Visualizing iron in multiple sclerosis

doi:10.1016/j.mri.2012.11.011

Magnetic Resonance Imaging

Volume 31, Issue 3, April 2013, Pages 376-384

https://doi.org/10.1016/j.mri.2012.11.011 Get rights and content

Abstract

Magnetic resonance imaging (MRI) protocols that are designed to be sensitive to iron typically take advantage of (1) iron effects on the relaxation of water protons and/or (2) iron-induced local magnetic field susceptibility changes. Increasing evidence sustains the notion that imaging iron in brain of patients with multiple sclerosis (MS) may add some specificity toward the identification of the disease pathology. The present review summarizes currently reported in vivo and post mortem MRI evidence of (1) iron detection in white matter and gray matter of MS brains, (2) pathological and physiological correlates of iron as disclosed by imaging and (3) relations between iron accumulation and disease progression as measured by clinical metrics.

Introduction

Multiple sclerosis (MS) is a disease of the central nervous system (CNS). It affects young adults and may lead patients to a substantial accretion of physical, cognitive and emotional disability over time [1]. The pathogenesis of MS, although widely studied, remains not fully elucidated. Several factors puzzle the comprehension of MS disease mechanisms. Among these factors is the challenge in characterizing pathological specificity of MS-induced disease in vivo using magnetic resonance imaging (MRI) [2]. To overcome this limitation, in recent years research has been focused toward the understanding of the role of iron as possible in vivo tracer of disease pathology in MS. Several authors have contributed to the notion that tracking iron may add some specificity toward the identification of pathological processes in MS [3], [4].

In the present review, we will appraise the current knowledge on iron imaging in MS. We will first briefly elucidate on the current knowledge on iron as a possible indicator of different physiological and pathological processes in MS as demonstrated by histopathological studies. Thereafter, we will describe the physical mechanisms at the basis of iron detection by MRI. Last, we will appraise on the current in vivo and post mortem imaging evidence of iron detection in white matter (WM) and gray matter (GM) of MS brains as well as on its relation with measures of MS-induced disability and other imaging measurable disease parameters. By using the term iron in the present assay, we refer to the non-heme iron in contrast to the heme-bound iron, which is attached to hemoglobin.

Section snippets

Non-hemeiron in normal brain tissue

Iron is essential for many cellular functions. Iron is however also potentially detrimental due to its ability to produce toxic oxygen radicals [5]. Therefore iron metabolism is tightly regulated. Many neurodegenerative conditions including MS have been linked to excess brain iron and subsequent oxidative injury [6], [7]. Iron accumulates with age in the healthy human brain, reaching a plateau after the age of 50 [6]. Most of the non-heme iron found in human brain parenchyma is stored within

MRI protocols sensitive to iron

MRI protocols that are designed to be sensitive to iron typically take advantage of one of two primary effects of iron on the magnetic environment of water molecule protons. First, iron affects the relaxation of water protons including shortening the longitudinal spin-lattice (T₁), transverse spin–spin (T₂) and apparent transverse (T₂*) relaxation times where 1/T₂* = 1/T₂ + 1/T₂′ = 1/T₂ + γ∆B₀. T₂′ characterizes the reversible signal that can be refocused by a spin-echo radiofrequency (RF) pulse, γ is

Conventional MRI

Indirect evidence of iron accumulation predominantly in the deep GM is derived from the measurement of signal intensity changes (i.e., reduction) in T₂-weighted MRI. To measure signal intensity of the deep-GM nuclei, regions of interest (ROI) are drawn in each nucleus. Thereafter, intensity from an identical sized ROI placed in the ventricular cerebrospinal fluid (CSF) is taken for each subject as a method of intensity normalization. Taking ratios of the deep-GM nucleus to the CSF background

Conclusions

Iron-sensitive MR imaging is an attractive modality for the identification of disease in MS as well as for the specific characterization of MS pathology. In recent years, primarily indirect evidence of the sensitivity of some MRI techniques to the iron content of brain tissue in patients with MS has been reported. Pathological characterization of the identified iron in normal-appearing and lesional-WM tissue has been successfully performed. However, questions still remain about the

Acknowledgments

Dr. Bagnato's contribution to this research was supported by the Intramural Research Program of the NINDS, NIH. We thank Drs. S. Pawate and R. Zivadinov for permitting the authors to use images of their work.

