Abstract
The nature of brain interstitial fluid (ISF) has long been a subject of controversy. Most of the previous studies on brain ISF were carried out in vitro. In the present study, a novel method was developed to characterize ISF in the living rat brain by magnetic resonance (MR) imaging using gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) as a tracer. Sprague Dawley rats (n=8) were subjected to MR scanning before and after the introduction of Gd-DTPA into the caudate nucleus. A one-way drainage of brain ISF was demonstrated on the dynamic MR images. According to the traditional diffusion model, the diffusion and clearance rate constants of the tracer within brain extracellular space (ECS) were derived as (3.38+-1.07)×10(-4) mm(2) s(-1) and (7.60±4.18)×10(-5) s(-1). Both diffusion and bulk flow contributed to the drainage of ISF from the caudate nucleus, which demonstrated an ISF-cerebrospinal fluid confluence in the subarachnoid space at the lateral and ventral surface of the brain cortex at 3 h after the injection. By using this newly developed method, the brain ECS and ISF can be quantitatively measured simultaneously in the living brain, which will enhance the understanding of ISF and improve the efficiency of drug therapy via the brain interstitium.
Highlights
Introduction of GdDTPA Skin overlying the calvaria was shaved and disinfected with iodated alcohol
An in vivo measurement should be the basic requirement for any functional or physiological study of living organs, and is the key to ending the speculation and controversy regarding the nature of brain interstitial fluid (ISF)
Several techniques have been developed to measure the biophysical properties of the space around ISF (ECS), such as early studies with the radiotracer method [14], the real-time iontophoresis (RTI) method using small ions [15,16] and integrative optical imaging (IOI) by macromolecular fluorescent substance [17], the observation of the drainage of ISF in living brain is not available and the diffusion properties of brain extracellular space (ECS) can be determined only within a very short distance or a limited thickness [4]
Summary
1.1 Phantom experiments for establishing the linear relationship between ΔSI and Gd-DTPA concentration. Gd-DTPA (Magnevist; Bayer Schering Pharma AG, Berlin, Germany) was diluted with double distilled water in tubes. Magnetic resonance (MR) scanning was performed at 37°C by submerging tubes in a water bath when they were placed in the scanner. Parameters for the imaging sequence were as follows: echo time (TE)=3.7 ms, repetition time (TR)=1500 ms, flip angle (FA)=9°, inversion time (TI)=900 ms, slice thickness (SL)=1 mm, field of view (FOV)=267 mm, voxel=0.5 mm×0.5 mm×0.5 mm. Signal intensity (SI) was measured by selecting the region of interest (ROI) of every tube in the center of the coronal image. ΔSI was calculated from ΔSI=SIsample SIwater, ΔSI-C curve was fitted using linear regression analysis in SPSS 13.0 statistical software
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