Magnetic Resonance Imaging 23 (2005) 1 25

Review article
Imaging iron stores in the brain using magnetic resonance imaging
E. Mark Haackea,b,*, Norman Y.C. Chengb, Michael J. Housec, Qiang Liub, Jaladhar Neelavallib,
Robert J. Oggd, Asadullah Khanb, Muhammad Ayazb, Wolff Kirsche, Andre Obenause
a
The MRI Institute for Biomedical Research, 440 East Ferry Street, Detroit, MI 48202, USA
b
Department of Radiology, Wayne State University, 3990 John R Road, Detroit, MI 48202, USA
c
University of Western Australia, School of Physics, Crawley, WA 6009, Australia
d
Department of Radiological Sciences, St. Jude Childrens Research Hospital, Memphis, TN 38105, USA
e
Departments of Neurosurgery and Radiation Science, Loma Linda University, 11175 Campus St., SP Ste. 1113, Loma Linda, CA 92350, USA
Received 7 October 2004; accepted 7 October 2004

Abstract
For the last century, there has been great physiological interest in brain iron and its role in brain function and disease. It is well known that
iron accumulates in the brain for people with Huntingtons disease, Parkinsons disease, Alzheimers disease, multiple sclerosis, chronic
hemorrhage, cerebral infarction, anemia, thalassemia, hemochromatosis, Hallervorden-Spatz, Down syndrome, AIDS and in the eye for
people with macular degeneration. Measuring the amount of nonheme iron in the body may well lead to not only a better understanding of
the disease progression but an ability to predict outcome. As there are many forms of iron in the brain, separating them and quantifying each
type have been a major challenge. In this review, we present our understanding of attempts to measure brain iron and the potential of doing
so with magnetic resonance imaging. Specifically, we examine the response of the magnetic resonance visible iron in tissue that produces
signal changes in both magnitude and phase images. These images seem to correlate with brain iron content, perhaps ferritin specifically, but
still have not been successfully exploited to accurately and precisely quantify brain iron. For future quantitative studies of iron content we
propose four methods: correlating R2V and phase to iron content; applying a special filter to the phase to obtain a susceptibility map; using
complex analysis to extract the product of susceptibility and volume content of the susceptibility source; and using early and late echo
information to separately predict susceptibility and volume content.
D 2005 Elsevier Inc. All rights reserved.
Keywords: Iron measurements; Magnetic susceptibility; Nonheme iron

1. Introduction people with macular degeneration. We review here quanti-

tative attempts to measure iron using magnetic resonance
For much of the last century there has been great
imaging (MRI) and T2, T2* and T2V methods. We present
physiological interest in brain iron. The general research
our current approaches to measure susceptibility from the
community believes that the ability to quantitatively and
magnitude and phase images as a new means to quantify
longitudinally assess regional brain iron has a potential role
iron. The references were chosen to cover major headings
in the diagnosis of disease, as well as understanding
related to observations of iron effects in brain [1131], liver
pathogenesis, disease progression and the monitoring of
iron [132146], MRI developments related to signal effects
treatment. We now know that iron accumulation occurs in
of iron [147174], relaxation effects [175209], magnetic
the brain for people with Huntingtons disease (HD),
field artifacts [210218], measuring field effects [219231]
Parkinsons disease (PD), Alzheimers disease (AD), multi-
and targeted contrast agents [232241].
ple sclerosis (near plaques), chronic hemorrhage, cerebral
infarction, anemia, thalassemia, hemochromatosis, Haller-
vorden-Spatz, Down syndrome, AIDS and in the eye for 2. Iron in the brain

* Corresponding author. The MRI Institute for Biomedical Research,

Detroit, MI 48202, USA. Tel.: +1 313 758 0065; fax: +1 313 758 0068.
E-mail address: nmrimaging@aol.com (E.M. Haacke).
0730-725X/$ see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.mri.2004.10.001
To preface our discussion on imaging iron stores using
MRI, we provide an overview of iron in the brain. This
overview is not intended to give an in-depth physiological
2 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
review of brain iron and the interested reader is referred to
other articles [10,34] for a detailed discussion of iron in
neurobiology. Iron plays a major role as a critical part of
hemoglobin that transports oxygen from the lung to tissues.
Furthermore, nonhemoglobin iron is also important in brain
physiology because nonheme iron is involved in electron
transport facilitating cellular aerobic metabolism [82]
through its role in the production of adenosine triphosphatase
[34]. However, if iron is not properly regulated, it can lead
to oxidative stress and the production of free radicals. Any
overload of ferrous iron will lead to a reaction with hydro-
gen peroxide and the formation of aggressive hydroxyl
radicals by means of the Fenton reaction, or peroxynitrates,
and the subsequent death of neurons by apoptosis [55].
2.1. Nonheme iron
There are two categories of iron in the brain: heme iron,
in hemoglobin and some enzymes like perioxidases, and
nonheme iron. The types of nonheme iron in the brain
include (i) low-molecular-weight complexes; (ii) metal-
loproteins like transferrin, melanotransferrin and lactofer-
rin; (iii) storage proteins such as ferritin and hemosiderin
[126] and (iv) ionic iron. Ferromagnetic material, in the
form of biogenic magnetite, has also been reported [72,79].
Of these components, the two most important to iron
regulation are transferrin (iron transport) and ferritin (iron
storage) [29]. Transferrin carries iron from the blood into
brain tissue via transferrin receptors located in the brains
microvasculature [10]. It has a single chain of amino acids
and two carbohydrate groups. A single Fe3+ iron can be
bound to each carbohydrate group. The molecular weight of
transferrin is 79.6 kg/mol [75].
Ferritin stores excess iron atoms, which are not imme-
diately engaged in metabolic activities [24 38,82]. Ferritin
has a large spherical protein coat, about 12 nm in diameter,
that surrounds a crystalline core of hydrous ferric oxide
[5Fe2O3d 9H20] [55]. There can be up to 4500 iron atoms
stored in the 8-nm-diameter internal cavity of one ferritin
protein. Iron(II) passes into the core through six channels in
the protein coat and is oxidized to iron(III) for storage. The
molecular weight of ferritin is 474 kg/mol [75].
The apoferritin coat (ferritin without an internal iron
core) is composed of 24 subunits containing varied
combinations of two homologous proteins, derived from
separate genes, referred to as L-ferritin (light) and H-ferritin
(heavy). Variation in H and L composition produces ferritin
isoforms that confer specific physiochemical properties that
best suit particular cells and tissues. H-rich ferritin is
efficient at iron sequestration and is predominant in organs
with high iron utilization and little iron storage. In contrast,
L-rich ferritin is efficient at iron nucleation and is associated
with iron storage [33,59,81].
Hemosiderin, considered to be a degradation product of
ferritin [13], is a related iron-storage material that is water-
insoluble. It appears to be associated with iron overload
disorders and hemorrhage [13].
2.2. Regional distribution of iron, ferritin and transferrin in
the normal human brain
2.2.1. Iron
The heterogeneous distribution of iron in the brain was
first demonstrated by histochemical techniques (Prussian
blue or Perls stain), which showed intense staining of
ferric iron in parts of the extrapyramidal system, weaker
staining of the cerebral cortex and no detectable staining in
the white matter [110]. Gelman [55] comments that:
bRelative to the basal ganglia there is much less stainable
iron in the cerebral hemispheric white matter and cortex.Q
Using Perls stain, Drayer et al. [46] found no iron in the
most posterior portion of the internal capsule and optic
radiations, but more iron in frontal than occipital white
matter regions. They also found prominent iron levels in
the temporal lobe (the subcortical bU Q fibers).
Biochemical assays of postmortem brain tissue
[22,23,39,43,44,68,69,73,109,114] have since quantified
the amount of total iron in various brain regions,
confirming that the highest concentrations of iron (up to
200 Ag/g tissue wet weight) can be found in the globus
pallidus, red nucleus, substantia nigra and putamen regions
(Table 1). Contrary to the histochemical results, the
biochemical assays indicate that white matter, in general,
has similar levels of iron to cortical gray matter (typically
about 30 40 Ag/g tissue wet weight, see Table 1) and in
some regions (e.g., motor cortex) there may be more iron
in the white matter than in the adjacent cortical gray
matter [29].
The results from the biochemical determinations of
brain iron, which use a variety of analysis techniques
[atomic absorption spectrophotometry (AAS), inductively
coupled plasma spectroscopy (ICP), instrumental neutron
activation (INAA), colorimetry], are generally in good
agreement where it can be established a whole sample, as
opposed to the supernatant fraction of a homogenate, has
been used in the analysis. A factor that may also con-
tribute to the variability of iron measured is the prepara-
tion of the brain tissue. For example, prolonged immersion
in formalin leaches iron out of the tissue and this could
explain the low results of Thomas et al. [113]. Some
researchers [29,82] express the amount of iron in terms of
the protein content (see Table 1). While their results
cannot be directly compared to other groups [22,23,39,
43,44,68,69,73,109,114], the ratio of basal ganglia iron
to cortical iron (between 4:1 and 2:1) measured by Connor
et al. [29] and Loeffler et al. [82] is consistent with
these studies.
The landmark work of Hallgren and Sourander [69],
whose data still provide the largest quantitative survey of
brain iron content with age, indicates that iron typically
increases rapidly from birth until about 20 years of age for
nearly all brain regions. After this age, brain iron increases
less rapidly, and in some regions approaches a distinct
plateau in middle age.
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 3

Table 1
Iron concentrations in brain tissue
Brain Region Iron Ag Ratio to No. of Analysis Sample Ref. Reference
Fe/g ww GM cortex samples technique analyzed No.
Gray matter
Globus pallidus 213.0 4.2 55 Colorimetry Whole [69] Hallgren and Sourander (1958)
Globus pallidus 175.3 3.8 10 AAS Whole [22] Chen et al. (1989)
Globus pallidus 182.0 6 AAS Whole [23] Chen et al. (1993)
Globus pallidus lateral 159.4 24 ICP Whole [44] Dexter et al. (1991)
Globus pallidus lateral 207.0 6 AAS Whole [68] Griffiths and Crossman (1993)
Globus pallidus medial 141.2 23 ICP Whole [44] Dexter et al. (1991)
Globus pallidus medial 163.8 6 AAS Whole [68] Griffiths and Crossman (1993)
Globus pallidus total 300.6 5.0 23 ICP Whole [44] Dexter et al. (1991)
Globus pallidus total 370.8 7.4 6 AAS Whole [68] Griffiths and Crossman (1993)
Globus pallidus 108.0 4 AAS Uncertain [98] Riederer et al. (1989)
Globus pallidus 81.0 2.9 8 Colorimetry Supernatant [98] Riederer et al. (1989)
Substantia nigra 185.0 3.7 52 Colorimetry Whole [69] Hallgren and Sourander (1958)
Substantia nigra ZC 159.4 2.6 59 ICP Whole [44] Dexter et al. (1991)
Substantia nigra 139.8 2.8 6 AAS Whole [68] Griffiths and Crossman (1993)
Substantia nigra oral 65.0 4 AAS Uncertain [98] Riederer et al. (1989)
Substantia nigra caudal 45.0 4 AAS Uncertain [98] Riederer et al. (1989)
Substantia nigra 48.0 1.7 8 Colorimetry Supernatant [98] Riederer et al. (1989)
Substantia nigra ZC 63.0 9 Colorimetry Supernatant [109] Sofic et al. (1991)
Substantia nigra ZR 94.0 9 Colorimetry Supernatant [109] Sofic et al. (1991)
Substantia nigra ZC+ZR 157.0 9 Colorimetry Supernatant [109] Sofic et al. (1991)
Substantia nigra 84.0 6 Colorimetry Uncertain [113] Thomas et al. (1993)
Putamen 130.0 2.6 56 Colorimetry Whole [69] Hallgren and Sourander (1958)
Putamen 120.8 2.6 10 AAS Whole [22] Chen et al. (1989)
Putamen 110.0 6 AAS Whole [23] Chen et al. (1993)
Putamen 164.8 2.7 31 ICP Whole [44] Dexter et al. (1991)
Putamen 119.8 2.4 6 AAS Whole [68] Griffiths and Crossman (1993)
Putamen 76.0 4 AAS Uncertain [98] Riederer et al. (1989)
Putamen 96.0 3.4 8 Colorimetry Supernatant [98] Riederer et al. (1989)
Putamen 78.0 6 Colorimetry Uncertain [113] Thomas et al. (1993)
Caudate 93.0 1.8 58 Colorimetry Whole [69] Hallgren and Sourander (1958)
Caudate 115.6 2.2 4 INAA Whole [18] Brooks et al. (1989)
Caudate 92.5 2.0 10 AAS Whole [22] Chen et al. (1989)
Caudate 117.4 1.9 59 ICP Whole [44] Dexter et al. (1991)
Caudate 99.6 2.0 6 AAS Whole [68] Griffiths and Crossman (1993)
Caudate 76.0 4 AAS Uncertain [98] Riederer et al. (1989)
Caudate 56.0 6 Colorimetry Uncertain [113] Thomas et al. (1993)
Hippocampus 52.0 21 INAA Whole [39] Cornett et al. (1998)
Hippocampus 43.2 11 INAA Whole [43] Deibel et al. (1996)
Hippocampus 42.1 15 INAA Whole [114] Thompson et al. (1988)
Hippocampus 24.0 0.9 8 Colorimetry Supernatant [98] Riederer et al. (1989)
Amygdala 49.0 21 INAA Whole [39] Cornett et al. (1998)
Amygdala 48.6 11 INAA Whole [43] Deibel et al. (1996)
Amygdala 48.9 15 INAA Whole [114] Thompson et al. (1988)
Amygdala 20.0 4 AAS Uncertain [98] Riederer et al. (1989)
Parietal cortex 38.0 37 Colorimetry Whole [69] Hallgren and Sourander (1958)
Inferior parietal 56.0 21 INAA Whole [39] Cornett et al. (1998)
Inferior parietal 54.4 11 INAA Whole [43] Deibel et al. (1996)
Parietal cortex 30.2 6 AAS Whole [68] Griffiths and Crossman (1993)
Prefrontal cortex 29.2 52 Colorimetry Whole [69] Hallgren and Sourander (1958)
Frontal cortex 53.6 4 INAA Whole [18] Brooks et al. (1989)
Frontal lobe 46.0 10 AAS Whole [22] Chen et al. (1989)
Frontal cortex 52.0 21 INAA Whole [39] Cornett et al. (1998)
Frontal cortex 41.8 6 AAS Whole [68] Griffiths and Crossman (1993)
Temporal cortex 31.3 38 Colorimetry Whole [69] Hallgren and Sourander (1958)
Temporal pole 51.0 21 INAA Whole [39] Cornett et al. (1998)
Temporal gyrus 53.2 11 INAA Whole [43] Deibel et al. (1996)
Temporal cortex 50.1 6 AAS Whole [68] Griffiths and Crossman (1993)
Temporal cortex 28.0 8 Colorimetry Supernatant [98] Riederer et al. (1989)
Motor cortex 50.3 46 Colorimetry Whole [69] Hallgren and Sourander (1958)
Occipital cortex 45.5 38 Colorimetry Whole [69] Hallgren and Sourander (1958)
(continued on next page)
4 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25

Table 1 (continued)
Brain Region Iron Ag Ratio to No. of Analysis Sample Ref. Reference
Fe/g ww GM cortex samples technique analyzed No.
Gray matter
Cerebral cortex 60.4 58 ICP Whole [44] Dexter et al. (1991)
Cerebral cortex 60.0 6 PIXE Whole [73] Hebbrecht et al. (1999)

White matter
Frontal white matter 42.4 1.5 38 Colorimetry Whole [69] Hallgren and Sourander (1958)
Frontal lobe white 38.3 0.8 10 AAS Whole [22] Chen et al. (1989)
Optic radiation 35.8 0.8 10 AAS Whole [22] Chen et al. (1989)
Central white 30.2 4 INAA Whole [18] Brooks et al. (1989)
Cerebral white matter 35.0 0.6 6 PIXE Whole [73] Hebbrecht et al. (1999)
Corpus callosum 15.0 6 Colorimetry Uncertain [113] Thomas et al. (1993)

Brain Region Iron mg Ratio to No. of Analysis Sample Ref. Reference

Fe/g protein GM cortex samples technique analyzed No.
Gray matter a
Motor cortex 0.89 11 Colorimetry Uncertain [30] Connor et al. (1992)
Occipital cortex 1.12 11 Colorimetry Uncertain [30] Connor et al. (1992)
Superior temporal 0.70 11 Colorimetry Uncertain [30] Connor et al. (1992)
Parietal cortex 0.29 11 Colorimetry Whole [42] Dedman et al. (1992)
Substantia nigra 5.60 3.5 8 Colorimetry Supernatant [82] Loeffler et al. (1995)
Putamen 4.50 2.8 8 Colorimetry Supernatant [82] Loeffler et al. (1995)
Globus pallidus 4.00 2.5 8 Colorimetry Supernatant [82] Loeffler et al. (1995)
Caudate 3.20 2.0 8 Colorimetry Supernatant [82] Loeffler et al. (1995)
Frontal cortex 1.60 8 Colorimetry Supernatant [82] Loeffler et al. (1995)

White matter a
Motor cortex 1.26 1.4 11 Colorimetry Uncertain [30] Connor et al. (1992)
Occipital cortex 0.89 0.8 11 Colorimetry Uncertain [30] Connor et al. (1992)
Superior temporal 0.74 1.1 11 Colorimetry Uncertain [30] Connor et al. (1992)
GM, gray matter; PIXE, particle-induced X-ray emission; ZC, zona compacta; ZR, zona reticulata.
a
These results are quoted per gram of protein rather than per gram of tissue.

