Dynamic contrast-enhanced MRI of Gd-albumin delivery to the rat hippocampus in vivo by convection-enhanced delivery

Abstract

Convection enhanced delivery (CED) shows promise in treating neurological diseases due to its ability to circumvent the blood-brain barrier (BBB) and deliver therapeutics directly to the parenchyma of the central nervous system (CNS). Such a drug delivery method may be useful in treating CNS disorders involving the hippocampus such temporal lobe epilepsy and gliomas; however, the influence of anatomical structures on infusate distribution is not fully understood. As a surrogate for therapeutic agents, we used gadolinium-labeled-albumin (Gd-albumin) tagged with Evans blue dye to observe the time dependence of CED infusate distributions into the rat dorsal and ventral hippocampus in vivo with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). For finer anatomical detail, final distribution volumes (Vd) of the infusate were observed with high-resolution T1-weighted MR imaging and light microscopy of fixed brain sections. Dynamic images demonstrated that Gd-albumin preferentially distributed within the hippocampus along neuroanatomical structures with less fluid resistance and less penetration was observed in dense cell layers. Furthermore, significant leakage into adjacent cerebrospinal fluid (CSF) spaces such as the hippocampal fissure, velum interpositum and midbrain cistern occurred toward the end of infusion. Vd increased linearly with infusion volume (Vi) at a mean Vd/Vi ratio of 5.51 ± 0.55 for the dorsal hippocampus infusion and 5.30 ± 0.83 for the ventral hippocampus infusion. This study demonstrated the significant effects of tissue structure and CSF space boundaries on infusate distribution during CED.

Voxelized Model of Brain Infusion That Accounts for Small Feature Fissures: Comparison With Magnetic Resonance Tracer Studies

“…It is expected that this percentage would increase with increasing infusion volume. These CED diversion effects are consistent with our previous CED tracer studies [16,17,32] where hyperintense regions were observed within and surrounding the hippocampal fissure in MR imaging, and high concentration of dye at the fissure surface was also shown in histological images. Also, the final CED distribution volume ratios decreased 16.5% in the dorsal hippocampus and 13.2% in the ventral hippocampus when fissures were accounted for in the model.…”

“…In previous MR studies, our group has experimentally measured CED into dorsal and ventral rat hippocampi [17,22,32]. Quantification of in vivo concentration patterns during CED was achieved through dynamic contrast enhanced MRI (DCE-MRI) by using measured relaxivities [17].…”

“…In this study, MR-based computational models were developed for these two CED infusion sites with or without hippocampal fissures to further investigate the transport role of these structural features. We compared simulation results from our computational model with CED measurements from our previous in vivo tracer experiments in rats [17,22,32]. Infusate distribution patterns, concentration, areas, and volumes were compared.…”

“…These smaller ratios essentially assume smaller fissure heights and greater resistance to flow within the fissure. [17,32]. In these studies, 5-10 ll of Gd-albumin with Evans Blue at 0.3 ll/min was infused to provide MR quantitation of in vivo distribution patterns.…”

“…In these studies, 5-10 ll of Gd-albumin with Evans Blue at 0.3 ll/min was infused to provide MR quantitation of in vivo distribution patterns. In the earlier study by Kim et al [32], both dorsal and ventral infusions were measured while the animal was in the magnet. In the study by Astary [17], in vivo concentration profiles were calculated using measured relaxivities with DCE-MRI through equations describing signal intensity to the contrast agent concentration [45].…”