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Neurotherapeutics. Author manuscript; available in PMC Sep 2, 2007.
Published in final edited form as:
PMCID: PMC1963417
NIHMSID: NIHMS26623

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

Summary

Iron is important for brain oxygen transport, electron transfer, neurotransmitter synthesis, and myelin production. Though iron deposition has been observed in the brain with normal aging, increased iron has also been shown in many chronic neurologic disorders including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. In vitro studies have demonstrated that excessive iron can lead to free radical production, which can promote neurotoxicity. However, the link between observed iron deposition and pathologic processes underlying various diseases of the brain is not well understood. It is not known whether excessive in vivo iron directly contributes to tissue damage or is solely an epiphenomenon. In this article we focus on the imaging of brain iron and the underlying physiology and metabolism relating to iron deposition. We conclude with a discussion of the potential implications of iron-related toxicity to neurotherapeutic development.

Keywords: Iron, Neurodegeneration, MRI, Chelation, Alzheimer’s disease, Parkinson’s disease, Multiple sclerosis

Introduction

Iron is vital for normal neuronal metabolism. Excessive iron, however, may be harmful. It has been demonstrated in vitro that free iron or iron overload can lead to free radical formation, lipid peroxidation, and neuronal damage.1 Iron accumulates as the brain ages and has been linked to motor and cognitive dysfunction in the elderly.2 Neuroferritinopathy, a genetic disorder of excessive brain iron storage, leads to cognitive and motor difficulties that resemble those seen in the elderly.3 A growing body of data suggests that brain iron accumulation in vivo may contribute to tissue damage in a variety of chronic neurologic disorders. Histologic and magnetic resonance imaging (MRI) data have suggested increases in iron levels in the gray matter in Parkinson’s disease (PD),410 Alzheimer’s disease (AD),1117 multiple sclerosis (MS),1821 and a host of other chronic neurologic disorders.22 Consequently, there is a growing interest in optimizing the ability of MRI to estimate iron deposition in vivo. Progress has been made in MRI assessments so that quantitative information can be obtained and related to brain iron levels. Several studies have linked MRI-based iron measures to clinical impairment in chronic neurologic disorders. In parallel with these developments, basic science investigators have continued to make strides in understanding the potential mechanisms by which iron could contribute to neurotoxicity. The interest in brain iron has driven the development of neurotherapeutic strategies such as chelation therapies, which have been tested in animal models and human studies. Successes in animal chelation therapy have spurred human clinical trials. Though chelation studies in humans have been performed on only a limited number of subjects with chronic neurologic disorders, results have been mixed and side effects remain a concern.2325 New compounds with high iron affinity, better CNS penetration, and more favorable side effect profiles are being developed. Future investigations of iron in the brain, including how to best monitor iron deposition in vivo, the clinical relevance of excessive iron deposition, and the mechanistic relationship between iron deposition and disease pathophysiology hold the promise of advancing the field of neurotherapeutics. In this article we will review the current status of the field of brain iron deposition with an emphasis on imaging, metabolism, histology, and pharmacologic developments. We will review the detection of iron on conventional MRI studies, and discuss new MRI techniques being developed to more sensitively and specifically quantify brain iron. We will review brain iron chemistry, iron trafficking, and how excessive iron may contribute to cellular damage and neurodegeneration. We will place these ideas into context with regard to chronic neurologic disorders associated with excessive brain iron deposition. We will conclude with a discussion of the current status of iron related neurotherapeutics.

MRI and Brain Iron: Technical Aspects

MRI has proven to be important for in vivo characterization of iron deposition in aging and neurodegenerative disorders. When using MRI to detect brain iron deposition in chronic neurologic disorders, ferritin and hemosiderin are considered to be the only forms of non-heme iron present in sufficient quantities to affect MR contrast.26 MR signal is the result of mobile protons in tissue that lead to contrast with differences in the density of the solvent water in tissues reflected in two relaxation times of the protons: longitudinal (T1) relaxation time and transverse (T2) relaxation time. Contrast in MR images on T1 and T2 sequences in the brain is due to the interaction of water with protons, and magnetic and paramagnetic ions.26 In general, magnetic and paramagnetic ions shorten the longitudinal and transverse relaxation times of the mobile protons in the brain. The end result is that areas with short T1 appear hyperintense on T1-weighted images, while areas with short T2 appear hypointense on T2-weighted images. A full discussion of the technical aspects of MRI-based iron assessment is beyond the scope of this review. The reader is referred to other excellent reviews.2628

