Iron in Multiple Sclerosis and Its Noninvasive Imaging with Quantitative Susceptibility Mapping

Abstract

Iron is considered to play a key role in the development and progression of Multiple Sclerosis (MS). In particular, iron that accumulates in myeloid cells after the blood-brain barrier (BBB) seals may contribute to chronic inflammation, oxidative stress and eventually neurodegeneration. Magnetic resonance imaging (MRI) is a well-established tool for the non-invasive study of MS. In recent years, an advanced MRI method, quantitative susceptibility mapping (QSM), has made it possible to study brain iron through in vivo imaging. Moreover, immunohistochemical investigations have helped defining the lesional and cellular distribution of iron in MS brain tissue. Imaging studies in MS patients and of brain tissue combined with histological studies have provided important insights into the role of iron in inflammation and neurodegeneration in MS.

Keywords: MRI; MS lesion; deep grey matter (DGM); quantitative susceptibility mapping (QSM).

Figure 1

Iron deposition in white matter MS lesions. The overview image (a) shows an oil-red O-stained with an actively demyelinating lesion (1) and a demyelinated lesion (2); The actively demyelinating lesion [1] contains myelin-laden macrophages as indicated by oil-red O (ORO) positive material within CD68⁺ macrophages (b,c); These macrophages do not contain iron, indicated by Perls’ staining (d); or the iron-storage protein ferritin (e); and display markers indicative of M2 polarization (iNOS⁻ (f) and CD206⁺ (g)); The demyelinated lesion center (2) shows CD68⁺ macrophages (black arrows) containing condensed myelin (h,i); occasionally containing iron (j) and correspondingly ferritin (k); and expressing CD206 (m); but not iNOS (l). In contrast, the demyelinated lesion rim (3) shows microglia (black arrows) containing no ORO positive material (n,o); but large amounts of iron (p) and iron-storing ferritin (q);. These cells are iNOS positive (r) and CD206 negative (s) suggestive of M1-like polarization. (Source: [10]). The black arrows are indicating macrophages.

Figure 2

QSM map of a HC subject (29 y) and an MS patient (29 y). Note increased susceptibility in the basal ganglia of the MS patient indicating increased iron content. Susceptibility differences are most evident in the putamen (white arrow, 0.049 vs. 0.092 ppm). (Source: [46]).

Figure 3

MS lesions on T1w (1st and 2nd row)/T2w (3rd and 4th row) and QSM at MRI1 (left, in blue) and a follow-up study at MRI2 (right, in black). The white boxes indicate the position of lesions identified on T1w, which are invisible on QSM. White arrows point at lesions in general; black arrows point at transient lesions, which disappear (appear T1 isointense) in the follow-up study (MRI2). Lower graphs: 32 cases are shown to exemplify lesions at various ages. The susceptibility of acute lesions (0 y) relative to NAWM jumped from MRI1 to MRI2 (red squares at bottom graph, interval between MR examinations = 0.43 ± 0.16 years). (Source: [42]).

Figure 4

Solid and shell susceptibility (ultrasmall superparamagnetic iron oxide particles (USPIO)) object appearance in MRI techniques. Solid and shell lesions can be identified on QSM images; however, they both appear shell-like on phase images. (Source: [170]).

Figure 5

WM lesion (in red circle) appearing hyperintense on QSM (a); indicating high susceptibility and corresponding significant iron deposition, isointense on phase (b); hypointense on T2*w (c) and R2* (d). Magnification of lesion within red circle (e-i): The LA-ICP-MS measures all forms of iron (Fe²⁺, Fe³⁺), shown in (g); QSM mainly reflects ferritin-stored Fe³⁺ (e); Thus, iron maps were converted into susceptibility maps assuming a molar susceptibility of iron similar to that of ferritin at room temperature. Using the Langevin equation, iron contributes χ_[Fe] = 1.4 ppb*[Fe], where [Fe] represents the local iron concentration. The phospholipid map (PF) (f), representing myelin, was calculated as χ_Myelin = QSM − 1.4 ppb*[Fe] assuming that myelin is the major susceptibility component in WM [163]. PF (f) and MBP (h) indicate demyelination in the lesion center. CD68 stain (i) and iron map (g) indicate iron-rich microglia at the lesion rim. (Source: [41]).

Figure 6

Non-enhancing lesions appear larger with hyperintense rim on QSM (red arrows) than on T2w, while enhancing lesions appear isointense on QSM (green arrow).

Figure 7

Lesion development over time showing various MS lesion activities (inflammation, iron deposition and emission (iron content)) and their manifestations on MRI (T1w+c, T2w, and QSM). Early inflammatory activity causes BBB damage, which is captured as Gd-enhancement on T1w+c; Immediate demyelination and iron deposition involving activated microglia cause rapid increase in magnetic susceptibility, which can be measured on QSM during MS lesion formation and development (approximately within the first 3 years (y)); Eventual old lesions (approx. >3 y) start to lose iron, which cancels the susceptibility increase of residual demyelination as measured by QSM. This time course indicates that QSM might be more sensitive than T1w+c in detecting inflammatory activity in lesions. QSM can detect both early and late inflammatory activity (remyelination is not frequently observed and not included here for simplicity).