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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,


To preface our discussion on imaging iron stores using
Detroit, MI 48202, USA. Tel.: +1 313 758 0065; fax: +1 313 758 0068. MRI, we provide an overview of iron in the brain. This
E-mail address: nmrimaging@aol.com (E.M. Haacke). overview is not intended to give an in-depth physiological
0730-725X/$ see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.mri.2004.10.001
2 E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25

review of brain iron and the interested reader is referred to 2.2. Regional distribution of iron, ferritin and transferrin in
other articles [10,34] for a detailed discussion of iron in the normal human brain
neurobiology. Iron plays a major role as a critical part of
hemoglobin that transports oxygen from the lung to tissues. 2.2.1. Iron
Furthermore, nonhemoglobin iron is also important in brain The heterogeneous distribution of iron in the brain was
physiology because nonheme iron is involved in electron first demonstrated by histochemical techniques (Prussian
transport facilitating cellular aerobic metabolism [82] blue or Perls stain), which showed intense staining of
through its role in the production of adenosine triphosphatase ferric iron in parts of the extrapyramidal system, weaker
[34]. However, if iron is not properly regulated, it can lead staining of the cerebral cortex and no detectable staining in
to oxidative stress and the production of free radicals. Any the white matter [110]. Gelman [55] comments that:
overload of ferrous iron will lead to a reaction with hydro- bRelative to the basal ganglia there is much less stainable
gen peroxide and the formation of aggressive hydroxyl iron in the cerebral hemispheric white matter and cortex.Q
radicals by means of the Fenton reaction, or peroxynitrates, Using Perls stain, Drayer et al. [46] found no iron in the
and the subsequent death of neurons by apoptosis [55]. most posterior portion of the internal capsule and optic
radiations, but more iron in frontal than occipital white
2.1. Nonheme iron
matter regions. They also found prominent iron levels in
There are two categories of iron in the brain: heme iron, the temporal lobe (the subcortical bU Q fibers).
in hemoglobin and some enzymes like perioxidases, and Biochemical assays of postmortem brain tissue
nonheme iron. The types of nonheme iron in the brain [22,23,39,43,44,68,69,73,109,114] have since quantified
include (i) low-molecular-weight complexes; (ii) metal- the amount of total iron in various brain regions,
loproteins like transferrin, melanotransferrin and lactofer- confirming that the highest concentrations of iron (up to
rin; (iii) storage proteins such as ferritin and hemosiderin 200 Ag/g tissue wet weight) can be found in the globus
[126] and (iv) ionic iron. Ferromagnetic material, in the pallidus, red nucleus, substantia nigra and putamen regions
form of biogenic magnetite, has also been reported [72,79]. (Table 1). Contrary to the histochemical results, the
Of these components, the two most important to iron biochemical assays indicate that white matter, in general,
regulation are transferrin (iron transport) and ferritin (iron has similar levels of iron to cortical gray matter (typically
storage) [29]. Transferrin carries iron from the blood into about 30 40 Ag/g tissue wet weight, see Table 1) and in
brain tissue via transferrin receptors located in the brains some regions (e.g., motor cortex) there may be more iron
microvasculature [10]. It has a single chain of amino acids in the white matter than in the adjacent cortical gray
and two carbohydrate groups. A single Fe3+ iron can be matter [29].
bound to each carbohydrate group. The molecular weight of The results from the biochemical determinations of
transferrin is 79.6 kg/mol [75]. brain iron, which use a variety of analysis techniques
Ferritin stores excess iron atoms, which are not imme- [atomic absorption spectrophotometry (AAS), inductively
diately engaged in metabolic activities [24 38,82]. Ferritin coupled plasma spectroscopy (ICP), instrumental neutron
has a large spherical protein coat, about 12 nm in diameter, activation (INAA), colorimetry], are generally in good
that surrounds a crystalline core of hydrous ferric oxide agreement where it can be established a whole sample, as
[5Fe2O3d 9H20] [55]. There can be up to 4500 iron atoms opposed to the supernatant fraction of a homogenate, has
stored in the 8-nm-diameter internal cavity of one ferritin been used in the analysis. A factor that may also con-
protein. Iron(II) passes into the core through six channels in tribute to the variability of iron measured is the prepara-
the protein coat and is oxidized to iron(III) for storage. The tion of the brain tissue. For example, prolonged immersion
molecular weight of ferritin is 474 kg/mol [75]. in formalin leaches iron out of the tissue and this could
The apoferritin coat (ferritin without an internal iron explain the low results of Thomas et al. [113]. Some
core) is composed of 24 subunits containing varied researchers [29,82] express the amount of iron in terms of
combinations of two homologous proteins, derived from the protein content (see Table 1). While their results
separate genes, referred to as L-ferritin (light) and H-ferritin cannot be directly compared to other groups [22,23,39,
(heavy). Variation in H and L composition produces ferritin 43,44,68,69,73,109,114], the ratio of basal ganglia iron
isoforms that confer specific physiochemical properties that to cortical iron (between 4:1 and 2:1) measured by Connor
best suit particular cells and tissues. H-rich ferritin is et al. [29] and Loeffler et al. [82] is consistent with
efficient at iron sequestration and is predominant in organs these studies.