Relaxometry

Measurements of transverse and longitudinal proton relaxation rates in the brain from MRI can estimate brain iron concentrations. In an attempt to find answers to how iron and other tissue properties affect MRI, we will discuss the most relevant relaxometry metrics. R2, R2*, and R2′ are the relaxation rates derived from T2, T2* and T2′ relaxation time decay curves. R2, R2*, R2′ are the inverse of T2, T2*, and T2 and are increased by the presence of non-heme iron (Figure 1). R2* is calculated from T2*-weighted gradient echo sequences, while R2′ is derived from the following equation: R2′=R2*−R2. R2′ was developed to improve specificity for tissue iron by reducing the known R2 and R2* signal losses associated with local field inhomogeneity.27 Many in-vitro2829 and in-vivo3038 studies have demonstrated a strong correlation between R2 and iron concentration as determined by histologic studies of brain gray matter. A weaker correlation is obtained for white matter iron. This is most likely due to the influence of tissue water on R2.29,39 The effect of water content on R2 hampers the ability to estimate iron concentration in neurologic diseases associated with a variety of pathologic processes that increase water content (i.e. inflammation, gliosis, edema, and axonal/neuronal loss). Ordidge et al.40 demonstrated that R2′ was significantly increased in the substantia nigra of patients with PD relative to controls while R2 was not. The R2′ increase better reflects histologic data which consistently demonstrates excessive iron deposition in the substantia nigra in PD. Other groups33,38,41 have also shown that R2′ estimates iron concentration more accurately than R2. Many other researchers36,42,43 demonstrated that both R2 and R2′ are affected by iron. Studies on R2* have reported limitations attributed to local background sources of magnetic field variation that reduce the specificity for iron.44 So in essence, R2 can be rendered somewhat insensitive by the water content in the brain, while R2* is susceptible to contributors other than iron and R2′ may have limited sensitivity. Sequences such as the gradient echo sampling of free induction decay and echo (GESFIDE)4547 and partially refocused interleaved multiple echo (PRIME)38 allow the derivation of R2, R2*, and R2′ from a single pulse sequence. The GESFIDE sequence consists of two echo trains, the first after an excitation pulse, the second following a 180 degree refocusing pulse. Hikita et al.47 studied various MRI sequences to see which of the metrics most accurately reflected brain iron and concluded that R2 obtained by GESFIDE sequence and R2 obtained by multiple spin echoes fitted to a single relaxation curve showed higher correlations with brain iron than R2′ obtained by GESFIDE sequences. Yablonskiy et al.48 has proposed a variation on the GESFIDE sequence called gradient echo sampling of the spin echo which samples only the rephrasing and dephasing spin echo signal components which they purport to have a lower signal-to-noise ratio compared to GESFIDE. The PRIME sequence comprises one spin-echo and five gradient recalled echoes acquired with each 180° RF pulse. Despite all of the above advances, there is no single relaxometric measure that can be universally said to reliably quantify iron in the brain. This has driven the continuing development of techniques to better quantify in vivo iron concentration.

Figure 1
T2 relaxometry at 3T (axial images). Figures A–D are from a 47 year-old patient with relapsing remitting multiple sclerosis (MS) and E–H are from a 47 year-old normal control. Figures A and E are R2 maps, B and F are R2* maps, C and G ...

A newer relaxometry measure, T2 rho, has been developed which is more sensitive to diffusion and exchange of water protons in environments with different local magnetic susceptibilities. Shortening of T2 rho likely reflects tissue iron concentration better than conventional MRI. Rather than a standard acquisition without radiofrequency irradiation, H2O MR signal is acquired in the presence of a radiofrequency pulse. Wheaton et al.49 demonstrated an increase in iron related contrast when comparing images created with T2 rho to conventional T2 in the normal human brain. Using a 4T magnet with a rotating frame and applying adiabatic pulses Michaeli et al.50 demonstrated a statistically significant shortening of relaxation times in substantia nigra tissue in patients with PD compared to normal controls with T2 rho but not with routine T2. This correlates with postmortem observations of excessive iron deposition associated with the disease and suggests that this novel technique generates better iron related contrast than conventional T2 methodology.

Field dependent rate increase

Field dependent rate increase (FDRI) is a technique studied extensively by Bartzokis et al.43 employing differing MRI field strengths (e.g., 1.5 and 3T) to compare T2 relaxation times in the same tissue area. Increasing R2 values with higher field strength are directly proportional to ferritin concentration as shown by correlations with published brain iron concentrations and iron levels in phantom solutions.

Magnetic field correlation

Developed by Jensen et al.,51 the new technique magnetic field correlation (MFC) uses asymmetric spin echoes to quantify brain iron. MFC is based on the influence of MR signal by magnetic field inhomogeneities (due to spatial variations in magnetic susceptibility). These changes can be due to macroscopic structures such as cavities, bones and vessels, microscopic structures such as capillaries, and the presence of paramagnetic substances (e.g., metals, contrast agents). MFC imaging is based on a theoretical model of MR relaxation in the presence of magnetic field inhomogeneities and uses a non-monoexponential decay curve. Jensen et al.51 reported that MFC maps showed more contrast between the basal ganglia and adjacent tissue than corresponding R2 maps. This led the investigators to conclude that MFC imaging can provide a more sensitive method for quantifying brain iron than R2 though there was no comparison made with R2* or R2′. Because MFC grows with the square of applied field strength, it was suggested that high field scanners (e.g., 3T or greater) are most suitable for MFC imaging. Because MFC is affected by water diffusion, non-uniform diffusion as seen in edematous tissues, may introduce error. It should also be noted that MFC measures magnetic field inhomogeneities, which may be due to any type of magnetic substance such as other transitional metals found in tissue.

Biochemistry and Physiology of Brain Iron

Iron plays an important role in the maintenance of many neurobiologic processes. It is essential for the transport of oxygen, electron transfer, synthesis of neurotransmitters and production of myelin.52,53 In addition, normal aging is characterized by increasing brain iron accumulation. The physiologic, biochemical, and anatomic aspects of iron homeostasis are important to understand in healthy individuals in order to lay a foundation for understanding the role of iron in chronic neurologic disorders.

Iron transport

The pathway that dietary iron takes to get to the brain begins in the intestines where Fe3+ (ferric iron) is reduced by duodenal cytochrome b to Fe2+ (ferrous iron). In this reduced form, the divalent metal transporter can carry iron across the duodenal epithelium into the blood. Multiple proteins regulate gut intake to help achieve homeostasis. In the blood, Fe2+ is oxidized to Fe3+ by ceruloplasmin or hephaestin so it can be coupled with a transferrin, a protein that is the predominant serum iron carrier.52,54,55

However, iron circulating in this form in the blood outside of the CNS cannot directly cross the blood brain barrier (BBB). There are several pathways that can transfer iron across the BBB. The first and probably most common is through transferrin receptors on brain endothelial cells, which bind iron circulating in the form of transferrin. The transferrin receptor-bound complex then enters the brain by endocytosis. Several other transporter systems may also deliver iron across the BBB, such as the divalent metal transporter and the lactoferrin receptor.52,56

