A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice

Abstract

Amyloid plaques are a characteristic feature in Alzheimer's disease (AD). A novel non-toxic contrast agent is presented, Gd-DTPA-K6A␤1-30, which is homologous to A␤, and allows plaque detection in vivo. MRI was performed on AD model mice and controls prior to and following intracarotid injection with Gd-DTPA-K6A␤1-30 in mannitol solution, to transiently open the blood-brain barrier. A gradient echo T2 * -weighted sequence was used to provide 100 m isotropic resolution with imaging times of 115 min. The scans were examined with voxel-based analysis (VBA) using statistical parametric mapping, for un-biased quantitative comparison of ligand-injected mice and controls. The results indicate that: (1) Gd-DTPA-K6A␤1-30 is an effective, non-toxic, ligand for plaque detection when combined with VBA (p ≤ 0.01-0.001), comparing pre and post-ligand injection scans. (2) Large plaques can be detected without the use of a contrast agent and this detection co-localizes with iron deposition. (3) Smaller, earlier plaques require contrast ligand for MRI visualization. Our ligand when combined with VBA may be useful for following therapeutic approaches targeting amyloid in transgenic mouse models.

Magnetic Resonance Imaging Detection and Time Course of Cerebral Microhemorrhages during Passive Immunotherapy in Living Amyloid Precursor Protein Transgenic Mice

“…This is unlikely in our study, because we did not use an extremely high resolution in MRI (100 m versus ϳ50 to 60 m; Jack et al, 2004;Lee et al, 2004;Zhang et al, 2004) as is required for potential interference by A␤ plaques. Sigurdsson et al (2008) have shown that very large plaque deposits are detectable in aged Tg2576 mice via T2*-weighted MRI at 100-m resolution. However, given the size of the plaques detected by Congo red in our work (Fig.…”

Immunotherapy Targeting Pathological Tau Conformers in a Tangle Mouse Model Reduces Brain Pathology with Associated Functional Improvements

“…The brains were then placed overnight in a phosphate buffer solution containing 20% glycerol and 2% DMSO, and subsequently serial coronal 40 m sections of the brain were prepared and subject to fluorescent microscopy. Our previous experience with developing peptidic ligands for magnetic resonance imaging of amyloid plaques indicates that identical method of intracarotid injection, without the use of an osmotic agent, does not disrupt the blood-brain barrier (Wadghiri et al, 2003;Sigurdsson et al, 2007). Work by others supports this observation (for review, see Rapoport, 2000).…”

Curcumin-conjugated magnetic nanoparticles for detecting amyloid plaques in Alzheimer's disease mice using magnetic resonance imaging (MRI)

“…These factors may hinder application of USPIO-Ab1-42 in future clinical trials. The authors have introduced a new nano formulation using a less toxic fragment of Ab peptide [23] and co-linking with polyethylene glycol (PEG) to replace co-injection of mannitol [24]. The Ab peptide and PEG require a special chemical linker (EDC/NHS) to attach to the USPIO surface.…”