In these preclinical studies, we describe ADx-001, an Aβ-targeted liposomal macrocyclic gadolinium (Gd) imaging agent, for MRI of amyloid plaques. The targeting moiety is a novel lipid-PEG conjugated styryl-pyrimidine. An MRI-based contrast agent such as ADx-001 is attractive because of the lack of radioactivity, ease of distribution, long shelf life, and the prevalence of MRI scanners. Dose-ranging efficacy studies were performed on a 1 T MRI scanner using a transgenic APP/PSEN1 mouse model of Alzheimer’s disease. ADx-001 was tested at 0.10, 0.15, and 0.20 mmol Gd/kg. Gold standard post-mortem amyloid immunostaining was used for the determination of sensitivity and specificity. ADx-001 toxicity was evaluated in rats and monkeys at doses up to 0.30 mmol Gd/kg. ADx-001 pharmacokinetics were determined in monkeys and its tissue distribution was evaluated in rats. ADx-001-enhanced MRI demonstrated significantly higher (p < 0.05) brain signal enhancement in transgenic mice relative to wild type mice at all dose levels. ADx-001 demonstrated high sensitivity at 0.20 and 0.15 mmol Gd/kg and excellent specificity at all dose levels for in vivo imaging of β amyloid plaques. ADx-001 was well tolerated in rats and monkeys and exhibited the slow clearance from circulation and tissue biodistribution typical of PEGylated nanoparticles.
The abnormal phosphorylation of tau is a necessary precursor to the formation of tau fibrils, a marker of Alzheimer's disease. We hypothesize that hyperphosphorylative conditions may result in unique cell surface markers. We identify and demonstrate the utility of such surrogate markers to identify the hyperphosphorylative state. Methods: Cell SELEX was used to identify novel thioaptamers specifically binding hyperphosphorylative cells. Cell surface vimentin was identified as a potential binding target of the aptamer. Novel molecular magnetic resonance imaging (M-MRI) probes using these aptamers and a small molecule ligand to vimentin were used for in vivo detection of this pre-pathological state. Results: In a mouse model of pathological tau, we demonstrated in vivo visualization of the hyperphosphorylative state by M-MRI, enabling the identification at a pre-pathological stage of mice that develop frank tau pathology several months later. In vivo visualization of the hyperphosphorylative state by M-MRI was further validated in a second mouse model (APP/PS1) of Alzheimer's disease again identifying the mutants at a pre-pathological stage. Conclusions: M-MRI of the hyperphosphorylative state identifies future tau pathology and could enable extremely early-stage diagnosis of Alzheimer's disease, at a pre-patholgical stage.
Background Hyperphosphorylated tau (pTau) is a precursor to tau tangle formation in Alzheimer's disease (AD). We have identified aptamers that bind to specific cell membrane receptors of human neuronal cells that are hyperphosphorylating tau. In this work, we built a novel targeted nanoparticle magnetic resonance imaging (MRI) contrast agent, TauX, that binds such neurons, and tested its efficacy in vivo in the P301S mouse model of tau pathology. Method DNA aptamers preferentially binding on the cell membrane of hyperphosphorylative SH‐SY5Y cells were selected using a modified SELEX protocol. Mass spectrometric proteomic analysis of the bound aptamers was used to identify the binding targets on the cell‐surface, and target presence was validated on both mouse and Alzheimer’s disease patient brain tissues. P301S transgenic mice (n=8) and age‐matched wild type mice (n=6) were intravenously injected TauX contrast agent and imaged by MRI using a T1‐weighted spin‐echo (T1w‐SE) sequence at 2 months of age. An additional control group of transgenic mice (n=8) received untargeted gadolinium nanoparticle contrast agent. T1‐weighted images were acquired on 1T MRI scanner at pre‐ and 4 days post‐contrast injection. Receiver operator characteristic (ROC) curves were generated with a six‐point ordinal scale to assess sensitivity and specificity for TauX. Mice were aged to 8 months and their brains were histologically assessed with AT100 antibody to confirm pTau pathology. Result TauX‐enhanced post‐contrast images showed MR signal enhancement in most of the transgenic mice that went on to develop tau pathology 4‐6 months later, but not in wild type animals lacking tau pathology (Figure 1). Transgenic mice given untargeted nanoparticle contrast also did not show MR signal enhancement (Figure 1). AT100 staining of P301S cortical brain sections demonstrated elevated pTau levels related to wild type counterparts (Figure 2). ROC curve constructed over the entire tested group, including controls, showed overall AUC and accuracy ∼0.8 (Figure 3). Conclusion A novel MRI contrast agent that can identify mice that develop tau pathology several months in the future has been demonstrated. If successful in humans, this agent could advance the identification of patients at risk of tau pathology to a very early pre‐symptomatic stage of the disease.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.