In addition, these pathways, especially the transferrin-receptor mediated pathway, are the main avenues for iron transport within the CNS (i.e., into various cell types of the brain). The amount of iron taken up and stored by the cells is a function of the abundance of the transferrin receptor and its ligand.56 This can be controlled at the post-transcriptional level by iron regulatory proteins (IRPs) that interact with iron responsive elements (IRE) on RNA to alter the expression of ferritin and the transferrin receptors on brain endothelial cells, neurons, glia and oligodendrocytes.55,56 When there is not enough iron in the milieu, IRPs bind to IREs to increase the stability of the transferrin receptor and decrease the expression of ferritin. This essentially allows the cell to uptake more iron and use it efficiently without it first being bound to the storage protein, ferritin.55 Ferritin is the most common iron-storage protein in the brain. It consists of two types of subunits, the heavy (H) and light (L) chains that work in complementary ways to store intracellular iron. H-ferritin efficiently sequesters iron and is found in organs with high iron utilization and little iron storage, while L-ferritin is associated with iron storage.57,58 Another sequestrant of iron found in high concentrations in the substantia nigra and locus ceruleus is neuromelanin. There is evidence to suggest that neuromelanin acts to reduce potentially toxic iron by chelating iron found in the cytosol of neurons.59,60 The CSF and brain interstitium probably also contain unbound extracellular iron which is likely complexed with citrate and taken into cells through a non-transferrin receptor mediated mechanism.61 Finally, after the brain uses the iron it has stored, the iron must leave the cell, and the copper-associated protein ceruloplasmin may facilitate cellular release of iron.52,54 Iron leaves the body via bleeding or through the shedding of skin and other cells.55

Iron toxicity

In vitro iron accumulation has been shown to lead to cell damage. Ferritin-bound iron is considered “safe” because the iron therein does not react with surrounding molecules in a detrimental way. But a breakdown of the protective ferritin molecule or an overload of free iron due to a lack of ferritin in cells is highly toxic.1,62 The release of free iron in the brain can result from the breakdown of heme by heme oxygenase-1, which can initiate oxidative stress.63 Free iron (unlike soluble stable ferritin) when converted into hemosiderin and other oxyhydroxide derivatives becomes more likely to exchange electrons with surrounding molecules. These hemosiderin and oxyhydroxide compounds may initiate and propagate the production of free radicals, leading to lipid peroxidation.1 Neurotoxicity may result from a biochemical reaction involving the production of a reactive oxygen species through iron-induced oxidation of hydrogen peroxide. Specifically, via the Fenton reaction,64 Fe2+ donates an electron to hydrogen peroxide. The resulting products are Fe3+, OH and the free radical OH.64 Polyunsaturated fats in the brain, such as in cell membranes can then donate an electron to this highly reactive free radical. The products of this reaction, organic free radicals, can interact with oxygen to create oxygen radicals that can continue the cycle of making organic free radicals, creating a self-perpetuating “viscous cycle”. Once the reactive oxygen species are generated, these species can participate in the oxidative destruction of the lipids, which are important parts of the cytostructure, such as cell membranes.1 This destructive pathway is continuously propagated by the excess of reactive iron and is a potential cause of cellular apoptosis. Thus, this hypothesis contends that iron deposition results in tissue damage by either directly damaging cells or changing the cellular environment so that it is more susceptible to toxins or other pathologic processes.

Endogenous protection from iron-related damage

In the brain, several endogenous antioxidants and enzymes are responsible for alleviating the deleterious effects of reactive oxygen species and free radicals that are created in normal metabolic processes. One antioxidant system in the brain involves glutathione. In this system, glutathione in a reduced state interacts with hydrogen peroxide and other organic peroxides to yield the oxidized form of glutathione, GSSG, water and alcohol. This reaction removes the likelihood of a reaction between the peroxides and iron that creates reactive radical species.65 Glutathione has been shown to protect murine astrocyte cultures from iron-induced neurotoxicity. This reaction is catalyzed by the enzyme glutathione peroxidase and is accomplished by the clearance of hydrogen peroxide.65 Experimental work has also demonstrated cells that are able to survive iron-induced toxicity do so by increasing the intracellular level of glutathione.66 A form of Vitamin E, alpha tocopherol, also plays a role as an antioxidant in limiting lipid peroxidation by donating a proton to reactive oxygen species thus making them more stable and less reactive.67 When the alpha tocopherol analogue, MDL 74,722 was added to cerebellar granule cell cultures before treatment with iron, brain injury and cell toxicity were attenuated.68 Similarly, even transient alpha tocopherol administration to hippocampal neurons results in decreased iron-induced oxidative damage.69

Histology, topography, and in vivo characterization of brain iron with aging

Microscopic iron distribution

It is important to understand the normal cellular and anatomic age-dependent distribution of iron so that differences may be appreciated when considering abnormal iron deposition.70 Immunohistochemical iron staining reveals that iron, ferritin, and transferrin are found in various cell types and in widespread brain regions. Strong staining for iron, ferritin, and transferrin indicates that oligodendrocytes are the primary repository for iron in the brain.71 Microglia in the cerebral cortex and astrocytes in the basal ganglia also stain positive for ferritin. Neurons inconsistently stain for transferrin, while neuronal iron is present predominantly in the form of neuromelanin.59,72 In microglia and astrocytes, an increase in iron staining correlates positively with age of the subject. Conversely, oligodendrocytes do not show an increase in staining iron with age.71,73 In neurons, it is believed that the iron-ferritin complex is assembled in the cell body and then transported along axons. Presumably axonal disruption as a result of disease processes or normal aging could disrupt this transport. This could be one way that a neuropathologic process leads to iron accumulation. In the absence of injury, ferritin that reaches its target area is then degraded by lysosomes so that the iron can be used.74

