Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer’s disease

Badachhape, Andrew; Srivastava, Mayank; Bhandari, Prajwal; Stupin, Igor; Devkota, Laxman; Tanifum, Eric A.; Annapragada, Ananth; Ghaghada, Ketan B.

doi:10.1038/s41598-020-73233-7

Cited by 13 publications

(24 citation statements)

References 38 publications

(49 reference statements)

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“…Delayed post-contrast MRI was performed 4 days later. MR images were acquired using a T1-weighted spin-echo (T1w-SE) sequence and a T1-weighted fast spin echo inversion recovery (FSE-IR) sequence 46 . Transgenic mice administered TauT1 and TauT3 demonstrated signal enhancement in the cortex and the hippocampus regions of the brain ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Coil calibration, RF calibration, and shimming were performed at the beginning of study for each subject. The pre-contrast scans provide a baseline for calculation of signal enhancement from resulting post-contrast scans 46 . Two-standard deviations above the mean variation within WT control animals was used as the cutoff signal intensity for identifying tau positive animals.…”

Section: Methodsmentioning

confidence: 99%

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Early Detection of Tau Pathology

Parekh

Badachhape

et al. 2021

Preprint

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While a definitive Alzheimer's disease (AD) diagnosis remains a post-mortem exercise, the ATN Research Framework proposed by the National Institute on Aging and the Alzheimer's Association utilizes a score representing the presence of amyloid deposits (A), tau deposits (T) and neuronal degeneration markers (N), with A+T+ necessary for a positive diagnosis. Current detection of tau pathology lags amyloid detection by years and by the time both markers are detected the disease is fairly advanced. We describe the development of a new generation of molecular imaging probes for in vivo detection of cells undergoing abnormal phosphorylation representing the initial stages of pTau pathology, potentially enabling a very early stage diagnosis of AD. We describe a novel nanoparticle formulation that binds such abnormally phosphorylating cells in a mouse model of tau pathology, enabling in vivo visualization of the hyperphosphorylative state by magnetic resonance imaging. Our results demonstrate the potential of this novel platform to identify a correlative marker signifying the development of future tau pathology, and has implications for early-stage diagnosis of Alzheimer's disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Early Detection of Tau Pathology

Parekh

Badachhape

et al. 2021

Preprint

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“…Chelates of Gadolinium (Gd), Gd 3+ is usually available as standard T1 (longitudinal) MRI contrast agents. In addition, the use of Gd-based small molecules [ 128 , 129 ] and Gd ions in NPs have been used in imaging applications [ 130 , 131 ]. More details about these contrast agents can be found in the interesting reviews by Ulanova et al [ 125 ] and Sharma et al [ 124 ].…”

Section: In Vivo Imaging Detection Platforms Of Ad Using Plasmonicmentioning

confidence: 99%

Plasmonic Nanoparticles as Optical Sensing Probes for the Detection of Alzheimer’s Disease

Oyarzún

Tapia-Arellano

Cabrera

et al. 2021

Sensors

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Alzheimer’s disease (AD), considered a common type of dementia, is mainly characterized by a progressive loss of memory and cognitive functions. Although its cause is multifactorial, it has been associated with the accumulation of toxic aggregates of the amyloid-β peptide (Aβ) and neurofibrillary tangles (NFTs) of tau protein. At present, the development of highly sensitive, high cost-effective, and non-invasive diagnostic tools for AD remains a challenge. In the last decades, nanomaterials have emerged as an interesting and useful tool in nanomedicine for diagnostics and therapy. In particular, plasmonic nanoparticles are well-known to display unique optical properties derived from their localized surface plasmon resonance (LSPR), allowing their use as transducers in various sensing configurations and enhancing detection sensitivity. Herein, this review focuses on current advances in in vitro sensing techniques such as Surface-enhanced Raman scattering (SERS), Surface-enhanced fluorescence (SEF), colorimetric, and LSPR using plasmonic nanoparticles for improving the sensitivity in the detection of main biomarkers related to AD in body fluids. Additionally, we refer to the use of plasmonic nanoparticles for in vivo imaging studies in AD.