2.2.2. Ferritin suggests that transferrin may be more evenly distributed in

The few quantitative studies on ferritin [22,35,42,44,98]
in the human brain show considerable variation in the
amount of ferritin measured (Table 2). The results of Dexter
et al. [44] and Reiderer et al. [98] are similar, but they are
between 5 and 10 times lower than the concentrations
obtained by Connor et al. [29,35] and about 100 times
greater than the results of Chen et al. [22]. Some of this
discrepancy may result from the use of non-isoferritin-
specific polyclonal antibodies [44,98] that may have under-
estimated the ferritin concentration.
Despite these controversies, individual studies indicate
that ferritin distribution closely matches iron distribution with
concentrations in the basal ganglia two to three times greater
than in the cerebral cortex (Table 2). Ferritin levels in cortical
gray and adjacent white matter are also similar (Table 2). The
study by Connor et al. [35], which measured the amounts
of both the H-ferritin and L-ferritin isoforms, indicates that
H-ferritin is the dominant isoform in the brain and its con-
centration increases with age. In the elderly, the ratio of H to
L-ferritin is between 1.5:1 and 3:1 depending on the region.
2.2.3. Transferrin
Quantitative analyses measuring the regional distribution
of transferrin in the brain are rare [29,35]. One study [35]
gray matter, compared to ferritin and iron, with similar
levels in the cortex and basal ganglia (Table 2). However,
transferrin levels are typically between 10 and 50 times lower
than ferritin concentrations per unit of protein (Table 2).
White matter has about 2.53.5 times more transferrin than
the corresponding gray matter [29].
2.3. Cellular distribution of iron, ferritin and transferrin in
the normal human brain
Very early in iron research, iron deposits were ob-
served in oligodendroglia cells, endothelial cells of
capillaries and giant pyramidal (Betz) cells of the motor
cortex [110], but it is the oligodendrocytic cells, both in
gray and white matter, that stain most strongly for iron,
ferritin and transferrin [26]. Oligodendrocytes are common
in white matter, as these cells are responsible for producing
myelin, but iron-positive oligodendrocytes are also found
throughout the iron-rich basal ganglia [37]. In white
matter, iron-positive oligodendrocytes have a patchy
distribution [31].
Immunostaining [26] indicates that, in addition to
oligodendrocytes, microglia in the cerebral cortex and
astrocytes, particularly in the basal ganglia, also contain
ferritin. The two isoforms of ferritin appear to have different
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 5

Table 2
Ferritin and transferrin concentrations in brain tissue
Brain Region Ferritin Ag/g tissue ww Ratio to GM cortex No. of samples Samples Ref. No. Reference
Gray matter
Globus pallidus 1.6 0.5 10 Supernatant [22] Chen et al. (1989)
Globus pallidus 1440 2.5 8 Supernatant [35] Connor et al. (1995)
Globus pallidus medial 262 7.5 24 Supernatant [44] Dexter et al. (1991)
Globus pallidus lateral 250 26 Supernatant [44] Dexter et al. (1991)
Substantia nigra 1535 2.7 8 Supernatant [35] Connor et al. (1995)
Substantia nigra 292 8.3 17 Supernatant [44] Dexter et al. (1991)
Substantia nigra ZC 218 6.2 19 Supernatant [44] Dexter et al. (1991)
Substantia nigra 223 5 Uncertain [98] Riederer et al. (1989)
Putamen 1.9 0.7 10 Supernatant [22] Chen et al. (1989)
Putamen 1125 2.0 8 Supernatant [35] Connor et al. (1995)
Putamen 237 6.8 38 Supernatant [44] Dexter et al. (1991)
Putamen 240 5 Uncertain [98] Riederer et al. (1989)
Caudate nucleus 2.5 0.9 10 Supernatant [22] Chen et al. (1989)
Caudate nucleus 1080 1.9 8 Supernatant [35] Connor et al. (1995)
Caudate nucleus 168 4.8 62 Supernatant [44] Dexter et al. (1991)
Frontal lobe 2.91 10 Supernatant [22] Chen et al. (1989)
Frontal cortex 575 8 Supernatant [35] Connor et al. (1995)
Cerebral cortex 35 58 Supernatant [44] Dexter et al. (1991)

White matter
Frontal lobe 1.93 0.7 10 Supernatant [22] Chen et al. (1989)
Optic radiation 1.84 0.6 10 Supernatant [22] Chen et al. (1989)

Brain Region Ferritin ng/Ag protein Ratio to GM cortex No. of Samples Sample Ref. no. Reference
Gray matter
Globus pallidus 208 2.4 8 Supernatant [35] Connor et al. (1995)
Substantia nigra 132 1.5 8 Supernatant [35] Connor et al. (1995)
Putamen 121 1.4 8 Supernatant [35] Connor et al. (1995)
Caudate nucleus 131 1.5 8 Supernatant [35] Connor et al. (1995)
Frontal cortex 86 8 Supernatant [35] Connor et al. (1995)
Motor cortex 23 11 Supernatant [30] Connor et al. (1992)
Occipital cortex 34.5 11 Supernatant [30] Connor et al. (1992)
Superior temporal 25 11 Supernatant [30] Connor et al. (1992)
Parietal cortex 1.445 11 Supernatant [42] Dedman et al. (1992)

White matter
Motor cortex 22.5 1.0 11 Supernatant [30] Connor et al. (1992)
Occipital cortex 32 0.9 11 Supernatant [30] Connor et al. (1992)
Superior temporal 34 1.4 11 Supernatant [30] Connor et al. (1992)

Brain region Transferrin ng/Ag protein Ratio to GM cortex No. of samples Sample Ref. no. Reference
Gray matter
Globus pallidus 4.8 1.2 8 Supernatant [35] Connor et al. (1995)
Substantia nigra 3.4 0.9 8 Supernatant [35] Connor et al. (1995)
Putamen 4.4 1.1 8 Supernatant [35] Connor et al. (1995)
Caudate nucleus 4.4 1.1 8 Supernatant [35] Connor et al. (1995)
Frontal cortex 4.0 8 Supernatant [35] Connor et al. (1995)
Motor cortex 3.0 11 Supernatant [30] Connor et al. (1992)
Occipital cortex 1.8 11 Supernatant [30] Connor et al. (1992)
Superior temporal 1.0 11 Supernatant [30] Connor et al. (1992)

White matter
Motor cortex 7.4 2.5 11 Supernatant [30] Connor et al. (1992)
Occipital cortex 6.2 3.4 11 Supernatant [30] Connor et al. (1992)
Superior temporal 2.5 2.5 11 Supernatant [30] Connor et al. (1992)

cellular distributions in the brain related to iron utilization L-ferritin predominates in macrophages and microglia and
requirements [37]. H-ferritin is predominant in neurons, suggests that these cells are associated with long-term iron
favoring high iron uptake and exhibiting peroxidase activity. storage [10]. Oligodendrocytes have both isoforms of
 6
Table 3
Transverse relaxation times in brain tissue
Tissue T2 (ms) T2* (ms) T2V (ms) Subject B 0 field (T) Ref no. Reference
White matter 72F3.7 1.5 [47] Drayer et al. (1986)
~63 60 patients aged from newborn to 85 years, T2 decrease with age 1.5 [112] Taylor et al. (1991)
74.1F6.6 37-year-old volunteer 0.5 [154] Gomori and Grossman (1993)
77.5F7.2 2.0
69.00F2.7 Six subjects aged 2130 years 0.5 [4] Bartzokis et al. (1993)
64.29F1.8 1.5
76.3F6.2 18 healthy age-matched control subjects 1.5 [124] Vymazal et al. (1997)
81.3F7.8 Eight patients with multiple system atrophy 1.5
81.5F5.2 23 patients with PD 1.5
64.60F2.82 20 healthy adult male volunteers aged 2081 years 1.5 [8] Bartzokis et al. (1997)

E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25

70.92F3.73 0.5
63F14.8 19 patients, various echo sets 1.5 [182] Darwin et al. (1986)
61F16.3 1.5
68F16.6 1.5
72F6.9 Subgroup (13 of 19), various echo sets 1.5
70F8.0 1.5
77F8.6 1.5
75 Mean T2 of five healthy individuals 1.5
141 Posterior white matter, averaged from 151 volunteers aged 1.5 [181] Breger et al. (1991)
590 years
144 Anterior white matter, averaged from 151 volunteers aged 1.5
590 years
~63.370.4 13 normal adult male volunteers 0.5 [8] Bartzokis et al. (1997)
~59.9 658 1.5
78F11 Five subjects, four died from non-neurological cause, one 2.35 [18] Brooks et al. (1989)
from PD
94 Subject (among the five), died from PD 2.35
36F4 Five subjects, four died from non-neurological cause, one 8.5
from PD
40 Subject (among the five), died from PD 8.5
76.5F16.1 10 subjects, all were neurologically intact before death 1.5 [22] Chen et al. (1989)
~100113 Human subjects aged 1.3 45 years 1.5 [197] Ogg et al. (1997)
84F3 Frontal WM, eight normal adult volunteers 1.5 [209] Zhou et al. (2001)
83F3 Parietal WM, eight normal adult volunteers 1.5
87F3 Occipital WM, eight normal adult volunteers 1.5
55.8F3.9 285.4F112.0 Six healthy adults aged 19 42 years 3.0 [56] Gelman et al. (1999)
Gray matter 73F2.5 1.5 [47] Drayer et al. (1986)
65F14.6 19 patients, various echo sets 1.5 [182] Darwin et al. (1986)
61F16.8 1.5
69F17.8 1.5
73F5.7 Subgroup (13 of 19), various echo sets 1.5
72F6.6 1.5
79F11.3 1.5
76 Mean T2 of five healthy individuals 1.5
129.6F19.3 All subjects were neurologically intact before death 1.5 [22] Chen et al. (1989)
88F2 Frontal GM, eight normal adult volunteers 1.5 [211] Bakker et al. (2001)
 84F2 Parietal GM, eight normal adult volunteers 1.5
79F1 Occipital GM, eight normal adult volunteers 1.5
87.7F1.5 Two human volunteers, multi-echo BOLD imaging 0.5 [184] Gati et al. (1997)
69.4F2.4 Two human volunteers, multi-echo BOLD imaging 1.5
37.7F0.8 Eight human volunteers, multi-echo BOLD imaging 4.0
Caudate ~68 60 patients aged from newborn to 85 years 1.5 [112] Taylor et al. (1991)
87.0F5.3 37-year-old volunteer 0.5 [154] Gomori and Grossman (1993)
80.6F7.2 2.0
82.97F3.2 Six subjects aged 2130 years 0.5 [4] Bartzokis et al. (1993)
73.71F2.2 1.5
83.2F6.1 18 healthy age-matched control subjects 1.5 [124] Vymazal et al. (1997)
83.0F6.3 Eight patients with multiple system atrophy 1.5
85.1F6.8 23 patients with PD 1.5
65.88F3.03 20 healthy adult male volunteers aged 2081 years 1.5 [8] Bartzokis et al. (1997)

E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25

77.28F2.39 0.5
8384 Averaged from 151 volunteers aged 590 years 1.5 [181] Breger et al. (1991)
~71.481.3 13 normal adult male volunteers 0.5 [8] Bartzokis et al. (1997)
~60.672.5 1.5
71F13 Five subjects, four died from non-neurological cause, one from 2.35 [18] Brooks et al. (1989)
PD
82 Subject (among the five), died from PD 2.35
35F5 Five subjects, four died from non-neurological cause, one from 8.5
PD
36 Subject (among the five), died from PD 8.5
93.1F11.9 10 subjects, all were neurologically intact before death 1.5 [22] Chen et al. (1989)
59.3F4.2 151.1F31.6 Six healthy adults aged 1942 years 3.0 [56] Gelman et al. (1999)
Thalamus 73F2.2 1.5 [47] Drayer et al. (1986)
114.9F9.2 37-year-old volunteer 0.5 [154] Gomori and Grossman (1993)
153.8F21.3 2.0
86.6F3.4 18 healthy age-matched control subjects 1.5 [124] Vymazal et al. (1997)
85.9F5.4 Eight patients with multiple system atrophy 1.5
87.1F5.6 23 patients with PD 1.5
71F12.7 19 patients, various echo sets 1.5 [182] Darwin et al. (1986)
70F13.3 1.5
72F8.6 1.5
73F12.2 Subgroup (13 of 19), various echo sets 1.5
72F11.8 1.5
73F8.0 1.5
75 Mean T2 of five healthy individuals 1.5
55 Averaged from 151 volunteers aged 590 years 1.5 [181] Breger et al. (1991)
Substantia nigra ~55 60 patients aged from newborn to 85 years 1.5 [112] Taylor et al. (1991)
35.1F4.3 26.6F2.2 109.9F56.8a Seven age-matched normal controls 3.0 [94] Ordidge et al. (1994)
35.9F4.3 18.8F1.0 39.5F6.7a Four PD patients with normal T2 3.0
123F82 26.0F1.2 32.9F6.2a Three PD patients with abnormal T2 3.0
41.8F3.5 88.8F17.8 Six healthy adults aged 19 42 years 3.0 [56] Gelman et al. (1999)
36.5F7.2 26.7F2.5 99.0F54.9 Left substantia nigra, nine healthy controls 3.0 [18] Brooks et al. (1989)
32.2F4.4 26.7F2.5 158.7F118.4 Right substantia nigra, nine healthy controls 3.0
45.2F17.8 19.6F4.4 35.0F9.2 Left substantia nigra, 12 or 13 PD 3.0
43.3F16.5 18.6F3.6 33.2F8.8 Left substantia nigra, 12 or 13 PD 3.0
(continued on next page)