Macroscopic iron distribution

Using conventional MRI, iron deposition in the brain has been observed to appear in the globus pallidus as early as six months after birth.75 The same study showed evidence of iron deposition in the substantia nigra at 9–12 months, the red nucleus 18–24 months, and the dentate nucleus at 3–7 years of age. In a landmark postmortem study of 81 normal brains, Hallgren76 showed a progressive increase in whole brain iron deposition until the end of the third decade of life. Levels then stabilized until approximately the sixth decade of life and then increased slowly. Thomas et al.77 added that during the first three decades the substantia nigra exhibits the most profound T2 hypointensity. Using conventional MRI, Milton et al.78 noted a relative paucity of iron deposition in the thalamus and caudate with aging and added that iron deposition occurs significantly in the putamen only in those aged 60 or above. The locus ceruleus accumulates iron more slowly than the substantia nigra.73 With increasing age, iron increases in astrocytes and microglia while the primary cellular repository for iron, oligodendrocytes, experience little accumulation.72,74 Bartzokis79,80 has demonstrated by MRI that women have significantly lower ferritin iron in areas such as the caudate, thalamus and white matter than men. The group speculates that the slower increase of iron in the female brain may to a certain extent explain why women tend to develop AD and PD at a more advanced age then men. Interestingly, in rhesus monkeys, increases in MRI-based brain iron content were strongly correlated with age-related motor dysfunction.81 There is a suggestion that this result may extend to humans: even in “healthy” adults, decreased signal T2 intensities were correlated with deficits in motor and cognitive tasks.2

Iron Deposition in Chronic Brain Disorders

Views concerning the role of iron deposition in the CNS have undergone considerable advances during the last decade. It has now become clear that iron deposition occurs in the adult brain in a variety of chronic neurologic disorders such as AD and PD, and probably also MS.22, 74 However, it is still unclear whether the increased iron content is purely an epiphenomenon or actually contributes to tissue damage in these disorders. In this section, we provide an overview of histologic, experimental, and MRI findings that help to shed light on the role of brain iron in a variety of neurologic disorders.

Alzheimer’s disease

Iron deposition is gaining increased recognition as a putative factor in the pathogenesis of AD. Animal models, pathologic studies, and MRI have linked iron to AD. Animal studies suggest that excessive iron contributes to oxidative stress and neuronal injury through the production of hydroxyl free radicals.74,82 Animal models also suggest that increases in iron may either worsen the course or increase the risk of developing AD. It is also established from postmortem pathology studies that iron deposition occurs in neurons, neurofibrillary tangles and plaques of patients with AD.17 Progress has been made in identifying the role of iron in AD using experimental in vivo and in vitro models. For example, iron exacerbates amyloid-induced neuronal injury in human neuroblastoma cell line M1783 and also enhances aggregation of beta amyloid proteins in vitro.84 Bishop and Robinson85 used an in vivo rat model of AD to show that iron augments beta amyloid neurotoxicity. Furthermore, genetics studies have also indicated that mutations of genes involved in iron management can increase the risk of AD. Mutations in the transferrin86 and hereditary hemochromatosis (HFE) gene87 lead to deranged iron metabolism and confer a risk for development of AD.

Investigators have used MRI to detect increased brain iron content in vivo in patients with AD. Using FDRI, Bartzokis et al. 30,32,88 demonstrated increased iron levels in the caudate and putamen in patients with AD compared to normal controls. Interestingly, increased iron levels were found in patients with young-onset AD compared to patients with older-onset AD88 supporting the notion that high brain ferritin may be a risk factor for early age of AD onset.89 A study by House et al.90 measured R2 in 14 brain regions in patients suffering from memory dysfunction and showed increased iron in the temporal gray matter (most notably the hippocampus) when compared to normal controls. In these cohorts no difference in white matter iron was found.90 In a separate study using high-resolution 4.7T MRI, this same group of investigators showed a direct correlation between R2 and iron concentrations in postmortem brain tissue obtained from patients with AD.11 The study also corroborates previous studies demonstrating increased basal ganglia iron levels in patients with AD.30,32 Collectively these studies suggest that brain gray matter iron deposition may facilitate some of the early neurodegenerative changes seen in AD. It is now evident that excessive brain iron deposition occurs in AD. Further investigations need to be performed to better establish the link between iron-mediated toxicity and AD pathogenesis, to ultimately determine if this link provides new therapeutic targets. Inhibition of beta-amyloid production in AD patients would likely either slow or halt disease progression. Decreased iron, copper, and zinc-mediated damage may disrupt beta amyloid production and its potential toxic effects. It has been demonstrated in vitro that neurons pretreated with desferrioxamine (DES), an iron chelator, then exposed to beta-amyloid beta experience less toxicity than neurons not pretreated with DES.83 Small clinical studies of both DES and another iron related therapy have been conducted in AD. In the DES trial, 48 patients with probable AD were randomly assigned to receive DES (125 mg intramuscularly twice daily, five days per week, for 24 months), oral placebo (lecithin), or no treatment. DES treatment led to significant reduction in the rate of decline of daily living skills as assessed by both group means (p = 0.03).24 It is interesting that this effect was achieved despite DES’s inability to cross the BBB. It is speculated that the BBB may be damaged in AD, allowing for the observed treatment effect. The chelator Clioquinol is thought to act not only on iron but to inhibit zinc and copper ions from binding to beta amyloid. In a mouse model of AD clioquinol decreased brain beta amyloid deposition.91 Based on the strength of these data, a pilot study of clioquinol in patients with AD was performed.23 AD patients (n = 18) who received clioquinol showed a decrease in plasma beta amyloid levels when compared with 18 patients receiving placebo. After 36 weeks of treatment there was a trend toward improved cognition in the clioquinol group that approached statistical significance (p<.07). Though the drug was well tolerated in this study the manufacturer recently stopped making clioquinol because of difficulties with the manufacturing process.

