A surrogate marker for very early-stage tau pathology is detectable by molecular magnetic resonance imaging

Abstract

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.

Advances in nanoprobes for molecular MRI of Alzheimer's disease

“…Aptamers are short strands of nucleic acid probes that recognize a target with high specificity and sensitivity, in this case hyperphosphorylated cells (Parekh et al, 2013). The selection of aptamers specific for the hyperphosphorylative state of the cell led us to two aptamers that bound cell-surface vimentin identified as the potential target differentially expressed on the surface of hyperphosphorylative cells (Parekh et al, 2022). To enable mMRI of prepathological state, targeted liposomal-Gd nanoprobes (TauX) using aptamers and a small molecule ligand to vimentin were fabricated and tested in vivo (Figure 11).…”

“…The rich experience using liposomal agents in clinical trials and the availability of FDA‐approved liposome‐based drug products make this platform particularly attractive for the development of clinically translatable mMRI agents. Liposome‐based gadolinium contrast agents have been investigated for mMRI of Alzheimer's disease (Badachhape et al, 2020; Parekh et al, 2022; Tanifum et al, 2016). Mechanistic and in vivo imaging studies have shown that covalently presented Gd‐chelates on liposome surface slow down rotational correlation times of gadolinium moieties, boosting T1 relaxivity, and transforming them into ultra‐sensitive T1‐based contrast agents (Ghaghada et al, 2009; Mulder et al, 2013).…”

“…These studies demonstrated transportation of ~10 (Lanoiselée et al, 2017) nanoparticles into the brain. Subsequent studies using ultra‐high T1 relaxivity MR nanoprobes demonstrated that this number of particles is sufficient for mMRI of AD pathology (Badachhape et al, 2020; Parekh et al, 2022; Tanifum et al, 2016). Furthermore, these studies showed that the choroid plexus is the dominant route for brain entry of nanoparticles in both non‐AD and AD mice.…”

“…Since in vivo pharmacokinetics and biodistribution profile of mMRI nanoprobes will be fundamentally different from conventional small molecule Gd‐chelates agents, attention should be paid to understanding in vivo stability and body clearance of agent even during the early stages of product development. The use of strong Gd chelating agents with high kinetic and thermodynamic stability, such as DOTA, in the development of next generation mMRI nanoprobes would help mitigate this concern (Badachhape et al, 2020; Parekh et al, 2022). Another safety factor that needs attention is the risk for infusion reactions.…”

“…Noncontrast MRI is routinely used for structural imaging of brain atrophy in AD (Park & Moon, 2016). There has been a growing interest in developing targeted contrast agents for mMRI of AD pathology given the numerous advantages of MRI (Badachhape et al, 2020; Laforce et al, 2018; Nordberg, 2011; Parekh et al, 2022; Tanifum et al, 2016; Wahl et al, 2011).…”