Label-Free Assessment of Mannitol Accumulation Following Osmotic Blood–Brain Barrier Opening Using Chemical Exchange Saturation Transfer Magnetic Resonance Imaging

Abstract

Purpose: Mannitol is a hyperosmolar agent for reducing intracranial pressure and inducing osmotic blood–brain barrier opening (OBBBO). There is a great clinical need for a non-invasive method to optimize the safety of mannitol dosing. The aim of this study was to develop a label-free Chemical Exchange Saturation Transfer (CEST)-based MRI approach for detecting intracranial accumulation of mannitol following OBBBO. Methods: In vitro MRI was conducted to measure the CEST properties of D-mannitol of different concentrations and pH. In vivo MRI and MRS measurements were conducted on Sprague-Dawley rats using a Biospec 11.7T horizontal MRI scanner. Rats were catheterized at the internal carotid artery (ICA) and randomly grouped to receive either 1 mL or 3 mL D-mannitol. CEST MR images were acquired before and at 20 min after the infusion. Results: In vitro MRI showed that mannitol has a strong, broad CEST contrast at around 0.8 ppm with a mM CEST MRI detectability. In vivo studies showed that CEST MRI could effectively detect mannitol in the brain. The low dose mannitol treatment led to OBBBO but no significant mannitol accumulation, whereas the high dose regimen resulted in both OBBBO and mannitol accumulation. The CEST MRI findings were consistent with 1H-MRS and Gd-enhanced MRI assessments. Conclusion: We demonstrated that CEST MRI can be used for non-invasive, label-free detection of mannitol accumulation in the brain following BBBO treatment. This method may be useful as a rapid imaging tool to optimize the dosing of mannitol-based OBBBO and improve its safety and efficacy.

Imaging blood-brain barrier dysfunction: A state-of-the-art review from a clinical perspective

“…CEST is based on application of radiofrequency pluses to a selected pool of molecules at a frequency that causes loss of magnetization (saturation) of its protons to the protons of the surrounding and larger water pool ( Kogan et al, 2013 ). This exchange of protons or ‘chemicals’ is the CEST signal that is further enhanced using exogenous agents, of which D-glucose is commonly used in indirect imaging of BBB ( Elschot et al, 2021 ; Harris et al, 2023 ) - although other agents such as Salicylic Acid Analogues ( Song et al, 2016 ) and Mannitol have been demonstrated in intra-arterial administration in rodent ischemic stroke models ( Song et al, 2016 ; Liu et al, 2022 ). Challenges with obtaining the arterial input function to model glucose concentration in the parenchyma, its transport and utilization, the relatively long imaging time from application of multiple long TR saturation pulses, and importantly the lack of validation of CEST agents for BBB, present limitations its routine clinical use ( Kogan et al, 2013 ; Harris et al, 2023 ).…”

Non-Invasive Drug Delivery across the Blood–Brain Barrier: A Prospective Analysis

“…To tackle the invasive nature of the hyperosmolar process, researchers have devised an MRI technique that relies on unenhanced chemical exchange saturation transfer to identify the buildup of mannitol in the intracranial region after the opening of the BBB. This technique holds promise as a prompt imaging tool for optimizing the administration of mannitol-based BBB opening, thereby enhancing its safety and effectiveness [116]. Moreover, implementing hyperosmolar BBB opening techniques in murine models using MRI guidance can effectively mitigate the limitations of inconsistent reproducibility and heterogeneous experimental results commonly observed with the intra-arterial administration of hyperosmolar mannitol [117].…”

Label-Free Chemically and Molecularly Selective Magnetic Resonance Imaging

“…Detailed descriptions of CEST MRI can be found in several excellent review papers. − As NMR-rooted techniques, CEST MRI and MRS share many common physics and chemistry principles and practices. They are also complementary and can be used in combination, as it was demonstrated by Liu et al in their work on using CEST MRI and MRS to investigate mannitol accumulation following the osmotic blood–brain barrier (BBB), in which mannitol in the brain can be directly measured by both CEST and MRS signals . Their results suggested that MRS had low spatial resolution but high specificity, whereas those by CEST MRI had high spatial resolution and high sensitivity.…”

“…They are also complementary and can be used in combination, as it was demonstrated by Liu et al in their work on using CEST MRI and MRS to investigate mannitol accumulation following the osmotic blood–brain barrier (BBB), in which mannitol in the brain can be directly measured by both CEST and MRS signals. 93 Their results suggested that MRS had low spatial resolution but high specificity, whereas those by CEST MRI had high spatial resolution and high sensitivity. Quantifying CEST images is much more complicated than MRS as signals are from exchangeable protons with an exchange rate that is dependent on various chemical and biochemical conditions.…”