Quantifying iron deposition within the substantia nigra of Parkinson's disease by quantitative susceptibility mapping

doi:10.1016/j.jns.2018.01.008

Journal of the Neurological Sciences

Volume 386, 15 March 2018, Pages 46-52

https://doi.org/10.1016/j.jns.2018.01.008 Get rights and content

Highlights

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Quantitative susceptibility mapping has been proved the most sensitive technique of brain-iron imaging.
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Iron deposition in the substantia nigra of PD patients is in line with the course of PD.
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Iron content in the substantia nigra have a certain impact on the clinical symptoms of PD.
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Akinetic/rigidity-prominent PD subgroup may be the most affected phenotype of PD.

Abstract

Background

Iron deposition within the substantia nigra (SN) has been postulated to play a vital role in Parkinson's disease (PD). The aim of this study was to explore the inherent link of PD patients between their substantia nigra iron accumulation and clinical status using quantitative susceptibility mapping (QSM) which is now considered to be the only quantitative imaging technique of brain iron deposition.

Methods

44 PD patients and 31 age- and gender-matched healthy controls underwent quantitative susceptibility mapping (QSM) were recruited in this study. We firstly divided the patients into mild symptom severity (MSP) and advanced symptom severity (ASP) groups concerning their disease stage, aiming to illuminate the relationship between iron deposition in SN of PD and disease progression. Then, we classified the patients with Parkinson's disease into three subgroups: tremor-dominant PD (TD), akinetic/rigidity-dominant PD (AR), mixed-PD (M) according to their dominant motor symptoms in order to investigate whether there are any effects of SN iron accumulation to different subtypes of PD patients.

Results

Compared to healthy controls, patients with PD have increased QSM magnetic values in the substantia nigra (138.039 ± 37.320 vs 179.553 ± 65.715; P = 0.001). More prominent statistically significance of the difference of SN iron deposition between healthy controls (HC) and advanced symptom severity (ASP) subgroup was displayed (138.039 ± 37.320 vs 232.827 ± 92.040; P < 0.001). Besides, among the three clinical phenotypes both TD and AR subgroup showed significant difference compared with healthy controls concerning the QSM values (138.039 ± 37.320 vs 185.864 ± 99.851; P = 0.013; 188.148 ± 52.958 vs 138.039 ± 37.320; P = 0.001). Furthermore, the iron content in the SN of PD patients was significantly correlated with the Hoehn-Yahr stage, the Unified Parkinson's Disease Rating Scale (UPDRS), Montgomery Asberg Depression Rating Scale (MADRS) and Hamilton Anxiety Scale (HAMA) scores (r = 0.417, P = 0.005; r = 0.300, P = 0.048; r = 0.540, P < 0.001; r = 0.553, P < 0.001). In MSP the significantly correlation was displayed only in MADRS, HAMA scores (r = 0.429, P = 0.013; r = 0.492, P = 0.004), when disease progressed into advanced severity stage all these clinical measures (Hoehn-Yahr stage, UPDRS-3, UPDRS, HAMA, and MADRS scores) we had recruited into this study shown prominent correlation to SN iron content (r = 0.650, P = 0.030; r = 0.709, P = 0.015; r = 0.708, P = 0.015; r = 0.758, P = 0.007; r = 0.683, P = 0.020). In the three phenotypes the correlation between iron content and MADRS, HAMA scores (r = 0.686, P = 0.002; r = 0.633, P = 0.006) was found in AR subgroups exclusively.

Conclusions

Patients with PD exhibited significantly higher magnetic susceptibility values, especially in those who are in advanced disease severity stage, which confirmed that iron accumulation in the SN is in line with Parkinson's disease progression. Furthermore, we testified that there are actually some inherent effects of substantia nigra iron deposition to the clinical symptoms of Parkinson's disease. Moreover, it seems that akinetic/rigidity-dominant PD subgroup was affected most by SN iron accumulation.

