Comparison of USPIO-enhanced MRI and Gd-DTPA enhancement during the subacute stage of focal cerebral ischemia in rats

Abstract

Background

Being one class of magnetic resonance imaging (MRI) contrast agents, ultrasmall superparamagnetic particles of iron oxides (USPIO) bear the potential to study neuroinflammation following stroke, but there is still debate over whether the iron oxides particles may enter the brain tissue passively over a damaged blood–brain barrier (BBB).

Purpose

To compare the enhancement patterns of USPIO and gadopentate dimeglumine (Gd-DTPA) during the subacute stage of focal cerebral ischemia, to examine the relationship between USPIO enhancement and BBB disturbance, as well as with neuroinflammatory cell response.

Material and Methods

Multiple MR sequences were obtained on days 3 and 6 after transient middle cerebral artery occlusion induced in rats with and without the application of USPIO and Gd-DTPA. The enhancement patterns of the two contrast agents were compared and correlated to histology, including IgG for BBB permeability, Prussian Blue staining for iron particle detection, and CD68 immunohistochemistry staining to identify macrophage/microglia.

Results

Gd-DTPA enhancement depicted BBB breakdown being in line with IgG leakage. The USPIO enhanced images demonstrated both diffuse and focal signal alteration in ischemic lesions. The diffuse enhanced pattern had a similar spatial and temporal profile as with Gd-DTPA enhancement. In addition, focal enhanced signal loss was visible on T1-, T2-, and T2*-weighted images, with a peak tendency of MR signal loss, macrophage/microglia concentration and iron particle accumulation at a later phase of the study.

Conclusion

After focal cerebral ischemia, Gd-DTPA-enhanced MRI showed a higher sensitivity in detecting BBB alterations than did USPIO enhancement. USPIO provided complementary information regarding inflammatory cell activity in neuroinflammatory to cerebral ischemia that had not been visualized using conventional Gd-DTPA. The assessment using multiple MR parameters may identify intracellular and extracellular USPIO in vivo.

Keywords

Focal cerebral ischemia neuroinflammation blood brain barrier USPIO Gd-DTPA magnetic resonance imaging

Get full access to this article

View all access options for this article.

References

Denes

Vidyasagar

Feng

. Proliferating resident microglia after focal cerebral ischaemia in mice. J Cereb Blood Flow Metab 2007; 27: 1941–1953.

Cho

Nighoghossian

Wiart

. USPIO-Enhanced MRI of neuroinflammation at the sub-acute stage of ischemic stroke: preliminary data. Cerebrovasc Dis 2007; 24: 544–546.

Nighoghossian

Wiart

Cakmak

. Inflammatory response after ischemic stroke: a USPIO-enhanced MRI study in patients. Stroke 2007; 38: 303–307.

Rausch

Sauter

Frohlich

. Dynamic patterns of USPIO enhancement can be observed in macrophages after ischemic brain damage. Magn Reson Med 2001; 46: 1018–1022.

Schroeter

Saleh

Wiedermann

. Histochemical detection of ultrasmall superparamagnetic iron oxide (USPIO) contrast medium uptake in experimental brain ischemia. Magn Reson Med 2004; 52: 403–406.

Kleinschnitz

Bendszus

Frank

. In vivo monitoring of macrophage infiltration in experimental ischemic brain lesions by magnetic resonance imaging. J Cereb Blood Flow Metab 2003; 23: 1356–1361.

Kleinschnitz

Schutz

Nolte

. In vivo detection of developing vessel occlusion in photothrombotic ischemic brain lesions in the rat by iron particle enhanced MRI. J Cereb Blood Flow Metab 2005; 25: 1548–1555.

Engberink

Blezer

Hoff

. MRI of monocyte infiltration in an animal model of neuroinflammation using SPIO-labeled monocytes or free USPIO. J Cereb Blood Flow Metab 2008; 28: 841–851.

Saleh

Wiedermann

Schroeter

. Central nervous system inflammatory response after cerebral infarction as detected by magnetic resonance imaging. NMR Biomed 2004; 17: 163–169.

