A novel MRI contrast agent for identifying hyperphosphorylative neurons as a marker of future tau pathology

Abstract

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.

Early Diagnosis of Neurodegenerative Diseases: What Has Been Undertaken to Promote the Transition from PET to Fluorescence Tracers

“…Notably, this product demonstrated enhancing the MRI signal in the transgenic PS19 mice line, 4 to 6 months before the subjects showed tauopathy symptoms. As a further note, studies employing artificial intelligence (AI) techniques to analyze MRI-image-related data and other readily available information for predicting the clinical status of patients with neurodegenerative diseases have very recently been proposed and applied for amyloids [150][151][152][153]. An example of this comes from a very recent study by Lew and colleagues [154], who reported the development and application of a deep learning approach able to predict the PETdetermined amyloid-tau-neurodegeneration (ATN) biomarker status from MRI and other patient-related data reported in the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.adni-info.org, accessed on 29 November 2023).…”

Magnetic Resonance Imaging in Tauopathy Animal Models

“…The detection was verified by colocalization with anti-phosphorylated tau antibody AT8-positive tau deposits. Badachhape et al (2020) and Parekh et al (2021) demonstrated tau imaging using the DNA aptamer-targeted liposomal-Gd nanoparticle TauX, which binds to the surface of hyperphosphorylative cells, for T 1 -weighted spin echo MRI in PS19 mice ( Figure 1A ). Increased TauX-enhanced post-contrast MR signal enhancement was detected at 2 months of age in PS19 mice (which showed tauopathy 4–6 months later) compared with wild-type mice, with an accuracy of approximately 0.8 ( Figure 1B ).…”

“…Sensitivity describes the true positive rate for transgenic mice given TauX, while specificity is the true negative rate for wild-type mice given TauX and transgenic mice receiving untargeted gadolinium nanoparticle contrast. Reproduced from Badachhape et al (2020) with permission from Elsevier. (C) Functional connectivity matrices of transgenic rTg4510 and wild-type mice at baseline and after 8weeks of treatment with doxycycline.…”

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…(1) Gadolinium (Gd) based: Gd-diethylenetriamine pentaacetate (DTPA)-Aβ1-40, Gd-DTPA-K6Aβ1-30, cyanine-conjugated Gd (III) complex, Gd-pF(ab’)24, and liposomal macrocyclic Gd-ADx-001 [ 34 , 35 , 36 , 37 , 38 , 39 ] ( Figure 1 f).…”