7
 8
E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
Table 3 (continued )
Tissue T2 (ms) T2* (ms) T2V (ms) Subject B 0 field (T) Ref no. Reference
Putamen 68F1.3 1.5 [47] Drayer et al. (1986)
~62 60 patients aged from newborn to 85 years 1.5 [112] Taylor et al. (1991)
79.07F2.1 Six subjects aged 2130 0.5 [4] Bartzokis et al. (1993)
69.09F2.5 1.5
77.3F4.7 18 healthy age-matched control subjects 1.5 [124] Vymazal et al. (1997)
76.1F7.5 Eight patients with multiple system atrophy 1.5
77.8F5.7 23 patients with PD 1.5
51.7F2.2 153.4F26.5 3.0 [56] Gelman et al. (1999)
63.65F3.38 20 healthy adult male volunteers aged 2081 years 1.5 [5] Bartzokis et al. (1994)
75.59F1.86 0.5
67F9.2 19 patients, various echo sets 1.5 [182] Darwin et al. (1986)
65F11.9 1.5
69F7.5 1.5
68F8.3 Subgroup (13 of 19), various echo sets 1.5
68F9.8 1.5
70F7.1 1.5
71 Mean T2 of five healthy individuals 1.5
5152 Averaged from 151 volunteers aged 590 years 1.5 [181] Breger et al. (1991)
~69.976.9 13 normal adult male volunteers 0.5 [8] Bartzokis et al. (1997)
~52.669.9 1.5
72.7F10.9 10 subjects, all were neurologically intact before death 1.5 [22] Chen et al. (1989)
Globus pallidus 60F2.5 1.5 [47] Drayer et al. (1986)
70.31F1.3 Six subjects aged 2130 0.5 [4] Bartzokis et al. (1993)
54.77F3.0 1.5
70.1F4.0 18 healthy age-matched control subjects 1.5 [124] Vymazal et al. (1997)
65.6F4.2 Eight patients with multiple system atrophy 1.5
70.9F6.1 23 patients with PD 1.5
38.8F1.6 85.1F13.6 3.0 [56] Gelman et al. (1999)
49.90F3.26 20 healthy adult male volunteers aged 2081 years 1.5 [8] Bartzokis et al. (1997)
67.75F2.97 0.5
 59F7.9 19 patients, various echo sets 1.5 [182] Darwin et al. (1986)
58F10.0 1.5
60F7.2 1.5
60F7.3 Subgroup (13 of 19), various echo sets 1.5
60F8.7 1.5
60F7.0 1.5
64 Mean T2 of five healthy individuals 1.5
~61.773.0 13 normal adult male volunteers 0.5 [8] Bartzokis et al. (1997)
~42.058.8 1.5
72.5 10 subjects, all were neurologically intact before death 1.5 [22] Chen et al. (1989)
~3663 12 Friedreichs ataxia patients, T2* decrease with age [203] Waldvogel et al. (1999)
~3367 23 normal controls, T2* decrease with age
~80 123 Human subjects aged 1.3 45 years 1.5 [197] Ogg (1997)
Red nucleus ~57 60 patients aged from newborn to 85 years 1.5 [112] Taylor et al. (1991)

E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25

45.8F4.2 96.7F24.2 Six healthy adults aged 19 42 years 3.0 [56] Gelman et al. (1999)
Cortex 93.5F7.5 18 healthy age-matched control subjects 1.5 [124] Vymazal et al. (1997)
106.8F9.0 Eight patients with multiple system atrophy 1.5
101.2F7.9 23 patients with PD 1.5
89F7 Five subjects, four died from non-neurological cause, one from 2.35 [18] Brooks et al. (1989)
PD
92 Subject (among the five), died from PD 2.35
42F3 Five subjects, four died from non-neurological cause, one from 8.5
PD
40 Subject (among the five), died from PD 8.5
Prefrontal cortex 70.7F10.4 317.7F102.0 Six healthy adults aged 19 42 years 3.0 [56] Gelman et al. (1999)
Frontal cortex ~112133 Human subjects aged 1.3 45 years old 1.5 [197] Ogg (1997)
Motor ~97123 Human subjects aged 1.3 45 years old 1.5 [197] Ogg (1997)
a
Recalculated from T2 and T2* from Ref. [94].

9
10 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
ferritin and the H-ferritin-stained cells have a similarly
patchy distribution in white matter [37].
As mentioned, transferrin is predominantly associated
with oligodendrocytes, but with ageing, astrocytes appear to
accumulate transferrin, particularly in white matter [26].
Neurons can also stain for transferrin, but the immunostain-
ing is inconsistent suggesting that transferrin is not common
to these cells. Interestingly, the distributions of transferrin
and ferritin/iron do not appear to overlap. This pattern is
particularly obvious in white matter where iron/ferritin have
a patchy distribution compared to the uniformity of
transferrin [26,28]. Another example of the nonoverlapping
distribution can be found in astrocytes, which tend to be
transferrin-positive in white matter, but ferritin-positive
almost exclusively in gray matter [26].
2.4. Brain iron changes associated with disease
Brain iron appears to be elevated in several neurodegen-
erative diseases. In PD, increased iron concentrations have
been detected in the substantia nigra [68,98] and globus
pallidus [23,44,68,82]. An increase in Fe(III) relative to
Fe(II) suggests that these changes might contribute to
pathophysiologic processes underlying PD [98,109]. Similar
effects have been seen in iron regulatory protein-2 knockout
mice [97]. Gerlach et al. [59] remark that there is an increase
in iron stores in the hippocampus in AD and PD, and the
entorhinal cortex and substantia inomminata are thought to
play an important role as markers for iron in AD [107,108].
More recent results suggest a shortening of T2 on MRI in
the entorhinal cortex [107,108], and the globus pallidus,
putamen and caudate [9] in AD. These MR observations are
consistent with postmortem biochemical studies, which
have measured excessive brain iron in cortical and basal
ganglia regions of the AD brain [29,39,43,82,114]. In HD,
one research group [23] reported a 50% increase in palladial
iron and a 150% increase in the putamen.
Multiple sclerosis plaques show globular structures of
nonheme iron on the periphery of older plaques [37].
Similar patterns have been reported for iron and beta-
amyloid plaques [61]. A robust ferritin immunoreaction
accompanies senile plaques and many blood vessels in the
Alzheimers brain tissue [28] and ferritin-containing cells
accumulate around the periphery of the core of the plaque.
In the hippocampal gray matter, ferritin is found with many
of the blood vessels. This suggests that increased iron in AD
patients may be related to blood escaping from the vessels
and into the tissue. The iron-containing cells that extend into
the cores of the plaques are thought to be microglia. The
cellular ferritin seen may, therefore, be due to the brains
attempt at detoxification of the extravasated free iron.
The recent discovery of linkage between a mutation in
an iron-storage protein and neuroferritinopathy, a rare,
dominantly inherited, adult-onset neurodegenerative disease
[41], suggests iron dysmetabolism can be a causal factor in
neurodegeneration and may not be just a secondary asso-
ciation. Hemochromatosis is a liver iron-overload disease
that may also result in excessive brain-iron accumulation
and potential vulnerability to brain dysfunction and demen-
tia [71,91]. Most people with hemochromatosis carry one or
more genetic mutations in the hemochromatosis (HFE)
gene. New evidence suggests that mutations in the HFE
gene also lead to greater risk, earlier onset or faster prog-
ression of AD or other dementias [87,101].
Brain iron is also known to increase in the basal ganglia
under ischemic or anoxic conditions. Dietrich and Bradley
[45] state that bafter anoxic ischemic damage normal axonal
transportation of brain iron can no longer occurQ and
badditional iron concentration may occur more rapidly due
to the direct injury by lipid peroxidation degradation
products catalyzed by iron.Q
3. MRI and the brain
In human brain, the MR signal is generated primarily by
water molecule protons. The image contrast arises from
variations in the proton density and the longitudinal (T1)
and transverse (T2) relaxation times of the associated
protons [104]. Relaxation times are determined by the
amount of tissue water, but also the microscopic and
macroscopic distribution of water in different sites, and
the macromolecular water interactions [192]. For example,
in pure water, T1 and T2 are similar, but in brain tissue, T1
is typically 1020 times longer than T2 because of the
strong magnetic interactions between the water protons
and proteins and other macromolecules [102]. Macromo-
lecular interactions, which involve even small concen-
trations of paramagnetic material (which is one whose
atoms have a permanent magnetic dipole moment) are
also important in determining relaxation times because of
the large magnetic moment these molecules have com-
pared to a proton (about 1000 times greater, Ref. [192]).
Ferritin and hemosiderin are considered to be the only
forms of nonheme iron present in sufficient quantities to
affect MR contrast in the human brain [104]. Early
biochemical analysis [69] suggested at least one third of
the nonheme iron in the brain was in the form of ferritin,
but concentrations can be much greater in iron-rich gray
matter [19]. For example, Mossbauer spectroscopy meas-
urements on monkey brains [123] indicate that at least 80%
of the nonheme iron in the globus pallidus is in a ferritin-like
form and Dedman et al. [42] suggest that 8588% of the
nonheme iron in the parietal cortex is located in ferritin. As
discussed above, transferrin concentrations in brain tissue
are at least 10 times lower than ferritin and it can only bind
two iron atoms compared to thousands of iron atoms within
each ferritin molecule. The concentrations of other iron
species, like free iron aqua ions, the labile iron pool, or non-
transferrin-bound iron are also considered to be too low to
affect MR contrast [104]. The human brain also contains
other paramagnetic ions, like copper and manganese, which
can potentially affect relaxivities if present in sufficient
quantities. Again, Schenck [104] suggests that nonpatho-
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
logical concentrations of copper and manganese are too
small to produce detectable MR contrast.
3.1. Relaxation mechanisms of ferritin
It has been well documented through in vitro studies that
paramagnetic iron will increase proton transverse relaxation
rates (R2 = 1/T2) and that the relaxation of solvent protons is
proportional to the concentration of paramagnetic ions.
[175]. While ferritin behaves like a simple paramagnetic
system at room temperature, in that magnetization is
proportional to applied field strength, the observed linear
dependence of R2 with field strength [123,126] is contrary
to the quadratic dependence predicted by relaxation due to
diffusion. In the outer sphere theory, protein-shielded
magnetic particles dephase the spins of diffusing water
protons increasing R2, but relaxation rates attributed to
ferritin are generally found to be too high to be explained by
simple paramagnetism. In fact, the ferrihydrite crystal
structure of ferritin is antiferromagnetic and, because of
the nanometric size of the grains, ferritin is also super-
paramagnetic. These unusual magnetic properties of ferritin
require a reconsideration of relaxation theories.
A new theory to explain the relaxation mechanism of
ferritin solutions has been proposed by Gossuin et al. [66].
Their proton-exchange dephasing model (PEDM) uses a
fast-exchange mechanism between two water fractions
(adsorbed protons, diffusing protons), each with their own
relaxation rate, to explain the relaxation rate of the whole
system. The PEDM is similar to the static field dephasing
model [170], which applies to R2*, but it also accounts for
irreversible dynamics that govern R2 [66].
4. Previous attempts to quantify brain iron using MRI
There are two critical questions to ask about iron from
the perspective of MRI:
1. bHow does it affect the signal of the tissue in which
it is embedded and the tissue around it via MR
relaxation mechanisms?Q
2. bWhat is its magnetic moment as determined by its
molecular environment?Q
The answers to these questions impact how we can
visualize the effects of iron in tissue. The former relates to
T1, T2 and diffusion effects, while the latter relates to
susceptibility effects and, therefore, to T2* and diffusion.
To date, a full theoretical description of observed iron
effects has not been forthcoming.
Since the mid-1980s, clinicians and researchers have
observed qualitative correlations between MRI signal
intensity and regions of the brain known to have high iron
concentrations. Typically, these high-iron regions, like the
globus pallidus, have a hypointense (dark) signature on T2-
weighted MR images. The presence of iron also leads to
signal changes (both magnitude and phase) in T2*-weighted
gradient echo images and to signal changes in diffusion-
11
weighted spin echo images. Ferritin has a weaker effect on
T1 relaxation, but the resulting reduction in T1 times can
produce hyperintensity on T1-weighted images [92,121].
However, quantitative studies to verify the relationship
between a range of MRI parameters R2, R2*, R2V= R2*-R2,
phase images and brain-iron concentration have not
universally agreed on the strength of the correlation (e.g.,
between R2 and iron) or the most appropriate parameter to
use. The current literature results for T2, T2* and T2V in
the brain are given in Tables 3 and 4, and the relationship
between brain iron and various MRI parameters is
summarized in Table 5. Several studies have observed
T1 effects as a function of iron content [57,92,120,123]
and these results are also presented in Table 5.
4.1. R2 and brain iron
Both in vitro [22,123] and in vivo [5,6,9,56,84,102,
125,155] data on healthy subjects show strong linear
correlations between R2 in gray matter regions and iron
concentrations derived from the literature [69] or measured
directly from the tissue sample (Table 5). Schenker et al.
[105] also demonstrate that the correlation between R2 and
age in healthy subjects follows the same relationship to that
of iron and age. However, opinions on the correlation
between R2 and iron diverge when gray and white matter
regions are considered together in healthy adults (see, e.g.,
[18,22] or when certain neurodegenerative diseases (HD,
PD, AD) are considered [5,6,9,23,64,94].
These discrepancies arise because, although R2 is
strongly affected by iron concentration, the water content
of brain tissue also influences R2. On average, there is a
12% difference in water content between white matter
(roughly 72%), with its high lipid content, and gray matter
(roughly 84%) [12,111,116]. The lower water content
results in a higher R2 value in white matter tissue com-
pared to gray matter regions with the same iron concen-
tration and could explain why some studies [22] did not
obtain a strong correlation with iron. The observation by
Curnes et al. [40] that the heavily myelinated compact fiber
pathways, such as the anterior commissure, the internal
capsule and the fornix, show prominent signal decreases on
T2-weighted images is consistent with the low-water, high-
protein content of these typically iron-poor (Table 3)
regions. Furthermore, Whittall et al. [127] have measured
a short T2 component (15 ms compared to more typical
50- to 150-ms range) in brain tissue attributed to water
compartmentalization in myelin membranes, termed myelin
water. Their research indicates that white matter contains on
average 11% of the short-T2 myelin water compared to 3%
in gray matter. In diseased brain tissue (substantia nigra in
PD, putamen in HD) the neuron loss is likely to increase
local water content (e.g., from reduction in lipids), decreas-
ing R2, opposing and potentially reducing the effect of iron.
To overcome the limitations of R2 in disease, the
Bartzokis group adopted the field-dependent rate increase
(FDRI) technique [46,8,9], which measures the difference
12 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25