10.

Rausch

Baumann

Neubacher

. In-vivo visualization of phagocytotic cells in rat brains after transient ischemia by USPIO. NMR Biomed 2002; 15: 278–283.

11.

Farr

Seehafer

Nelles

. Challenges towards MR imaging of the peripheral inflammatory response in the subacute and chronic stages of transient focal ischemia. NMR Biomed 2011; 24: 35–45.

12.

Kim

Lee

. Imaging of the inflammatory response in reperfusion injury after transient cerebral ischemia in rats: correlation of superparamagnetic iron oxide-enhanced magnetic resonance imaging with histopathology. Acta Radiol 2008; 49: 580–588.

13.

Desestret

Brisset

Moucharrafie

. Early-stage investigations of ultrasmall superparamagnetic iron oxide-induced signal change after permanent middle cerebral artery occlusion in mice. Stroke 2009; 40: 1834–1841.

14.

Wiart

Davoust

Pialat

. MRI monitoring of neuroinflammation in mouse focal ischemia. Stroke 2007; 38: 131–137.

15.

Saleh

Schroeter

Jonkmanns

. In vivo MRI of brain inflammation in human ischaemic stroke. Brain 2004; 127: 1670–1677.

16.

Saleh

Schroeter

Ringelstein

. Iron oxide particle-enhanced MRI suggests variability of brain inflammation at early stages after ischemic stroke. Stroke 2007; 38: 2733–2737.

17.

Yang

Feng

Yao

. Magnetic resonance angiography of carotid and cerebral arterial occlusion in rats using a clinical scanner. J Neurosci Meth 2008; 167: 176–183.

18.

Sekeljic

Bataveljic

Stamenkovic

. Cellular markers of neuroinflammation and neurogenesis after ischemic brain injury in the long-term survival rat model. Brain Struct Funct 2012; 217: 411–420.

19.

Simon

Bauer

Saborovski

. T1 and T2 relaxivity of intracellular and extracellular USPIO at 1.5T and 3T clinical MR scanning. Eur Radiol 2006; 16: 738–745.

20.

Brisset

Desestret

Marcellino

. Quantitative effects of cell internalization of two types of ultrasmall superparamagnetic iron oxide nanoparticles at 4.7 T and 7 T. Eur Radiol 2010; 20: 275–285.

21.

Stroh

Zimmer

Werner

. Tracking of systematically administrated mononuclear cells in the ischemic brain by high-field magnetic resonance imaging. Neuroimage 2006; 33: 886–897.

22.

Schroeter

Jander

Witte

. Local immune responses in the rat cerebral cortex after middle cerebral artery occlusion. J Neuroimmunol 1994; 55: 195–203.

23.

Stoll

Jander

. The role of microglia and macrophages in the pathophysiology of the CNS. Prog Neurobiol 1999; 58: 233–247.

24.

Zhang

Dharmakumar

Mascheri

. Comparison of superparamagnetic and ultrasmall superparamagnetic iron oxide cell labelling for tracking green fluorescent protein gene marker with negative and positive contrast magnetic resonance imaging. Mol Imaging 2009; 8: 148–155.

25.

Schilling

Besselmann

Muller

. Predominant phagocytic activity of resident microglia over hematogenous macrophages following transient focal cerebral ischemia: an investigation using green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 2005; 196: 290–297.

26.

Reimer

Bremer

Allkemper

. Myocardial perfusion and MR angiography of chest with SH U 555 C: results of placebo-controlled clinical phase I study. Radiology 2004; 231: 474–481.

27.

Allkemper

Bremer

Matuszewski

. Contrast-enhanced blood-pool MR angiography with optimized iron oxides: effect of size and dose on vascular contrast enhancement in rabbits. Radiology 2002; 223: 432–438.

28.

Tombach

Reimer

Bremer

. First-pass and equilibrium-MRA of the aortoiliac region with a superparamagnetic iron oxide blood pool MR contrast agent (SH U 555 C): results of a human pilot study. NMR Biomed 2004; 3: 500–506.