with high iron utilization and little iron storage. In contrast, The landmark work of Hallgren and Sourander [69],
L-rich ferritin is efficient at iron nucleation and is associated whose data still provide the largest quantitative survey of
with iron storage [33,59,81]. brain iron content with age, indicates that iron typically
Hemosiderin, considered to be a degradation product of increases rapidly from birth until about 20 years of age for
ferritin [13], is a related iron-storage material that is water- nearly all brain regions. After this age, brain iron increases
insoluble. It appears to be associated with iron overload less rapidly, and in some regions approaches a distinct
disorders and hemorrhage [13]. 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] gray matter, compared to ferritin and iron, with similar
in the human brain show considerable variation in the levels in the cortex and basal ganglia (Table 2). However,
amount of ferritin measured (Table 2). The results of Dexter transferrin levels are typically between 10 and 50 times lower
et al. [44] and Reiderer et al. [98] are similar, but they are than ferritin concentrations per unit of protein (Table 2).
between 5 and 10 times lower than the concentrations White matter has about 2.53.5 times more transferrin than
obtained by Connor et al. [29,35] and about 100 times the corresponding gray matter [29].
greater than the results of Chen et al. [22]. Some of this
2.3. Cellular distribution of iron, ferritin and transferrin in
discrepancy may result from the use of non-isoferritin-
the normal human brain
specific polyclonal antibodies [44,98] that may have under-
estimated the ferritin concentration. Very early in iron research, iron deposits were ob-
Despite these controversies, individual studies indicate served in oligodendroglia cells, endothelial cells of
that ferritin distribution closely matches iron distribution with capillaries and giant pyramidal (Betz) cells of the motor
concentrations in the basal ganglia two to three times greater cortex [110], but it is the oligodendrocytic cells, both in
than in the cerebral cortex (Table 2). Ferritin levels in cortical gray and white matter, that stain most strongly for iron,
gray and adjacent white matter are also similar (Table 2). The ferritin and transferrin [26]. Oligodendrocytes are common
study by Connor et al. [35], which measured the amounts in white matter, as these cells are responsible for producing
of both the H-ferritin and L-ferritin isoforms, indicates that myelin, but iron-positive oligodendrocytes are also found
H-ferritin is the dominant isoform in the brain and its con- throughout the iron-rich basal ganglia [37]. In white
centration increases with age. In the elderly, the ratio of H to matter, iron-positive oligodendrocytes have a patchy
L-ferritin is between 1.5:1 and 3:1 depending on the region. distribution [31].
Immunostaining [26] indicates that, in addition to
2.2.3. Transferrin oligodendrocytes, microglia in the cerebral cortex and
Quantitative analyses measuring the regional distribution astrocytes, particularly in the basal ganglia, also contain
of transferrin in the brain are rare [29,35]. One study [35] 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 that may also result in excessive brain-iron accumulation
patchy distribution in white matter [37]. and potential vulnerability to brain dysfunction and demen-
As mentioned, transferrin is predominantly associated tia [71,91]. Most people with hemochromatosis carry one or
with oligodendrocytes, but with ageing, astrocytes appear to more genetic mutations in the hemochromatosis (HFE)
accumulate transferrin, particularly in white matter [26]. gene. New evidence suggests that mutations in the HFE
Neurons can also stain for transferrin, but the immunostain- gene also lead to greater risk, earlier onset or faster prog-
ing is inconsistent suggesting that transferrin is not common ression of AD or other dementias [87,101].
to these cells. Interestingly, the distributions of transferrin Brain iron is also known to increase in the basal ganglia
and ferritin/iron do not appear to overlap. This pattern is under ischemic or anoxic conditions. Dietrich and Bradley
particularly obvious in white matter where iron/ferritin have [45] state that bafter anoxic ischemic damage normal axonal
a patchy distribution compared to the uniformity of transportation of brain iron can no longer occurQ and
transferrin [26,28]. Another example of the nonoverlapping badditional iron concentration may occur more rapidly due
distribution can be found in astrocytes, which tend to be to the direct injury by lipid peroxidation degradation
transferrin-positive in white matter, but ferritin-positive products catalyzed by iron.Q
almost exclusively in gray matter [26].
