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IMAGING OF MACROPHAGE ACTIVITY The differential uptake of ferumoxytol infusion can
be used to determine the degree of inflammatory
A recent sub-analysis of a large population-based activity of macrophages in cerebral vessels [Figure 1].
prospective study of unruptured aneurysms A histological study of unruptured aneurysms imaged
demonstrated the protective effect of aspirin on the using this modality prior to surgical resection detected
rupture risk of cerebral aneurysms. [15] The authors iron particles as well as macrophage infiltration in the
posit that the antiinflammatory effects of aspirin confer aneurysm wall, while only macrophages were detected
this risk reduction. In the presence of inflammation, in the tissue of a control group without ferumoxytol
the upregulation of cyclooxygenase-2 (COX-2) and infusion. [19]
microsomal prostaglandin E2 synthase-1 (mPGES-1)
increases prostaglandin production, which in turn A further study of ferumoxytol correlated its early
increases matrix metalloproteinase-9 (MMP-9) uptake on serial MRIs with impending aneurysm
production by macrophages. This causes the degradation rupture. [20] Twenty-two patients with thirty unruptured
of proteins in the extracellular environment. This activity aneurysms underwent MRI after ferumoxytol infusion
may lead to the weakening of the aneurysm wall, which at 3 time points: immediately, after 24 h, and after 72 h.
when exposed to increased hemodynamic stress, leads The presence of ferumoxytol uptake was defined as a
to aneurysmal rupture. [5,6] Aspirin has been shown to reduction in aneurysmal T2 signal when compared
attenuate the expression of COX-2 and mPGES-1, thus to baseline MRI. Ferumoxytol activity was defined
reducing the production of MMP-9 by macrophages. [16] as “early” if this change was detected in 24 h, and
“late” if detected only 72 h after infusion. Fourteen
Histological studies of ruptured versus unruptured aneurysms underwent subsequent surgical clipping,
aneurysms have demonstrated an early (< 12 h) while sixteen were observed based on small aneurysm
macrophage infiltrate, which some authors postulate size, patient age or co-morbidity, or patient preference.
may be responsible for an acute inflammatory reaction Histological analysis was performed on all surgically
[8]
that precipitates aneurysm rupture. The imaging treated aneurysms, as well as five ruptured aneurysms
of macrophage activity, therefore, could aid in the not imaged using ferumoxytol.
detection of a prerupture inflammatory state signaling
aneurysm wall instability and urgent need for treatment. Among surgically repaired aneurysms with early
uptake (n = 4), immunohistochemical analysis revealed
Macrophage imaging has recently been piloted in COX-2, mPGES-1 and M1 macrophage activity similar
humans in part due to the development of ferumoxytol. to that of ruptured aneurysms. Those unruptured
Ferumoxytol is a superparamagnetic form of iron aneurysms with late uptake (n = 5) had significantly
oxide originally developed for the treatment of iron less COX-2 and mPGES-1 activity compared to both
[17]
deficiency anemia. Because ferumoxytol is detectable ruptured aneurysms and unruptured aneurysms with
using conventional magnetic resonance imaging (MRI), early ferumoxytol uptake.
and cleared by macrophagocytosis, [18] imaging after
ferumoxytol infusion can highlight macrophage activity Of the fourteen aneurysms not surgically treated,
and hence inflammation. three demonstrated early signal changes, eight late

a b c d

Figure 1: Histology and ferumoxytol-enhanced magnetic resonance imaging (MRI) of an unruptured middle cerebral artery (MCA) aneurysm: (a) HE ×100; (b)
Prussian Blue stain showing iron oxide nanoparticles seen mostly in the adventitia; (c) higher magnification of Prussian blue stain demonstrating iron oxide
nanoparticles; (d) CD68 showing positive staining for macrophages MRI illustrates right MCA aneurysm with ferumoxytol uptake. Figure adapted with permission
from Hasan et al. [19]

52 Neuroimmunol Neuroinflammation | Volume 2 | Issue 2 | April 15, 2015