Susceptibility weighted imaging offers a unique way to view tissue affected by iron deposition whether in the form of deoxyhemoglobin, ferritin or hemosiderin. Not only have we demonstrated that there are nearly 50% more lesions seen in total combining conventional imaging with SWI, but the iron content that makes lesions visible in SWI can also be quantified. The distribution of iron in the lesions in shows that the peak iron can reach 60µg Fe/g tissue. This is as large as the iron content expected in the motor cortex. With the imaging parameters used here, recent results suggest that at 1.5T in a region-of-interest of 100 pixels, it is possible to determine changes in iron of just 1µg Fe/g tissue (35
). This may serve as a means to monitor iron changes over time in the lesions.
Of the six different types of lesions observed, most seem to have a fairly uniform distribution of iron. In 13 cases, we can see the direct connectivity of lesions with veins. In six others, only the center of the lesion is dark. There were, however, lesions that exhibited a ring-like structure of high iron content (11 cases). This may be similar to the ring-like effects seen both pathologically in leukoencephalopathy and also sometimes visible on FLAIR and T2WI. The ability to see these rims of iron () may also have an impact on disease progress (15
). Finally, there is some evidence of gray matter abnormality.
The rims of lesions (arrows) are seen more clearly in SWI phase (a) than in FLAIR (b). The rims are not defined in magnitude (c) or T2 (d). This data was acquired at 4T.
Differentiating simple changes in phase from veins was done by looking for connectivity. Usually, it was fairly easy to discriminate between signal changes caused by veins and those corresponding to lesions because we could view the minimum intensity projection (mIP) of three or more slices centered on the slice of interest. These mIP images show the connectivity of the vessels and make it clear if the vessel runs through the lesion of interest. Most of the lesions, however, showed fairly large non-vascular structures that were not circular in nature. Since these lesions often sat in white matter, and since the phase of white matter is close to zero, it is fairly obvious, with practice, what represents abnormal phase signal and hence its probability of being a lesion. We read the phase images separately and then compared the results to the FLAIR or T2 data. Since many of the lesions do overlap with T2 lesions, this gave us good confidence that our interpretations of these new findings were likely correct. As a comparison with T1, T2 and FLAIR, we used a “copy ROI” feature of our software to ensure the appropriate interpretation and registration of the lesions. Since all sequences were run with the same FOV, this was a particularly easy way to ensure that we were looking at the same lesions. When these ROIs were copied from one image to the next, we observed that the shapes of the ring lesions seen on the SWI data were essentially identical to the shape on the corresponding T2W images.
Why is this new biomarker for iron potentially important in the study of MS with SWI? The current MR imaging biomarkers of MS pathology focus on: the breakdown of the blood brain barrier, multi-focal inflammation, demyelination, oligodendrocyte loss, axonal and neuronal degeneration, gliosis, and remyelination and repair (40
). In a systematic analysis of all studies published in the last 20 years, it was found that none of the proposed biomarkers could serve as a surrogate marker for clinical outcome (41
). In a disease with a complex pathogenesis, such as MS, an individual biomarker is likely to reflect only one aspect of many pathogenic processes. The ability to predict the outcome of MS is complicated due to the underlying diversity and variability of the lesions. Although clinical judgment and experience provide the foundation for medical decisions, advances in neuroimaging may enhance the management of these patients if more specific biomarkers can be found.
Iron may be yet another critical means by which to assess the status of MS patients. Iron is a paramagnetic substance that reduces T2 relaxation time resulting in hypointensity on T2-weighted images. The different types of non-heme iron in the brain include low-molecular-weight complexes, ionic iron, metalloproteins such as transferrin, melanotransferrin and lactoferrin, as well as storage proteins such as ferritin and hemosiderin (34
). Transferrin carries iron from the blood into tissues, while ferritin stores excess iron atoms that are not immediately engaged in metabolic activities. There can be up to 4500 iron atoms stored in the 8-nm-diameter internal cavity of one ferritin protein (34
). Hemosiderin is considered to be a water-soluble iron storage molecule that is a breakdown product of ferritin and appears to be associated with iron overload disorders and hemorrhage (34
). Brain iron accumulation has been shown histologically in MS and recently, an iron increase from 24% to 39.5% was reported in the deep gray matter in MS patients compared to control subjects (25
The source of iron deposition may be myelin/oligodendrocyte debris (17
), concentrated iron in the macrophages (that phagocytize the destructed myelin/oligodendrocyte), or the product of hemorrhages from damaged brain vessels. The mechanism of direct damage to the brain by iron might be related to oxidative stress and the generation of toxic free radicals (12
). The amount of iron deposition could reflect the extent of tissue damage, thus iron could be used as a biomarker to predict clinical outcome. This is a reasonable hypothesis given recent findings (27
), which show very clear iron deposition encircling dilated veins in MS. The source of this iron is still unclear, but it could result from microhemorrhaging and hemosiderin buildup (27
). Additionally, our results appear to indicate that chronic lesions may vanish on T2WI in some instances. If this is the case, then it may explain why the number of lesions on T2WI has not been very specific to the severity of the disease.
Apart from signal-to-noise, one of the key points about phase contrast is that it is independent of field strength if the product of field strength and echo time is kept constant. Therefore, for the first time, it is possible to make comparisons of studies across systems and across field strengths and reasonably expect to get the same images. This should make SWI globally applicable in clinical trials on all manufacturers’ systems.
In conclusion, we have shown that SWI has the potential to recognize the presence of iron in MS lesions, visualize lesions missed by conventional methods and visualize different lesion characteristics. The iron may be from blood or other iron sources sequestered by macrophages in the form of hemosiderin. Future studies should focus on monitoring iron levels along with cognitive and motor evaluations of the patient as a possible means to have a more specific imaging test of the patient’s clinical status.