Parkinson’s disease

Many but not all92,93 studies have reported excessive iron deposition in the substantia nigra of patients with PD. Years of research using postmortem and in vivo MRI, histochemical methods and transcranial ultrasound have yielded many advances in heightening the awareness of iron deposition in PD. Quantitative studies have shown a 25% to 100% increase in substantia nigra iron levels in patients with PD compared to normal controls.6 Additionally, iron-associated proteins and receptors are upregulated in the striatum and substantia nigra of patients with PD.60,94 Increased iron levels are thought to produce free radicals and predispose dopamine striatonigral neurons to oxidative damage.60,9496 Oxidative stress compromises lipid, protein and DNA molecular integrity, leading to neuronal injury. Dexter et al.97 were unable to demonstrate a significant increase in iron levels in the intracellular Lewy body found in the substantia nigra. There is controversy whether or not Lewy bodies have increased iron (Figure 2). Using in vivo transcranial sonography, Zecca et al.98 recently showed increased iron levels in subjects with Lewy bodies and suggested that iron may be involved in initiating and promoting the neurodegenerative cascade in PD. Although there is evidence that increased iron has a role in the pathogenesis of PD it remains possible that iron is a simply an epiphenomenon.

Figure 2
Viable pigmented neurons of the substantia nigra pars compacta in two cases of Parkinson’s disease show strong iron (I or III) labeling of the Lewy bodies. The most pronounced staining involves the Lewy body core. Iron labeling of neuromelanin ...

MRI has emerged as a powerful tool in detecting abnormal brain iron deposition in vivo in patients with PD. Patients with PD may show T2 hypointensity in many anatomic areas compared to normal controls including the substantia nigra pars compacta, dentate nucleus, subthalamic nucleus and basal ganglia; probably reflecting excessive iron content.22 Using the FDRI method, Bartzokis et al. 31 showed increased basal ganglia iron deposition in patients with young-onset PD compared to normal controls. In a study involving 20 patients with PD, Atasoy et al.99 demonstrated a correlation between T2 hypointensity of the substantia nigra compacta and clinical severity. In a study of 13 patients with PD, using 3T MRI and iron relaxometry techniques, Gorell et al.41 demonstrated elevated iron levels in the substantia nigra compared to normal controls. There was also a strong association between iron concentration and motor performance.41 Using the PRIME MRI sequence Graham et al.38 showed an increase in R2′ and R2* in the substantia nigra of PD patients when compared with normal controls. However, R2′ and R2* did not correlate with clinical impairment. In another study, using the T2 rho MRI method, Michaeli et al.50 showed increased substantia nigra iron levels in patients with PD vs. normal controls. Kosta et al.100 compared T2 intensity in the substantia nigra pars compacta and subthalamic nucleus in 40 patients with PD and 40 normal controls. The authors demonstrated that patients with PD had significantly lower T2 intensity in the substantia nigra pars compacta and subthalamic nucleus. The degree of T2 hypointensity in the subthalamic nucleus was correlated with the disease duration.

Though no human trials have been completed to date, a variety of iron chelators have been used in rat and mouse models of PD. Animals induced with a PD like illness develop heavy iron loads in the substantia nigra pars compacta, which is anatomically analogous to the iron deposition that has been demonstrated in human PD.101 Interestingly, a nutritional reduction of iron in a kainate rat model has shown reduced cellular damage in piriform and entorhinal cortex, thalamus, and in hippocampal layers CA1-3.102 There was also attenuated gliosis when compared with controls. The iron chelator, DES, has been studied extensively in animal models of PD. Despite some concern about use in humans due to an unfavorable side effect profile, it has been successful in rat 6-hydroxydopamine and MPTP induced PD models. DES, when injected periventricularly before the administration of 6-hydroxydopamine, resulted in significant protection of striatal dopamine and a normalization of behaviors that were impaired in the rat control group.103 A similar effect was shown in the MPTP model.104 Clioquinol pretreated MPTP mice had total substantia nigra iron levels decreased 30% when compared to control animals.105 The iron levels obtained after clioquinol pretreatment were below known toxic levels.105

Multiple sclerosis

There is growing interest regarding the significance and impact of iron in the pathophysiology of MS. It has generally been found that patients with MS often show T2 hypointensity or other MRI changes suggestive of iron deposition in gray matter areas including the red nucleus, thalamus, dentate nucleus, lentiform nucleus, caudate, and rolandic cortex compared to age-matched normal controls (Figures 1, ,33).18,19,21,106108 Supporting evidence for the role of iron in MS come from studies involving postmortem human brain histology, in vivo human MRI, and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In an autopsy-based study, Craelius et al.20 found abnormal brain iron deposits in the neurons and oligodendrocyte of five patients with MS. Drayer and colleagues18 demonstrated increased ferric iron content in the putamen and thalamus in an MS brain at autopsy. LeVine109 showed iron deposits in macrophages and microglia in postmortem MS brain tissue. Mehindate et al.110 showed upregulation of heme oxygenase-1, a stress protein that helps regulate iron metabolism, in MS spinal cord astrocytes and suggested that iron metabolism is deranged in patients with MS. Chakrabarty et al.111 demonstrated that the motor deficits seen in mice suffering from EAE can be improved by suppression of heme oxygenase activity. Iron deposits have also been found intracellularly (inside macrophages and astrocytes) and in extracellular CNS areas in EAE mice compared to control mice.112

Figure 3
Gray matter T2 hypointensity and brain atrophy in multiple sclerosis (MS). Fast spin-echo axial T2-weighted images are shown of a 43 year-old man with relapsing-remitting MS (disease duration of four years, mild-to-moderate physical disability - Expanded ...

While laboratory based studies suggest a role for iron in MS, MRI-based human studies suggest a link between iron deposition, gray matter damage, and clinical status. Gray matter T2 hypointensity can be detected in patients with MS (Figures 1, ,3)3) and with more severity in patients with secondary progressive than relapsing-remitting MS18,19,21,106108,113,114 as compared to age-matched normal controls. In a study involving 68 patients with early relapsing-remitting MS, Bermel et al.115 demonstrated that baseline T2 hypointensity in the gray matter was the best predictor of whole brain atrophy compared to conventional MRI findings. These results in addition to cross-sectional analyses19 link T2 hypointensity to brain atrophy. Numerous studies show a link between T2 hypointensity in the gray matter and clinical manifestations of MS. Tjoa et al.107 showed a correlation between dentate nucleus T2 hypointensity and ambulatory function as measured by the timed 25-foot walk (r = −.355, p = .007) and physical disability score (r = −0.463, p = .004) in 47 patients with MS.107 Brass et al.114 demonstrated a correlation between gray matter T2 hypointensity and cognitive impairment in patients with MS. In each of these studies, T2 hypointensity in the gray matter was more closely associated with neurologic status than were conventional MRI lesion measures. Additional data supporting a role for excessive gray matter iron deposition in MS comes from recent work using advanced MRI techniques such as T2 intensity measures with 3T MRI116 and MFC.21 In addition, our group is in the process of measuring R2, R2*, and R2′ with 3T MRI to assess potential brain iron deposition in patients with MS (Figure 1).