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“…ADx-001 was tested at three dose levels to determine the effect of contrast agent dose on the detection of amyloid plaques in vivo. Conventional MR metric of signal enhancement (percentage change between pre-and postcontrast MRI) demonstrated excellent performance at 0.2 mmol Gd/kg dose but suboptimal performance (< 0.7) at lower dose levels (0.15 and 0.1 mmol Gd/kg) [3]. In this study, we examined if nano-radiomics (radiomic analysis of nanoparticle contrast-enhanced images) could augment performance at lower dose levels of ADx-001 for detection of amyloid pathology in mice with higher plaque burden.…”

Section: Introductionmentioning

confidence: 95%

“…Studies have also indicated that certain brain regions such as the cerebral cortex and hippocampus are more vulnerable to AD than other regions, which may be related to the memory deficits observed in human AD [2]. In our previous preclinical work, we examined the efficacy of an amyloid targeted liposomal macrocyclic gadolinium contrast agent (ADx-001) for in vivo molecular MRI of amyloid pathology in a mouse model of Alzheimer's disease with high plaque burden [3]. ADx-001 was tested at three dose levels to determine the effect of contrast agent dose on the detection of amyloid plaques in vivo.…”

Section: Introductionmentioning

confidence: 99%

Standardized MR nano-radiomics for early detection and amyloid burden classification in Alzheimer’s disease

Ngan,

Badachhape,

Tanifum

et al. 2024

Medical Imaging 2024: Clinical and Biomedical Imaging

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Extracellular deposits of amyloid- (A) aggregates are pathological hallmarks of Alzheimer's disease (AD). In our previous work, we showed that an amyloid-targeted liposomal gadolinium (Gd) contrast agent, ADx-001, demonstrated dose-related varying performance (accuracy 50% -100%) for in vivo MRI-based detection of amyloid plaques in a mouse model of AD. The goal of this study was to determine if nano-radiomics (radiomic analysis of nanoparticle contrastenhanced images) could improve performance in differentiating amyloid-positive transgenic (TG) APP/PSEN1 mice and age-matched amyloid-negative wild type (WT) mice. Nanoparticle contrast-enhanced MRI (nCE-MRI) was performed using a T1w-SE sequence in wild type (amyloid negative) and transgenic APP/PSEN1 mice (amyloid positive). The effect of ADx-001 dose and plaque burden on the performance of radiomics was determined. nCE-MRI was performed at three ADx-001 dose levels (0.10, 0.15, 0.20 mmol Gd/kg) in mice with high plaque burden and single ADx-001 dose level (0.20 mmol Gd/kg) in mice with low plaque burden. Following semi-automatic registration and segmentation of brain atlas on mouse MR images, two sets of radiomic features (RFs), including the RFs recommended by Image Biomarker Standardization Initiative, were calculated and evaluated for their performance in classifying TG and WT mice. Linear and nonlinear classifiers using RFs were examined to improve the model performance. 5-fold cross-validation was performed to confirm the accuracy of group separation. Nano-radiomic analysis in mice with high plaque burden achieved superb classification performance in terms of accuracy, sensitivity, and specificity, with one universal classifier for all dose levels of ADx-001. In comparison, conventional MR metric of signal enhancement demonstrated dose-related varying performance with suboptimal accuracy (<0.7) at lower dose levels. In mice with low plaque burden, radiomic analysis outperformed conventional MR metric for detection of amyloid pathology. In conclusion, nano-radiomics exhibited excellent performance for early detection and amyloid burden classification in a mouse model of Alzheimer's disease.

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Pre-clinical dose-ranging efficacy, pharmacokinetics, tissue biodistribution, and toxicity of a targeted contrast agent for MRI of amyloid deposition in Alzheimer’s disease

Cited by 13 publications

References 38 publications

Early Detection of Tau Pathology

Early Detection of Tau Pathology

Plasmonic Nanoparticles as Optical Sensing Probes for the Detection of Alzheimer’s Disease

Standardized MR nano-radiomics for early detection and amyloid burden classification in Alzheimer’s disease

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