Contribution of metals to brain MR signal intensit

Authors: Tomonori Kanda Yudai Nakai Shuri Aoki Hiroshi Oba Keiko Toyoda Kazuhiro Kitajima Shigeru Furui

Publish Date: 2016/03/01

Volume: 34, Issue: 4, Pages: 258-266

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Abstract

Various metals are essential nutrients in humans and metal shortages lead to a variety of deficiency diseases Metal concentration abnormalities may cause metal deposition in the brain and magnetic resonance imaging MRI is the most potent and sensitive technique now available for detecting metal deposition given the difficulties associated with performing brain tissue biopsy However the brain contains many kinds of metals that affect the signal intensity of MRI which has led to numerous misunderstandings in the history of metal analysis We reviewed the history of brain metal analysis with histologic findings Typically manganese overload causes high signal intensity on T1weighted images T1WI in the globus pallidus iron overload causes low signal intensity in the globus pallidus on T2weighted images and gadolinium deposition causes high signal intensity in the dentate nucleus globus pallidus and pulvinar of thalamus on T1WI However because nonparamagnetic materials and other coexisting metals also affect the signal intensity of brain MRI the quantitative analysis of metal concentrations is difficult Thus when analyzing metal deposition using MRI caution should be exercised when interpreting the validity and reliability of the obtained dataMetals play an important role in diverse biochemical and physiological functions in humans and various enzymes and vitamins contain metals Several metals are essential nutrients in humans and metal shortages lead to a variety of deficiency diseases or syndromes On the other hand excess amounts of such metals induce cellular and tissue damage leading to a variety of adverse effects and diseases The appropriate concentration of a metal lies within a very narrow range and any excess or shortage easily causes toxic effects in vivo 1 2 3 The method for quantifying the metal content in affected organs is important not only for diagnostic purposes but also for the assessment of disease progression and treatment effects Magnetic resonance imaging MRI is the most potent and sensitive technique for detecting abnormal metal deposition this technique involves evaluating small changes in relaxation times 4 5 Most substances in the body are diamagnetic and thus barely influence magnetic fields On the other hand most metals are classified as paramagnetic and show magnetization only in the presence of a surrounding magnetic field Paramagnetism influences the T1 and T2 relaxation times due to the influence of unpaired electrons Some metals such as nonionic nickel iron and gadolinium at temperatures below 18 °C are ferromagnetic and present very strong magnetization that causes metal artifacts in MRI However ferromagnetic metals do not exist in the body except in surgical or traumatic implants 6 Most metal deposition causes high signal intensity on T1weighted images T1WI 7 8 and low signal intensity on T2weighted images T2WI 9 and these signal intensity changes are rather specific for metal deposition in vivo This article focuses on the diseases associated with metal deposition in the brain and metal detectability on brain MRISeveral factors make metal analysis uncertain First brain tissue from patients is not easily acquired Many studies of metal deposition have based diagnoses on clinical or image analysis while only a small number of studies have relied on histological analysis However except for brain tissue analysis the cause of the abnormal signal intensity on MRI cannot be determined accurately 5 Second excess concentrations of multiple metals are often observed in the same subject For example patients with metal poisoning from exposure in mines frequently have excess deposition of multiple metals since metal ores usually include multiple kinds of metals In addition abnormal metal storage in the human body occasionally affects the absorption of other metals Iron deficiency induces enhanced absorption of iron mediated by greater expression of metal transporters of iron as well as the increased absorption of other metals such as manganese nickel lead and/or cadmium 10 11 12 13 Third the magnetism of a metal varies according to the oxidation state and the type of compound involved and its signal intensity on MRI varies according to these parameters and the status of the metal The oxidation state of a metal and the compound it is in frequently change in the body so the MRI signal intensity of a metal is not constant 14 15 Below we review the effects of metals on brain MRIs in order of the atomic number of the metalCalcium deposition in the brain occurs with Fahr disease various metabolic diseases and tumors 5 Calcification is easily detected on CT but it is difficult to detect on MRI because of the variety of signal intensities produced by calcified regions 16 This variety of signal intensities from calcification is not caused by its paramagnetic effect but by a surface effect whereby the irregular surface of calcium restricts the motion of water close to the Larmor frequency with the T1 relaxation time of water shortening as the protein content in the water increases The surface effect varies according to the surface structure of the calcification so the signal intensity from calcification on T1WI can vary even when there is the same concentration of calcium 17 18 On T1WI the signal intensity of calcification is strongest at 30  calcium concentration by weight while on T2 the signal intensity and calcium concentration show a linear correlation 18 19 However these results were obtained in vitro and the true mechanism of the high signal intensity from the calcified region has not yet been determined because calcium tends to accumulate in the basal ganglia where other paramagnetic metals such as iron and manganese also accumulate Calcium causes a high signal intensity on T1WI due to the surface effect in vitro but the cause of the high signal intensity from calcified regions in vivo is unclearManganese neurotoxicity was first reported by Couper 20 in 1837 in a case series of 5 manganese miners Patients with manganese neurotoxicity suffer from Parkinson’s symptoms including tremor in the extremities gait disturbance and whispering speech 20 21 22 Manganese is highly paramagnetic and MRI is expected to detect its presence in the brain The first study used monkeys that were administered MnCl2 by intravenous injection or inhaled aerosol Regardless of the administration route of MnCl2 an increasing signal intensity on MRI is observed in the caudate nucleus globus pallidus substantia nigra ventromedial hypothalamus and pituitary gland 23 Even in man a hyperintense globus pallidus was found in patients receiving longterm total parenteral nutrition therapy that included manganese 24 and in workers exposed to manganese 25 26 27 with these hyperintensities diminishing after cessation of the manganese exposure 25 28 29 Intravenous administration or inhalation of manganese causes manganese deposition in the brain but the oral intake of manganese rarely results in manganese deposition Intellectual impairment in children after excess oral intake of manganese has been reported albeit without histological proof 30 Most orally ingested manganese does not remain in the human body due to several mechanisms Manganese is present in food and water but the intestine adjusts manganese absorption and only 1–5  of the manganese ingested is absorbed 31 In addition the absorbed excess manganese is promptly excreted into the bile from the liver and rarely causes manganese toxicity 22 32 Iron deficiency anemia promotes manganese absorption in the intestine and elevation of the manganese concentration in the blood but the signal intensity of the globus pallidus on T1WI is not affected 33 In this way manganese neurotoxicity is caused by mine dust inhalation or intravenous administration but rarely by oral intake 34 35 The manganese metabolic pathway adapts to oral MRI contrast agents containing manganese and the contrast effect of this oral contrast agent based on manganese is limited to liver and intestine 36 37Transient hyperintensity of the striatum on T1WI after an ischemic event is also associated with the manganese concentration In a study on brief focal ischemia in rats transient hyperintensity of the striatum was observed from 5 days to 4 weeks after the ischemia as was a synchronous increase in the manganese concentration in the striatum The increased manganese was due to increases in mitochondrial manganese superoxide dismutase and glutamine synthetase which are manganesecontaining metalloproteins Endogenous manganese also can affect the signal intensity from the brain 49

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