Assessment of ferritin content in multiple sclerosis brains using temperature‐induced R*2 changes

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Iron is the most abundant trace element in the human brain, where it plays an important role for normal development and metabolism. Iron homeostasis appears disturbed in several inflammatory and neurodegenerative diseases, including multiple sclerosis (MS), Alzheimer's disease, and Parkinson's disease 1. To assess the topographic distribution and quantification of brain iron in vivo, sensitive imaging techniques are required. MRI can exploit the paramagnetic properties of iron in magnetic fields 5, and as a result a whole raft of MRI techniques to assess iron content has been proposed, including relaxation time mapping 7, phase imaging 9, magnetic field correlation 10, direct saturation imaging 11 and quantitative susceptibility mapping 12. Most of these techniques can be used to assess the iron concentration in gray matter (GM); however, whether they can reliably quantify iron in white matter (WM) has remained uncertain. One reason for this is the confounding effect of WM tissue susceptibility caused by the diamagnetism of myelin and the orientational dependency with respect to the magnetic field B015. To overcome this limitation, we recently proposed a new technique for iron mapping, which is based on Curie's law (i.e., the increase of the paramagnetic susceptibility with decreasing temperature). By obtaining the temperature coefficient of JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM1/v/2018-01-24T161827Z/r/image-png ( JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM2/v/2018-01-24T161827Z/r/image-png ) from JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM3/v/2018-01-24T161827Z/r/image-png measurements at different temperatures, diamagnetic background effects are eliminated thereby enabling quantification of the iron content in WM 19. Evidence suggests that there is a linear association between JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM4/v/2018-01-24T161827Z/r/image-png and iron concentration 19.
Normally, WM shows only little variation in iron content, typically in the range of 35–46 mg/kg wet weight 20. However, some MS WM lesions have been described as being surrounded by iron “rings”, whereas normal‐appearing WM shows reduced iron levels when compared with healthy controls 21. Both observations may have pathophysiological implications. Because of the variable iron content in the MS brain, we decided to use post mortem MS brain for a histopathologic validation of our temperature‐based iron mapping approach. Given the fact that most of the brain iron is stored in ferritin 22, we opted for ferritin‐specific staining, which also allows a quantitative assessment 24. Apart from the validation of JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM5/v/2018-01-24T161827Z/r/image-png , we additionally wanted to compare JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM6/v/2018-01-24T161827Z/r/image-png with JOURNAL/mrim/04.02/01445475-201803000-00041/math_41MM7/v/2018-01-24T161827Z/r/image-png as indicators of iron distribution and to explore their potential to show MS typical changes.

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