In vivo MRI of brain inflammation in human ischaemic stroke

Abstract

Inflammation contributes to brain damage caused by ischaemic stroke. Macrophages, as the prevailing inflammatory cell population in stroke lesions, can be visualized using ultrasmall superparamagnetic iron oxide (USPIO) as a cell-specific contrast agent for MRI. In this single-centre open-labelled clinical phase II study we tested the potential of USPIO-enhanced MRI for macrophage imaging in human ischaemic stroke lesions. In a series of 10 consecutive patients, USPIO contrast agent was infused at the end of the first week after symptom onset. Two follow-up MRI scans were performed 24-36 h and 48-72 h after infusion. Two distinct components of USPIO-related signal changes were discernible, one associated with blood vessels and one representing parenchymal enhancement. Vessel-associated changes appeared as signal loss on T2/T2*-weighted images and decreased from the first to second scan after USPIO infusion, most likely reflecting a transient blood pool effect of the contrast agent. Conversely, parenchymal enhancement was mainly evident on T1-weighted images, increased over time, and matched with the expected distribution of macrophages. Importantly, USPIO-induced signal alterations throughout differed from signatures of conventional gadolinium-enhanced MRI, thus being independent from breakdown of the blood-brain barrier. We suggest that increasing USPIO-enhancement on T1-weighted images indicates brain infiltration by USPIO-laden macrophages. Thus, USPIO-enhanced MRI may provide an in vivo surrogate marker of cellular inflammation in stroke and other CNS pathologies.

Superparamagnetic Iron Oxide Nanoparticle Probes for Molecular Imaging

“…Although the ability of SPIO to significantly reduce the spin-spin relaxation (T2) time is generally relied on for generating MR contrast, 68,99 it has also been demonstrated that SPIO can generate sufficient T1 contrast for biomedical applications as well; SPIO possess both high R1 and R2 relaxivities. 118,127 Upon removal of the magnetic field, Brownian motion is sufficient to randomize the SPIO orientations leaving no magnetic remanence. Brownian forces also prevent the aggregation of the SPIO due to magnetic attraction in solution.…”

“…90 Typically, in vivo, smaller nanoparticles (15-30 nm hydrodynamic diameter) with longer circulation times exhibit improved contrast at sites of inflammation compared with larger nanoparticles. 53 The role of macrophages in pathologic tissue alterations in the central nervous system (CNS) has also provided the opportunity for the use of SPIO agents for the imaging of strokes 127 (Fig. 3), multiple sclerosis, 33 brain tumors, 2,37 and carotid atherosclerotic plaques.…”

Superparamagnetic Iron Oxide Nanoparticles in Biomedicine: Applications and Developments in Diagnostics and Therapy

“…The suitability of SPIO for MRI of the CNS was able to be shown in neurovascular (infarction [88]), neuro-oncological (tumors [89]) or neuroinflammatory processes (multiple sclerosis (MS) [90]) as well as for angiography and perfusion diagnosis [91]. Increased accumulation of SPIO in the microglia of the CNS in the case of disruption of the blood brain barrier (BBB) in tumorous CNS lesions [89] or inflammatory CNS lesions [92] which can be imaged with the help of T2w/T2*w MR sequences is observed in the case of the former applications.…”

Magnetic Resonance Imaging of Human Brain Macrophage Infiltration

“…Saleh et al 46 performed the first clinical MRI study of ischemic stroke in 10 patients comparing Gd and USPIO contrast agents. Corresponding to the defined time delay of macrophage CNS infiltration in experimental studies, MRI scans were performed 4 to 6 days after stroke onset.…”