Therefore, these findings suggest that a quantitative analysis of DGM iron can provide valuable information for understanding these two

Conflicts of interest

The authors declare no conflicts of interest.

Role of the funding source

This study was sponsored by the National Natural Science Foundation of China (81171309), the Chongqing Municipal Natural Science Foundation of China under Grant (CSTC2011JJA1073) and the Medicine Scientific key Research Project of Chongqing Health Bureau Grant (2011-1-031).

Acknowledgments

Dr. Xuan Chen and Dr. Chun Zeng equally contributed to this work. The authors would like to thank all of the subjects who participated in this study. The authors would also like to thank Professor Sally Brown for a critical reading of this manuscript.

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Magnetic resonance imaging detection of deep gray matter iron deposition in multiple sclerosis: A systematic review
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Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease involving immune-mediated damage. Iron deposition in deep gray matter (DGM) structures like the thalamus and basal ganglia have been suggested to play a role in MS pathogenesis. Magnetic Resonance Imaging (MRI) imaging methods like T2 and T2* imaging, susceptibility-weighted imaging, and quantitative susceptibility mapping can track iron deposition storage in the brain primarily from ferritin and hemosiderin (paramagnetic iron storage proteins) with varying levels of tissue contrast and sensitivity. In this systematic review, we evaluated the role of DGM iron deposition as detected by MRI techniques in relation to MS-related neuroinflammation and its potential as a novel therapeutic target. We searched through PubMed, Embase, and Web of Science databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, against predetermined inclusion and exclusion criteria. We included 89 articles (n = 6630 patients), and then grouped them into different categories: i) methodological techniques to measure DGM iron, ii) cross-sectional and group comparison of DGM iron content, iii) longitudinal comparisons of DGM iron, iv) associations between DGM iron and other imaging and neurobiological markers, v) associations with disability, and vi) associations with cognitive impairment. The review revealed that iron deposition in DGM is independent yet concurrent with demyelination, and that these iron deposits contribute to MS-related cognitive impairment and disability. Variability in iron distributions appears to rely on a positive feedback loop between inflammation, and release of iron by oligodendrocytes. DGM iron seems to be a promising prognostic biomarker for MS pathophysiology.
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In contrast, few NMOSD lesions have central vein sign (Kister et al., 2013; Sinnecker et al., 2012). Additionally, significantly higher degree of abnormal iron deposition has been observed in deep gray-matter regions in MS compared to those of NMOSD patients (Chen et al., 2012). Moreover, NMOSD lesions are not associated with abnormal iron accumulation, while most MS patients will have at least some iron-containing lesions (Chawla et al., 2016; Sinnecker et al., 2016; Schumacher et al., 2016).
In neuromyelitis optica spectrum disorder (NMOSD), clinical disability in NMOSD patients is relapse-related and progressive phase is rare. This observation raises the question whether there is any radiographic disease activity. The aim of present study was to determine the longitudinal changes in cerebral lesion number, lesion size, lesion-to-venule relationship, and morphological patterns of lesions in NMOSD using multiparametric 7T MR imaging. We also aimed to assess brain volume changes in NMOSD.
A cohort of 22 patients with NMOSD underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo (GRE-T2*) weighted imaging on 7T MRI of brain at baseline and after ~2.8 years of follow-up. Morphologic imaging characteristics, and signal intensity patterns of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on GRE-T2* images and/or SWI as well as hyperintense signal on quantitative susceptibility mapping (QSM). Lesions were considered "non-iron-laden" if they were hyperintense on GRE-T2*/SWI and isointense or hyperintense on QSM. Additionally, fractional brain parenchymal volume (fBPV) was computed at both time points.
A total of 169 lesions were observed at baseline. At follow-up, 6 new lesions were found in 5 patients. In one patient, a single lesion could not be detected on the follow-up scan. No appreciable change in lesion size and vessel-lesion relationship was observed at follow up. All lesions demonstrated hyperintense signal intensity on GRE-T2* weighted images and isointense signal on QSM at both time points. Therefore, these lesions were considered as non-associated with iron pathology. Additionally, no significant change in brain volume was observed: fBPV 0.78 ± 0.06 at baseline vs. 0.77 ± 0.05 at follow up, p>0.05.
Cerebral lesions in NMOSD patients remain ‘inert’ and do not show any substantial variations in morphological characteristics during a 2–3-year follow-up period.
Iron deposition in the gray matter in patients with relapse-remitting multiple sclerosis: A longitudinal study using three-dimensional (3D)-enhanced T2∗-weighted angiography (ESWAN)
