Non-invasive visualization of amyloid-beta deposits in Alzheimer amyloidosis mice using magnetic resonance imaging and fluorescence molecular tomography

Abstract

Abnormal cerebral accumulation of amyloid-beta peptide (Aβ) is a major hallmark of Alzheimer’s disease. Non-invasive monitoring of Aβ deposits enables assessing the disease burden in patients and animal models mimicking aspects of the human disease as well as evaluating the efficacy of Aβ-modulating therapies. Previous in vivo assessments of plaque load in mouse models of cerebral amyloidosis have been predominantly based on two-dimensional diffuse fluorescence reflectance imaging (2D-FRI) and two-photon microscopy (2PM) using Aβ-specific imaging agents. However, 2D-FRI lacks depth resolution, whereas 2PM is restricted by the limited field of view preventing coverage of large brain regions. Here, we utilized a magnetic resonance imaging (MRI) and fluorescence molecular tomography (FMT) pipeline with the curcumin derivative fluorescent probe CRANAD-2 to achieve full 3D brain coverage for detecting Aβ accumulation in the arcAβ mouse model of cerebral amyloidosis. A homebuilt FMT system was used for data acquisition in combination with a customized software platform enabling the integration of anatomical information derived from MRI as prior information for FMT image reconstruction. The results obtained from the FMT-MRI study were compared to data obtained from conventional 2D-FRI recorded under similar physiological conditions. The two methods yielded comparable time courses of the fluorescence intensity following intravenous injection of CRANAD-2 in a region of interest comprising the mouse brain. The depth resolution inherent to FMT allowed separation of signal contributions from the scalp and different brain regions, indicating preferential accumulation of the fluorescent tracer in the cerebral cortex, a region characterized by significant plaque deposition in arc Aβ mice. In conclusion, we have demonstrated the feasibility of visualizing Aβ deposition in 3D using a multimodal FMT-MRI method. This hybrid imaging method provides complementary anatomical, physiological and molecular information, thereby enabling the detailed characterization of the disease status in mouse models of cerebral amyloidosis, which is also important for monitoring the efficacy of putative treatments targeting Aβ.

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

“…The advantage of MRI molecular imaging stems from its superior resolution and improved signal-to-noise ratio, enabled by the development in high-field MRI and coil arrays. MRI provides versatile functional, structural, and molecular readouts and longitudinal, large field-of-view imaging capacity compared to other imaging modalities, such as two-photon microscopy, fluorescence molecular tomography, and optoacoustic microscopy [ 225 , 226 , 227 , 228 , 229 , 230 ]. The disadvantages and limitations of preclinical MRI methods include the following:…”