There is a relatively small body of literature regarding the effect of iron chelation therapy in MS. Trials of DES and dexrazoxane, a chelator similar to DES, have been completed in animals. Rats with EAE treated with DES before symptom development experienced total symptom suppression, while rats treated after symptom manifestation had a rapid marked attenuation of symptoms.117 A study with a myelin basic protein induced rat EAE model failed to show a treatment effect when DES was administered in the preclinical stage.118 Postulating that DES scavenges and prevents free radical formation and consequently will only be efficacious during active disease, Pedchenko et al.119 treated rats in the active stage of EAE and observed significantly reduced clinical signs when compared to vehicle-treated animals. Dexrazoxane, when injected alone into rats slightly attenuated the course of EAE, while rats given dexrazoxane concomitantly with mitoxantrone experienced improvement on clinical indices when compared with rats treated solely with mitoxantrone.120 This result is of special interest because mitoxantrone carries a significant risk of cardiotoxicity even though it is an effective FDA approved MS therapy while dexrazoxane is known to have cardioprotective effects.121 Only one human trial of iron-related therapy has been performed in human MS (DES in secondary progressive MS); after two years there was no significant improvement in disability score following up to eight courses of DES.25 This lack of treatment effect may potentially be attributed to the advanced disease in the patient population and the small number of the study participants (n=9).

It is evident from the studies presented above that iron deposition occurs in MS and that iron chelation is effective at ameliorating symptoms in animal models. It is unclear, however, the precise role that iron deposition plays in humans and whether chelation therapy or other therapies targeting iron related toxicity can benefit MS patients. Additional studies are warranted to further define the role of iron deposition in MS.

Other chronic brain disorders

Brain iron deposition has been implicated as playing a role in other neurologic diseases. A few of these disorders will be discussed briefly.

Neuroferritonopathy, a disorder characterized by extrapyramidal symptoms, is thought to be due to a mutation in ferritin light chain gene 1. Serum ferritin levels are typically low. Conversely, brain accumulation of ferritin and iron has been demonstrated.122 Iron accumulation likely directly causes clinical symptoms and neurodegeneration by free radical toxicity as discussed above. Affected individuals have MRI evidence of iron deposition in the basal ganglia. As the disease progresses T2* gradient echo MRI reveal worsening hypointensity in the dentate, thalamus, globus pallidus, lentiform, and caudate nuclei.123

Friedrich’s ataxia (FA), an autosomal recessive disease which presents neurologically with progressive ataxia, areflexia, and sensory loss is thought to originate from a deficiency of the mitochrondrial protein frataxin. Interestingly, elevated iron levels and oxidative damage have been observed in a yeast frataxin knockout model.124 Patients with abnormal FRDA, the gene that leads to frataxin expression, show increased oxidative damage. This may accelerate disease progression. MRI showed significantly increased iron concentration in the cerebellar dentate nucleus of patients with FA when compared with normal controls.125 Though no chelation trials have been performed in FA, there is evidence that the antioxidants coenzyme q10 and vitamin E may improve cardiac and skeletal muscle function.126 Recently a novel iron chelator, 2-pyridylcarboxaldehyde isonicotinoyl hydrazone (PCIH), has been suggested as a potential therapeutic agent for FA. PCIH is known to enter mitochondria and bind mitochondrial iron. Presumably, because a dearth of the mitochondrial protein frataxin leads to toxic mitochondrial iron accumulation, a compound like PCIH may be able to attenuate mitochondrial damage and either slow or halt disease progression. However, PCIH has yet to be tested in clinical trials.82

Patients with neurodegeneration with brain iron accumulation (NBIA) typically develop retinopathy, dystonia, speech disturbances and psychiatric manifestations. Iron stains have shown pallidal and nigral iron accumulation.127 T2-weighted brain MRI typically shows an “eye of the tiger” sign which is a ring of marked hypointensity surrounding a core of hyperintensity involving the bilateral globus pallidus. This hypointense ring has been correlated histologically with iron deposition. Pantothenate kinase 2 (PANK-2) has been identified as defective in most cases of NBIA.128,129 Excessive iron deposition is believed to occur after PANK-2 deficiency leads to accumulation of cysteine containing neurotoxins, which lead to cell damage.

Individuals with aceruloplasminemia show pathologic iron accumulation in the brain, retina, and pancreas due to a gene mutation that produces an abnormal ceruloplasmin protein lacking ferroxidase activity.130 The disease typically causes extrapyramidal symptoms, ataxia, and retinal degeneration. MRI shows widespread parenchymal gray matter iron deposits in areas such as the basal ganglia, thalamus, and cerebral cortex (Figure 4).131,132 An absence of functioning ceruloplasmin may lead to an increase in cellular iron deposition due to an inability to remove iron from brain tissue. In a transgenic mouse model Harris et al.133 demonstrated that mice with a mutated ceruloplasmin gene were unable to remove iron from reticuloendothelial cells and hepatocytes. Presumably, ceruloplasmin works to determine the rate of iron efflux in the CNS as well. Thus, a mutated ceruloplasmin gene is likely responsible for the brain iron accumulation seen on MRI in patients with aceruloplasminemia. In addition, ceruloplasmin is thought to have ferroxidase activity which helps shield tissue from free iron Fe2+ induced oxidative damage. This can produce potentially toxic hydrogen peroxidase rather than the oxygen and water that would be generated by a normal ceruloplasmin protein.134 There is a case report of a patient with aceruloplasminemia exhibiting decreased brain iron, retarded disease progression, and attenuated lipid peroxidation after ten months of treatment with DES.135 Another case report found no effect from DES treatment in a patient heterozygous for the aceruloplasminemia gene.136 Recently, zinc sulfate, a compound with known antioxidant activity, has been tested with success in a single heterozygote patient with aceruloplasminemia.137

Figure 4
MRI findings in aceruloplasminemia. Axial T2-weighted spin-echo MRI at 3T (2 mm slice thickness, field-of-view 22 cm, TR 9000 ms, TE 18 ms) of a 56 year-old patient with aceruloplasminemia (left) and a 65 year-old normal control. Marked T2 shortening ...

