Detection of amyloid plaques targeted by USPIO-Aβ1–42 in Alzheimer's disease transgenic mice using magnetic resonance microimaging

Abstract

Amyloid plaques are one of the pathological hallmarks of Alzheimer's disease (AD). The visualization of amyloid plaques in the brain is important to monitor AD progression and to evaluate the efficacy of therapeutic interventions. Our group has developed several contrast agents to detect amyloid plaques in vivo using magnetic resonance microimaging (μMRI) in AD transgenic mice, where we used intra-carotid mannitol to enhance blood brain barrier (BBB) permeability. In the present study, we used ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, chemically coupled with Aβ 1-42 peptide to detect amyloid deposition along with mannitol for in vivo μMRI by femoral intravenous injection. A 3D gradient multi-echo sequence was used for imaging with a 100 μm isotropic resolution. The amyloid plaques detected by T2*-weighted μMRI were confirmed with matched histological sections. Furthermore, two different quantitative analyses were used. The region of interest-based quantitative measurement of T2* values showed contrast injected APP/PS1 mice had significantly reduced T2* values compared to wild-type mice. In addition, the scans were examined with voxel-based morphometry (VBM) using statistical parametric mapping (SPM) for comparison of contrast injected AD transgenic and wild-type mice. The regional differences seen in VBM comparing USPIO-Aβ1-42 injected APP/PS1 and wild type mice correlated with the amyloid plaque distribution histologically, contrasting with no differences between the two groups of mice without contrast agent injection in regions of the brain with amyloid deposition. Our results demonstrated that both approaches were able to identify the differences between AD transgenic mice and wild type mice, after injected with USPIO-Aβ1-42. The feasibility of using less invasive intravenous femoral injections for amyloid plaque detection in AD transgenic mice facilitates using this method for longitudinal studies in the pathogenesis of AD.

Quantification of β-Amyloidosis and rCBF with Dedicated PET, 7 T MR Imaging, and High-Resolution Microscopic MR Imaging at 16.4 T in APP23 Mice

“…On the other hand, other groups have shown the feasibility of using high-resolution microscopic MR imaging to detect single amyloid plaques (1,9,(24)(25)(26). This approach, however, lacks sensitivity and specificity as signal voids originating from T 2 -or T 2 *-weighted MR imaging may be related to blood vessels oriented in the orthogonal direction relative to the imaging plane or to microhemorrhages.…”

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

“…Moreover, it was able to be shown that early stages of post-radiogenic brain damage can be imaged via targeted SPIO-AB against ICAM-1 [183]. With respect to the use of SPIO in the imaging of neurodegenerative diseases such as Alzheimer's disease, amyloid beta plaques were able to be successfully addressed via MION-AB [184] or SPIO-AB against amyloid-beta 42 [185]. …”

The Ins and Outs of Nanoparticle Technology in Neurodegenerative Diseases and Cancer

“…SPION coupled NPs were tested by in vitro imaging of Aβ-related aggregates [155] and in vivo with a transgenic AD mouse model [156][157][158]. This type of approach by coupling Aβ-targeting antibodies to NPs give rise to the question of a double function of such nanocarriers which could have positive side-effect capturing toxic protein species, and activating elimination pathways adding a possible therapeutic action [159][160][161].…”