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Iron Compounds in the Human Brain

 

Overview

Ferritin is the primary iron storage protein in the brain. It consists of a 12nm diameter spherical protein shell with an 8nm cavity capable of storing up to 4500 iron atoms in the form of ferrihydrite. Ferrihydrite is superparamagnetic at body temperature and it exists in varying degrees of crystallinity in the human body. In addition to ferritin, biomineralization of ferrimagnetic magnetite is known to occur in a number of organisms including animals [e.g. 1]. Recent investigations have revealed the presence of biogenic magnetite in human brain tissue as well [2,3,4,5]. The presence of magnetite in the brain has been established using a variety of magnetic and electron microscopic techniques. In addition, anomalous concentrations of iron are known to be associated with virtually all neurodegenerative diseases, however, since this relationship was first discovered 50 years ago, very little progress has been made in understanding their composition, origin or role in disease processes [6,7].

Magnetometry Studies of Neurodegenerative Tissue

A major aspect of these projects is comparing and quantifying the physical properties of biogenic magnetite present in both normal and pathologic brain tissue samples in order to evaluate its possible role in diseases and disorders of the brain such as epilepsy, Alzheimer's disease, Huntington's disease and Parkinson's disease [8,9]. In order to accomplish this, methods have been developed to quantify contamination levels and accurately measure tissue magnetite content using Superconducting QUantum Interference Device (SQUID) magnetometry [10]. We are also investigating the effects of iron loading on magnetic iron biomineralization using rat brain models [11] and the effects of age on the formation of magnetic iron compounds in the brain [12]. Some or our most striking recent results show a correlation between elevated levels of biogenic magnetite in tissue and Alzheimer's disease in female subjects [13]. This appears to correlate with disease stage and has major implications for early diagnosis via MRI.

Imaging

Elevated iron levels are associated with many neurodegenerative disorders, however, they are not well characterized and their role is not understood [for review see 7 & 9]. In order to address this problem, imagnig studies of iron biomineralization in brain tissue samples are underway using scanning and transmission electron microscopy (SEM and TEM), Magnetic force microscopy (MFM), electron energy loss spectroscopy (EELS) and energy filter TEM (EFTEM) imaging in order to locate the particles in the tissue and determine their relationships to structures in the brain [14]. We recently have begun work at the Advanced Photon Souce (APS) Synchrotorn at Argonne National Laboratories using microfocussed synchrotron radication for tissue scanning and high-resolution structural iron mapping related to neurodegenerative disorders. These data are combined with other imaging data and provide, for the first time, a technique for high-resolution mapping of iron anomalies (including identification of the iron compound responsible for the anomaly) to structures in the brain.

Early Diagnosis of Neurodegenerative Disease

Also under investigation is the use of MRI for early diagnosis in neurodegenerative disease based on the presence of nanoscale iron oxides (biogenic magnetite and ferritin) associated with diseased tissue. Hypointensity artefacts have been observed in MRI images of the brains of patients suffering from Parkinson's Disease as well as other neurodegenerative disorders. These artefacts are thought to be indicative of the region of the brain affected by such diseases. Attempts to explain these artefacts and correlate them to tissue iron and ferritin distribution in post mortem tissue samples have been unsuccessful. We are presently synthesizing and characterizing nanoscale, magnetite-based ferrofluid phantoms which will be used to evaluate the effects of biogenic magnetite found in the human brain on MRI image intensity in order to assess whether these biominerals may be a source of the artefacts.

We already have demonstrated that there are natural variations in biogenic magnetite concentration in different parts of the human brain [3,5,10,12]. Increased accumulation of these particles may produce areas of hypointensity due to enhancement of local magnetic fields and there are indications that magnetic iron compounds accumulate in Alzheimer's tissue before clinical symptoms are apparent [13]. Present work is concentrating on evaluating MRI detection limits [15] and developing pulse sequences to find anomalous accumulations of magnetic iron via their effects on proton relaxation rates due to the introduction of local field inhomogeneities [16]. It is hoped that this will lead to a mechanism for early detection of Parkinson's Disease, Shy-Drager Syndrome, Alzheimer's Disease and other neurodegenerative disorders through the use of MRI and SQUID magnetometry. Early detection is particularly important and drugs being developed for Alzheimer's disease depend on slowing the progression of the disease rather than reversing the effects. In this case, early detection is critical to the effectiveness of the treatments.

References:

[1] Kirschvink, JL, DS Jones, BJ MacFadden (1985) Magnetite biomineralization and magnetoreception in organisms: a new biomagnetism. New York: R.P. Plenum Publishing Corp.

[2] Kirschvink, JL, A Kobayashi-Kirschivink, BJ Woodford (1992) Magnetite biomineralization in the human brain. Proc. Natl. Acad. Sci. USA, 89: 7683-7687.

[3] Dunn, JR, M Fuller, J Zoeger, JP Dobson, F Heller, E Caine and BM Moskowitz (1995) Magnetic material in the human hippocampus. Brain Res. Bull. 36: 149-153.

[4] Dobson, JP, M Fuller, S Moser, HG Wieser, JR Dunn and J Zoeger (1995) Evocation of epileptiform activity by weak D.C. magnetic fields and iron biomineralization in the human brain. In: Biomagnetism: Fundamental Research and Applications, eds. C Baumgartner, L Deecke, G Stroink, SJ Williamson. Elsevier, Amsterdam: 16-19.

[5] Dobson, JP and P Grassi (1996) Magnetic Properties of Human Hippocampal Tissue - Evaluation of Artefact and Contamination Sources. Brain Res. Bull. 39: 255-259.

[6] Goodman, L (1953) Alzheimer's disease - a clinicopathologic analysis of 23 cases with a theory on pathogenesis. J. Nerv. Ment. Dis. 118: 97-130.

[7] Dobson, J (2004) Magnetic iron compounds in neurological disorders. Ann. NY Acad. Sci. 1012: 183-192.

[8] Dobson, J (2001) On the structural form of iron in ferritin cores associated with Progressive Supranuclear Palsy and Alzheimer's disease. Cell. Mol. Biol. In Press.

[9] Dobson, J (2001) Nanoscale biogenic iron oxides and neurodegenerative disease. FEBS Lett. 496: 1-5

[10] Schultheiss-Grassi, PP and J Dobson (1999) Magnetic analysis of human brain tissue. BioMetals 12: 67-72.

[11] Pardoe, H and J Dobson (1999) Magnetic iron biomineralization in rat brains: Effects of iron loading. BioMetals 12: 77-82.

[12] Dobson, J (2002) Investigation of age-related variations in biogenic magnetite levels in the human hippocampus. Exp. Brain Res. 144: 122-126.

[13] Hautot, D, QA Pankhurst, N Kahn, J Dobson (2003) Preliminary evaluation of nanoscale biogenic magnetite and Alzheimer's disease. Proceedings of the Royal Society B - Biology Letters 270: S62-S64.

[14] Schultheiss-Grassi, PP, R Wesiken and J Dobson (1999) TEM observation of biogenic magnetite extracted from the human hippocampus. Biochim. Biophys. Acta 1426: 212-216.

[15] Pardoe, H, W Chua-anusorn, TG St. Pierre and J Dobson (2003) Detection limits for ferrimagnetic particle concentrations using magnetic resonance imaging-based proton transverse relaxation rate measurements. Physics in Medicine and Biology 48: 89-95.

[16] Pankhurst, QA, J Connoly, SK Jones, J Dobson (2003) Applications of magnetic nanoparticles in biomedicine. J. Phys. D. 36: R167-R181.



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