Protein aggregation linked to Alzheimer's disease revealed by saturation transfer MRI

ABSTRACT The goal of this study was to develop a molecular biomarker for the detection of protein aggregation involved in Alzheimer's disease (AD) by exploiting the features of the water saturation transfer spectrum (Z‐spectrum), the CEST signal of which is sensitive to the molecular configuration of proteins. A radial‐sampling steady‐state sequence based ultrashort echo time (UTE) readout was implemented to image the Z‐spectrum in the mouse brain, especially the contributions from mobile proteins at the frequency offsets for the composite protein amide proton (+3.6 ppm) and aliphatic proton (−3.6 ppm) signals. Using a relatively weak radiofrequency (RF) saturation amplitude, contributions due to strong magnetization transfer contrast (MTC) from solid‐like macromolecules and direct water saturation (DS) were minimized. For practical measure of the changes in the mobile protein configuration, we defined a saturation transfer difference (&Dgr;ST) by subtracting the Z‐spectral signals at ±3.6 ppm from a control signal at 8 ppm. Phantom studies of glutamate solution, protein (egg white) and hair conditioner show the capability of the proposed scheme to minimize the contributions from amine protons, DS, and MTC, respectively. The ST signal at ±3.6 ppm of the cross‐linked bovine serum albumin (BSA) solutions demonstrated that the &Dgr;ST signal can be used to monitor the aggregation process of the mobile proteins. High‐resolution &Dgr;ST images of AD mouse brains at ±3.6 ppm of mouse brains showed significantly reduced &Dgr;ST (‐3.6) signal compared to the age‐matched wild‐type (WT) mice. Thus, this signal has potential to serve as a molecular biomarker for monitoring protein aggregation in AD. HIGHLIGHTSA low‐B1 radial‐sampling steady‐state MRI acquisition scheme was developed to acquire high‐resolution saturation transfer difference (&Dgr;ST) maps.Low B1 was used to focus on the chemical exchange saturation transfer from mobile proteins and minimize the direct water saturation and the magnetization transfer effects in tissue.&Dgr;ST maps at offset frequencies of ±3.6ppm from water reflected changes in protein aggregation, providing a novel imaging biomarker.Detection of protein aggregation associated with Alzheimer's disease using a mouse model by a UTE‐CEST sequence.

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