Dynamic monitoring of blood–brain barrier integrity using water exchange index (WEI) during mannitol and CO<sub>2</sub> challenges in mouse brain

Huang, Shuning; Farrar, Christian T.; Dai, Guangping; Kwon, Sun‐Jung; Bogdanov, Alexei A.; Rosen, Bruce R.; Kim, Young R.

doi:10.1002/nbm.2871

Cited by 7 publications

(12 citation statements)

References 39 publications

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“…[28][29][30] Other possible mechanisms for the elevated water exchange include, but are not limited to, the upregulation of AQP4 at a highly acute stage of reperfused mouse brains and disjointing of the endothelial tight junctions. 31,32 Many previous studies have reported significantly decreased ADC and R 2 in cases of overt BBB disruption, suggesting that these parameters may be correlative indices for describing strokeinduced BBB damage. [13][14][15][16][17] On the contrary, in the current study, we observed similar infarct ADC and R 2 values that were independent of the WEI.…”

Section: Discussionmentioning

confidence: 99%

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Huang

Kim

Atochin

et al. 2013

J Cereb Blood Flow Metab

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Insufficient vascular reserve after an ischemic stroke may induce biochemical cascades that subsequently deteriorate the blood-brain barrier (BBB) function. However, the direct relationship between poor cerebral blood volume (CBV) restoration and BBB disruption has not been examined in acute stroke. To quantify BBB integrity at acute stages of transient stroke, in particular for cases in which extravasation of the standard contrast agent (Gd-DTPA) is not observed, we adopted the water exchange index (WEI), a novel magnetic resonance image-derived parameter to estimate the water permeability across the BBB. The apparent diffusion coefficient (ADC) and R 2 relaxation rate constant were also measured for outlining the tissue abnormality, while fractional CBV and WEI were quantified for assessing vascular alterations. The significantly decreased ADC and R 2 in the ischemic cortices did not correlate with the changes in CBV or WEI. In contrast, a strong negative correlation between the ipsilesional WEI and CBV was found, in which stroke mice were clustered into two groups: (1) high WEI and low CBV and (2) normal WEI and CBV. The low CBV observed for mice with a disrupted BBB, characterized by a high WEI, indicates the importance of CBV restoration for maintaining BBB stability in acute stroke.

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Section: Discussionmentioning

confidence: 99%

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Huang

Kim

Atochin

et al. 2013

J Cereb Blood Flow Metab

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“…Despite these limitations, this approach has undergone the most validation. Several studies have shown alterations in WEI in acute stroke models [29,60] and further studies have demonstrated its sensitivity to BBB changes caused by hypertonic mannitol and CO2 challenge in the mouse brain [30].…”

Section: Water Exchange Index (Wei) Methodsmentioning

confidence: 98%

“…In the experiments by Schwarzbauer et al [26] and resulting work that followed [27][28][29][30][31], the effect of exchange was quantified by measuring the effect on T1, not T2 as in the earlier redblood cell studies.…”

Section: Exchange Models For Contrast Agent Based Measurementsmentioning

confidence: 99%

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Measuring water exchange across the blood-brain barrier using MRI

Dickie¹,

Parker

Parkes

2020

Progress in Nuclear Magnetic Resonance Spectroscopy

106

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The blood-brain barrier (BBB) regulates the transfer of solutes and essential nutrients into the brain. Growing evidence supports BBB dysfunction in a range of acute and chronic brain diseases, justifying the need for novel research and clinical tools that can non-invasively detect, characterize, and quantify BBB dysfunction in-vivo. Many approaches already exist for measuring BBB dysfunction in man using positron emission tomography and magnetic resonance imaging (e.g. dynamic contrast-enhanced-MRI measurements of gadolinium leakage). This review paper focusses on MRI measurements of water exchange across the BBB, which occurs through a wide range of pathways, and is likely to be a highly sensitive marker of BBB dysfunction. Key mathematical models and acquisition methods are discussed for the two main approaches: those that utilize contrast agents to enhance relaxation rate differences between the intravascular and extravascular compartments and so enhance the sensitivity of MRI signals to BBB water exchange, and those that utilize the dynamic properties of arterial spin labelling to first isolate signal from intravascular spins and then estimate the impact of water exchange on the evolving signal. Data from studies in healthy and pathological brain tissue are discussed, in addition to validation studies in rodents. Table of Contents 1. Introduction 2. Evidence for limited BBB water exchange 3. Definitions of physical parameters governing BBB water exchange 4. The effect of inter-compartmental water exchange on measured relaxation rates and diffusion coefficients 5. Modelling the effects of BBB water exchange on MRI signals 5.1 Exchange models for contrast agent based measurements 5.2 Exchange models for arterial spin-labelling based measurements 6. MRI approaches for quantifying BBB water exchange 6.1 Contrast agent-based approaches 6.1.1 Dose ramping at steady state with a varied infusion rate 6.1.2 First pass methods 6.1.3 Water exchange index (WEI) method 6.1.4 Multiple flip angle multi-echo (MFAME)-MRI 6.2 Approaches based on arterial spin labelling (ASL) 6.2.1 Multi-TE ASL 6.2.2 Diffusion-weighted ASL 6.2.3 Magnetisation transfer weighted ASL 6.2.4 Contrast-enhanced ASL 6.2.5 Phase-contrast ASL 6.3 Approaches based on injection of MRI-detectable water tracers 6.3.1 Indirect detection of 17 O-labeled water via its effect on 1 H T2 6.3.2 Indirect detection of 2 H-labeled water by proton replacement 7. Summary of published results 7.1 Water exchange across the BBB in healthy brain tissue 7.2 Water exchange across the BBB in disease 7.2.1 Water exchange across the BBB in stroke 7.2.2 Water exchange across the BBB in neurodegeneration 7.2.3 Water exchange across the BBB in obstructive sleep apnea 7.2.4 Water exchange across the BBB in multiple sclerosis (MS) 7.2.5 Water exchange across the BBB in brain tumours 7.3. Water exchange across the BBB in knockout models 7.4 Technical validation in rodents 7.5 Precision of water exchange measurements8. Validity of a two-site model for BBB water exchange 9. Physiologic...