Table 4
Transverse relaxation values of liver
Tissue T2 (ms) T2* (ms) T2V (ms) Subject B 0 field (T) Ref. no. Reference
Liver 4.4 41.2 14 thalassemia patients, 1.5 [137] Fenzi et al. (2001)
0.23237.15 mg Fe/g dry tissue
39.1F6.4 Four normal control subjects 1.5
12.7F0.5 One liver iron-overloaded patient 1.5 [135] Clark and
St. Pierre (2000)
45.5F2.5 11 health control subjects 0.5 [200] Pardoe et al. (2003)
36.9F5.4 Eight patients with grade 1 of 0.5
siderosis
26.6F1.5 Five patients with grade 2 of 0.5
siderosis
22.9F3.6 10 patients with grade 3 of 0.5
siderosis
15.6F2.7 Eight patients with grade 4 of 0.5
siderosis
33.5F8.1 10 normal control subjects Picker Edge, 1.5 [207] Westwood
et al. (2003)
~230 25 patients with beta-thalassemia Picker Edge, 1.5
major
23.5F3.6 10 normal control subjects Siemens Sonata, 1.5
~227 25 patients with beta-thalassemia Siemens Sonata, 1.5
major
33F7 15 normal control subjects Picker Edge, 1.5
~223 30 beta-thalassemic patients, Picker Edge, 1.5 [1] Anderson
226 mg/g dry weight et al. (2001)

in R2 at 1.5 and 0.5 T and is claimed to be a specific
measure of ferritin content [4]. The Bartzokis group has
consistently reported higher FDRI values in the basal
ganglia region of AD and PD brains, which are significantly
different (statistically) to healthy controls [5,6,9]. The
correlation between the FDRI and iron concentration in
healthy adults is also strong (Table 5).
4.2. R2V, phase, T2* and brain iron
The anomalous recovery of signal (R2-reduction pheno-
mena) caused by water changes in diseased tissue, despite
a local increase in iron, has led researchers to investigate
other MR protocols and parameters to quantify brain iron. A
number of researchers [56,64,94,155] suggest that the key
information for quantifying brain iron lies in R2V (those
signal changes caused by local susceptibility) not R2.
Ordidge et al. [94] developed a method to measure R2V
despite the presence of background field variations that
dephase the signal and would otherwise yield a falsely high
value for R2V. Ordidge et al. [94] measured significant
increases in R2V, but not R2 (typically reduced), in the
substantia nigra of PD patients, consistent with several
postmortem studies [44,68,98,109] on PD that have mea-
sured elevated levels of iron in the substantia nigral region.
Graham et al. [155] and Gorell et al. [64] confirmed that R2V
is increased in the substantia nigra of PD patients in
subsequent studies. The data from Graham et al. [155] and
Gelman et al. [56] also demonstrate that R2V strongly
correlates to brain iron concentrations (Table 5).
We have shown that phase and iron content correlate
with age [92,93]. Ordidge et al. [94] and Gorell et al.
[64] have shown that R2V has the best correlation with
iron in the substantia nigra of PD patients and we agree
with this assertion.
There has also been some high-field work [61] that
uses T2* measurements to investigate brain iron in the
mouse lemur. Gilissen et al. [61] have a well- established
primate model which presents the neuropathological hall-
marks of AD, both senile plaques and neurofibrillary tangles.
They use a 3D gradient echo structure with a TE = 9 ms at a
field strength of 11.7 T (almost exactly the equivalent of
what we use at 1.5 T for the best phase contrast images, but
we use a TE of 80 ms in that case). They observe comparable
MR contrast (hypointense signal) resulting from the iron
content in the basal forebrain cholinergic structures, such
as the basalis of Meynert, and also in the globus pallidus,
which is consistent with their histochemistry. However,
T2* has its own difficulties related to other local
background sources of magnetic field variation that cause
signal loss unrelated to the internal iron content of the
tissue [165].
4.3. New developments
More recently, two groups have developed a theory of
spin dephasing in the static or slow diffusion regime [170]
and in the fast diffusion regime [160]. Our theory directly
suggests a means by which the source of the susceptibility
can be quantified through its magnetic moment and volume
content [164,167]. This unique and exciting feature has
been considered when evaluating parallel fibers [171] and
to measure oxygen content in the brain either directly in
vessels [158] or in tissue [175177].
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 13

Table 5
Tissue parameter variation as a function of iron content
Field Tissue type MRI Slope (s
1/mg Intercept R corr. No. of Age [range Ref. Reference
strength (T) (no. regions) parameter Fe/g ww) (s
1) coeff. samples (mean)] no.
In vitro
1.5 GM (4) R2 23.5 .77 24 23 63 [123] Vymazal et al. (1996)
1.5 GM+WM (6) R2 20.8 10.1 .50 10 183 (45) [22] Chen et al. (1989)
1.5 GM (4) R2 48.9 6.3 .91 10 183 (45) [22] Chen et al. (1989)
1.45 GM (4) R1 2.2 .43 12 23 63 [123] Vymazal et al. (1996)

In vivo
0.5 GM (4) R2 19.8 31 555 (30) [120] Vymazal et al. (1995)
1.5 GM+WM (5) R2 16.3 13.0 .98 13 16 63 [47] Drayer et al. (1986)
1.5 GM (5) R2 17.1 10.2 .97 58 8 4 (24) [84] Metafrazi et al. (2001)
1.5 GM (5) R2 17.3 14.5 .85 10 2258 [102] Schenk (1995)
1.5 GM (7) R2 18.9 10.3 .83 18 4774 (62) [125] Vymazal et al. (1999)
1.5 GM+WM (5) R2 23.1 10.7 .90 13 (64) [155] Graham et al. (2000)
1.5 GM+WM (4) R2 23.6 14.1 .96 68 5982 (69) [7] Bartzokis and Tishler (2000)
1.5 GM+WM (4) R2 28.4 13.3 .90 12 (64) [6] Bartzokis et al. (1999)
1.5 GM+WM (4) R2 29.2 13.2 .94 6 6881 (72) [5] Bartzokis et al. (1994)
1.5 GM (4) R2 40.1 48 555 (30) [120] Vymazal et al. (1995)
3.0 GM+WM (7) R2 61 12.7 .92 6 19 42 (30) [56] Gelman et al. (1999)
4.0 GM (5) R2 43.6 22.2 .70 10 2258 [102] Schenk (1995)
1.5 GM+WM (5) R2* 67.3 9.8 .98 13 (64) [155] Graham et al. (2000)
1.5 GM+WM (5) R2V 45.6
1.1 .99 13 (64) [155] Graham et al. (2000)
3.0 GM+WM (7) R2V 50 2.2 .90 6 19 42 (30) [56] Gelman et al. (1999)
1.5/0.5 GM+WM (4) FDRI 24.2 0.30 .98 6 6881 (72) [5] Bartzokis et al. (1994)
1.5/0.5 GM+WM (4) FDRI 22.4 0.08 .93 12 (64) [6] Bartzokis et al. (1999)
1.5/0.5 GM+WM (4) FDRI 18.4 0.70 .99 68 5982 (69) [7] Bartzokis and Tishler (2000)
1.5 GM (5) phase (deg)
1.4
0.70 .85 18 1 45 (15) [93] Ogg et al. (1999)
0.5 GM (4) R1 2.5 26 555 (30) [120] Vymazal et al. (1995)
1.5 GM (5) R1 2.3 0.74 .81 10 2258 (39) [102] Schenk (1995)
1.5 GM (3) R1 2.4 0.83 .76 115 4.572 (26) [92] Ogg and Steen (1998)
1.5 GM (7) R1 2.7 0.65 .88 18 4774 (62) [125] Vymazal et al. (1999)
1.5 GM (4) R1 2.8 53 555 (30) [120] Vymazal et al. (1995)
4.0 GM (5) R1 2.3 0.45 .75 10 2258 (39) [102] Schenk(1995)

A new approach in MR imaging referred to as
susceptibility-weighted imaging (SWI) also offers a means
to quantify iron content differences between tissues in the
brain. This approach [164,167] uses local phase differences
to map the iron. Its predictions could be used to validate the
results from the previous static dephasing regime approach
or at least demonstrate a consistency in the MR approach.
In summary, R2V is from static field dephasing and
although it is well known that R2 also depends on iron
concentration, R2V is more powerful because of its far-
reaching effects from the local fields it produces. Unfortu-
nately, both R1 and R2 can be reversible depending on the
water content and other local structural changes that can
affect relaxation times. In these cases, the effect of iron
remains invisible. However, this is not true for R2V (as
discussed above) or phase. Therefore, we believe that phase
and R2V will be the strongest and most accurate means to
map iron content, while R1 and R2 will still play impor-
tant complementary roles.
A further complication relates to tissue geometry. It is
well known that the shape and distribution of the source of
magnetization change the response of the field. How this
takes place in objects as complicated as human tissue,
whether it be in the brain or liver, remains unanswered and
is critical to an absolute quantification of body iron.
5. New directions in MRI methodology
5.1. High-resolution 3D, gradient echo imaging
5.1.1. Magnitude imaging
Obtaining a sensitivity to small local field susceptibility
effects requires imaging with long echo times or at high
fields. Unfortunately, there are background field effects
caused by airtissue interfaces and these lead to dramatic
signal losses in tissues adjacent to these areas for long
echo times. We have previously shown that dephasing
across a voxel can be reduced by using very small voxels
so that the phase variation from background (or other)
fields is reduced to less than 2p across the voxel [165].
Measuring T2* properly means eliminating all other
sources of background error, no simple task. If there is
time to do a high-resolution multi-echo scan, then this is
the best way to both reduce dephasing and to be able to
predict any remnant dephasing once the local phase
information is available.
14 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
We have collected some example data at both 1.5T and
4.0T to illustrate the information content in a T2* image.
The values for T2* for white matter and gray matter (motor
cortex) are roughly as follows: 70 and 60 ms at 1.5T and
60 and 40 ms at 4T. The presence of iron in gray matter
would tend to reduce the T2 of gray matter faster than that
of white matter. Now, using R2* = R2o+kB 0, we find
R241:5 T R2o R2V R2 o 1:5k 1
R244:0 T R2o R2V R2 o 4:0k 2
where k is a constant independent of the field strength. First,
we take R2o to be 10/s and since T2* at 1.5 T for gray
matter is 6070 ms, R2V will be 4.3/s
6.7/s. Next,
multiplying R2V by 8/3 predicts R2V to be 11.5/s to 17.9/s,
and R2* = 21.5/s to 27.9/s at 4 T. Therefore, T2* is
predicted to be 36 47 ms. Now R2o likely decreases a
bit at higher fields which would predict an even lower T2*
at 4 T than those results predicted here. Still, the fact that
these T2* values are actually in the range of what is seen
for most gray matter at 4 T is rather encouraging (T2* is
quoted as being 38 ms for gray matter at 4 T [184], a value
that our own measurements also find for the motor cortex).
The fact that white matter now has a higher T2* than gray
matter again suggests that iron content in the gray matter is
higher than that in the white matter, in agreement with our
interpretation of the phase images.
5.1.2. Phase imaging
The use of phase images is a natural way to begin
evaluating the presence of paramagnetic (or diamagnetic)
differences between tissues in the brain. The phase in an MR
image is given by
u
cDBt 3
where c is the gyromagnetic ratio, DB is the induced
magnetic field in one tissue and t is the time at which the
data are measured (usually the echo time TE from a gra-
dient echo sequence). The problem with visualizing these
differences comes from the extra phase effects from a
poorly shimmed field or background field effects from air/
tissue interfaces, all of which lead to unwanted phase
information. We developed a high-pass phase filter to re-
move these low spatial frequency effects [164,167].
Phase imaging has been successfully used to map oxy-
gen saturation in the brain and even small changes in
oxygen saturation during functional brain activation [158].
To measure oxygen saturation at 1.5 T with an echo time of
40 ms required measuring a susceptibility on the order of
0.4 ppm (in SI units). To measure the changes in oxygen
saturation during a functional brain imaging experiment
required measuring a susceptibility on the order of 0.12 ppm
(in SI units). To do this with any confidence requires an
error that is significantly less than the measurement of
interest. We find that the error in measuring the phase of a
vessel parallel to the field when the SNR in the image is
15:1 is 3*0.004 ppm (where the term 0.004 ppm is the
error for the bulk phase measurement itself when geometry
does not play a role) for the particular 3D sequence used for
those experiments. This implies that for a P value of .025,
we can assert that susceptibility differences as small as
0.024 ppm (for blood) or 0.008 ppm (for bulk phase) would
be measurable with this sequence at 1.5 T (the sequence
used was a 5-min, 3D gradient echo method with a TE = 40
ms and a resolution of 0.51.0 2.0 mm3). Figs. 13
illustrate the information available in phase images. Fig. 1
shows the differences in gray matter and white matter.
Fig. 2 shows more structures such as veins and the globus
pallidus. Fig. 3 shows the variability of the phase (and hence
the iron content) in the putamen and globus pallidus.
We have collected phase images at 40, 80 and as long as
120 ms at 1.5 T in 1995 [157] and shown that phase images
represent a means to visualize susceptibility differences
between tissues while still maintaining high-quality magni-
tude images. It was obvious at that time that venous
structures, gray matter/white matter susceptibility differ-
ences and some form of iron in the basal ganglia were
visible. Imaging at higher field strengths, such as 3, 4 and
7 T will give the potential to reduce these echo times or to
increase the sensitivity of the scans.
Using the above approach, we demonstrated on a series of
volunteers the correlation of phase with age [93]. We also
showed that T1 in the regions of increased phase decreased
[92]. This makes a strong connection to the iron content
because iron acts like a paramagnetic contrast agent. We
show in Fig. 1 an example phase image and the corres-
ponding T1-weighted magnitude image. Clearly, the regions
of high phase (iron) contrast correlate with the regions of
lowest T1 contrast (see arrows), as expected from the re-
duction in T1 that iron causes in those tissues. The central
sulcus particularly has a high iron content and therefore
Fig. 1. A comparison of a TE = 40 ms phase image (left-hand image) at 1.5
T with a T1-weighted short TR, short TE (5 ms) image (right-hand image).
The short arrows show the frontal gray matter that has poor phase contrast
but good T1 contrast. The long arrows show the motor cortex region with
excellent phase contrast but poor white matter/gray matter contrast. This is
in line with expectations that an increase in iron content leads to a decrease
in T1 for the gray matter in that area. Similar contrast to this is seen in other
structures as well such as the dentate nucleus.
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 15

show an enhancement in the basal ganglia because of the

Fig. 2. A phase image with a TE = 40 ms at 1.5 T. The different types of
available contrast are labeled for a number of structures.
should show the poorest contrast on the T1-weighted image,
and it does. However, there is a potential confounding
problem. Gelman et al. [57] suggests that water content
correlates better with T1 content than iron. Clearly, there is
more detective work to be done to determine if the source
is iron or water.
Finally, we note that the use of the phase images as a mask
to enhance the magnitude image to improve the visualization
of iron content has been proposed and is referred to as SWI
[164]. It is well known that T2-weighted images already
presence of iron, and this is also seen even in spin echo
images. However, using SWI, the contrast is significantly
enhanced because of the presence of a phase difference
between those tissues with iron and those without. One could
well imagine the phase image being used to enhance the
motor cortex gray matter in the images in Fig. 1.
5.2. Measuring susceptibility differences between
macroscopic objects
As discussed above, the complex images acquired in
MR lead to both magnitude and phase images. One
fascinating element of the phase images is that they give
a mapping of the field changes independent of the
magnitude response. As such, they are a robust means to
measure local changes in susceptibility. The usual approach
is to try and measure the field outside of, say, a cylinder or
an object that has a known external field behavior with
distance. Two such cases are spheres or cylinders, both
having relatively simple dipole solutions. The problem
occurs when there are many objects in an image all having
different susceptibilities. The ideal solution would be to
have a method that fits the most general phase response to a
set of shapes. In a sense, the work of Salomir et al. [230]
does just that. They show that, given a particular suscep-
tibility distribution, the resultant field perturbations and,

Fig. 3. Two phase images of the putamen and globus pallidus (A, B) from two different people with TE = 40 ms at 1.5 T. The different contrasts in the putamen
and globus pallidus reflect different iron content for the two individuals. It is important to realize that iron may vary significantly from region to region even
within a given structure. Two phase images from two different subjects show the red nucleus (see arrow in image C) and substantia nigra. Both the substantia
nigra (long arrow in image D) and crus cerebri (short arrow in image D) are visible in these images.
16 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
hence, phase can be calculated. They do this by the
following transformation of the susceptibility distribution:


