We proposed a novel MRI tracer-based method for the determination of water diffusion in the brain extracellular space (ECS). The measuring system was validated in 32 Sprague Dawley rats. The rats were randomly divided into four groups with different injection sites: 1) caudate nucleus (Cn.); 2) thalamus (T.); 3) cortex (Cor.); and 4) substantia nigra (Sn.). The spin-lattice relaxation time of hydrogen nuclei in water molecules were shortened, which presented as high signal on MRI after the injection of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) into the rat brain ECS. The enhancement on MRI decreased over time due to the water diffusion and clearance process within the brain ECS. The process was dynamically recorded on a series of magnetic resonance (MR) images. As the increment in signal intensity (ΔSI) could be converted to local Gd-DTPA concentration, the water diffusion parameters were further calculated voxel by voxel based on a modified diffusion model. The most tortuous ECS (λ = 1.77 ± 0.71) was found in Sn. with D∗(Sn) of (2.06 ± 1.01) × 10(-4) mm(2)·s(-1) ( P < 0.05). No statistical difference was demonstrated among D∗(Cn), D∗(T.), and D∗(Cor). with an average D∗ values of (3.28 ± 0.88) × 10(-4) mm(2)·s(-1)( F = 0.18, P > 0.05). By using the tracer-based MRI method, the local diffusion parameters of the brain ECS can be quantitatively measured. The different distribution territories and clearance rates of the tracer in four brain areas indicated that the brain ECS is a physiologically partitioned system.

ObjectiveSeveral studies have demonstrated that compromised blood–brain barrier (BBB) integrity may play a pivotal role in the pathogenesis of individual cerebral small vessel disease (cSVD) markers, but the association between BBB permeability and total magnetic resonance imaging (MRI) cSVD burden remains unclear. This study aimed to investigate the relationship between BBB permeability and total MRI cSVD burden.MethodsConsecutive participants without symptomatic stroke history presented for physical examination were enrolled in this cross-sectional study. The presence of lacunes, white matter hyperintensities (WMH), cerebral microbleeds, and enlarged perivascular spaces was recorded in an ordinal score (range 0–4). We used dynamic contrast-enhanced-MRI and Patlak pharmacokinetic model to quantify BBB permeability in the normal-appearing white matter (NAWM), WMH, cortical gray matter (CGM), and deep gray matter (DGM).ResultsAll 99 participants averaged 70.33 years old (49–90 years). Multivariable linear regression analyses adjusted for age, sex, and vascular risk factors showed that leakage rate and area under the leakage curve in the NAWM, WMH, CGM, and DGM were positively associated with total MRI cSVD burden (all P < 0.01). Moreover, fractional blood plasma volumes in the NAWM, CGM, and DGM were negatively associated with total MRI cSVD burden (all P < 0.05).ConclusionThis study verified that compromised BBB integrity is associated with total MRI cSVD burden, suggesting that BBB dysfunction may be a critical contributor to the pathogenesis of cSVD. Longitudinal studies are required to determine whether there is a causal relationship between BBB permeability and total MRI cSVD burden.

Background Blood-brain barrier (BBB) breakdown, as an early biomarker for vascular mild cognitive impairment (vMCI), has only been validated by a few studies. The aim of this study was to investigate whether compromised BBB integrity is involved in vMCI patients, and detect the relationship between BBB breakdown and cognitive function. BBB leakage in vMCI was explored, and the relationship between BBB leakage and cognitive function was discussed in this study. Methods This is a cross-sectional study involving 26 vMCI patients and 21 sex- and age-matched healthy controls. Dynamic contrast-enhanced-magnetic resonance imaging was performed for all participants, to determine BBB leakage. Leakage volume, leakage rate, and fractional blood plasma volume (Vp) in the grey and white matter were evaluated. Neuropsychological tests were used to determine cognitive function. Leakage rate, leakage volume, and Vp in different brain locations, including deep grey matter, cortical grey matter, white matter hyperintensity, and normal-appearing white matter were compared between the two groups. Results Multivariable linear regression analyses revealed that in all regions of interest, the leakage rate was significantly higher in vMCI patients relative to controls. Leakage volume in normal-appearing white matter and white matter hyperintensity were significantly higher, while Vp in normal-appearing white matter, deep grey matter, and cortical grey matter were significantly lower in vMCI patients. Moreover, Montreal Cognitive Assessment scores decreased with the increase of leakage rate in white matter hyperintensity. Conclusion Increased BBB permeability was detected in vMCI patients and was related to cognitive decline, which suggested that BBB breakdown might be involved in cognitive dysfunction pathogenesis.

The transportation of substances in the interstitial space (ISS) is crucial for the maintenance of brain homeostasis, however its link to neuronal activity remains unclear. Here, we report a marked reduction in substance transportation in the ISS after neuronal excitation. Using a tracer-based method, water molecules in the interstitial fluid (ISF) could be specifically visualized in magnetic resonance (MR) imaging. We first observed the flow of ISF in the thalamus and caudate nucleus of a rat. The ISF flow was then modulated using a painful stimulation model. We demonstrated that the flow of ISF slowed significantly following neuronal activity in the thalamus. This reduction in ISF flow continued for hours and was not accompanied by slow diffusion into the ISS. This observation suggests that the transportation of substances into the ISS can be regulated with a selective external stimulation.

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Purposes to estimate parameters for gadolium-diethylenetriaminepentaacetic acid (Gd-DTPA) diffusion and distribution after drug delivery in the rat brain extracellular space (ECS). Methods An isotropic diffusion pattern in the homogeneous media was presumed for Gd-DTPA diffusion in the rat brain ECS, and a mathematical model was established to describe the pharmacokinetics of Gd-DTPA. Results the analytical solution of the diffusion equation was obtained by Laplace transform, and the least square method was utilized to calculate the diffusion coefficient (D) and the clearance rate (k) of drugs in the sphere coordinates. Animal experimental data of Gd-DTPA-related intensity was acquired by magnetic resonance imaging (MRI). D and k were computed as 0.0129 mm2/h and 0.0957 /h, respectively. Conclusions By the proposed method, drug diffusion, distribution, and clearance in the rat brain can be quantitatively analyzed, which will enhance our understanding of drug delivery in the central nervous system.