Quantification of blood-brain barrier permeability by dynamic contrast-enhanced NIRS.

The blood-brain barrier (BBB) is integral to maintaining a suitable microenvironment for neurons to function properly. Despite its importance, there are no bedside methods of assessing BBB disruption to help guide management of critical-care patients. The aim of this study was to demonstrate that dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) can quantify the permeability surface-area product (PS) of the BBB. Experiments were conducted in rats in which the BBB was opened by image-guided focused ultrasound. DCE-NIRS data were acquired with two dyes of different molecular weight, indocyanine green (ICG, 67 kDa) and 800CW carboxylate (IRDye, 1166 Da), and PS maps were generated by DCE computer tomography (CT) for comparison. Both dyes showed a strong correlation between measured PS values and sonication power (R<sup>2</sup> = 0.95 and 0.92 for ICG and IRDye respectively), and the PS values for IRDye were in good agreement with CT values obtained with a contrast agent of similar molecular weight. These proof-of-principle experiments demonstrate that DCE NIRS can quantify BBB permeability. The next step in translating this method to critical care practice will be to adapt depth sensitive methods to minimize the effects of scalp contamination on NIRS PS values.

Introduction

Purpose Other

Study Objective To demonstrate that dynamic contrast-enhanced near-infrared spectroscopy (DCE-NIRS) can quantify the blood–brain barrier (BBB) permeability surface-area product (PS).

Animal model / Human subject Rattus norvegicus (Wistar), age not reported, male, weight 480 ± 120 g

Disease model Blood-brain barrier disruption (BBB opening)

MRI or image guidance method Image-guided FUS with the FUS system co-registered to the spatial coordinates of the CT scanner (CT-based image guidance)

Targeted brain region(s) Cerebral Hemisphere

Cargo name and characteristics Indocyanine green (ICG) — near‑infrared fluorescent small‑molecule dye (reported as 67 kDa in paper), IV bolus 0.1 mg/kg; IRDye 800CW carboxylate (IRDye) — near‑infrared fluorescent small‑molecule dye (~1,166 Da), IV bolus 0.1 mg/kg; Isovue-300 (iopamidol) — iodine-based low‑molecular‑weight CT contrast agent (~777 Da), IV bolus 2.5 ml/kg (300 mg I/ml)

Route of administration intravenous (rapid bolus via tail vein catheter)

Outcomes and Safety

Summary of Outcomes Focused ultrasound produced dose-dependent opening of the blood–brain barrier with increases in permeability surface-area product (PS) detected by DCE-NIRS that correlated strongly with CT (R²≈0.95 for ICG, 0.92 for IRDye); cerebral blood flow decreased after sonication and the small dye (IRDye) showed baseline leakage. Successful sonication powers tested: 0.5 W, 1.0 W, 1.5 W, and 2.0 W (with larger PS increases at 1.5–2.0 W).

Safety-related matter A significant reduction in cerebral blood flow (CBF) was observed after sonication, but the authors state it is uncertain whether this was due to focused ultrasound or confounding factors (≈1 h delay, anesthesia, handling). No other adverse effects or safety issues were reported in the study.

Brain Region

Ultrasound Parameters

Ultrasound instrument RK-100 (FUS Instruments Inc., Toronto, ON); spherically focused transducer, 7.5 cm diameter (f#=0.8), 0.25–1.0 MHz, acoustic power ≤50 W

FUS Frequency 0.563 MHz (transducer operating range 0.25–1.0 MHz)

FUS Mode pulsed

Pulse duration 10 ms

Duration of a single FUS session 360 s

Focal Characteristics Focal depth: None; Focal length: 6.0 cm (derived from f# = 0.8 and diameter 7.5 cm); Aperture size: 7.5 cm (diameter)

Treatment frequency single

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