Superficial siderosis can cause hearing loss, ataxia, and a myelopathy as a result of chronic slow or repeated bleeding into the subarachnoid space.138 Typically, a rust brown discoloration of the eighth cranial nerve and cerebellum can be seen on gross examination which is primarily due to hemosiderin deposition. Postmortem iron staining reveals deposition of hemosiderin in the leptomeninges and subpial tissue. This manifests as T2 hypointensity of the meninges which is especially evident in the brainstem and spinal cord.138 Though poorly understood, there is reason to believe that subpial hemosiderin deposition causes parenchymal damage in the brain and spinal cord.139

Chronic toluene abusers can develop a chronic progressive neurologic illness characterized by dementia, ataxia, tremor, and nystagmus. Postmortem examination has revealed brain iron deposits in the cerebral gray matter.140 T2-weighted brain MRI typically shows symmetric hypointensity in the thalamus and basal ganglia.141 Hypointensity in the motor and visual cortices has been reported as well.141 Currently, it is unclear whether chronic toluene abuse promotes direct iron toxicity. Rather it remains possible that toluene abuse can lead to demyelination and axonal damage. This in turn can cause secondary iron accumulation from disruption of axonal iron transport.

Hemochromatosis is a disease of iron overload, which typically has no neurologic sequelae. There are, however, case reports of patients with either extrapyramidal or cognitive dysfunction.142 Berg et al.143 performed CT and MRI in 14 patients with hereditary hemochromatosis and found signal changes in the basal ganglia even though all patients remained neurologically asymptomatic. T2 hypointensity in the basal ganglia of patients with hemochromatosis represents excessive iron deposition.142 Individuals with multi-system atrophy,144 striatonigral degeneration,145 and other Parkinson’s plus syndromes146 typically show gray matter T2 hypointensity that has been correlated with iron deposition.

Iron may contribute to the pathogenesis of hypoxic/ischemic brain injury. Children undergoing MRI after global anoxia show increased iron deposition in the basal ganglia, thalamus, periventricular and subcortical white matter.147 An absence of proper brain oxygenation leads to local increases in lactic acid which in turn decrease the ability of transferrin to bind iron. An ischemic environment can also cause the release of ferritin-bound iron in a potentially toxic form. A few iron chelating agents have shown an ability to attenuate infarct size and lead to improved neurologic outcome in animal models of stroke,148150 DES lessened brain injury and mortality in a rat model of global cerebral anoxia.151 Methyl tirilazad, a compound thought to inhibit iron-dependent lipid peroxidation, was administered to patients within 6 hours of initial stroke onset. Functional outcome at 3 months was not significantly different when compared to placebo.152,153

Iron may mediate tissue damage in traumatic brain injury (TBI) as well. There are multiple potential effectors of oxidative damage in TBI, at least two of which may be iron related. Oxidative damage driven by iron may occur through anoxic free iron release (as described above) or through degradation products of heme that may accumulate after TBI.154 Studies of DES in TBI animal models have shown a treatment effect.155,156 In a randomized controlled trial, adults with moderate to severe TBI treated with tirilazad mesylate failed to show any benefit when compared with placebo.157

Iron-Related Neurotherapeutics

Chelators seek to bind iron so that the iron is not free to cause neuronal damage. Numerous mechanisms may explain the neuroprotection provided by DES, but the most common interpretation is that DES acts within the cell to bind iron, forming a hexadentate complex that is nonreactive, thereby inhibiting iron’s ability to participate in chemical reactions. However, DES may also exert a neuroprotective effect at extracellular sites. Qian and Eaton158 proposed that in diabetics or in aging humans, advanced glycation end-products accumulate, especially in the endothelial internal elastic lamina/basement membranes, and these glycated sites can easily bind transition metals, particularly iron and copper. Thus, when bound in the intima between the endothelium and the vascular smooth muscle, copper and iron are capable of scavenging nitric oxide that is secreted by the endothelial cells to relax the smooth muscle. Therefore, these vessels are in a constant state of vasoconstriction. When chelators are administered, these transition metals are temporarily removed, and nitric oxide can reach the smooth muscle; this results in vasodilation followed by increased blood flow.

Support for this interpretation can be gleaned from the literature in diabetes and cardiology. In a model of diabetic neuropathy in rats, diabetes is induced by injection of streptozotocin and is allowed to develop untreated for 6 weeks. During this time, a significant sciatic nerve neuropathy develops, characterized by decreased nutritive blood flow to the nerve and decreased nerve conduction velocity. After 6 weeks, rats are treated with daily subcutaneous DES injections, 8 mg/kg, for 2 weeks. Both blood flow and nerve conduction velocity deficits were significantly ameliorated.159

In the same model, a single injection of a high-molecular-weight version of DES (DES coupled to soluble starch) completely reversed the deficit in nutritive blood flow within 24 h to almost 150% of normal, and the nerve conduction velocity deficit was normalized 7 days following treatment. Both deficits returned to pretreatment states 28 days following treatment.160 Thus, a temporary state of hypoferremia created by infusing the iron chelator DES results in increased nutritive blood flow in diabetic rats.

