In several studies, evidence for increased iron accumulation, preferentially in deep gray matter areas of the brain, was mainly derived from the signal reduction on T2-weighted MR images [5
First reports on a regionally signal reduction on T2-weighted brain MRI images in MS indicative of increased iron deposition were published by Drayer et al. [6
] and Grimaud et al. [7
Several studies then followed with a focus on the clinical implication of increased iron accumulation in MS. Increased deep gray matter T2 hypointensities were found to be correlated with disease duration [8
], physical disability [9
], and cognitive impairment [14
]. Clinical followup studies in MS revealed that baseline gray matter T2 hypointensities were associated with disability progression over time [12
]. Another consistent finding is that deep gray matter T2 hypointensity, suggestive of increased iron content, is correlated with brain atrophy [8
]. While this was evidenced in patients with definite MS, there is only little information available regarding the extent and clinical significance of increased iron deposition in patients with a clinically isolated syndrome. Ceccarelli et al. found only minor changes of signal reductions on T2-weighted images compared to healthy controls, and the extent did not predict conversion to clinically definite MS [17
]. The approaches used in the studies mentioned above suffered from the methodological drawback of deducing iron concentrations from a visual grading of the reduction of signal intensity on T2-weighted images even though more recent studies have determined the extent of T2 hypointensity in a semiquantitative manner [8
In recent years, methodical development of MRI enabled to assess brain iron concentrations quantitatively. In addition, quantitative iron mapping by MRI offers a more sensitive discrimination of iron levels and, therefore, is especially advantageous in longitudinal studies and monitoring of long-term disease progression.
The techniques utilized for quantitative iron mapping are mainly based on relaxation time mapping [18
] () but also other approaches such as phase mapping [21
], magnetic field correlation [23
], or direct saturation imaging [24
] are applied.
R2* map of a 50-year-old female MS patient. Higher iron concentrations in basal ganglia structures are reflected by brighter signal intensities.
Susceptibility weighted imaging (SWI), a technique that takes advantage from the full complex MR signal by combining magnitude and phase images, has gained attention as a means to assess brain iron [25
]. However, the complexity of the postprocessing involved in SWI renders comparative studies challenging and remains an objective of research [27
]. Quantitative susceptibility mapping (QSM) is an approach using solely phase images and produces susceptibility maps which are independent of the orientation of the tissue to the main magnetic field [28
]. Because paramagnetic iron is considered a main determinant of brain tissue susceptibility, QSM seems especially useful to assess brain iron.
2.1. Validation of MRI Methods
Several methods have been proposed for the measurement of brain iron concentration; however, the majority of them lack validation and, therefore, the specificity and sensitivity of these techniques are not reliably known.
From theoretical considerations based on susceptibility models for brain tissue, it can be concluded that iron is a main determinant of susceptibility-induced contrast in MRI [30
]. Several studies have indirectly investigated the relation of MRI parameters with iron by using the age-dependency of iron accumulation in the basal ganglia as reported in [4
Recently, high-pass filtered SWI phase images were compared to regional iron concentrations in postmortem tissue determined by synchrotron X-ray fluorescence and revealed a correlation between phase shifts and iron [32
Other recent work acquired quantitative MRI directly after death from seven human brains and subsequently determined brain iron concentrations by using inductively coupled plasma mass spectrometry [33
]. This study showed that the relaxation rates R2 and R2* can be used as sensitive and linear measures for brain iron concentration.
These quantitative MRI techniques together with a better understanding of pathophysiologic concepts of increased iron levels [1
] have put more interest on elucidating the role of iron in MS.
In recently performed studies on quantitative brain iron levels in MS, based on R2* relaxometry at 3 Tesla, increased iron levels have been found in patients with advancing MS compared to clinically isolated syndrome [20
]. Using this validated quantitative technique, higher R2* levels in basal ganglia structures reflecting higher iron content were correlated with gray matter atrophy and also with T2-lesion volume [20
]. These findings are supported by earlier studies where MRI T2 hypointensities suggestive of increased brain iron, preferentially located in deep gray matter areas, were linked to physical disability and gray mater atrophy in MS [8
]. Further support comes from a followup study showing that MRI T2 shortenings in deep gray matter areas at baseline are predictive of the evolution of brain atrophy [16
Apart from gray matter regions with known high iron levels (putamen, globus pallidus, caudate nucleus, substantia nigra, and red nucleus) efforts were made to investigate iron levels in white matter by MRI [22
]. Using SWI, the phase values of MS lesions were investigated and compared to adjacent white matter [36
]. However, compared with chemically determined iron concentrations of postmortem studies, the iron levels within MS lesions were not substantially altered than in reference white matter structures [4
]. Due to the confounding impacts of iron and myelin to MRI contrast generation, disease-induced alterations of iron levels in white matter need to be treated with caution and are an objective of ongoing research [37
Further interest on iron deposition in MS has been generated by the idea of chronic cerebrospinal venous insufficiency (CCSVI) [38
] that might be associated with the accumulation of iron in the brain due to a reduction in venous outflow [39
]. Following this hypothesis, CCSVI is postulated to be implicated in the etiology of MS. The underlying mechanism is believed to originate from increased iron accumulation in patients due to a reduced venous blood flow caused by constrictions of cerebral veins. This then leads to extravasation of erythrocytes with subsequent iron deposition [41
], subsequently triggering inflammation-dependent tissue damage [42
]. However, the existence of CCSVI as well as its etiologic role in MS are currently controversially debated [43
], and there is an increasing amount of papers published now that challenge this hypothesis [44
]. Furthermore, histopathologic studies do not provide clear evidence for extravasation of erythrocytes into lesions caused by increased intraluminal venous pressure [48