2.4. Brain iron changes associated with disease 3. MRI and the brain
Brain iron appears to be elevated in several neurodegen- In human brain, the MR signal is generated primarily by
erative diseases. In PD, increased iron concentrations have water molecule protons. The image contrast arises from
been detected in the substantia nigra [68,98] and globus variations in the proton density and the longitudinal (T1)
pallidus [23,44,68,82]. An increase in Fe(III) relative to and transverse (T2) relaxation times of the associated
Fe(II) suggests that these changes might contribute to protons [104]. Relaxation times are determined by the
pathophysiologic processes underlying PD [98,109]. Similar amount of tissue water, but also the microscopic and
effects have been seen in iron regulatory protein-2 knockout macroscopic distribution of water in different sites, and
mice [97]. Gerlach et al. [59] remark that there is an increase the macromolecular water interactions [192]. For example,
in iron stores in the hippocampus in AD and PD, and the in pure water, T1 and T2 are similar, but in brain tissue, T1
entorhinal cortex and substantia inomminata are thought to is typically 1020 times longer than T2 because of the
play an important role as markers for iron in AD [107,108]. strong magnetic interactions between the water protons
More recent results suggest a shortening of T2 on MRI in and proteins and other macromolecules [102]. Macromo-
the entorhinal cortex [107,108], and the globus pallidus, lecular interactions, which involve even small concen-
putamen and caudate [9] in AD. These MR observations are trations of paramagnetic material (which is one whose
consistent with postmortem biochemical studies, which atoms have a permanent magnetic dipole moment) are
have measured excessive brain iron in cortical and basal also important in determining relaxation times because of
ganglia regions of the AD brain [29,39,43,82,114]. In HD, the large magnetic moment these molecules have com-
one research group [23] reported a 50% increase in palladial pared to a proton (about 1000 times greater, Ref. [192]).
iron and a 150% increase in the putamen. Ferritin and hemosiderin are considered to be the only
Multiple sclerosis plaques show globular structures of forms of nonheme iron present in sufficient quantities to
nonheme iron on the periphery of older plaques [37]. affect MR contrast in the human brain [104]. Early
Similar patterns have been reported for iron and beta- biochemical analysis [69] suggested at least one third of
amyloid plaques [61]. A robust ferritin immunoreaction the nonheme iron in the brain was in the form of ferritin,
accompanies senile plaques and many blood vessels in the but concentrations can be much greater in iron-rich gray
Alzheimers brain tissue [28] and ferritin-containing cells matter [19]. For example, Mossbauer spectroscopy meas-
accumulate around the periphery of the core of the plaque. urements on monkey brains [123] indicate that at least 80%
In the hippocampal gray matter, ferritin is found with many of the nonheme iron in the globus pallidus is in a ferritin-like
of the blood vessels. This suggests that increased iron in AD form and Dedman et al. [42] suggest that 8588% of the
patients may be related to blood escaping from the vessels nonheme iron in the parietal cortex is located in ferritin. As
and into the tissue. The iron-containing cells that extend into discussed above, transferrin concentrations in brain tissue
the cores of the plaques are thought to be microglia. The are at least 10 times lower than ferritin and it can only bind
cellular ferritin seen may, therefore, be due to the brains two iron atoms compared to thousands of iron atoms within
attempt at detoxification of the extravasated free iron. each ferritin molecule. The concentrations of other iron
The recent discovery of linkage between a mutation in species, like free iron aqua ions, the labile iron pool, or non-
an iron-storage protein and neuroferritinopathy, a rare, transferrin-bound iron are also considered to be too low to
dominantly inherited, adult-onset neurodegenerative disease affect MR contrast [104]. The human brain also contains
[41], suggests iron dysmetabolism can be a causal factor in other paramagnetic ions, like copper and manganese, which
neurodegeneration and may not be just a secondary asso- can potentially affect relaxivities if present in sufficient
ciation. Hemochromatosis is a liver iron-overload disease quantities. Again, Schenck [104] suggests that nonpatho-
E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 11

logical concentrations of copper and manganese are too weighted spin echo images. Ferritin has a weaker effect on
small to produce detectable MR contrast. T1 relaxation, but the resulting reduction in T1 times can
produce hyperintensity on T1-weighted images [92,121].
3.1. Relaxation mechanisms of ferritin
However, quantitative studies to verify the relationship
It has been well documented through in vitro studies that between a range of MRI parameters R2, R2*, R2V= R2*-R2,
paramagnetic iron will increase proton transverse relaxation phase images and brain-iron concentration have not
rates (R2 = 1/T2) and that the relaxation of solvent protons is universally agreed on the strength of the correlation (e.g.,
proportional to the concentration of paramagnetic ions. between R2 and iron) or the most appropriate parameter to
[175]. While ferritin behaves like a simple paramagnetic use. The current literature results for T2, T2* and T2V in
system at room temperature, in that magnetization is the brain are given in Tables 3 and 4, and the relationship
proportional to applied field strength, the observed linear between brain iron and various MRI parameters is
dependence of R2 with field strength [123,126] is contrary summarized in Table 5. Several studies have observed
to the quadratic dependence predicted by relaxation due to T1 effects as a function of iron content [57,92,120,123]
diffusion. In the outer sphere theory, protein-shielded and these results are also presented in Table 5.
magnetic particles dephase the spins of diffusing water
4.1. R2 and brain iron
protons increasing R2, but relaxation rates attributed to
ferritin are generally found to be too high to be explained by Both in vitro [22,123] and in vivo [5,6,9,56,84,102,
simple paramagnetism. In fact, the ferrihydrite crystal 125,155] data on healthy subjects show strong linear
structure of ferritin is antiferromagnetic and, because of correlations between R2 in gray matter regions and iron
the nanometric size of the grains, ferritin is also super- concentrations derived from the literature [69] or measured
paramagnetic. These unusual magnetic properties of ferritin directly from the tissue sample (Table 5). Schenker et al.
