Advancing neuroimaging: novel manganese- and iron-based MRI contrast agents for cerebral ischemic diseases

Abstract

Cerebral ischemic diseases remain a significant clinical challenge, necessitating advancements in imaging technologies to improve diagnosis and therapeutic monitoring. This review highlights the limitations of gadolinium-based contrast agents (GBCAs), particularly their nephrotoxicity and limited specificity, and explores the emerging role of manganese- and iron-based MRI contrast agents as promising alternatives. Manganese-based agents demonstrate exceptional sensitivity to neuronal activity and metabolic changes, making them highly effective for assessing functional and cellular dynamics. Meanwhile, iron-based agents leverage their superparamagnetic properties to enhance ischemic lesion detection, particularly in T₂-weighted imaging. However, the clinical translation of these novel agents faces significant challenges, including biosafety concerns, suboptimal targeting efficiency, and the need for multimodal integration to improve diagnostic precision. Future research should focus on the development of low-toxicity, biodegradable contrast agents with enhanced targeting capabilities, the application of artificial intelligence for probe optimization, and the creation of theranostic nanoprobes that combine imaging with targeted therapy. Additionally, rigorous clinical validation and the establishment of standardized protocols will be critical for integrating these agents into routine practice. These advancements hold the potential to revolutionize ischemic stroke diagnosis and enable precision neuroimaging, driving the broader adoption of novel MRI contrast agents in clinical workflows.

Keywords: Cerebral ischemic; Iron-based MRI contrast agents; Magnetic resonance imaging; Manganese-based MRI contrast agents; Theranostic.

Fig. 1

Temporal progression of neurovascular events after ischemic stroke. Neuronal release of damage-associated molecular patterns (DAMPs) rapidly activates microglia and endothelial cells. M1-polarized microglia secrete IL-1, IL-6, tumor necrosis factor-alpha (TNF-α), matrix metalloproteinases (MMPs), and reactive oxygen species (ROS), disrupting the blood–brain barrier (BBB). Simultaneously, pericytes and astrocytic endfeet retract from the basement membrane, facilitating BBB leakage and leukocyte infiltration. Infiltrating immune cells amplify inflammation via IL-1 and monocyte chemotactic protein 1 (MCP-1). During the subacute phase, microglia shift to an M2 phenotype, promoting debris clearance and repair through insulin-like growth factor 1 (IGF-1), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF). These mediators support glial scarring, BBB restoration, and regeneration, including neurogenesis, astrogliogenesis, and angiogenesis. reproduced from Anamaria Jurcau et al. [25]

Fig. 2

Longitudinal manganese-enhanced MRI (MEMRI) findings after middle cerebral artery occlusion (MCAO) and histological comparison. A Longitudinal MEMRI at 1 (a), 11 (b), and 22 (c) days after MCAO. Enlarged caudate putamen (CPu) regions (a’–c’) show markedly reduced signal at day 1. By day 11, ring-shaped signal enhancement appears around the ischemic core (yellow arrows), which persists through day 22, with the strongest signal near the lateral ventricle (red arrows). Signal quantification (d–f) shows significant reduction in the CPu at day 1 (*p < 0.05), and significant increases in the ischemic periphery at days 11 and 22 compared to day 1 and sham (***p < 0.001), B at day 11 post-MCAO, MEMRI enhancement (a, black arrow) corresponds to glial fibrillary acidic protein (GFAP)-positive astrocytic regions (b, black arrow). Ionized calcium-binding adapter molecule 1 (Iba1) immunostaining (c), HE staining (d), and T2-weighted MRI (e) show broader ischemic damage (white arrows). Reproduced from Kawai et al. [46]

Fig. 3

Left: Schematic representation of bovine serum albumin (BSA)-MnO₂ nanoparticles (BM NPs) for MRI-based assessment of BBB permeability and prediction of hemorrhagic transformation (HT) in an MCAO rat model. Right: MRI visualization of BBB permeability changes with BM NPs in MCAO rats. a Timeline for MRI acquisition post-injection of BM NPs. b, c MR images and signal intensity curves for ipsilateral and contralateral regions in MCAO rats without b and with c HT. d, e HE staining of brain tissues shows extravascular red blood cells and occasional microthrombi in hemorrhagic regions (black arrows). Reproduced from Hou et al. [47]

Fig. 4

Polyethylene glycol-coated iron oxide nanoclusters (PEG–IONC) enhanced vascular imaging and ischemic assessment in beagle and macaque. A Three-dimensional MRA following intravenous injection of PEG–IONCs. (a, b) Whole-body arterial imaging of beagle; (c) upper-body arterial branches of beagle; (d) upper-body vasculature of macaque demonstrating high spatial resolution, B multimodal imaging of left cerebral ischemia in macaque. (a) DSA after vascular occlusion; (b–c) T1 and T2-weighted imaging; (d) diffusion-weighted imaging (DWI) and apparent diffusion coefficient (ADC) maps at 5 h post-occlusion reveal acute infarction in the left hemisphere. (e) Dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) after PEG–IONC administration shows decreased cerebral blood volume (CBV) and cerebral blood flow (CBF), along with prolonged mean transit time (MTT) and time to peak (TTP) in the ischemic area (white dashed circle); red dashed circle indicates the brain region. (f, g) Susceptibility-weighted imaging (SWI) pre- and post-PEG–IONC injection shows increased venous contrast in the ischemic hemisphere (white dashed circle). (h) Gross brain photograph and (i) HE staining confirm multifocal necrosis resulting from arterial occlusion. Reproduced from Lu et al. [71]

Fig. 5

In vivo near-infrared fluorescence imaging (NIRFI) of PLT membrane biomimetic nanocarriers (PAMNs) in ischemic stroke mice. a Schematic timeline showing ischemic stroke induction and NIRFI protocol, b NIRFI of mice before (pre) and after PAMN injection over time (0.5–6 h), c quantitative analysis of DiR fluorescence intensity in the brain pre- and post-PAMN injection (0.5–24 h), d Ex vivo NIRFI of major organs 6 h post-injection, e quantitative analysis of DiR fluorescence intensities in excised organs, showing significant brain accumulation (p < 0.01), f in vivo T2 MRI of the brain pre- and post-injection of PAMNs over time (1–12 h). Reproduced from Li et al. [88]