References (59)

R. Bakshi et al.
MRI in multiple sclerosis: current status and future prospects
Lancet Neurol
(2008)
A.H. Koeppen
The history of iron in the brain
J Neurol Sci
(1995)
C. Francois et al.
Topographical and cytological localization of iron in rat and monkey brains
Brain Res
(1981)
T. Yoshida et al.
Activated microglia cause superoxide-mediated release of iron from ferritin
Neurosci Lett
(1995)
R. Bakshi et al.
Gray matter T₂ hypointensity is related to plaques and atrophy in the brains of multiple sclerosis patients
J Neurol Sci
(2001)
J. Vymazal et al.
Magnetic resonance imaging of brain iron in health and disease
J Neurol Sci
(1995)
A. Pfefferbaum et al.
MRI estimates of brain iron concentration in normal aging: comparison of field-dependent (FDRI) and phase (SWI) methods
Neuroimage
(2009)
R.J. Ogg et al.
The correlation between phase shifts in gradient-echo MR images and regional brain iron concentration
Magn Reson Imaging
(1999)
E.M. Haacke et al.
Imaging iron stores in the brain using magnetic resonance imaging
Magn Reson Imaging
(2005)
R.P. McCrea et al.
A comparison of rapid-scanning x-ray fluorescence mapping and magnetic resonance imaging to localize brain iron distribution
Eur J Radiol
(2008)

X. Xu et al.

Age, gender, and hemispheric differences in iron deposition in the human brain: an in vivo MRI study

Neuroimage

(2008)

J.F. Schenck

Magnetic resonance imaging of brain iron

J Neurol Sci

(2003)

G.E. Hagberg et al.

The sign convention for phase values on different vendor systems: definition and implications for susceptibility-weighted imaging

Magn Reson Imaging

(2010)

C.W. Tjoa et al.

MRI T₂ hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis

J Neurol Sci

(2005)

I. Pirko et al.

Deep gray matter T₂ hypointensity correlates with disability in a murine model of multiple sclerosis

Neuroimage

(2011)

R. Zivadinov et al.

Abnormal subcortical deep-gray matter susceptibility-weighted imaging filtered phase measurements in patients with multiple sclerosis: a case-control study

Neuroimage

(2012)

K. Rejdak et al.

Multiple sclerosis: a practical overview for clinicians

Br Med Bull

(2010)

J. Petkau et al.

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

Mult Scler

(2008)

M. Khalil et al.

Iron and neurodegeneration and multiple sclerosis

Mult Scler Int

(2011)

D.B. Kell

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

BMC Med Genomics

(2009)

L. Zecca et al.

Iron, brain ageing and neurodegenerative disorders

Nat Rev Neurosci

(2004)

R. Williams et al.

Pathogenic implications of iron accumulation in multiple sclerosis

J Neurochem

(2012)

R. Meguro et al.

Nonheme-iron histochemistry for light and electron microscopy: a historical, theoretical and technical review

Arch Histol Cytol

(2007)

F. Bagnato et al.

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

Brain

(2011)

B. Hallgren et al.

The effect of age on the non-haemin iron in the human brain

J Neurochem

(1958)

S.M. LeVine et al.

Iron-enriched oligodendrocytes: a reexamination of their spatial distribution

J Neurosci Res

(1990)

B. Todorich et al.

Oligodendrocytes and myelination: the role of iron

Glia

(2009)

M. Khalil et al.

Determinants of brain iron in multiple sclerosis: a quantitative 3 T MRI study

Neurology

(2011)

B. Drayer et al.

Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: increased iron content?

AJR Am J Roentgenol

(1987)

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Published by Elsevier Inc.

Review articleVisualizing iron in multiple sclerosis

Abstract

Introduction

Section snippets

Non-hemeiron in normal brain tissue

MRI protocols sensitive to iron

Conventional MRI

Conclusions

Acknowledgments

Lancet Neurol

J Neurol Sci

Brain Res

Neurosci Lett

J Neurol Sci

J Neurol Sci

Neuroimage

Magn Reson Imaging

Magn Reson Imaging

Eur J Radiol

Neuroimage

J Neurol Sci

Magn Reson Imaging

J Neurol Sci

Neuroimage

Neuroimage

Multiple sclerosis: a practical overview for clinicians

Br Med Bull

Magnetic resonance imaging as a surrogate outcome for multiple sclerosis relapses

Mult Scler

Iron and neurodegeneration and multiple sclerosis

Mult Scler Int

Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases

BMC Med Genomics

Iron, brain ageing and neurodegenerative disorders

Nat Rev Neurosci

Pathogenic implications of iron accumulation in multiple sclerosis

J Neurochem

Nonheme-iron histochemistry for light and electron microscopy: a historical, theoretical and technical review

Arch Histol Cytol

Tracking iron in multiple sclerosis: a combined imaging and histopathological study at 7 Tesla

Brain

The effect of age on the non-haemin iron in the human brain

J Neurochem

Iron-enriched oligodendrocytes: a reexamination of their spatial distribution

J Neurosci Res

Oligodendrocytes and myelination: the role of iron

Glia

Determinants of brain iron in multiple sclerosis: a quantitative 3 T MRI study

Neurology

Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: increased iron content?

AJR Am J Roentgenol

Review article
Visualizing iron in multiple sclerosis