1 k2
u
c4B0 4TE4FT
1
z2 4FT v Distribution
3 K
4 v FT
where FT
1 refers to the process of inverse Fourier
transform, FT to Fourier transform, k z to the z component
of k-space and K 2 = k x2+k y2+k z2. The amazing element of this
transformation is that it appears to require no a priori
knowledge of the shape of the object (although we have
shown that it begins to break down by more than a few
percentage for objects that become larger than one quarter of
the field of view). Now, if an inverse relation between
susceptibility and phase could be obtained, that is, if it
were possible to predict the susceptibility distribution from
phase images, it would be of great scientific and clinical
significance. For example, in quantifying iron deposits in
the body, removal of susceptibility artifacts in SWI, EPI
and other gradient echo sequences using long TE is
critical. The ability to produce a susceptibility map itself
is tantamount to solving the question of iron quantifica-
Fig. 4. The original phase image (A) is used as input to obtain the susceptibility map (B). The phase profile (C) and its remapped form to a v map (D) illustrate
the potential of the method.
tion once either the magnet moment or volume content of
the susceptibility-producing source is known. A crude but
straightforward approach to predict the susceptibility map
is given by the inverse of the above filter in Eq. (4):
" !#



1 u 1
FT 4 kz2
5

c4B0 4TE 1
3
K2
Clearly, the method fails at the poles of the k-space
filter 1/[(1/3)
(k z2/K 2)]. To avoid division by 0, the value
of the filter is forced to 0 at its poles. In practice, because
of the discrete values of k taken in the matrix implemen-
tation, the poles are not encountered. The result of such a
calculation for a phase image of a cylinder perpendicular to
the main magnetic field, having a susceptibility value
inside of v i =1 ppm and 0 outside, and with a TE of 15 ms,
is shown below in Fig. 4. This method is tantamount to
fitting the phase profile when the object is known but
avoids the need to know anything about the object.
5.3. The use of complex analysis to measure the product of
volume fraction and susceptibility
With the ability of obtaining non-obscured phase images,
the next goal is to quantify the susceptibilities of tissues from
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 17

images. For example, we are developing a complex sum
method when an infinitely long cylindrical object is imaged.
If we draw a coaxial cylinder volume around the object,
not only we can sum the complex MR signals enclosed by
this cylinder (that we draw), but also we can theoretically
calculate the total complex MR signal inside it as a
function of susceptibility difference, volume fraction, spin
densities and other appropriate imaging parameters. If the
susceptibility difference is the only unknown parameter,
then it can be found through comparing the theoretical
calculation to the complex sum of the MR signals.
In order to demonstrate this concept, we have done the
following simulations. On a magnitude image, we consider
a disk (which is the cross section of an infinitely long
cylinder) with a radius of 20 pixels and no spin density inside
the disk and unity spin density outside the disk. On its asso-
ciated phase image, assuming that the cylinder is per-
pendicular to the main field and the region outside the disk
has a constant susceptibility, the phase is then distributed as
shown by Haacke et al. [225]. In this simulation, we have
modeled a susceptibility of
9 ppm outside the disk with a
field strength of 1.5 T and an echo time of 5 ms. Now we
draw a concentric circle around the disk. The theoretical sum
of the signal is:
Z 1
dz
c  changed accordingly. For example, if the product of the
SComplexSum pR2 q0 k 2
J 0 pd dDvd zdsin 2
hdB0dTE ;
k z 2p
6 of susceptibility discussed here.
where R is the radius of the circle, q 0 is the spin density, k
is the volume fraction which is the ratio of the disk area to
the area within the circle, J 0 is the Bessel function, c is
the gyromagnetic ratio, Dv is the susceptibility difference
inside and outside the disk, h is the angle between the
cylinder and the main field, B 0 is the main field and TE
is the echo time. This equation is a rearranged version of
Eq. 1 of Cheng and Haacke [149]. By changing the
radius of the circle from 60 to 200 pixels, we can obtain
different values of the object susceptibility outside the
disk and use these values to calculate the susceptibility.
This approach yields a susceptibility of
9.02F0.01 ppm.
The numerical error is likely due to the discretization of
the simulated disk.
Next, we consider a uniform but unknown spin density
of the object in our simulation. In this case, we will need to
draw two circles (see Fig. 5), use the above equation twice
for two different volume fractions and then numerically
solve the susceptibility of the object outside the disk. We
can again generate different susceptibilities by varying the
radii of circles. Doing so yields a susceptibility of

9.03F0.01 ppm. However, we have found that when the
small circle is smaller than two times the disk radius, we
may not be able to obtain an accurate susceptibility of the
object. This is due to the oscillatory nature of the Bessel
function in the equation. In this case, the correct suscepti-
bility can still be obtained from the theory if a rough value
of the susceptibility is known when solving the equation. It
is also important to note that when the product of the echo
time and the susceptibility differs from our numbers here,
the above findings of the circle radii may have to be
susceptibility and echo time becomes too small, then the
equation we intend to solve becomes insensitive to the range
The complex sum method potentially offers a lower
noise from the data analysis. Instead of a least-squared
fitting of several data points to obtain the susceptibility,
using a complex sum of the signal within a specified
region gives us a reliable susceptibility with a low noise
thanks to the average over many points. Furthermore, the
partial volume effect is taken care of naturally by the

Fig. 5. (A) The simulated magnitude image. The black disk refers to a region with no spin density and the white region represents a region with a uniform spin
density. (B) The associated simulated phase image. The susceptibility used in the simulation outside the disk is
9 ppm.
18 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
complex sum method. Such a feature can become a power-
ful basis for quantifying ferritin or iron imbedded inside
the brain.
5.4. Extraction of susceptibility using a special spin
echo/gradient echo imaging method
In an attempt to quantify signal losses in T2*-weighted
imaging, we developed a theory that makes it possible to
predict signal behavior in the presence of small randomly
distributed local sources of susceptibility change. Specif-
ically, we showed that the signal change is not exponential
in nature near the time origin and is exponential in the
intermediate (and long) time domains [170,222]. The
theory can be used to extract the volume susceptibility of
the random sources as well as their volume fraction within
a voxel. The exact quantitative nature of this method has
not yet been validated for a set of random structures in
vivo but rather only via Monte Carlo approaches.
In order to account for background field inhomogeneities
across a slice or voxel that are not caused by these micro-
scopic effects, and to eliminate any dependence on the rf
pulse shape, we and others have designed special combined
gradient echo and spin echo acquisition methods [169,177].
A series of gradient echoes are collected around the spin
echo and used to remove background field effects as
follows. The last gradient echo is divided by the first gra-
dient echo image to create the equivalent of a T2-weighted
image without dephasing across the voxel. Once T2 is
known, its effect on the multiple gradient echoes is removed
so that only the pristine changes due to T2V (those signal
changes caused by the local sources of susceptibility)
remain. The signal dependence can be shown to have a
quadratic behavior in time and, when fit, both the magnetic
moment and volume content of the sources can be
extracted quantitatively. In fact, it has already been shown
by Ordidge et al. [94] that T2V is the most sensitive of the
methods to the presence of iron in the study of iron build-
up in the substantia nigra in PD. Unfortunately, their
method to measure T2V is a multistep approach, whereas
our method allows extraction of all parameters in a single
experiment in a single sitting. A similar method using the
free induction decay signal rather than the gradient echo
information after the spin echo has been proposed by Ma
and Wehrli [161]. The latter method has some dependence
on the ability of the 1808 pulse to not introduce scale
changes, whereas the method we propose has no such de-
pendence since all the data are collected after the refo-
cusing pulse.
It is possible from the theory of static field dephasing to
extract the absolute iron content and volume of iron in a
voxel. Practically, however, it is usually just the product of
these two that can be found with any accuracy. We have
both theoretically predicted, and experimentally verified,
the following theory [166,170]. The signal behavior for a
random set of spheres of volume k (this is an excellent
approximation for iron, which is known to conglomerate in
spherical shapes, especially given the large voxels we are
using) is given by:
S t q1
kexp
0:41tdx2 for tdx b1:5 and
7
S t q1
kexp
itDxexp
R2Vjt
ts j
8
for tdx N1:5
where dx =c4p(M
M o)/3, R2V=1.21kdx, t s = 1/(1.21dx)
and Dx =
0.16kdx. Note that the early signal can be seen
to be Gaussian in nature while the signal at longer times is
Lorentzian. By measuring the short-time and long-time
components, we can get a numerical estimate for the
arguments in each exponential and, therefore, for (M
M o)
(extracted from dx) and for k (extracted from R2V since dx
is now known). When the susceptibility is known, R2V can
be used directly as a measure of the volume fraction k.
For much smaller susceptibilities on the order of parts
per million, such as diamagnetic or paramagnetic substances,
then 1/dx is on the order of several dozen ms. For example,
for a vein with a hematocrit of 0.4 and oxygen saturation
of 55%, the value of dx is about 54 Hz at 1.5 T.
Ironically, the smaller the susceptibility, the longer 1/dx
and the easier it is to measure. By measuring the signal
say up to 100 ms around the spin echo would allow these
unknown parameters to be fit to extract the volume
content and the susceptibility of the source producing the
signal loss.
5.5. Separating heme from nonheme iron
Given the numerous ambiguities discussed in this paper,
it is not clear how much of the phase effects seen in the
gradient echo images comes from nonheme iron and how
much comes from the blood or heme iron. To investigate
this, one might inject a known quantity of contrast agent
(the conventional gadolinium-based contrast agents have a
phase effect of 18 mM
1 ms
1) to mimic the susceptibility
of blood [159,167]. By doubling the effect of blood, it
would be possible to obtain an estimate as to what the
effect the blood itself has on the phase. Other types of
contrast agents could be used to change local blood flow
and local de-oxyhemoglobin to look again for changes in the
phase caused by heme iron. This could be accomplished by
breathing carbogen or ingesting caffeine for example. Any
other means of affecting the local blood signal would also
work such as saturating the signal from the blood to see
if that affects the local phase.
Then there is the issue of resolution and scale depen-
dence. If some phase effects come from major vessels they
will manifest themselves differently for different resolu-
tions. Uniformly distributed sources of susceptibility will
usually be invariant to resolution. Any changes to the
phase of the image in the parenchyma or in the critical
time 1/dx will be a marker of the bloods contribution
since the iron is assumed to be uniformly distributed at
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 19

these scales. The results of any such experiments would
then show what the fractional role of heme iron is in MRI
experiments. If heme iron has little contribution, then any
variations in phase can be assumed to be linearly related to
the iron content. If this is not the case, then the
relationship between phase and T2*, for example, may
still be linear with iron concentration but will have an
offset related to the heme iron component. These contrast
and phase issues remain open areas of research.
6. Conclusion
The ability to measure accurately brain iron using MRI
is still evolving. The motivation is to be able to predict
dangerous levels of iron in tissue. This may have other
important applications in the future with the advent of new
iron chelation drugs [106]. These drugs make it possible to
remove iron from ferritin and low-molecular-weight com-
plexes. An equally exciting application is the ability to
quantify iron to determine how much of a specific iron-
based contrast agent reaches a certain target. Quantification
of iron would also be important for detecting targeted
contrast agents [232241].
exponential growth by design and was fit for different
regions as follows:
Frontal white matter y 3:95f1
exp
0:10xg 0:31
Globus pallidus y 21:41f1
exp
0:09xg 0:37
Cerebellar cortex y 2:70f1
exp
0:085xg 0:68
Prefrontal cortex y 2:43f1
exp
0:07xg 0:58
Temporal cortex y 2:70f10
exp
0:07xg 0:55
Sensory cortex y 3:97f1
exp
0:07xg 0:49
Parietal cortex y 3:311
exp
0:06x 0:60
Occipital cortex y 4:03f1
exp
0:06xg 0:72
Motor cortex y 4:79f1
exp
0:05xg 0:40
Caudate nucleus y 9:66f1
exp
0:05xg 0:33
Putamen y 14:62f1
exp
0:04xg 0:46
where y is the nonheme iron in milligrams per 100 g fresh
weight and x is the age in years.

Acknowledgments
This work was supported in part by NIH grants HL62983
and AG20948. We would like to thank M. Sohail Dawood
for his editing of the references.