Introduction

The selective and progressive loss of dopaminergic neurons in the substantia nigra (SN) is postulated to be the principal pathogenesis of PD which is paralleled by increased iron deposition and secondary degenerative changes in the basal ganglia [1], [2], [3]. Iron in the human brain is essential for numerous biological processes such as neuronal development, enzyme function, DNA synthesis, oxidative phosphorylation, neurotransmitter synthesis, as well as mitochondrial respiration [3], [4]. By contrast, excessive iron content often assumed to have a causal role of disease by enhancing free radical formation and contributing to oxidative stress and neuronal death in iron-overloaded cells [4], [5], [6], which lead to a variety of neurodegenerative diseases including Parkinson's Disease, Alzheimer's disease, and Huntington's disease [4], [6]. Although increased iron content in the brain has been detected in various neurodegenerative diseases, the contribution of iron overload to the pathogenesis of PD remains unclear. Still, genetic analyses, neuropathologic investigations, and new imaging techniques of PD are providing important new insights into the pathogenesis of PD [1], [11], [12]. Magnetic resonance imaging (MRI) is a non-invasively powerful means to assess brain iron content with unprecedented high spatial resolution within reasonable scan times [13], which have been applied to in vivo iron mapping and quantification [1], [10], [11], [13]. However, clinical use of phase images is limited due to the non-local relation between phase and the underlying magnetic susceptibility distribution. Quantitative susceptibility mapping (QSM) is a novel post-processing technique, which provides a quantitative assessment of the magnetic susceptibility of the tissue under investigation has recently received increased scientific and clinical attention [8], [14]. This method has been proposed to be more sensitive with respect to magnetic tissue properties than conventional magnitude-based techniques and enabled the identification of several substructures of the human brain that were in part indiscernible on the other GRE-based contrasts. There are already several studies observed relationships among increased brain iron accumulation, disease duration and motor severity [2], [7], [8]. However, it remains unclear as to the effect of iron accumulation on different motor symptoms, as previous studies investigating tremor and akinetic/rigid predominance yield conflicting results [9], [10]. However, owing to technological obstacles, our understanding of brain iron metabolism continues to lag behind our knowledge about systemic iron metabolism. It is not known whether iron accumulation contributes to disease progression or whether accumulation of iron occurs only after widespread neuronal death.

In this explorative study we utilized QSM to investigate the cerebral iron content focus on substantia nigra of PD patients aiming to illuminate whether magnetic susceptibility is correlated differently with clinical characteristics in PD at mild severity-stage versus those at advanced severity-stage. Additionally, we explore the underlying differences in the level of iron among different motor subtypes of PD include (tremor dominant PD, akinetic/rigid dominant PD and mixed motor symptoms PD). Furthermore, we compare the magnetic susceptibility with their clinical characteristics such as gender, Hoehn-Yahr, UPDRS, HAMA, and MADRS scales among different subgroups, respectively.

Section snippets

Subjects

This study received approval from the local ethics committee and all subjects gave written informed consent before participation. In this study, 54 PD patients (26 males, 28 females; mean age = 67.7 ± 9.486 years) with a diagnosis made by neurologists specializing in movement disorders according to the criteria of the United Kingdom Parkinson's Disease Society Brain Bank for idiopathic Parkinson's disease [15], and 32 age- and gender-matched healthy controls (13 males,19 females; mean age = 66.6 ± 9.065

Demographic data

Demographic and clinical data are summarized in Table 1. In the present study, there were no significant statistical differences between PD and healthy controls regarding gender and age. Although the male/female ratio was higher in the PD group (P = 0.491), no significant gender differences in iron accumulation were found. As expected, patients with PD showed significantly increase of iron deposition in substantia nigra (SN) (138.039 ± 37.320 vs 179.553 ± 65.715; mean ± SD, P = 0.001; Table 2; Fig. 2(A)).

Discussion

In the present study, the relation between Parkinson's disease and magnetic susceptibility values in the substantia nigra of PD patients was assessed by QSM. The key findings were the progressiveness accumulation of iron in the SN which is in line with the disease progression as well as the inherent correlation between SN QSM values and clinical manifestations of patients with PD, which provide a non-invasive biomarker to assess trajectories of disease, as well as potentially contributes to the

Limitations

In the current study, some limitations should be noted. First, the sample size of the patients was relatively small, and the results should be interpreted cautiously. Therefore, repeated studies with larger samples should be carried out in the future to capture the dynamic changes of QSM during PD progression. Second, despite the technical advantage of QSM in quantifying iron in vivo, the QSM signal also may be affected by a number of other factors such as calcium, lipid, or myelin content.