require a reconsideration of relaxation theories. [105] also demonstrate that the correlation between R2 and
A new theory to explain the relaxation mechanism of age in healthy subjects follows the same relationship to that
ferritin solutions has been proposed by Gossuin et al. [66]. of iron and age. However, opinions on the correlation
Their proton-exchange dephasing model (PEDM) uses a between R2 and iron diverge when gray and white matter
fast-exchange mechanism between two water fractions regions are considered together in healthy adults (see, e.g.,
(adsorbed protons, diffusing protons), each with their own [18,22] or when certain neurodegenerative diseases (HD,
relaxation rate, to explain the relaxation rate of the whole PD, AD) are considered [5,6,9,23,64,94].
system. The PEDM is similar to the static field dephasing These discrepancies arise because, although R2 is
model [170], which applies to R2*, but it also accounts for strongly affected by iron concentration, the water content
irreversible dynamics that govern R2 [66]. of brain tissue also influences R2. On average, there is a
12% difference in water content between white matter
4. Previous attempts to quantify brain iron using MRI (roughly 72%), with its high lipid content, and gray matter
(roughly 84%) [12,111,116]. The lower water content
There are two critical questions to ask about iron from results in a higher R2 value in white matter tissue com-
the perspective of MRI: pared to gray matter regions with the same iron concen-
1. bHow does it affect the signal of the tissue in which tration and could explain why some studies [22] did not
it is embedded and the tissue around it via MR obtain a strong correlation with iron. The observation by
relaxation mechanisms?Q Curnes et al. [40] that the heavily myelinated compact fiber
pathways, such as the anterior commissure, the internal
2. bWhat is its magnetic moment as determined by its
capsule and the fornix, show prominent signal decreases on
molecular environment?Q
T2-weighted images is consistent with the low-water, high-
The answers to these questions impact how we can protein content of these typically iron-poor (Table 3)
visualize the effects of iron in tissue. The former relates to regions. Furthermore, Whittall et al. [127] have measured
T1, T2 and diffusion effects, while the latter relates to a short T2 component (15 ms compared to more typical
susceptibility effects and, therefore, to T2* and diffusion. 50- to 150-ms range) in brain tissue attributed to water
To date, a full theoretical description of observed iron compartmentalization in myelin membranes, termed myelin
effects has not been forthcoming. water. Their research indicates that white matter contains on
Since the mid-1980s, clinicians and researchers have average 11% of the short-T2 myelin water compared to 3%
observed qualitative correlations between MRI signal in gray matter. In diseased brain tissue (substantia nigra in
intensity and regions of the brain known to have high iron PD, putamen in HD) the neuron loss is likely to increase
concentrations. Typically, these high-iron regions, like the local water content (e.g., from reduction in lipids), decreas-
globus pallidus, have a hypointense (dark) signature on T2- ing R2, opposing and potentially reducing the effect of iron.
weighted MR images. The presence of iron also leads to To overcome the limitations of R2 in disease, the
signal changes (both magnitude and phase) in T2*-weighted Bartzokis group adopted the field-dependent rate increase
gradient echo images and to signal changes in diffusion- (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 [64] have shown that R2V has the best correlation with
measure of ferritin content [4]. The Bartzokis group has iron in the substantia nigra of PD patients and we agree
consistently reported higher FDRI values in the basal with this assertion.
ganglia region of AD and PD brains, which are significantly There has also been some high-field work [61] that
different (statistically) to healthy controls [5,6,9]. The uses T2* measurements to investigate brain iron in the
correlation between the FDRI and iron concentration in mouse lemur. Gilissen et al. [61] have a well- established
healthy adults is also strong (Table 5). primate model which presents the neuropathological hall-
marks of AD, both senile plaques and neurofibrillary tangles.
4.2. R2V, phase, T2* and brain iron
They use a 3D gradient echo structure with a TE = 9 ms at a
The anomalous recovery of signal (R2-reduction pheno- field strength of 11.7 T (almost exactly the equivalent of
mena) caused by water changes in diseased tissue, despite what we use at 1.5 T for the best phase contrast images, but
a local increase in iron, has led researchers to investigate we use a TE of 80 ms in that case). They observe comparable
other MR protocols and parameters to quantify brain iron. A MR contrast (hypointense signal) resulting from the iron
number of researchers [56,64,94,155] suggest that the key content in the basal forebrain cholinergic structures, such
information for quantifying brain iron lies in R2V (those as the basalis of Meynert, and also in the globus pallidus,
signal changes caused by local susceptibility) not R2. which is consistent with their histochemistry. However,
Ordidge et al. [94] developed a method to measure R2V T2* has its own difficulties related to other local
despite the presence of background field variations that background sources of magnetic field variation that cause
dephase the signal and would otherwise yield a falsely high signal loss unrelated to the internal iron content of the
value for R2V. Ordidge et al. [94] measured significant tissue [165].