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“…Seven years ago, the water exchange index (WEI), an approximate, dimensionless, non‐linear τ b −1 estimate, was demonstrated in the mouse, an approach also requiring a single intravascular CA injection . Recently however, the authors of Reference 59 themselves showed that, unfortunately, the WEI approximation formally depends on the v b value . As noted above, an important feature of the actual τ b −1 ( k po ) biomarker is its v b independence if r does not vary.…”

Section: Technical Backgroundmentioning

confidence: 99%

Mapping human brain capillary water lifetime: high‐resolution metabolic neuroimaging

et al. 2015

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Shutter-speed analysis of Dynamic-Contrast-Agent-(CA)-Enhanced normal, multiple sclerosis [MS], and glioblastoma [GBM] human brain data gives the mean capillary water molecule lifetime [τb] and blood volume fraction [vb; capillary density·volume product (′†·V)] in a high-resolution 1H2O MRI voxel [40 μL] or ROI. The equilibrium water extravasation rate constant, kpo [τb−1], averages 3.2 and 2.9 s−1 in resting-state normal white matter [NWM] and gray matter [NGM], respectively [n = 6]. The results {parenthesized} lead to three major conclusions. A) kpo differences are dominated by capillary water permeability [PW†], not size, differences. {NWM and NGM voxel kpo and vb values are independent. Quantitative analyses of concomitant population-averaged kpo,vb variations in normal and normal-appearing MS brain ROIs confirm PW† dominance.} B) PW† is dominated [> 95%] by a trans[endothelial]cellular pathway, not the PCA† para-cellular route. {In MS lesions and GBM tumors, PCA† increases but PW† decreases.} C) kpo tracks steady-state ATP production/consumption flux per capillary. {In normal, MS, and GBM brain, regional kpo correlates with literature MRSI ATP [positively] and Na+ [negatively] tissue concentrations. These suggest the PW† pathway is metabolically active. Excellent agreement of the relative NGM/NWM kpo·vb product ratio with the literature 31PMRSI-MT CMRoxphos ratio confirms the flux property.} We have previously shown the cellular water molecule efflux rate constant [kio] is proportional to plasma membrane P-type ATPase turnover, likely due to active trans-membrane water cycling. With synaptic proximities and synergistic metabolic co-operativities, polar brain endothelial, neuroglial, and neuronal cells form “gliovascular units.” We hypothesize a chain of water cycling processes transmits brain metabolic activity to kpo, letting it report neurogliovascular unit Na+,K+-ATPase activity. Cerebral kpo maps represent metabolic (functional) neuroimages. The NGM 2.9 s−1 kpo means an equilibrium unidirectional water efflux of ~1015 H2O molecules/s/capillary [in 1 μL tissue]: consistent with the known ATP consumption rate and water co-transporting membrane symporter stoichiometries.

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Dynamic monitoring of blood–brain barrier integrity using water exchange index (WEI) during mannitol and CO₂ challenges in mouse brain

Cited by 7 publications

References 39 publications

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Measuring water exchange across the blood-brain barrier using MRI

Mapping human brain capillary water lifetime: high‐resolution metabolic neuroimaging

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Dynamic monitoring of blood–brain barrier integrity using water exchange index (WEI) during mannitol and CO2 challenges in mouse brain

Cited by 7 publications

References 39 publications

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Cerebral Blood Volume Affects Blood–Brain Barrier Integrity in an Acute Transient Stroke Model

Measuring water exchange across the blood-brain barrier using MRI

Mapping human brain capillary water lifetime: high‐resolution metabolic neuroimaging

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Product

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Dynamic monitoring of blood–brain barrier integrity using water exchange index (WEI) during mannitol and CO₂ challenges in mouse brain