Conclusion

Quantitative susceptibility mapping (QSM) is now regarded as the most sensitive technique for measuring iron content in the substantia nigra to explore the underlying pathologic mechanism of PD. In this study, the progressiveness pattern of iron deposition in the substantia nigra of PD patients which is in line with PD's course was discovered. In addition, the amount of iron content in the SN appears to have a certain impact on the clinical manifestation of Parkinson's disease, with the

Funding

This work was supported by the Shanghai Municipal Commission of Health and Family Planning (grant numbers 201540392).

Conflicts of interest

The authors have no conflicts of interest to declare.

Acknowledgement

We are very grateful to all the participants who made this research possible. We acknowledge the MRI technical support of Professor Jianqi Li and his team.

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Parkinson's disease (PD) is a degenerative disease of the central nervous system, and its specific etiology is still unclear. At present, it is believed that the main pathological basis is the reduction of dopamine concentration in the brain striatum. Although many previous studies have believed that iron as an important nutrient element participates in the occurrence and development of PD, whether there is a causal correlation between total iron binding capacity(TIBC), transferring saturation(TSAT), ferritin and serum iron in iron homeostasis indicators and PD, there has been a lack of effective genetic evidence.
We used Mendelian randomization (MR) as an analytical method to effectively evaluate the genetic association between exposure and outcome, based on the largest genome-wide association study (GWAS) data to date. By using randomly assigned genetic instrumental variables (SNPs, Single Nucleotide Polymorphisms) that are not affected by any causal relationship, we effectively evaluated the causal relationship between iron homeostasis indicators and PD while controlling for confounding factors.
By coordinated analysis of 86 SNPs associated with iron homeostasis markers and 12,858,066 SNPs associated with PD, a total of 56 SNPs were finally screened for genome-wide significance of iron homeostasis associated with PD. The results of inverse variance weighting(IVW) analysis suggested that iron（ β = - 0.524; 95%cl=-0.046 to −0.002; P=0.032) was considered to have a genetic causal relationship with PD. Cochran's Q, Egger intercept and MR-PRESSO global tests did not detect the existence of heterogeneity and pleiotropy (P>0.05). Mr Steiger directionality test further confirmed our estimation of the potential causal direction of iron and PD (P=0.001). In addition, TIBC (β=-0.142; 95%Cl=-0.197–0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861–0.229; P=0.255), and ferritin (β=-0.387; 95%Cl=-1.179–0.405; P=0.338) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). In addition, TIBC (β=-0.142; 95%Cl=-0.197–0.481; P=0.414), TSAT (β=-0.316; 95%Cl=-0.861–0.229; P=0.255), and ferritin (β=-0.101; 95%Cl=--0.987 to −0.405; P=0.823) did not have genetic causal relationships with PD, and the results were not heterogeneous and pleiotropic (P>0.05). TIBC (P=0.008), TSAT (P=0.000) and ferritin (P=0.013) were all consistent with the estimation of MR Steiger directivity test.
Our study found that among the four iron homeostasis markers, there was a genetic causal association between serum iron and PD, and the serum iron level was negatively correlated with the risk of PD. In addition, TIBC, TSAT, ferritin had no genetic causal relationship with PD.
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Parkinson's disease (PD) is a common neurodegenerative disease, and apart from a few rare genetic causes, its pathogenesis remains largely unclear. Recent scientific interest has been captured by the involvement of iron biochemistry and the disruption of iron homeostasis, particularly within the brain regions specifically affected in PD. The advent of Quantitative Susceptibility Mapping (QSM) has enabled non-invasive quantification of brain iron in vivo by MRI, which has contributed to the understanding of iron-associated pathogenesis and has the potential for the development of iron-based biomarkers in PD. This review elucidates the biochemical underpinnings of brain iron accumulation, details advancements in iron-sensitive MRI technologies, and discusses the role of QSM as a biomarker of iron deposition in PD. Despite considerable progress, several challenges impede its clinical application after a decade of QSM studies. The initiation of multi-site research is warranted for developing robust, interpretable, and disease-specific biomarkers for monitoring PD disease progression.
Increased iron in the substantia nigra pars compacta identifies patients with early Parkinson's disease: A 3T and 7T MRI study
