Pathophysiology of Brain Iron

Introduction: The role of iron stored in the human brain has been studied for more than 120 years. As described by Koeppen a German researcher, S. S. Zaleski, reported in 1886 on the presence of a remarkable level of iron present in the human brain. Working with a single autopsied brain he made several observations that have stood the test of time: (i) the majority of the iron was not present as inorganic iron salts such as iron chloride, but was bound to organic molecules, (ii) unlike in the blood, the iron was not bound to hemoglobin, (iii) the iron was predominately in the ferric not the ferrous oxidation state and (iv) the iron was more concentrated in the gray matter rather than the white matter of the brain. In subsequent decades this work was confirmed and extended, particularly by the German pathologist Hugo Spatz. He stained brain tissue by immersing it in hydrochloric acid followed by potassium ferrocyanide (Perls' stain or the Prussian Blue stain) to produce bright blue precipitates in brain regions with high ferric iron concentrations. Using brains from normal subjects he demonstrated strong concentrations of ferric iron in the deep brain nuclei of the extrapyramidal motor system including the globus pallidus, the caudate nucleus, the red nucleus, the dentate nucleus and the substantia nigra. Later studies revealed that iron concentrations with a specific pattern of distribution are present in all normal brains. Iron deposits are particularly prominent in the deep brain nuclei (globus pallidus, putamen, caudate, substantia nigra, red nucleus, dentate nucleus) but are found in the white matter and cortex as well. These deposits are minimal at birth and gradually increase over the first three decades of life after which they tend to plateau. The role of these iron deposits in brain function is not yet entirely clear. One influential hypothesis has linked them to the process of myelination of the white matter tracts. Following the introduction of high-field (1.5 tesla) MRI whole-body imaging n the early 1980s, brain iron research entered a new era when B. P Drayer and his colleagues reported that T2-weighted MR images showed markedly decreased signal intensities (hypointensities) in the same brain regions that had previously been identified in autopsy studies as having high iron concentrations. It was soon demonstrated that this iron-dependent contrast mechanism became more prominent at higher field strengths. The availability of high-field MRI has made it possible to study brain iron non-invasively in living human subjects and has greatly expanded the knowledge of its role in brain physiology and pathology. In recent years brain iron has become a very active area of neuroscience research. Searching the PubMed database for the year 2008 returns 342 papers containing the phrase 'brain iron.' Therefore, at the present time there is well over one paper being published in this area each working day. MRI studies are partly responsible for this high level of research activity, but an equal, or greater activity is currently present in the fields of iron biochemistry and cellular biology. As a result there has been explosive increase in