Appendix A. Two key papers on quantitative iron

in the brain
A.1. Hallgren and Sourander: a landmark paper
Perhaps the most widely quoted papers in the area of
brain iron and aging are those of Hallgren and Sourander
[69]. From 81 patients, Hallgren and Sourander showed an
increase in iron vs. age in the following 11 tissues: frontal
white matter, globus pallidus, cerebellar cortex, prefrontal
cortex, temporal cortex, sensory cortex, parietal cortex,
occipital cortex, motor cortex, caudate nucleus, and puta-
men. Iron levels in most of these tissues were linearly
proportional to the age when the age was younger than
2030 years. When the person was older than 2030 years,
the iron content seemed to level off. Although Hallgren and
Sourander fitted their data to age in the globus pallidus,
their data in fact were scattered over a wide range of values.
Furthermore, this result is not consistent with the finding by
Loeffler et al. [82]. In the thalamus, Hallgren and
Souranders data suggested the iron content increased with
age when the subject was younger than 30 years and
decreased when the subject was older. They also showed no
Fig. 6. Bar charts of (A) transferrin and (B) iron per gram wet weight in five
correlation between the iron content and the medulla different tissues from Loeffler et al. [82]. The white and gray bars refer to
oblongata. Their empirical formulae for age dependence the results from young and elderly controls, respectively. Each vertical line
of iron content in different regions of brain follows an represents 1 S.D. from a set of eight subjects.
20 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
A.2. Loeffler et al.
The two charts in Fig. 6 show the results from Loeffler
et al. [82] for transferrin and ferritin. We show these here to
demonstrate the types of error present between subjects.
Even if measurements were perfect experimentally, the
large variance in the data shows that there can be
significant variation from person to person in their iron
content. Any quantification of iron with age must then be
taken with a grain of salt.
References
[1] Anderson LJ, Holden S, Davis B, Prescott E, Charrier CC, Bunce
NH, et al. Cardiovascular T2-star (T2*) magnetic resonance for the
early diagnosis of myocardial iron overload. Eur Heart J 2001;22:
2171 9.
[2] Aoki S, Okada Y, Nishimura K, et al. Normal deposition of brain
iron in childhood and adolescence: MR imaging at 1.5T. Radiology
1989;172:381 5.
[3] Babcock M, de Silva D, Oaks R, et al. Regulation of mitochondrial
iron accumulation by Yfh1p, a putative homolog of frataxin. Science
1997;276:1709 12.
[4] Bartzokis G, Aravagiri M, Oldendorf WH, Mintz J, Marder SR. Field
dependent transverse relaxation rate increase may be a specific
measure of tissue iron stores. Magn Reson Med 1993;29:459 64.
[5] Bartzokis G, Sultzer D, Mintz J, Holt LE, Marx P, Phelan CK, et al.
In-vivo evaluation of brain iron in Alzheimers-disease and normal
subjects using MRI. Biol Psychiatry 1994;35:480 7.
[6] Bartzokis G, Cummings JL, Markham CH, Marmarelis PZ,
Treciokas LJ, Tishler TA, et al. MRI evaluation of brain iron in
earlier- and later-onset Parkinsons disease and normal subjects.
Magn Reson Imaging 1999;17:213 22.
[7] Bartzokis G, Tishler TA. MRI evaluation of basal ganglia ferritin
iron and neurotoxicity in Alzheimers and Huntingtons disease. Cell
Mol Biol 2000;46:821 33.
[8] Bartzokis G, Beckson M, Hance DB, Marx P, Foster JA, Marder SR.
MR evaluation of age-related increase of brain iron in young adult
and older normal males. Magn Reson Imaging 1997;15:29 35.
[9] Bartzokis G, Sultzer D, Cummings J, Holt L, Hance DB, Henderson
VW, et al. In vivo evaluation of brain iron in Alzheimer disease using
magnetic resonance imaging. Arch Gen Psychiatry 2000;57:47 53.
[10] Beard JL, Connor JR, Jones BC. Iron in the brain. Nutr Rev 1993;51:
157 70.
[11] Benkovic SA, Connor JR. Ferritin, transferrin, and iron in selected
regions of the adult and aged rat brain. J Comp Neurol 1993;338:
97 113.
[12] Besson JA, Best PV, Skinner ER. Post-mortem proton magnetic
resonance spectrometric measures of brain regions in patients with a
pathological diagnosis of Alzheimers disease and multi-infarct
dementia. Br J Psychiatry 1992;160:187 90.
[13] Bizzi A, Brooks RA, Brunetti A, et al. Role of iron and ferritin in
MR imaging: a study of primates at different field strengths.
Radiology 1990;177:59 65.
[14] Blaise A, Chappert J, Girardet JL. Observation par measures
magnetique et effet Moessbauer dun antiferromagnetisme de grains
fin dans la ferritin. C R Acad Sci D 1965;261:2310 3.
[15] Blaise A, Feron J, Girardet JL, Lawrence JJ. Contributions a letude
des propertes magnetique de la ferritin. C R Acad Sci B 1967;265:
1077 80.
[16] Bradbury MWB. Transport of iron in the blood-brain-cerebrospinal
fluid system. J Neurochem 1997;69:443 54.
[17] Brittenham GW, Cohen AR, McLaren CE, et al. Hepatic iron stores
and plasma ferritin concentration in patients with sickle cell anemia
and thalassemia major. Am J Hematol 1993;42:81 5.
[18] Brooks DJ, Luthert P, Gadian D, Marsden CD. Does signal-
attenuation on high-field T2-weighted MRI of the brain reflect
regional cerebral iron deposition? Observations on the relationship
between regional cerebral water proton T2 and iron levels. J Neurol
Neurosurg Psychiatry 1989;52:108 11.
[19] Brooks RA, Vymazal J, Bulte JWM, Baumgarner C, Tran V.
Comparison of T2 relaxation in blood, brain, and ferritin. J Magn
Reson Imaging 1995;4:446 50.
[20] Brooks RA, Vymazal J, Goldfarb RB, Bulte JWM, Aisen P. Relax-
ometry and magnetometry of ferritin. Magn Reson Med 1998;40:
227 35.
[21] Cairo G, Pietrangelo A. Iron regulatory protein in pathobiology.
Biochem J 2000;352:241 50.
[22] Chen CJ, Hardy PA, Clauberg M, et al. T2 values in the human brain:
comparison with quantitative assays of iron and ferritin. Radiology
1989;173:521 6.
[23] Chen JC, Hardy PA, Kucharczyk W, Clauberg M, Joshi JG, Vourlas
A, et al. MR of human postmortem brain tissue: correlative study
between T2 and assays of iron and ferritin in Parkinson and
Huntington Disease. AJNR Am J Neuroradiol 1993;14:275 81.
[24] Connor JR, Phillips TM, Lakshman MR, Barron KD, Fine RE,
Csiza CK. Regional variation in the levels of transferrin in the
CNS of normal and myelin-deficient rats. J Neurochem 1987;49:
1523 9.
[25] Connor JR, Menzies SL. Altered cellular distribution of iron in the
central nervous system of myelin deficient rats. Neuroscience 1990;
34:265 71.
[26] Connor JR, Menzies SL, St Martin SM, Mufson EJ. Cellular
distribution of transferrin, ferritin, and iron in normal and aged
human brains. J Neurosci Res 1990;27:595 611.
[27] Connor JR, Menzies SL. Altered cellular distribution of iron in the
central nervous system of myelin deficient rats. Neuroscience 1990;
34:265 71.
[28] Connor JR. Proteins of iron regulation in the brain in Alzheimers
disease. In: Lauffer RB, editor. Iron and Human Disease. Boca
Raton7 CRC Press; 1992. p. 365 93.
[29] Connor JR, Snyder BS, Beard JL, Fine RE, Mufson EJ. Regional
distribution of iron and iron-regulatory proteins in the brain in aging
and disease. J Neurosci Res 1992;31:327 35.
[30] Connor JR, Menzies SL, St Martin SM, Mufson RJ. A histochemical
study of iron, transferrin, and ferritin in Alzheimers diseased brains.
J Neurosci Res 1992;31:75 83.
[31] Connor JR, Benkovic SA. Iron regulation in the brain: histochemical,
biochemical, and molecular considerations. Ann Neurol
1992;32(Supplement):51 61.
[32] Connor JR, Roskams AJI, Menzies SL, Williams ME. Transferrin in
the central nervous system of the shiverer mouse myelin mutant. J
Neurosci Res 1993;36:501 7.
[33] Connor JR, Boeshore SA, Benkovic SA, Menzies SL. Isoforms of
ferritin have a specific cellular distribution in the brain. J Neurosci
Res 1994;37:461 5.
[34] Connor JR. Iron acquisition and expression of iron regulatory
proteins in the developing brain: manipulation by ethanol exposure,
iron deprivation, and cellular dysfunction. Dev Neurosci 1994;16:
233 47.
[35] Connor JR, Snyder BS, Arosio P, Loeffler DA, LeWitt P. A
quantitative analysis of isoferritins in selected regions of aged,
parkinsonian, and Alzheimers diseased brains. J Neurochem
1995;65:717 24.
[36] Connor JR, Menzies SL. Relationship of iron to oligodendrocytes
and myelination. Glia 1996;17:83 93.
[37] Connor JR, Menzies SL, Burdo JR, Boyer PJ. Iron and iron ma-
nagement proteins in neurobiology. Pediatr Neurol 2001;25:118 29.
[38] Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo
WG, et al. Neuropathological examination suggests impaired brain
iron acquisition in restless legs syndrome. Neurology 2003;61:
304 9.
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
[39] Cornett CR, Markesbery WR, Ehmann WD. Imbalances of trace
elements related to oxidative damage in Alzheimers disease brain.
Neurotoxicology 1998;19:339 46.
[40] Curnes JT, Burger PC, Djang WT, Boyko OB. MR imaging of
compact white matter pathways. AJNR Am J Neuroradiol 1988;9:
1061 8.
[41] Curtis AR, Fey C, Morris CM, Bindoff LA, Ince PG, Chinnery PF,
et al. Mutation in the gene encoding ferritin light polypeptide
causes dominant adult-onset basal ganglia disease. Nat Genet 2001;
28:350 4.
[42] Dedman DJ, Treffry A, Candy JM, Taylor GA, Morris CM, Bloxham
CA, et al. Iron and aluminium in relation to brain ferritin in normal
individuals and Alzheimers-disease and chronic renal-dialysis
patients. Biochem J 1992;287:509 14.
[43] Deibel MA, Ehmann WD, Markesbery WD. Copper, iron, and zinc
imbalances in severely degenerated brain regions in Alzheimers
disease: possible relation to oxidative stress. J Neurol Sci 1996;143:
137 42.
[44] Dexter DT, Carayon A, Javoy-Agid F, Agid Y, Wells FR, Daniel
SE, et al. Alterations in the levels of iron, ferritin and other trace
metals in Parkinsons disease and other neurodegenerative
diseases affecting the basal ganglia. Brain 1991;114:1953 75.
[45] Dietrich RB, Bradley WG. Iron accumulation in the basal ganglia
following severe ischemic-anoxic insults in children. Radiology
1988;168:203 6.
[46] Drayer BP, Olanow W, Burger P, Johnson GA, Herfkens R, Riederer
SJ. Parkinsons plus syndrome: diagnosis using high field MR
imaging of brain iron. Radiology 1986;159:493 8.
[47] Drayer BP, Burger P, Darwin RH, Riederer SJ, Herfkens R, Johnson
GA. MRI of brain iron. AJNR Am J Neuroradiol 1986;7:373 80.
[48] Drayer BP. Imaging of the aging brain Part 1. Normal findings.
Radiology 1988;166:785 96.
[49] Drayer BP. Imaging of the aging brain Part II. Pathologic conditions.
Radiology 1988;166:797 806.
[50] Dwork AJ, Schon EA, Herbert J. Nonidentical distribution of trans-
ferrin and ferric iron in human brain. Neuroscience 1988;27:333 45.
[51] Dwork AJ, Lawler G, Zybert PA, et al. An autoradiographic study of
the uptake and distribution of iron by the brain of the young rat.
Brain Res 1990;518:31 9.
[52] Dwork AJ. Effects of diet and development upon the uptake and
distribution of cerebral iron. J Neurol Sci 1995;134:45 51.
[53] Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP.
Abnormalities in CSF concentrations of ferritin and transferrin in
restless legs syndrome. Neurology 2000;54:1698 700.
[54] Erb GL, Osterbur DL, LeVine SM. The distribution of iron in the
brain: a phylogenetic analysis using iron histochemistry. Dev Brain
Res 1996;93:120 8.
[55] Gelman BB. Iron in CNS disease. J Neuropathol Exp Neurol
1995;54:477 86.
[56] Gelman N, Gorell JM, Barker PB, et al. MR imaging of human brain
at 3.0 T: preliminary report on transverse relaxation rates and relation
to estimated iron content. Radiology 1999;210:759 67.
[57] Gelman N, Ewign JR, Gorell JM, Spickler EM, Solomon EG.
Interregional variation of longitudinal relaxation rates in human brain
at 3.0 T: relation to estimated iron and water contents. Magn Reson
Med 2001;45:71 9.
[58] Gerber MR, Connor JR. Do oligodendrocytes mediate iron regula-
tion in the human brain? Ann Neurol 1989;26:95 8.
[59] Gerlach M, Ben-Shachar D, Riederer P, Youdim MBH. Altered brain
metabolism of iron as a cause of neurodegenerative diseases? J
Neurochem 1994;63:793 807.
[60] Gerlach M, Trautwein AX, Zecca L, Youdim MBH, Riederer
Mossbauer P. Spectroscopic studies of purified human neuromelanin
isolated from the substantia nigra. J Neurochem 1995;65:923 6.
[61] Gilissen EP, Jacobs RE, Allman JM. Magnetic resonance microscopy
of iron in the basal forebrain cholinergic structures of the aged mouse
lemur. J Neurol Sci 1999;168:21 7.
21
[62] Gillis P, Koenig SH. Transverse relaxation of solvent protons
induced by magnetized spheres: application in ferritin, erythrocytes,
and magnetite. Magn Reson Med 1987;5:323 45.
[63] Good PF, Olanow CW, Perl DP. Neuromelanin-containing neurons of
the substantia nigra accumulate iron and aluminum in Parkinsons
disease: a LAMMA study. Brain Res 1991;593:343 6.
[64] Gorell JM, Ordidge RJ, Brown GG, Deniau J-C, Buderer NM,
Helpern JA. Increased iron-related MRI contrast in the substantia
nigra in Parkinsons disease. Neurology 1995;45:1138 43.
[65] Gossuin Y, Roch A, Muller RN, Gillis P. Relaxation induced by
ferritin and ferritin-like magnetic particles: the role of proton
exchange. Magn Reson Med 2000;43:237 43.
[66] Gossuin Y, Roch A, Bue FL, Muller RN, Gillis P. Nuclear
magnetic relaxation dispersion of ferritin and ferritin like magnetic
particle solutions: a pH-effect study. Magn Reson Med 2001;
46:476 81.
[67] Grabill C, Silva AC, Smith SS, Koretsky AP, Rouault TA. MRI
detection of ferritin iron overload and associated neuronal patho-
logy in iron regulatory protein-2 knockout mice. Brain Res 2003;
971:95 106.
[68] Griffiths PD, Crossman AR. Distribution of iron in the basal ganglia
and neocortex in postmortem tissue in Parkinsons disease and
Alzheimers disease. Dementia 1993;4:61 5.
[69] Hallgren B, Sourander P. The effect of age on the non-haemin iron in
the human brain. J Neurochem 1958;3:41 51.
[70] Hallgren B, Sourander P. The non-haemin iron in the cerebral cortex
in Alzheimers disease. J Neurochem 1960;5:307 10.
[71] Harvey RJ, Summerfield JA, Fox NC, Warrington EK, Rossor MN.
Dementia associated with haemochromatosis. A report of two cases.
Eur J Neurol 1997;4:318 22.
[72] Hautot D, Pankhurst Q, Khan N, Dobson J. Preliminary evaluation of
nanoscale biogenic magnetite in Alzheimers disease brain tissue,
biology letters. Proc R Soc Lond B 2003:S1S3.
[73] Hebbrecht G, Maenhaut W, De Reuckm J. Brain trace elements and