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Degeneration in the substantia nigra (SN) pars compacta (SNc) underlies motor symptoms in Parkinson’s disease (PD). Currently, there are no neuroimaging biomarkers that are sufficiently sensitive, specific, reproducible, and accessible for routine diagnosis or staging of PD. Although iron is essential for cellular processes, it also mediates neurodegeneration. MRI can localize and quantify brain iron using magnetic susceptibility, which could potentially provide biomarkers of PD.
We measured iron in the SNc, SN pars reticulata (SNr), total SN, and ventral tegmental area (VTA), using quantitative susceptibility mapping (QSM) and R2* relaxometry, in PD patients and age-matched healthy controls (HCs). PD patients, diagnosed within five years of participation and HCs were scanned at 3T (22 PD and 23 HCs) and 7T (17 PD and 21 HCs) MRI. Midbrain nuclei were segmented using a probabilistic subcortical atlas. QSM and R2* values were measured in midbrain subregions. For each measure, groups were contrasted, with Age and Sex as covariates, and receiver operating characteristic (ROC) curve analyses were performed with repeated k-fold cross-validation to test the potential of our measures to classify PD patients and HCs. Statistical differences of area under the curves (AUCs) were compared using the Hanley-MacNeil method (QSM versus R2*; 3T versus 7T MRI).
PD patients had higher QSM values in the SNc at both 3T (p_adj = 0.001) and 7T (p_adj = 0.01), but not in SNr, total SN, or VTA, at either field strength. No significant group differences were revealed using R2* in any midbrain region at 3T, though increased R2* values in SNc at 7T MRI were marginally significant in PDs compared to HCs (p_adj = 0.052). ROC curve analyses showed that SNc iron measured with QSM, distinguished early PD patients from HCs at the single-subject level with good diagnostic accuracy, using 3T (mean AUC = 0.83, 95 % CI = 0.82–0.84) and 7T (mean AUC = 0.80, 95 % CI = 0.79–0.81) MRI. Mean AUCs reported here are from averages of tests in the hold-out fold of cross-validated samples. The Hanley-MacNeil method demonstrated that QSM outperforms R2* in discriminating PD patients from HCs at 3T, but not 7T. There were no significant differences between 3T and 7T in diagnostic accuracy of QSM values in SNc.
This study highlights the importance of segmenting midbrain subregions, performed here using a standardized atlas, and demonstrates high accuracy of SNc iron measured with QSM at 3T MRI in identifying early PD patients. QSM measures of SNc show potential for inclusion in neuroimaging diagnostic biomarkers of early PD. An MRI diagnostic biomarker of PD would represent a significant clinical advance.
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Seventeen unmedicated MDD participants underwent MRI, evaluation of depression severity, and cognitive testing before and after receiving MBCT, compared to fourteen healthy controls (HC). Local field shift (LFS) values, measures of brain iron levels, were derived from phase images in the putamen, caudate, globus pallidus (GP), anterior cingulate cortex (ACC) and thalamus.
Compared to the HC group, the MDD group had significantly lower baseline LFS (indicative of higher iron) in the left GP and left putamen and had a higher number of subjects with impairment in a test of information processing speed. In the MDD group, lower LFS values in the left and right ACC, right putamen, right GP, and right thalamus were significantly associated with depression severity; and lower LFS in the right GP was correlated with worse performance on measures of attention. All MBCT participants experienced depression relief. MBCT treatment also significantly improved executive function and attention. MBCT participants with lower baseline LFS values in the right caudate experienced significantly greater improvement in depression severity with treatment; and those with lower LFS values in the right ACC, right caudate, and right GB at baseline performed better on measures of verbal learning and memory after MBCT.
Our study highlights the potential contribution of subtle differences in brain iron to MDD symptoms and their successful treatment.
Meta-analysis of iron metabolism markers levels of Parkinson's disease patients determined by fluid and MRI measurements
2023, Journal of Trace Elements in Medicine and Biology
Parkinson’ s disease (PD) is a progressive neurodegenerative disease featured neuropathologically by the loss of dopaminergic neurons of the substantia nigra (SN). Iron overload in the SN is mainly relative to the pathology and pathogenesis of PD. Postmortem samples of PD has indicated the increased levels of brain iron. However, there is no consensus on iron content through iron-sensitive magnetic resonance imaging (MRI) techniques and the alteration of iron and iron related metabolism markers levels in blood and cerebrospinal fluids (CSF) are still unclear based on the current studies. In this study, we performed a meta-analysis to explore the iron concentration and iron metabolism markers levels through iron-sensitive MRI quantification and body fluid.
