MRI of Neuroinflammation Using a Folate Receptor β‐Targeted Nanoparticle Contrast Agent

Abstract

AbstractBackgroundNeuroinflammation plays an important role in Alzheimer’s disease (AD) pathogenesis and disease progression leading to cognitive decline. Current efforts for non‐invasive imaging of neuroinflammation are based on using PET radiotracers. An MRI‐based contrast agent for imaging of neuroinflammation would be highly desirable due to widespread use of MRI in imaging of neurological disorders. Folate receptor β, a marker of pro‐inflammatory phenotype, is expressed in microglia. In this work, we investigated a folate‐targeted liposomal‐Gd contrast agent for molecular MRI of neuroinflammation in mouse models of AD.Method In vivo studies were performed in APP/PSEN1 mice, a model of amyloid pathology, and P301S mice, a model of tau pathology. Transgenic mice and wild‐type (WT) littermates (n = 6/genotype, 24 total) underwent pre‐contrast MRI using T1‐weighted spin echo sequences with 160 µm in‐plane resolution and 1.2 mm slice thickness. Delayed MRI was performed 4 days after systemic administration of a high T1 relaxivity liposomal‐Gd contrast agent bearing folic acid molecules. Animals were euthanized after the final imaging session for microscopic analysis of brain. Signal changes between pre‐contrast and post‐contrast MRI were determined in target regions of the brain.ResultTransgenic APP/PSEN1 and P301S mice demonstrated signal enhancement in post‐contrast T1w‐MRI compared to pre‐contrast MRI. In comparison, WT control mice did not show signal enhancement in post‐contrast MRI. APP/PSEN1 transgenic mice exhibited greater relative enhancement (+5.9%, p<0.005) and lower inter‐subject variance than P301S mice (3.9%, p<0.05). Immunofluorescence analysis demonstrated higher burden of activated microglia in brains of transgenic mice compared to WT control mice.ConclusionA folate receptor β‐targeted liposomal‐Gd contrast agent enables in vivo MRI of neuroinflammation in mouse models of Alzheimer’s disease. Such imaging agents could play an important role in monitoring of Alzheimer’s disease progression leading to cognitive decline and evaluation of therapies that target neuroinflammation.