increases in R2V, but not R2 (typically reduced), in the
4.3. New developments
substantia nigra of PD patients, consistent with several
postmortem studies [44,68,98,109] on PD that have mea- More recently, two groups have developed a theory of
sured elevated levels of iron in the substantia nigral region. spin dephasing in the static or slow diffusion regime [170]
Graham et al. [155] and Gorell et al. [64] confirmed that R2V and in the fast diffusion regime [160]. Our theory directly
is increased in the substantia nigra of PD patients in suggests a means by which the source of the susceptibility
subsequent studies. The data from Graham et al. [155] and can be quantified through its magnetic moment and volume
Gelman et al. [56] also demonstrate that R2V strongly content [164,167]. This unique and exciting feature has
correlates to brain iron concentrations (Table 5). been considered when evaluating parallel fibers [171] and
We have shown that phase and iron content correlate to measure oxygen content in the brain either directly in
with age [92,93]. Ordidge et al. [94] and Gorell et al. 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 (s1/mg Intercept R corr. No. of Age [range Ref. Reference
strength (T) (no. regions) parameter Fe/g ww) (s1) 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 whether it be in the brain or liver, remains unanswered and
susceptibility-weighted imaging (SWI) also offers a means is critical to an absolute quantification of body iron.
to quantify iron content differences between tissues in the
brain. This approach [164,167] uses local phase differences
5. New directions in MRI methodology
to map the iron. Its predictions could be used to validate the
results from the previous static dephasing regime approach 5.1. High-resolution 3D, gradient echo imaging
or at least demonstrate a consistency in the MR approach.
In summary, R2V is from static field dephasing and 5.1.1. Magnitude imaging
although it is well known that R2 also depends on iron Obtaining a sensitivity to small local field susceptibility
concentration, R2V is more powerful because of its far- effects requires imaging with long echo times or at high
reaching effects from the local fields it produces. Unfortu- fields. Unfortunately, there are background field effects
nately, both R1 and R2 can be reversible depending on the caused by airtissue interfaces and these lead to dramatic
water content and other local structural changes that can signal losses in tissues adjacent to these areas for long
affect relaxation times. In these cases, the effect of iron echo times. We have previously shown that dephasing
remains invisible. However, this is not true for R2V (as across a voxel can be reduced by using very small voxels
discussed above) or phase. Therefore, we believe that phase so that the phase variation from background (or other)
and R2V will be the strongest and most accurate means to fields is reduced to less than 2p across the voxel [165].
map iron content, while R1 and R2 will still play impor- Measuring T2* properly means eliminating all other
tant complementary roles. sources of background error, no simple task. If there is
A further complication relates to tissue geometry. It is time to do a high-resolution multi-echo scan, then this is
well known that the shape and distribution of the source of the best way to both reduce dephasing and to be able to
magnetization change the response of the field. How this predict any remnant dephasing once the local phase
takes place in objects as complicated as human tissue, 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 15:1 is 3*0.004 ppm (where the term 0.004 ppm is the
4.0T to illustrate the information content in a T2* image. error for the bulk phase measurement itself when geometry
The values for T2* for white matter and gray matter (motor does not play a role) for the particular 3D sequence used for
cortex) are roughly as follows: 70 and 60 ms at 1.5T and those experiments. This implies that for a P value of .025,
60 and 40 ms at 4T. The presence of iron in gray matter we can assert that susceptibility differences as small as
would tend to reduce the T2 of gray matter faster than that 0.024 ppm (for blood) or 0.008 ppm (for bulk phase) would
of white matter. Now, using R2* = R2o+kB 0, we find be measurable with this sequence at 1.5 T (the sequence
used was a 5-min, 3D gradient echo method with a TE = 40
R241:5 T R2o R2V R2 o 1:5k 1
ms and a resolution of 0.51.0 2.0 mm3). Figs. 13
illustrate the information available in phase images. Fig. 1
R244:0 T R2o R2V R2 o 4:0k 2
shows the differences in gray matter and white matter.
where k is a constant independent of the field strength. First, Fig. 2 shows more structures such as veins and the globus
we take R2o to be 10/s and since T2* at 1.5 T for gray pallidus. Fig. 3 shows the variability of the phase (and hence
matter is 6070 ms, R2V will be 4.3/s6.7/s. Next, the iron content) in the putamen and globus pallidus.
multiplying R2V by 8/3 predicts R2V to be 11.5/s to 17.9/s, We have collected phase images at 40, 80 and as long as
and R2* = 21.5/s to 27.9/s at 4 T. Therefore, T2* is 120 ms at 1.5 T in 1995 [157] and shown that phase images
predicted to be 36 47 ms. Now R2o likely decreases a represent a means to visualize susceptibility differences
bit at higher fields which would predict an even lower T2* between tissues while still maintaining high-quality magni-
at 4 T than those results predicted here. Still, the fact that tude images. It was obvious at that time that venous
these T2* values are actually in the range of what is seen structures, gray matter/white matter susceptibility differ-
for most gray matter at 4 T is rather encouraging (T2* is ences and some form of iron in the basal ganglia were
quoted as being 38 ms for gray matter at 4 T [184], a value visible. Imaging at higher field strengths, such as 3, 4 and
that our own measurements also find for the motor cortex). 7 T will give the potential to reduce these echo times or to
The fact that white matter now has a higher T2* than gray increase the sensitivity of the scans.