A comprehensive literature search was performed in PubMed, EMBASE and Cochrane Library databases for relevant published studies that analyzed iron load in the SN of PD patients using quantitative susceptibility mapping (QSM) or susceptibility weighting imaging (SWI), and iron metabolism markers, iron, ferritin, transferrin, total iron-binding capacity（TIBC）in CSF sample or serum/plasma sample (from Jan 2010 to Sep 2022 to filter these inaccurate researches attributed to unadvanced equipment, inaccurate analytical methods). Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI) with random or fixed effect model was used to estimate the results.
Forty-two articles fulfilled the inclusion criteria including 19 for QSM, 6 for SWI, and 17 for serum/plasma/CSF sample including 2874 PD patients and 2821 healthy controls (HCs). Our meta-analysis results founded a notable difference for QSM values increase (19.67, 95% CI=18.69–20.64) and for SWI measurements (−1.99, 95% CI= −3.52 to −0.46) in the SN in PD patients. However, the serum/plasma/CSF iron levels and serum/plasma ferritin, transferrin, total iron-binding capacity (TIBC) did not differ significantly between PD patients and HCs.
Our meta-analysis showed the consistent increase in the SN in PD patients using QSM and SWI techniques of iron-sensitive MRI measures while no significant differences were observed in other iron metabolism markers levels.
Distribution pattern of iron deposition in the basal ganglia of different motor subtypes of Parkinson's disease
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The quantitative susceptibility mapping (QSM) technique was used to analyze the distribution pattern of iron deposition in the basal ganglia region of patients with motor subtypes of Parkinson’s disease (PD) and to explore the difference in iron content in the basal ganglia region of PD motor subtypes on the major motor symptomatic side.
The study included 76 patients with PD and 37 healthy controls (HC). Patients with PD were divided into two groups: postural instability/gait disorder (PIGD)(n = 48), and tremor dominance (TD)(n = 28). We classified patients with PD according to the side of the major motor symptoms as left PIGD (n = 23), left TD (n = 14), right PIGD (n = 25), and right TD (n = 14). All subjects underwent brain magnetic resonance scanning to obtain QSM and susceptibility values in the corresponding regions of interest (ROI).
(1) Compared with the HC, the bilateral SN in the PD-PIGD and TD group showed greater susceptibility values. The susceptibility values in the left CN, bilateral PUT were also greater in the PD-PIGD group than the HC. (2) Compared with the TD, the left PUT susceptibility values were greater in the PIGD group, especially in patients whose major symptomatic side were on the right limb. (3) Correlation analysis showed that in the PD group, bilateral SN was positively correlated with the unified Parkinson's disease rating scale III part scores of the Movement Disorder Society (MDS-UPDRS III) and the Hoehn-Yahr stage. Bilateral dentate nucleus (DN) susceptibility values were significantly positively correlated with TD scores, and left PUT susceptibility values were positively correlated with PIGD scores. The left SN within the PIGD group was positively correlated with the PIGD score.
There were different iron deposition patterns in the basal ganglia between the PD-PIGD and TD groups. There also seems to be a difference in iron deposition in PD motor subtypes on different major motor symptom sides.

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¹: Xiaoyan Zeng and Hedi An contributed equally to this work (shared first authorship).

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Quantifying iron deposition within the substantia nigra of Parkinson's disease by quantitative susceptibility mapping

Highlights

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Subjects

Demographic data

Discussion

Limitations

Conclusion

Funding

Conflicts of interest

Acknowledgement

Lancet Neurol.

Brain Res.

Parkinsonism Relat. Disord.

NeuroImage

NeuroImage

Radiology

Parkinsonism Relat. Disord.

Quantitative Susceptibility Mapping (QSM) as a means to measure brain iron? A postmortem validation study[C]

Proc. Intl. Soc. Mag. Reson. Med.

Disease duration and the integrity of the nigrostriatal system in Parkinson's disease

Brain

Iron metabolism in the CNS: implications for neurodegenerative diseases

Nat. Rev. Neurosci.

Iron, brain ageing and neurodegenerative disorders

Nat. Rev. Neurosci.

Restless legs syndrome: pathophysiology, clinical presentation and management

Nat. Rev. Neurol.

Regionally progressive accumulation of iron in Parkinson's disease as measured by quantitative susceptibility mapping

NMR Biomed.

Nigral iron deposition occurs across motor phenotypes of Parkinson's disease

Eur. J. Neurol.