aging. Nucl Instrum Methods Phys Res B 1999;150:208 13.
[74] Hill JM, Switzer RCI. The regional distribution and cellular
localization of iron in the rat brain. Neuroscience 1984;11:
595 603.
[75] Hinzmann RD. Ferritin and transferrin in iron deficiency and
overload. Immunodiagn Today 1999;12:1 4.
[76] Jensen JH, Chandra R, Yu H. Quantitative model for the interecho
time dependence of the CPMG relaxation rate in iron-rich gray
matter. Magn Reson Med 2001;46:159 65.
[77] Jenner P. Oxidative damage in neurodegenerative disease. Lancet
1994;344:796 8.
[78] Kennard ML, Feldman H, Yamada T, Jefferies WA. Serum levels of
the iron binding protein p97 are elevated in Alzheimers disease. Nat
Med 1996;2:1230 5.
[79] Kirschvink JL, Kobayashi-Kirschvink A, Woodford BJ. Magnetite
biomineralization in the human brain. Proc Natl Acad Sci U S A
1992;89:7683 7.
[80] Kucharczyk W, Henkelman RM, Chen JC. Brain iron and T2 signal
[Letter]. AJNR Am J Neuroradiol 1994;15:1795 6.
[81] Levi S, Yewdall SJ, Harrison PM, et al. Evidence that H- and
L-chains have co-operative roles in the iron-uptake mechanism of
human ferritin. J Biochem 1992;288:591 6.
[82] Loeffler DA, Connor JR, Juneau PL, et al. Transferrin and iron in
normal, Alzheimers disease, and Parkinsons disease brain regions.
J Neurochem 1995;65:710 6.
[83] Lott JNA, Greenwood JS, Batten GD. Mechanisms and regulation of
mineral nutrient storage during seed development. In: Anonymous,
editor. Seed Development and Germination. New York7 Marcel
Dekker Inc; 1995. p. 215 35.
[84] Metafratzi Z, Argyropoulou MI, Kiortsis DN, Tsampoulas C,
Chaliassos N, Efremidis SC. T(2) relaxation rate of basal ganglia
and cortex in patients with beta-thalassaemia major. Br J Radiol
2001;74:407 10.
22 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
[85] Michel PP, Vyas S, Agid Y. Toxic effects of iron for cultured
mesencephalic dopaminergic neurons derived from rat embryonic
brains. J Neurochem 1992;59:118 27.
[86] Miller MW, Roskams AJI, Connor JR. Iron regulation in the
developing rat brain: effect of in utero ethanol exposure. J Neuro-
chem 1995;65:373 80.
[87] Moalem S, Percy ME, Andrews DF, Kruck TP, Wong S, Dalton AJ,
et al. Are haemochromatosis mutations involved in Alzheimers
disease? Am J Med Genet 2000;93:58 66.
[88] Morris CM, Keith AB, Edwardson JA, Pullen RGL. Uptake and
distribution of iron and transferrin in the adult rat brain. J Neurochem
1992;59:300 6.
[89] Neel L. Superparamgnetisme des grain tres fin antiferromagnetiques.
C R Acad Sci B 1961;252:4075 80.
[90] Nelson SR, Pazdernik TL, Samson FE. Measurement of loosely-
bound iron in brain regions using redox cycling and salicylate. Cell
Mol Biol I 2000;46:649 55.
[91] Nielsen JE, Jensen LN, Krabbe K. Hereditary haemochromatosis: a
case of iron accumulation in the basal ganglia associated with a
parkinsonian syndrome. J Neurol Neurosurg Psychiatry 1995;59:
318 21.
[92] Ogg RJ, Steen RG. Age related changes in brain T1 are correlated
with putative iron concentration. Magn Reson Med 1998;40:
749 53.
[93] Ogg RJ, Langston JW, Haacke EM, Steen RG, Taylor JS. The
correlation between phase shifts in gradient-echo MR images and
regional brain iron concentration. Magn Reson Imaging 1999;17:
1141 8.
[94] Ordidge RJ, Gorell JM, Deniau JC, Knight RA, Helpern JA.
Assessment of relative brain iron concentrations using T2-weighted
and T2*-weighted MRI at 3 Tesla. Magn Reson Med 1994;32:
335 41.
[95] Pastakia B, Polinksy R, Di Chiro G, Simmons JT, Brown R, Wener
L. Multiple system atrophy (Shy-Drager syndrome): MR imaging.
Radiology 1986;159:499 502.
[96] Perl DP, Good PF. Comparative techniques for determining cellular
iron distribution in brain tissues. Ann Neurol 1992;32:S76.
[97] Rouault TA. Iron on the brain. Nat Genet 2001;28:299 300.
[98] Riederer P, Sofic E, Rausch W-D, Schmidt B, Reynolds GP, Jellinger
K, et al. Transition metals, ferritin, glutathione, and ascorbic acid in
Parkinsonian brains. J Neurochem 1989;52:515 20.
[99] Roskams AJI, Connor JR. Iron, transferrin, and ferritin in the rat
brain during development and aging. J Neurochem 1994;63:709 16.
[100] Rutledge JN, Hilal SK, Silver AJ, et al. Study of movement disorders
and brain iron by MR. AJNR Am J Neuroradiol 1987;8:397 411.
[101] Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A,
Tagliabue J, et al. The haemochromatosis gene affects the age of
onset of sporadic Alzheimers disease. Neurobiol Aging 2001;22:
563 8.
[102] Schenck JF. Imaging of brain iron by magnetic resonance: T-2
relaxation at different field strengths. J Neurol Sci 1995;134:10 8.
[103] Schenck JF. The role of magnetic susceptibility in magnetic
resonance imaging: MRI magnetic compatibility of the first and
second kinds. Med Phys 1996;23:815 50.
[104] Schenck JF. Magnetic resonance imaging of brain iron. J Neurol Sci
2003;207:99 102.
[105] Schenker C, Meier D, Wichmann W, Boesiger P, Valavanis A. Age
distribution and iron dependency of the T2-relaxation time in the
globus pallidus and putamen. Neurology 1993;35:119 24.
[106] Silliman CC, Peterson VM, Mellman DL, et al. Iron chelation by
desferrioxamine in sickle cell patients with severe transfusion-
induced hemosiderosis: a randomized, double-blind study of the
doseresponse relationship. J Lab Clin Med 1993;122:48 54.
[107] Small SA, Perera GM, DelaPaz R, Mayeux R, Stern Y. Differential
regional dysfunction of the hippocampal formation among elderly
with memory decline and Alzheimers disease. Ann Neurol
1999;45:466 72.
[108] Small SA, Nava AS, Perera GM, DelaPaz R, Stern Y. Evaluating
the function of hippocampal subregions with high-resolution MRI
in Alzheimers disease and aging. Microsc Res Tech 2000;51:
101 8.
[109] Sofic E, Paulus W, Jellinger K, Riederer P, Youdim MB. Selective
increase of iron in substantia nigra zona compacta of parkinsonian
brains. J Neurochem 1991;56:978 82.
[110] Spatz H. Uber Den Eisennachweis im Gehrin, besonders in Zentren
des extrapyrimidal-motorishcen systems. Z Ges Neuronal Psychiat
Berl 1922;77:261.
[111] Takagi H, Shapiro K, Marmarou A, Wisoff H. Microgravimetric
analysis of human brain tissue: correlation with computerized
tomography scanning. J Neurosurg 1981;54:797 801.
[112] Taylor EM, Crowe A, Morgan EH. Transferrin and iron uptake by the
brain: effects of altered iron status. J Neurochem 1991;57:1584 92.
[113] Thomas LO, Boyko OB, Anthony DC, Burger PC. MR detection of
brain iron. AJNR Am J Neuroradiol 1993;4:1043 8.
[114] Thompson CM, Markesbery WR, Ehmann WD, Mao Y-M, Vance
DE. Regional brain trace element studies in Alzheimers disease.
Neurotoxicology 1988;9:1 8.
[115] Thulborn KR, Sorensen AG, Kowall NW, McKee A, Lai A,
McKinstry RC, et al. The role of ferritin and hemosiderin in the
MR appearance of cerebral hemorrhage: a histopathologic biochem-
ical study in rats. AJNR Am J Neuroradiol 1990;11:291 7.
[116] Torack R, Alcala H, Gado M, Burton R. Correlative assay of
computerized cranial tomography (CCT), water content and specific
gravity in normal and pathological postmortem brain. J Neuropathol
Exp Neurol 1976;35:385 92.
[117] Vichinsky E. Consensus document for transfusion-related iron
overloads. Semin Hematol 2001;38:2 4.
[118] Vymazal J, Brooks RA, Zak O, McRill C, Shen C, Dichiro G. T1 and
T2 of ferritin at different field strengthseffect on MRI. Magn Reson
Med 1992;27:368 74.
[119] Vymazal J, Bulte JWM, Frank JA, Di Chiro G, Brooks RA.
Frequency dependence of MR relaxation times I. Paramagnetic ions.
J Magn Reson Imaging 1993;3:637 40.
[120] Vymazal J, Hajek M, Patronas N, et al. The quantitative relation
between T1-weighted and T2-weighted MRI of normal gray matter
and iron concentration. J Magn Reson Imaging 1995;5:554 60.
[121] Vymazal J, Brooks RA, Patronas N, Hajek M, Bulte JWM, DiChiro
G. Magnetic resonance imaging of brain iron in health and disease.
J Neurol Sci 1995;134:19 26.
[122] Vymazal J, Zak O, Bulte JWM, Aisen P, Brooks RA. T1 and T2 of
ferritin solutions: effect of loading factor. Magn Reson Med 1996;36:
61 5.
[123] Vymazal J, Brooks RA, Baumgarner C, et al. The relation between
brain iron and NMR relaxation times: an in vitro study. Magn Reson
Med 1996;35:56 61.
[124] Vymazal J, Brooks RA, Zak O, McRill C, Shen C, Di Chiro G. T1
and T2 of ferritin at different field strengths: effects on MRI. Magn
Reson Med 1997;27:368 74.
[125] Vymazal J, Righini A, Brooks RA, Canesi M, Mariana C, Leonardi
M, et al. T1 and T2 in the brain of healthy subjects, patients with
Parkinson disease, and patients with multiple system atrophy:
relation to iron content. Radiology 1999;211:489 95.
[126] Vymazal J, Urgosik D, Bulte JW. Differentiation between hemosid-
erin- and ferritin-bound brain iron using nuclear magnetic resonance
and magnetic resonance imaging. Cell Mol Biol 2000;46:835 42.
[127] Whittall KP, MacKay AL, Graeb DA, Nugent RA, Li DKB, Paty
DW. In vivo measurement of T2 distributions and water contents in
normal human brain. Magn Reson Med 1997;37:34 43.
[128] Yefimova MG, Jeanny J-C, Keller N, Sergeant C, Guilloneau X,
Beaumont C, et al. Impaired retinal iron homeostasis associated with
defective phagocytosis in Royal College of Surgeons rats. Invest
Ophthalmol Vis Sci 2002;43:537 45.
[129] Yefimova MG, Jeanny J-C, Guilloneau X, Keller N, Nguyen-Legros
J, Sergeant C, et al. Iron, ferritin, transferring and transferring
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
receptor in the adult rat retina. Invest Ophthalmol Vis Sci 2002;41:
2343 51.
[130] Yehuda S, Youdim MBH. Brain iron: a lesson from animal models.
Am J Clin Nutr 1989;50:618 29.
[131] Zhang JR, Scherch HM, Hall ED. Direct measurement of lipid
hydroperoxides in iron-dependent spinal neuronal injury. J Neuro-
chem 1996;66:355 61.
[132] Alustiza JM, Artetxe J, Castiella A, Agirre C, Emparanza JI, Otazua
P, et al. MR quantification of hepatic iron concentration. Radiology
2004;230:479 84.
[133] Angelucci E, Brittenham GM, McLaren CE, Ripalti M, Baronciani
D, Giardini C, et al. Hepatic iron concentration and total body iron
stores in thalassemia major. N Engl J Med 2000;343:327 31.
[134] Bonkovsky HL, Rubin RB, Cable EE, Davidoff A, Pels Rijcken
TH, Stark DD. Hepatic iron concentration: noninvasive estimation
by means of MR imaging techniques. Radiology 1999;212:227 34.
[135] Clark PR, St. Pierre TG. Quantitative mapping of transverse
relaxivity (1/T2) in hepatic iron overload: a single spin-echo imaging
methodology. Magn Reson Imaging 2000;18:431 8.
[136] Fahlvik AK, Holtz E, Klaveness J. Relaxation efficacy of paramag-
netic and superparamagnetic microsphere in liver and spleen. Magn
Reson Imaging 1990;8:363 9.
[137] Fenzi A, Bortolazzi M, Marzola P, Colombari R. In vivo inves-
tigation of hepatic iron overload in rats using T2 maps: quantification
at high intensity field (4.7-T). J Magn Reson Imaging 2001;13:
392 6.
[138] Fretz CJ, Elizondo G, Weissleder R, Hahn PF, Stark DD, Ferrucci Jr
JT. Superparamagnetic iron oxide-enhanced MR imaging: pulse
sequence optimization for detection of liver cancer. Radiology 1989;
172:393 7.
[139] Hernandez RJ, Sarnaik SA, Lande I, Aisen AM, Glazer GM,
Chenevert T, et al. MR evaluation of liver iron overload. J Comput
Assist Tomogr 1988;12:91 4.
[140] Israel J, Unger E, Buetow K, Brown T, Blumberg B, London WT.
Correlation between liver iron content and magnetic resonance
imaging in rats. Magn Reson Imaging 1989;7:629 34.
[141] Kreeftenberg Jr HG, Mooyaart EL, Huizenga JR, Sluiter WJ.
Quantification of liver iron concentration with magnetic resonance
imaging by combining T1-, T2-weighted spin echo sequences and a
gradient echo sequence. Neth J Med 2000;56:133 7.
[142] Pouliquen D, Perdrisot R, Ermias A, Akoka S, Jallet P, Le Jeune JJ.
Superparamagnetic Iron oxide nanoparticles as a liver MRI contrast
agent: contribution of microencapsulation to improved biodistribu-
tion. Magn Reson Imaging 1989;7:619 27.
[143] Saini S, Stark DD, Hahn PF, Wittenberg J, Brady TJ, Ferrucci Jr JT.
Ferrite particles: a superparamagnetic MR contrast agent for the
reticuloendothelial system. Radiology 1987;162:211 6.
[144] Sampietro M, Caputo L, Casatta A, Meregalli M, Pellagatti A,
Tagliabue J, et al. The haemochromatosis gene affects the age of
onset of sporadic Alzheimers disease. Neurobiol Aging 2001;22:
563 8.
[145] Wang ZJ, Haselgrove JC, Martin MB, Hubbard AM, Li S, Loomes
K, et al. Evaluation of iron overload by single voxel MRS
measurement of liver T2. J Magn Reson Imaging 2002;15:395 400.
[146] Weissleder R, Stark DD, Compton CC, Wittenberg J, Ferrucci JT.
Ferrite-enhanced MR imaging of hepatic lymphoma: an experi-
mental study in rats. AJR Am J Roentgenol 1987;149:1161 5.
[147] Brittenham JM, Farrel DE, Harris JW, et al. Magnetic-susceptibility
measurement of human iron stores. N Engl J Med 1982;307:1671 5.
[148] Brooks RA. T2-shortening by strongly magnetized spheres: a chemical
exchange model. Magn Reson Med 2002;47:388 91.
[149] Cheng Y-CN, Haacke EM. Predicting BOLD signal changes as a
function of blood volume fraction and resolution. NMR Biomed
2001;14:468 77.
[150] Cho S, Jones D, Reddick WE, Ogg RJ, Steen RG. Establishing
norms for age-related changes in proton T1 of human brain tissue in
vivo. Magn Reson Imaging 1997;15:1133 43.
23
[151] Clark RA, Watanabe AT, Bradley WG, Roberts JD. Acute hema-
tomas: effects of deoxygenation, hematocrit, and fibrin-clot forma-
tion and retraction on T2 shortening. Radiology 1990;175:201 6.
[152] Edelman RR, Johnson K, Buxton R, et al. MR of hemorrhage: a new
approach. AJNR Am J Neuroradiol 1986;7:751 6.
[153] Gillis P, Moiny F, Brooks RA. On T2-shortening by strongly
magnetized spheres: a partial refocusing model. Magn Reson Med
2002;47:257 63.
[154] Gomori JM, Grossman RI. The relation between regional brain iron
and T2 shortening. AJNR Am J Neuroradiol 1993;14:1049 50.
[155] Graham JM, Paley MNJ, Grunewald RA, Hoggard N, Griffiths PD.
Brain iron deposition in Parkinsons disease imaged using the
PRIME magnetic resonance sequence. Brain 2000;123:2423 31.
[156] Gronemeyer SA, Langston JW, Hanna SL, Langston JWJ. MR
imaging detection of calcified intracranial lesions and differenti-
ation from iron-laden lesions. J Magn Reson Imaging 1992;2:
271 6.
[157] Haacke EM, Lai S, Yablonskiy DA, Lin W. In vivo validation of the
BOLD mechanism: a review of signal changes in gradient echo
functional MRI in the presence of flow. Int J Imaging Syst Technol
1995;6:153 63.
[158] Haacke EM, Lai S, Reichenbach JR, Kuppusamy K, Hoogenraad
