Macrophage Imaging Within Human Cerebral Aneurysms Wall Using Ferumoxytol-Enhanced MRI: A Pilot Study

Abstract

Objective Macrophages play a critical role in cerebral aneurysm formation and rupture. The purpose of this study is to demonstrate the feasibility and optimal parameters of imaging macrophages within human cerebral aneurysm wall using ferumoxytol-enhanced-MRI. Methods and Results 19 unruptured aneurysms in 11 patients were imaged using T2*-GE-MRI sequence. Two protocols were utilized. Protocol A: infusion of 2.5mg/kg of ferumoxytol and imaging at day 0 and 1. Protocol B: infusion of 5mg/kg of ferumoxytol and imaging at day 0 and 3. All images were reviewed independently by two neuroradiologists to assess for ferumoxytol-associated loss of MRI signal intensity within aneurysm wall. Aneurysm tissue was harvested for histologic analysis. Fifty percent(5/10) of aneurysms in protocol A showed ferumoxytol-associated signal changes in aneurysm walls compared to 78% (7/9) of aneurysms in protocol B. Aneurysm tissue harvested from patients infused with ferumoxytol stained positive for both CD68+, demonstrating macrophage infiltration, and Prussian-Blue, demonstrating uptake of iron particles. Tissue harvested from controls stained positive for CD68 but not Prussian-Blue. Conclusions Imaging with T2*-GE-MRI at 72 hours post-infusion of 5mg/kg of ferumoxytol establishes a valid and useful approximation of optimal dose and timing parameters for macrophages imaging within aneurysm wall. Further studies are needed to correlate these imaging findings with risk of intracranial aneurysm rupture.

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin‐17A Which Downregulates E‐Cadherin

“…E‐cadherin's role in the pathobiology of aneurysms and ruptures is compatible with findings of inflammatory cell infiltration of the vascular wall of human aneurysms 11, 12, 13. We demonstrate that E‐cadherin blockade causes significant infiltration of macrophages in cell migration assays and in vivo at the murine COW.…”

“…Experimental and human studies have demonstrated that aneurysms are the result of a vascular inflammatory process initiated by hemodynamic injury at bifurcations. Inflammatory cells, notably macrophages, infiltrate the vessel wall and contribute to matrix metalloproteinase–mediated degeneration of the extracellular matrix 11, 12, 13. This process leads to an eventual weakening of vascular structural integrity, leading to aneurysm formation and rupture 9, 10…”

Inflammation in human cerebral aneurysms: pathogenesis, diagnostic imaging, genetics, and therapeutics

“…[48] Given the role of macrophages in IA pathogenesis, several studies conducted by Hasan et al [49][50][51][52] investigated the possibility of in vivo aneurysm wall macrophage quantification through infusion of a carbohydrate coated superparamagnetic iron oxide nanoparticle, ferumoxytol (AMAG Pharmaceuticals, Lexington, Massachusetts, USA). Ferumoxytol is cleared by macrophages in either the arterial lumen or subendothelium of IAs, thus allowing for delayed visualization of macrophage activity as a surrogate biomarker for inflammatory status of a particular lesion.…”

“…[53] The optimal imaging chronology for this novel ferumoxytol enhanced MRI was found to be 5 mg/ kg ferumoxytol with imaging at 72 h postinjection. [49] A critical observation was made in a subsequent follow-up study. The authors found that the time of ferumoxytol uptake may be indicative of aneurysmal stability and rupture propensity.…”

Vascular Inflammation in a Growing Iliac Artery Aneurysm

“…It has been broadly applied in both pediatric and adult patients for intracranial, chest, and abdominal vascular MRI [10][11][12][13][14]. In addition to its role as a positive contrast vascular imaging agent, ferumoxytol has a unique property as a USPIO: It is phagocytosed by macrophages after a delay [15]. This macrophage-selective feature of ferumoxytol allows the identification of pathologic inflammation, which AJR:205, September 2015…”