matter again suggests that iron content in the gray matter is Using the above approach, we demonstrated on a series of
higher than that in the white matter, in agreement with our volunteers the correlation of phase with age [93]. We also
interpretation of the phase images. showed that T1 in the regions of increased phase decreased
[92]. This makes a strong connection to the iron content
5.1.2. Phase imaging because iron acts like a paramagnetic contrast agent. We
The use of phase images is a natural way to begin show in Fig. 1 an example phase image and the corres-
evaluating the presence of paramagnetic (or diamagnetic) ponding T1-weighted magnitude image. Clearly, the regions
differences between tissues in the brain. The phase in an MR of high phase (iron) contrast correlate with the regions of
image is given by lowest T1 contrast (see arrows), as expected from the re-
duction in T1 that iron causes in those tissues. The central
u  cDBt 3
sulcus particularly has a high iron content and therefore
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 Fig. 1. A comparison of a TE = 40 ms phase image (left-hand image) at 1.5
saturation during a functional brain imaging experiment T with a T1-weighted short TR, short TE (5 ms) image (right-hand image).
required measuring a susceptibility on the order of 0.12 ppm The short arrows show the frontal gray matter that has poor phase contrast
(in SI units). To do this with any confidence requires an 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
error that is significantly less than the measurement of in line with expectations that an increase in iron content leads to a decrease
interest. We find that the error in measuring the phase of a in T1 for the gray matter in that area. Similar contrast to this is seen in other
vessel parallel to the field when the SNR in the image is 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


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
Fig. 2. A phase image with a TE = 40 ms at 1.5 T. The different types of a mapping of the field changes independent of the
available contrast are labeled for a number of structures. magnitude response. As such, they are a robust means to
measure local changes in susceptibility. The usual approach
should show the poorest contrast on the T1-weighted image, is to try and measure the field outside of, say, a cylinder or
and it does. However, there is a potential confounding an object that has a known external field behavior with
problem. Gelman et al. [57] suggests that water content distance. Two such cases are spheres or cylinders, both
correlates better with T1 content than iron. Clearly, there is having relatively simple dipole solutions. The problem
more detective work to be done to determine if the source occurs when there are many objects in an image all having
is iron or water. different susceptibilities. The ideal solution would be to
Finally, we note that the use of the phase images as a mask have a method that fits the most general phase response to a
to enhance the magnitude image to improve the visualization set of shapes. In a sense, the work of Salomir et al. [230]
of iron content has been proposed and is referred to as SWI does just that. They show that, given a particular suscep-
[164]. It is well known that T2-weighted images already 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 tion once either the magnet moment or volume content of
following transformation of the susceptibility distribution: the susceptibility-producing source is known. A crude but
   straightforward approach to predict the susceptibility map
1 k2 is given by the inverse of the above filter in Eq. (4):
u  c4B0 4TE4FT 1  z2 4FT v Distribution " !#
3 K 
1 u 1
4 v FT FT 4 kz2
5
 c4B0 4TE 1
3  K2

where FT1 refers to the process of inverse Fourier Clearly, the method fails at the poles of the k-space
transform, FT to Fourier transform, k z to the z component filter 1/[(1/3)(k z2/K 2)]. To avoid division by 0, the value
of k-space and K 2 = k x2+k y2+k z2. The amazing element of this of the filter is forced to 0 at its poles. In practice, because
transformation is that it appears to require no a priori of the discrete values of k taken in the matrix implemen-
knowledge of the shape of the object (although we have tation, the poles are not encountered. The result of such a
shown that it begins to break down by more than a few calculation for a phase image of a cylinder perpendicular to
percentage for objects that become larger than one quarter of the main magnetic field, having a susceptibility value
the field of view). Now, if an inverse relation between inside of v i =1 ppm and 0 outside, and with a TE of 15 ms,
susceptibility and phase could be obtained, that is, if it is shown below in Fig. 4. This method is tantamount to
were possible to predict the susceptibility distribution from fitting the phase profile when the object is known but
phase images, it would be of great scientific and clinical avoids the need to know anything about the object.
significance. For example, in quantifying iron deposits in
5.3. The use of complex analysis to measure the product of
the body, removal of susceptibility artifacts in SWI, EPI
volume fraction and susceptibility
and other gradient echo sequences using long TE is
critical. The ability to produce a susceptibility map itself With the ability of obtaining non-obscured phase images,
is tantamount to solving the question of iron quantifica- the next goal is to quantify the susceptibilities of tissues from

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.