In another study, humans with high-ferritin type 2 diabetes were rendered hypoferremic by phlebotomy, and 18 weeks following the bleeding, researchers noted significantly increased vasoactivity of the brachial artery to nitric oxide donors.161 Finally, when patients with coronary artery disease and control patients were infused with 500 mg DES over 1 h, a significant drop in serum iron concentrations was observed.162 In addition, a significant increase in resting forearm blood flow was noted immediately after the start of infusion in both groups, and it persisted for the entire period of infusion.

These studies all report an increase in blood flow or vascular reactivity following a period of hypoferremia. A number of mechanisms can be invoked, but one particular mechanism may be more relevant to the role of iron in tissue damage from neurodegenerative diseases. If iron or copper bound to glycated end-products accumulate in the brain as they do in peripheral tissue, reduced nutritive blood flow could contribute significantly to neurodegeneration over time. This mechanism may explain, in part, the efficacy of long-term DES treatment of AD,24 as discussed earlier.

Though animal experiments have demonstrated effectiveness in PD,101,103,104 AD,83,91 and MS,117120 iron chelation therapy in chronic brain disorders in humans has not been studied extensively. A few studies have been successful24 while others have not.23,25 Because iron-mediated oxidative damage ultimately can lead to neurotoxicity another approach is to target downstream effects of iron such as with antioxidants. Such therapies, including coenzyme q10 and vitamin E, may improve cardiac and skeletal muscle function in FA.126 An antioxidant similar to coenzyme q10 has also been successful in FA.163

In AD, vitamin E (alpha tocopherol) administered to mice overexpressing amyloid precursor protein had delayed plaque formation and cognitive impairment.164 High dose vitamin E in AD patients was unable to prevent a transition from a state of mild cognitive impairment to AD but delayed disease progression in patients with moderately severe AD.165,166 Green tea extract (±)-epigallocatechin-3-gallate N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (ECGC), a putative antioxidant, has also shown neuroprotection in a mouse model of PD; i.e., preventing loss of substantia nigra dopaminergic neurons.167 A comprehensive open label study in humans with PD suggested that treatment with high doses of both Vitamin A and C, putative antioxidants, delayed the need for levodopa or dopamine agonist therapy by 2.5 years.168 Many antioxidants have been suggested for use in PD but have not reached human trials. For a more extensive review on antioxidant therapy in PD, the reader is referred to the recent review by Singh et al.169 EAE models have been attenuated by multiple antioxidants including tirilazide mesylate,148 n-acetylcysteine,170 catalase,171 butylated hydroxyanisole,172 Euk-8,173 alpha lipoate,174 and a green tea analogue.175 Care in applying antioxidant therapy to neurodegenerative disorders should be exercised; a recent meta-analysis identified an increased all cause mortality in patients in primary and secondary prevention trials treated with vitamins A, E and beta carotine.176

A metal-protein attenuating compound (MPAC) ideal for the treatment of iron mediated neurodegenerative disorders would possess a high affinity for iron, be readily absorbed through the GI tract, effectively cross the BBB, and carry few side effects. These qualities are found more readily in the MPACs currently being developed. None have proven efficacy in humans but a few have promising experimental results in animals. Hexadentate MPACs (DES, DP-109), in general, have lower toxicity but difficulty penetrating the BBB because of their high molecular weight and hydrophilicity. Conversely, bidentate MPACs (defiprone, bathocuproine, feralax, clioquinol, and VK-28) are smaller and more lipophilic but have greater toxicity. Currently, hexadentate and bidentate iron MPACs are the sole iron chelators that have demonstrated efficacy in either human or animal experiments. DP-109 is interesting because it is absorbed as a pro-drug that will only begin to chelate with the cleavage of two long chain esters. DP-109 has been shown to inhibit plaque formation in an AD mouse model.177 Feralax has been shown to disrupt the formation of a protein involved in formation of neurofibrillary tangles.178 It remains unclear whether either bathocuproine or feralax will be able to cross the blood brain barrier.179 Of the multiple iron chelators that have been developed recently, VK-28 has been designated for further study because of its ability to cross the BBB and provide a potentially more favorable side effect profile. VK-28, when given intraventricularly to rats in a model of PD, prevented depletion of striatal dopamine.180 M-30, a compound synthesized from VK-28 but with an additional monoamine oxidase moiety, has been found in mice to attenuate the dopamine depleting action of MPTP. It has also been found to increase striatal levels of dopamine, serotonin and norepinephrine, while decreasing their metabolites.181 Interestingly, Liu et al.182 have synthesized a chelator attached to a nanoparticle that complexes with iron. They demonstrate that this addition is likely to promote BBB absorption.182 Thus, clearly the neurotherapeutic pipeline for iron related neurotherapies is actively growing in depth and breadth.

Conclusion

In this review, we have examined MRI techniques, discussed current understandings of iron metabolism, and summarized studies attempting to understand the role of iron in neurotherapeutic development. We have seen that in vivo monitoring of iron by traditional MRI has been supplanted by emerging MR techniques. A range of MRI techniques will continue to be optimized so that even better sensitivity, specificity, and spatial resolution will be achieved. We have discussed the transport and metabolism of brain iron and where it normally accumulates with aging. We have examined the hypothesis that excessive brain iron can lead to free radical damage, lipid peroxidation, and cellular death. We have explored the potential link between excessive iron and many chronic brain disorders including AD, PD, and MS. We have reviewed animal and human studies exploiting the potential neurotherapeutic role of targeting iron mediated and oxidative damage. We have also discussed interesting new neurotherapeutic developments in the pipeline aimed at mitigating iron mediated and oxidative related brain injury. Future research will undoubtedly lead to a better understanding of the role that iron plays in neurodegenerative diseases and help facilitate development of better neurotherapies for patients.

Acknowledgments

This work was supported by research grants to Dr. Bakshi from the National Institutes of Health (NIH-NINDS 1 K23 NS42379-01) and National Multiple Sclerosis Society (RG3705A1; RG3798A2). We thank Ms. Sophie Tamm for editorial assistance.

Footnotes

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