Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides as plaques in the brain parenchyma and as deposits in the cerebral vasculature. Early detection of amyloid plaques and deposits is imperative for diagnosing AD before the onset of cognitive decline. Magnetic resonance (MR) imaging using Gd (III)-based agents for contrast enhancement and plaque targeting provides a promising avenue. However, there remains a challenge due to the limited permeability of these contrast agents across the blood-brain barrier (BBB), which restricts its delivery. Furthermore, clearance mechanisms in the brain also reduce retention of contrast agents. To identify mechanisms that limit the success of contrast agents, we investigated the pharmacokinetics and the brain distribution of contrast agent, GdN-4ab/Q-4abAβ30, using AD transgenic mouse models and compartmental modeling. Our results demonstrate that the contrast agent is internalized by parenchymal cells, which limits its availability to bind to extracellular plaques. Sensitivity analysis conducted on the compartmental model identified systemic clearance and plasma-to-brain influx as key parameters that limit the delivery of the contrast agent to the brain. The analysis also highlights the BBB as a formidable barrier for delivery and the importance of improving BBB permeability to increase the accumulation of the contrast agent in the brain. Furthermore, model simulations revealed that glymphatic drainage contributes to the poor retention and rapid elimination of the contrast agent from the brain. By elucidating the role of these biological processes and parameters, this study contributes to understanding factors limiting contrast agent efficacy in amyloid plaque imaging in the AD brain. These findings also reveal important targets for optimizing contrast agent design to improve its brain delivery.
Salian et al. (Mon,) studied this question.