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And these results were consistent with previous studies. Chen et al. [19] investigated the differences in the DGM iron concentration between MS and neuromyelitis optica (NMO), only the bilateral SN showed a significant statistical difference among the groups, suggesting that iron content also changes in different diseases. Al-Radaideh et al. [20] performed on a 7T Philips Achieva system, using a 3-dimensional, T2*-weighted gradient echo acquisition, and compared 19 Clinically Isolated Syndrome (CIS) patients to 20 age-matched, healthy controls.
To investigate the relationship between the iron content by magnetic resonance imaging (MRI) and clinic correlation in patients with relapse-remitting multiple sclerosis (RRMS) over a two-year period.
Thirty RRMS patients and 30 healthy control subjects were examined twice, two years apart, by undergoing brain conventional MRI and three-dimensional (3D)-enhanced T2*-weighted angiography (ESWAN) sequences at 3.0 T. Quantitative differences in iron content in deep gray matter (GM) nuclei and precentral gyrus GM between patients and control subjects with repeated-measures the mean phase values (MPVs) for ESWAN-ﬁltered phase images. Spearman's rank correlation coefficient analysis was used to evaluate correlations of the MPVs, both 2-year-difference and single-time measurements, to disease duration, expanded disability status scale (EDSS) and times of recurrence.
The RRMS patients had higher GM iron concentration than that of the healthy control subjects in both single-time measurements, but only the substantia nigra (SN), and the precentral gyrus GM (PGM) showed a significant statistical difference (p < 0.05). Using the paired samples t test, we found that there were significant differences in two-year-difference measurements of the MPVs in the putamen (PUT), the globus pallidus (GP), the head of the caudate nucleus (HCN), the thalamus (THA), SN, the red nucleus (RN), the dentate nucleus (DN) and PGM, especially in SN (t = 2.92, p = 0.007) in RRMS patients. The MPVs of the PUT, GP, HCN, THA, SN, RN, DN and PGM for the subgroup with RRMS patients in times of recurrence less than twice were similar to the healthy controls. There was no significant difference in all regions of interests (ROIs). However, there were significant differences in all ROIs except THA and GP for the other subgroup with RRMS patients in times of recurrence more than and equal to twice. Spearman's rank correlation coefficient analysis showed there were significant negative correlations between disease duration and the MPVs in the HCN (r = −0.516, p = 0.004), DN (r = −0.468, p = 0.009) and PGM (r = −0.84, p = 0). However, no correlations were found between the EDSS scores and the MPVs.
Iron content in the GM can be measurable using MRI and our results conﬁrmed that iron concentration was increasing in the GM of MS patients during two-year period compared to healthy controls. Furthermore, this study had also shown significant and substantial correlation of iron concentration with disease severity.
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And the limited size of our study may partially account for the discrepancy mentioned above. Furthermore, a study showed that there was no difference in brain iron deposition in the deep gray matter between NMO patients and HC [4], which might be partially explained by the result of our study that serum iron level was decreased in NMO patients. Certainly, it should be noted that the deep gray matter was chosen because it was the most frequently involved brain region in iron deposition but not the inflammatory lesions in that study.
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For these experiments, newborn piglets were subjected to HI/R injury, during which ESWAN scanning was performed, followed by H&E staining and immunohistochemistry of AQP-4 expression.
In the striatum, values from T2* weighted magnetic resonance imaging (MRI) increased and reached their highest level at 3 days post injury, whereas T2* values increased and peaked at 24 h in the subcortical region. The change in T2* values was concordant with brain edema. Phase values in the subcortical border region were not dependent on time post-injury. Magnitude values were significantly different from the control group, and increased gradually over time in the subcortical border region. Susceptibility-weighted images (SWI) indicated small petechial hemorrhages in the striatum and thalamus, as well as dilated intramedullary veins.
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Iron deposition of the deep grey matter in patients with multiple sclerosis and neuromyelitis optica: A control quantitative study by 3D-enhanced susceptibility-weighted angiography (ESWAN)

Abstract

Purpose

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Results

Discussion

Conflicts of interest

Role of the funding source

Acknowledgments

Brain Res

Lancet

Neurobiol Aging

Eur J Radiol

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson's, Huntington's, Alzheimer's, prions, bactericides, chemical toxicology and others as examples

Arch Toxicol

Iron and neurodegeneration in multiple sclerosis

Mult Scler Int

Multiple sclerosis and the accumulation of iron in the basal ganglia: quantitative assessment of brain iron using MRI T2 relaxometry

Eur Neurol

MRI assessment of iron deposition in multiple sclerosis

Neurol J Magn Reson Imaging

Susceptibility-weighted angiography (SWAN) of cerebral veins and arteries compared to TOF-MRA

Eur J Radiol

Susceptibility-weighted imaging: technical aspects and clinical applications, part 1

AJNR Am J Neuroradiol

Multiple sclerosis and the accumulation of iron in the basal ganglia: quantitative assessment of brain iron using MRI T₂ relaxometry