H, Takeichi H, et al. In vivo measurement of blood oxygen saturation
using magnetic resonance imaging: a direct validation of the blood
oxygen level-dependent concept in functional brain imaging. Hum
Brain Mapp 1997;5:341 6.
[159] Kennan RP, Scanley BE, Innis RB, Gore JC. Physiological basis for
BOLD MR signal changes due to neuronal stimulation: separation of
blood volume and magnetic susceptibility effects. Magn Reson Med
1998;40:840 6.
[160] Kiseliev VG, Posse S. Analytical model of susceptibility-induced
MR signal dephasing: effect of diffusion in a microvascular network.
Magn Reson Med 1999;41:499 509.
[161] Ma J, Wehrli FW. Method for image-based measurement of the
reversible and irreversible contribution to the transverse-relaxation
rate. J Magn Reson B 1996;111:61 9.
[162] Mavrogeni SI, Gotsis ED, Markussis V, Tsekos N, Politis C, Vretou
E, et al. T2 relaxation time study of iron overload in b-thalassemia.
MAGMA 1998;6:7 12.
[163] Ogg RJ, Reddick WE, Mao J, Steen RG. More than meets the eye:
significant regional heterogeneity in human cortical T1. Magn Reson
Imaging 2000;18:361 8.
[164] Reichenbach JR, Venkatesan R, Schillinger DJ, Kido DK, Haacke
EM. Small vessels in the human brain: MR venography with deoxy-
hemoglobin as an intrinsic contrast agent. Radiology 1997;204:
272 7.
[165] Reichenbach JR, Venkatesan R, Yablonskiy DA, Thompson MR, Lai
S, Haacke EM. Theory and application of static field inhomogeneity
effects in gradient-echo imaging. J Magn Reson Imaging
1997;7:266 79.
[166] Sukstanskii AL, Yablonskiy DA. Theory of FID NMR signal
dephasing induced by mesoscopic magnetic field inhomogeneities
in biological systems. J Magn Reson 2001;151:107 17.
[167] Wang Y, Yu Y, Li D, Bae KT, Brown JJ, Lin W, et al. Artery and vein
separation using susceptibility-dependent phase in contrast-enhanced
MRA. J Magn Reson Imaging 2000;12:661 70.
[168] Xu Y, Balschi JA, Springer CS. Magnetic susceptibility shift selected
imaging: MESSI. Magn Reson Med 1990;16:80 90.
[169] Yablonskiy DA, Haacke EM. An MRI method for measuring T2 in
the presence of static and RF magnetic field inhomogeneities. Magn
Reson Med 1997;37:872 6.
[170] Yablonskiy DA, Haacke EM. Theory of NMR signal behavior in
magnetically inhomogeneous tissues: the static dephasing regime.
Magn Reson Med 1994;32:749 63.
[171] Yablonskiy DA, Reinus WR, Stark H, Haacke EM. Quantitation of
TV2 anisotropic effects on magnetic resonance bone mineral density
measurement. Magn Reson Med 1996;36:214 21.
24 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
[172] Yamada N, Imakita S, Sakuma T, et al. Evaluation of the suscep-
tibility effect on the phase of a simple gradient echo. Radiology 1990;
175:561 5.
[173] Yang QX, Demeure RJ, Dardzinski BJ, Arnold BW, Smith MB.
Multi echo frequency-domain image contrast: improved signal-to-
noise ratio and T2 (T2*) weighting. Magn Reson Med 1999;41:
423 8.
[174] Yang QX, Smith MB, Briggs RW, Rycyna RE. Microimaging at 14
Tesla using GESEPI for removal of magnetic susceptibility artifacts
in T2*-weighted image contrast. J Magn Reson 1999;141:1 6.
[175] An H, Lin W. Impact of intravascular signal on quantitative measures
of cerebral oxygen extraction and blood volume under normo- and
hypercapnic conditions using an asymmetric spin echo approach.
Magn Reson Med 2003;50:708 16.
[176] An H, Lin W. Cerebral oxygen extraction fraction and cerebral
venous blood volume measurements using MRI: effects of magnetic
field variation. Magn Reson Med 2002;47:958 66.
[177] An H, Lin W. Quantitative measurements of cerebral blood oxygen
saturation using magnetic resonance imaging. J Cereb Blood Flow
Metab 2000;20:1225 36.
[178] Bartzokis G, Mintz J, Sultzer D, Marx P, Herzberg JS, Phelan CK,
et al. In vivo MR evaluation of age-related increases in brain iron.
AJNR Am J Neuroradiol 1994;15:1129 38.
[179] Bloembergen N, Purcell EM, Pound RV. Relaxation effects in
nuclear magnetic resonance absorption. Phys Rev 1948;73:678.
[180] Brittenham GM, Sheth S, Allen CJ, Farrell DE. Noninvasive
methods for quantitative assessment of transfusional iron overload
in sickle cell disease. Semin Hematol 2001;38:37 56.
[181] Breger RK, Yetkin FZ, Fischer ME, Papke RA, Haughton VM,
Rimm AA. T1 and T2 in the cerebrum: correlation with age, gender,
and demographic factors. Radiology 1991;181:545 7.
[182] Darwin RH, Drayer BP, Riederer SJ, Wang HZ, MacFall JR. T2
estimates in healthy and diseased brain tissue: a comparison using
various MR pulse sequences. Radiology 1986;160:375 81.
[183] De Bisschop E, Luypaert R, Allein S, Osteaux M. Quantification of
trabecular structure in the distal femur using magnetic resonance
phase imaging. Magn Reson Imaging 1996;14:11 20.
[184] Gati JS, Menon RS, Ugurbil K, Rutt BK. Experimental determina-
tion of the BOLD field strength dependence in vessel and tissue.
Magn Reson Med 1997;38:296 302.
[185] Gore JC, Majumdar S. Superparamagnetic iron oxide particles.
Radiology 1988;169:657 8.
[186] Hardy PA, Henkelman RM. Transverse relaxation rate enhance-
ment caused by magnetic particulates. Magn Reson Imaging 1989;7:
265 75.
[187] Irving MG, Brereton IM, Field J, Doddrell DM. In vivo determina-
tion of body iron stores by natural-abundance deuterium magnetic
resonance spectroscopy. Magn Reson Med 1987;4:88 92.
[188] Majumdar S, Gore JC. Studies of diffusion in random fields
produced by variations in susceptibility. J Magn Reson 1988;78:
41 55.
[189] Majumdar S, Zoghbi S, Pope CF, Gore JC. Quantitation of MR
relaxation effects of iron oxide particles in liver and spleen.
Radiology 1988;169:653 5.
[190] Majumdar S, Zoghbi S, Pope CF, Gore JC. A quantitative study
of relaxation rate enhancement produced by iron oxide particles
in polyacrylamide gels and tissue. Magn Reson Med 1989;9:
185 202.
[191] Majumdar S, Zoghbi S, Gore JC. The influence of pulse sequence on
the relaxation effects of superparamagnetic iron oxide contrast
agents. Magn Reson Med 1989;10:289 301.
[192] Mathur-De Vre R. Biomedical implications of the relaxation
behaviour of water related to NMR imaging. Br J Radiol 1984;57:
955 76.
[193] Mazzara GP, Briggs RW, Wu Z, Steinbach BG. Use of a modified
polysaccharide gel in developing a realistic breast phantom for MRI.
Magn Reson Imaging 1996;14:639 48.
[194] Mitchell MD, Kundel HL, Axel L, Joseph PM. Agarose as a tissue
equivalent phantom material for NMR imaging. Magn Reson
Imaging 1986;4:263 6.
[195] Mosher TJ, Smith MB. Magnetic susceptibility measurement using
a double-DANTE tagging sequence. Magn Reson Med 1991;18:
251 5.
[196] Noseworthy MD, Kim JK, Stainsby JA, Stanisz GJ, Wright GA.
Tracking oxygen effects on MR signal in blood and skeletal muscle
during hyperoxia exposure. J Magn Reson Imaging 1999;9:814 20.
[197] Ogg RJ. Bulk susceptibility and regional brain iron concentration.
Proc ISMRM 1997;5:217.
[198] Ooi GC, Khong PL, Chan GC, Chan KN, Chan KL, Lam W, et al.
Magnetic resonance screening of iron status in transfusion-dependent
beta-thalassaemia patients. Br J Haematol 2004;124:385 90.
[199] Papakonstantinou OG, Maris TG, Kostaridou V, Gouliamos AD,
Koutoulas GK, Kalovidouris AE, et al. Assessment of liver iron
overload by T2-quantitative magnetic resonance imaging: correla-
tion of T2-QMRI measurements with serum ferritin concentration
and histologic grading of siderosis. Magn Reson Imaging 1995;13:
967 77.
[200] Pardoe H, Clark PR, St Pierre TG, Moroz P, Jones SK. A magnetic
resonance imaging based method for measurement of tissue iron
concentration in liver arterially embolized with ferrimagnetic
particles designed for magnetic hyperthermia treatment of tumors.
Magn Reson Imaging 2003;21:483 8.
[201] Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y. Differential
regional dysfunction of the hippocampal formation among elderly
with memory decline and Alzheimers disease. Ann Neurol 1999;45:
466 72.
[202] Small SA, Nava AS, Perera GM, Delapaz R, Stern Y. Evaluating the
function of hippocampal subregions with high-resolution MRI in
Alzheimers disease and aging. Microsc Res Tech 2000;51:101 8.
[203] Waldvogel D, van Gelderen P, Hallett M. Increased iron in the
dentate nucleus of patients with Friedrichs ataxia. Ann Neurol 1999;
46:123 5.
[204] Wang ZJ, Li S, Haselgrove JC. Magnetic resonance imaging
measurement of volume magnetic susceptibility using a boundary
condition. J Magn Reson 1999;140:477 81.
[205] Weisskoff RM, Kiihne S. MRI susceptometry: image-based mea-
surement of absolute susceptibility of MR contrast agents and human
blood. Magn Reson Med 1992;24:375 83.
[206] Wendt REI, Wilcott MRI, Nitz W, Murphy PH, Bryan RN. MR
imaging of susceptibility-induced magnetic field inhomogeneities.
Radiology 1988;168:837 41.
[207] Westwood MA, Anderson LJ, Firmin DN, Gatehouse PD, Lorenz
CH, Wonke B, et al. Interscanner reproducibility of cardiovascular
magnetic resonance T2* measurements of tissue iron in thalassemia. J
Magn Reson Imaging 2003;18:616 20.
[208] Wright GA, Hu BS, Macovski A. Estimating oxygen saturation of
blood in vivo with MR imaging at 1.5 T. J Magn Reson Imaging
1991;3:275 83.
[209] Zhou JY, Golay X, van Zijl PCM, Silvennoinen MJ, Kauppinen R,
Pekar J, et al. Inverse T2 contrast at 1.5 Tesla between gray matter
and white matter in the occipital lobe of normal adult human brain.
Magn Reson Med 2001;46:401 6.
[210] Augustiny N, van Schulthess GK, Meier D, Bfsiger P. MR imaging
of large nonferromagnetic metallic implants at 1.5 T. J Comput
Assist Tomogr 1987;11:678 83.
[211] Bakker CJG, Moerland MA, Bhagwandien R, Beersma R. Analysis
of machine-dependent and object-induced geometric distortion in
2DFT MR imaging. Magn Reson Imaging 1992;10:597 608.
[212] Cho ZH, Kim DJ, Kim YK. Total inhomogeneity correction
including chemical shifts and susceptibility by view angle tilting.
Med Phys 1988;15:7 11.
[213] Farahani K, Sinha U, Sinha S, Chiu LCL, Lufkin RB. Effect of
field strength on susceptibility artifacts in magnetic resonance
imaging. Comput Med Imaging Graph 1990;14:409 13.
 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25
[214] James R, Bartlett CR, Renicker J, Orchard K. Unusual MR metal-
lic artifact due to steel threads. J Comput Assist Tomogr 1987;11:
722 3.
[215] Saini S, Frankel RB, Stark DD, Ferrucci Jr JT. Magnetism: a primer
and review. AJR Am J Roentgenol 1988;150:735 43.
[216] Schick RM, Wismer GL, Davis KR. Magnetic susceptibility effects
secondary to out-of-plane air in fast MR scanning. AJNR Am J
Neuroradiol 1988;9:439 42.
[217] Teitelbaum GP, Yee CA, Horn DD, Kim HS, Colletti PM. Metallic
ballistic fragments: MR imaging safety and artifacts. Radiology
1990;175:855 9.
[218] Song AW. Single-shot EPI with signal recovery from the suscepti-
bility-induced losses. Magn Reson Med 2001;46:407 11.
[219] Brateman L, Bowman TT, Dbnstrup S, Scott KN. Magnetic
field shimming by Fourier analysis. Magn Reson Med 1988;6:
459 73.
[220] Cheng N, Haacke EM, Vu Y-J. An exact form for the magnetic
field density of states for a dipole. Magn Reson Imaging 2001;19:
1017 23.
[221] Chu SCK, Xu Y, Balschi JA, Springer Jr CS. Bulk magnetic
susceptibility shifts in NMR studies of compartmentalized sam-
ples: use of paramagnetic reagents. Magn Reson Med 1990;13:
239 62.
[222] Ford JC, Wehrli FW. In vivo quantitative characterization of
trabecular bone by NMR interferometry and localized proton
spectroscopy. Magn Reson Med 1991;17:543 51.
[223] Frahm J, Merboldtr KD, H7nicke W. Direct FLASH MR imaging of
magnetic field inhomogeneities by gradient compensation. Magn
Reson Med 1988;6:474 80.
[224] Grimes DI, Lennard RF, Swithenby SJ. Macroscopic ionic currents
within the human leg. Phys Med Biol 1985;30:1101 12.
[225] Haacke EM, Brown RW, Thompson MR, Venkatesan R. Magnetic
resonance imaging: physical principles and sequence design. New
York7 John Wiley & Sons, Inc; 1999. p. 741 80.
[226] Hornak JP, Szumowski J, Bryant RG. Magnetic field mapping. Magn
Reson Med 1988;6:158 63.
[227] Joy M, Scott G, Henkelman M. In vivo detection of applied electric
currents by magnetic resonance imaging. Magn Reson Imaging
1989;7:89 94.
[228] Mackenzie IS, Robinson EM, Wells AN, Wood B. A simple field
map for shimming. Magn Reson Med 1987;5:262 8.
25
[229] Peto S, Gillis P. Fiber-to-field angle dependence of proton nuclear
magnetic relaxation in collagen. Magn Reson Imaging 1990;8:
705 12.
[230] Salomir R, Baudouin DDS, Moonen C. A fast calculation method for
magnetic field inhomogeneity due to an arbitrary distribution of bulk
susceptibility. Concepts Magn Reson B 2003126 34.
[231] Xu Y, Balschi JA, Springer Jr CS. Magnetic Susceptibility Shift
Selected Imaging: MESSI. Magn Reson Med 1990;16:80 90.
[232] Allen MJ, Meade TJ. Synthesis and visualization of membrane-
permeable MRI contrast agent. J Biol Inorg Chem 2003;8:746 50.
[233] Dardzinski BJ, Schmithorst VJ, Holland SK, Boivin GP, Imagawa T,
Watanabe S, et al. MR imaging of murine arthritis using ultrasmall
superparamagnetic iron oxide particles. Magn Reson Imaging 2001;
19:1209 16.
[234] Hahn P, Miam AH, Dunaief JL. Maculas affected by age-related
macular degeneration contain increased chelatable iron in the retinal
pigment epithelium and Bruchs membrane. Arch Ophthalmol 2003;
121:1099 105.
[235] Louie AY, Huber MM, Ahrens ET, Rothbacher U, Moats R, Jacobs
RE, et al. In vivo visualization of gene expression using magnetic
resonance imaging. Nat Biotechnol 2000;18:321 5.
[236] Meade TJ, Taylor AK, Bull SR. New magnetic resonance contrast
agents as biochemical reporters. Curr Opin Neurobiol 2003;13:
597 602.
[237] Modo M, Mellowdew K, Cash D, Fraser SE, Meade TJ, Williams
SC. Mapping transplanted stem cell migration after a stroke: a serial,
in vivo magnetic resonance imaging study. Neuroimage 2004;21:
311 7.
[238] Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic
resonance imaging of atherosclerosis plaque with ultrasmall super-
paramagnetic particles of iron oxide in hyperlipidemic rabbits.
Circulation 2001;103:415 22.
[239] Wang YX, Hyssain SM, Krestin GP. Superparamagnetic iron oxide
contrast agents: physicochemical characteristics and applications in
MR imaging. Eur Radiol 2001;11:2319 31.
[240] Weinmann HJ, Ebert W, Misselwitz B, Schmitt-Willich H. Tissue-
specific MR contrast agents. Eur J Radiol 2003;46:33 44.
[241] Weissleder R, Elizondo G, Wittenberg J, Rabito CA, Bengele HH,
Josephson L. Ultrasmall superparamagnetic iron oxide: character-
ization of new class of contrast agents for MR imaging. Radiology
1990;175:489 93.