E.M. Haacke et al. / Magnetic Resonance Imaging 23 (2005) 1 25 17

images. For example, we are developing a complex sum is the echo time. This equation is a rearranged version of
method when an infinitely long cylindrical object is imaged. Eq. 1 of Cheng and Haacke [149]. By changing the
If we draw a coaxial cylinder volume around the object, radius of the circle from 60 to 200 pixels, we can obtain
not only we can sum the complex MR signals enclosed by different values of the object susceptibility outside the
this cylinder (that we draw), but also we can theoretically disk and use these values to calculate the susceptibility.
calculate the total complex MR signal inside it as a This approach yields a susceptibility of 9.02F0.01 ppm.
function of susceptibility difference, volume fraction, spin The numerical error is likely due to the discretization of
densities and other appropriate imaging parameters. If the the simulated disk.
susceptibility difference is the only unknown parameter, Next, we consider a uniform but unknown spin density
then it can be found through comparing the theoretical of the object in our simulation. In this case, we will need to
calculation to the complex sum of the MR signals. draw two circles (see Fig. 5), use the above equation twice
In order to demonstrate this concept, we have done the for two different volume fractions and then numerically
following simulations. On a magnitude image, we consider solve the susceptibility of the object outside the disk. We
a disk (which is the cross section of an infinitely long can again generate different susceptibilities by varying the
cylinder) with a radius of 20 pixels and no spin density inside radii of circles. Doing so yields a susceptibility of
the disk and unity spin density outside the disk. On its asso- 9.03F0.01 ppm. However, we have found that when the
ciated phase image, assuming that the cylinder is per- small circle is smaller than two times the disk radius, we
pendicular to the main field and the region outside the disk may not be able to obtain an accurate susceptibility of the
has a constant susceptibility, the phase is then distributed as object. This is due to the oscillatory nature of the Bessel
shown by Haacke et al. [225]. In this simulation, we have function in the equation. In this case, the correct suscepti-
modeled a susceptibility of 9 ppm outside the disk with a bility can still be obtained from the theory if a rough value
field strength of 1.5 T and an echo time of 5 ms. Now we of the susceptibility is known when solving the equation. It
draw a concentric circle around the disk. The theoretical sum is also important to note that when the product of the echo
of the signal is: time and the susceptibility differs from our numbers here,
the above findings of the circle radii may have to be
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 ; susceptibility and echo time becomes too small, then the
k z 2p
equation we intend to solve becomes insensitive to the range
6 of susceptibility discussed here.
The complex sum method potentially offers a lower
where R is the radius of the circle, q 0 is the spin density, k noise from the data analysis. Instead of a least-squared
is the volume fraction which is the ratio of the disk area to fitting of several data points to obtain the susceptibility,
the area within the circle, J 0 is the Bessel function, c is using a complex sum of the signal within a specified
the gyromagnetic ratio, Dv is the susceptibility difference region gives us a reliable susceptibility with a low noise
inside and outside the disk, h is the angle between the thanks to the average over many points. Furthermore, the
cylinder and the main field, B 0 is the main field and TE 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- spherical shapes, especially given the large voxels we are
ful basis for quantifying ferritin or iron imbedded inside using) is given by:
the brain.

S t q1  kexp  0:41tdx2 for tdx b1:5 and
5.4. Extraction of susceptibility using a special spin
echo/gradient echo imaging method 7

In an attempt to quantify signal losses in T2*-weighted S t q1  kexp  itDxexp  R2Vjt  ts j


imaging, we developed a theory that makes it possible to 8
for tdx N1:5
predict signal behavior in the presence of small randomly
distributed local sources of susceptibility change. Specif- where dx =c4p(MM o)/3, R2V=1.21kdx, t s = 1/(1.21dx)
ically, we showed that the signal change is not exponential and Dx = 0.16kdx. Note that the early signal can be seen
in nature near the time origin and is exponential in the to be Gaussian in nature while the signal at longer times is
intermediate (and long) time domains [170,222]. The Lorentzian. By measuring the short-time and long-time
theory can be used to extract the volume susceptibility of components, we can get a numerical estimate for the
the random sources as well as their volume fraction within arguments in each exponential and, therefore, for (MM o)
a voxel. The exact quantitative nature of this method has (extracted from dx) and for k (extracted from R2V since dx
not yet been validated for a set of random structures in is now known). When the susceptibility is known, R2V can
vivo but rather only via Monte Carlo approaches. be used directly as a measure of the volume fraction k.
In order to account for background field inhomogeneities For much smaller susceptibilities on the order of parts
across a slice or voxel that are not caused by these micro- per million, such as diamagnetic or paramagnetic substances,
scopic effects, and to eliminate any dependence on the rf then 1/dx is on the order of several dozen ms. For example,
pulse shape, we and others have designed special combined for a vein with a hematocrit of 0.4 and oxygen saturation
gradient echo and spin echo acquisition methods [169,177]. of 55%, the value of dx is about 54 Hz at 1.5 T.
A series of gradient echoes are collected around the spin Ironically, the smaller the susceptibility, the longer 1/dx
echo and used to remove background field effects as and the easier it is to measure. By measuring the signal
follows. The last gradient echo is divided by the first gra- say up to 100 ms around the spin echo would allow these
dient echo image to create the equivalent of a T2-weighted unknown parameters to be fit to extract the volume
image without dephasing across the voxel. Once T2 is content and the susceptibility of the source producing the
known, its effect on the multiple gradient echoes is removed signal loss.
so that only the pristine changes due to T2V (those signal
5.5. Separating heme from nonheme iron
changes caused by the local sources of susceptibility)
remain. The signal dependence can be shown to have a Given the numerous ambiguities discussed in this paper,
quadratic behavior in time and, when fit, both the magnetic it is not clear how much of the phase effects seen in the
moment and volume content of the sources can be gradient echo images comes from nonheme iron and how
extracted quantitatively. In fact, it has already been shown much comes from the blood or heme iron. To investigate
by Ordidge et al. [94] that T2V is the most sensitive of the this, one might inject a known quantity of contrast agent
methods to the presence of iron in the study of iron build- (the conventional gadolinium-based contrast agents have a
up in the substantia nigra in PD. Unfortunately, their phase effect of 18 mM1 ms1) to mimic the susceptibility
method to measure T2V is a multistep approach, whereas of blood [159,167]. By doubling the effect of blood, it
our method allows extraction of all parameters in a single would be possible to obtain an estimate as to what the
experiment in a single sitting. A similar method using the effect the blood itself has on the phase. Other types of
free induction decay signal rather than the gradient echo contrast agents could be used to change local blood flow
information after the spin echo has been proposed by Ma and local de-oxyhemoglobin to look again for changes in the
and Wehrli [161]. The latter method has some dependence phase caused by heme iron. This could be accomplished by
on the ability of the 1808 pulse to not introduce scale breathing carbogen or ingesting caffeine for example. Any
changes, whereas the method we propose has no such de- other means of affecting the local blood signal would also
pendence since all the data are collected after the refo- work such as saturating the signal from the blood to see
cusing pulse. if that affects the local phase.
It is possible from the theory of static field dephasing to Then there is the issue of resolution and scale depen-
extract the absolute iron content and volume of iron in a dence. If some phase effects come from major vessels they
voxel. Practically, however, it is usually just the product of will manifest themselves differently for different resolu-
these two that can be found with any accuracy. We have tions. Uniformly distributed sources of susceptibility will
both theoretically predicted, and experimentally verified, usually be invariant to resolution. Any changes to the
the following theory [166,170]. The signal behavior for a phase of the image in the parenchyma or in the critical
random set of spheres of volume k (this is an excellent time 1/dx will be a marker of the bloods contribution
approximation for iron, which is known to conglomerate in 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 exponential growth by design and was fit for different
then show what the fractional role of heme iron is in MRI regions as follows:
experiments. If heme iron has little contribution, then any
variations in phase can be assumed to be linearly related to Frontal white matter y 3:95f1  exp  0:10xg 0:31
the iron content. If this is not the case, then the Globus pallidus y 21:41f1  exp  0:09xg 0:37
relationship between phase and T2*, for example, may
still be linear with iron concentration but will have an Cerebellar cortex y 2:70f1  exp  0:085xg 0:68
offset related to the heme iron component. These contrast
Prefrontal cortex y 2:43f1  exp  0:07xg 0:58
and phase issues remain open areas of research.
Temporal cortex y 2:70f10  exp  0:07xg 0:55
6. Conclusion Sensory cortex y 3:97f1  exp  0:07xg 0:49
The ability to measure accurately brain iron using MRI Parietal cortex y 3:311  exp  0:06x 0:60
is still evolving. The motivation is to be able to predict
dangerous levels of iron in tissue. This may have other Occipital cortex y 4:03f1  exp  0:06xg 0:72
important applications in the future with the advent of new Motor cortex y 4:79f1  exp  0:05xg 0:40
iron chelation drugs [106]. These drugs make it possible to
remove iron from ferritin and low-molecular-weight com- Caudate nucleus y 9:66f1  exp  0:05xg 0:33
plexes. An equally exciting application is the ability to
Putamen y 14:62f1  exp  0:04xg 0:46
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 where y is the nonheme iron in milligrams per 100 g fresh
contrast agents [232241]. 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. [18] Brooks DJ, Luthert P, Gadian D, Marsden CD. Does signal-
attenuation on high-field T2-weighted MRI of the brain reflect
The two charts in Fig. 6 show the results from Loeffler regional cerebral iron deposition? Observations on the relationship
et al. [82] for transferrin and ferritin. We show these here to between regional cerebral water proton T2 and iron levels. J Neurol
demonstrate the types of error present between subjects. Neurosurg Psychiatry 1989;52:108 11.
[19] Brooks RA, Vymazal J, Bulte JWM, Baumgarner C, Tran V.
Even if measurements were perfect experimentally, the Comparison of T2 relaxation in blood, brain, and ferritin. J Magn
large variance in the data shows that there can be Reson Imaging 1995;4:446 50.
significant variation from person to person in their iron [20] Brooks RA, Vymazal J, Goldfarb RB, Bulte JWM, Aisen P. Relax-
content. Any quantification of iron with age must then be ometry and magnetometry of ferritin. Magn Reson Med 1998;40:
taken with a grain of salt. 227 35.
[21] Cairo G, Pietrangelo A. Iron regulatory protein in pathobiology.
Biochem J 2000;352:241 50.
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