Filter exchange imaging with crusher gradient modelling detects increased blood–brain barrier water permeability in response to mild lung infection

Blood–brain barrier (BBB) dysfunction occurs in many brain diseases, and there is increasing evidence to suggest that it is an early process in dementia which may be exacerbated by peripheral infection. Filter-exchange imaging (FEXI) is an MRI technique for measuring trans-membrane water exchange. FEXI data is typically analysed using the apparent exchange rate (AXR) model, yielding estimates of the AXR. Crusher gradients are commonly used to remove unwanted coherence pathways arising from longitudinal storage pulses during the mixing period. We first demonstrate that when using thin slices, as is needed for imaging the rodent brain, crusher gradients result in underestimation of the AXR. To address this, we propose an extended crusher-compensated exchange rate (CCXR) model to account for diffusion-weighting introduced by the crusher gradients, which is able to recover ground truth values of BBB water exchange (kin) in simulated data. When applied to the rat brain, kin estimates obtained using the CCXR model were 3.10 s−1 and 3.49 s−1 compared to AXR estimates of 1.24 s−1 and 0.49 s−1 for slice thicknesses of 4.0 mm and 2.5 mm respectively. We then validated our approach using a clinically relevant Streptococcus pneumoniae lung infection. We observed a significant 70 ± 10% increase in BBB water exchange in rats during active infection (kin = 3.78 ± 0.42 s−1) compared to before infection (kin = 2.72 ± 0.30 s−1; p = 0.02). The BBB water exchange rate during infection was associated with higher levels of plasma von Willebrand factor (VWF), a marker of acute vascular inflammation. We also observed 42% higher expression of perivascular aquaporin-4 (AQP4) in infected animals compared to non-infected controls, while levels of tight junction proteins remain consistent between groups. In summary, we propose a modelling approach for FEXI data which removes the bias in estimated water-exchange rates associated with the use of crusher gradients. Using this approach, we demonstrate the impact of peripheral infection on BBB water exchange, which appears to be mediated by endothelial dysfunction and associated with an increase in perivascular AQP4

J Magn Reson Imaging

BackgroundBlood-brain barrier (BBB) disruption may lead to endothelium dysfunction and inflammation in sickle cell disease (SCD). However, abnormalities of BBB in SCD, especially in pediatric patients for whom contrast agent administration less than optimal, have not been fully characterized.PurposeTo examine BBB permeability to water in a group of pediatric SCD participants using a non-invasive MRI technique. We hypothesized that SCD participants will have increased BBB permeability.Study TypeProspective cross-sectional.Population26 pediatric participants (10\ub11 years, 15F/11M) were enrolled, including 21 SCD participants and 5 sickle cell trait (SCT) participants, who were siblings of SCD patients.Field Strength/Sequence3T. Water-extraction-with-phase-contrast-arterial-spin-tagging (WEPCAST) with echo-planer imaging, phase-contrast and T1-weighted magnetization-prepared-rapid-acquisition-of-gradient-echo (MPRAGE).AssessmentWater extraction fraction (E), BBB permeability-surface area product (PS), cerebral blood flow (CBF), hematological measures (hemoglobin, hematocrit, hemoglobin S), neuropsychological scores (including domains of intellectual ability, attention and executive function, academic achievement and adaptive function, and a composite score). ROIs were drawn by Z.L. (6 years of experience).Statistical TestsWilcoxon rank sum test and chi-square test for group comparison of demographics. Multiple linear regression analysis of PS with diagnostic category (SCD or SCT), hematological measures and neuropsychological scores. A two-tailed p value of 0.05 or less was considered statistically significant.ResultsCompared with SCT participants, SCD participants had a significantly higher BBB permeability to water (SCD: 207.0\ub133.3mL/100g/min, SCT: 171.2\ub127.2mL/100g/min,). SCD participants with typically more severe phenotypes also had a significantly leakier BBB than those with typically milder phenotypes (severe: 217.3\ub131.7mL/100g/min, mild: 193.3\ub131.8mL/100g/min,). Furthermore, more severe BBB disruption was associated with worse hematological symptoms, including lower hemoglobin concentrations (\u3b2= 128.84, 95% CI [ 1214.69, 123.00]), lower hematocrits (\u3b2= 122.96, 95% CI [ 124.84, 121.08]), and higher hemoglobin S fraction (\u3b2=0.77, 95% CI [0.014, 1.53]).Data ConclusionThese findings support a potential role for BBB dysfunction in SCD pathogenesis of ischemic injury.P41 EB031771/EB/NIBIB NIH HHSUnited States/K23 HL133455/HL/NHLBI NIH HHSUnited States/U54 HD079123/HD/NICHD NIH HHSUnited States/R01 NS106702/NS/NINDS NIH HHSUnited States/RF1 AG071515/AG/NIA NIH HHSUnited States/P50 HD103538/HD/NICHD NIH HHSUnited States/P41 EB015909/EB/NIBIB NIH HHSUnited States/S10 OD021648/OD/NIH HHSUnited States/S10 OD021648/CD/ODCDC CDC HHSUnited States/19PRE34380371/American Heart Association/R01 NS106711/NS/NINDS NIH HHSUnited States/K23 HL133455-01A1/HL/NHLBI NIH HHSUnited States/R01 AG064792/AG/NIA NIH HHSUnited States

Blood–brain barrier water exchange measurements using contrast-enhanced ASL

A technique for quantifying regional blood–brain barrier (BBB) water exchange rates using contrast-enhanced arterial spin labelling (CE-ASL) is presented and evaluated in simulations and in vivo. The two-compartment ASL model describes the water exchange rate from blood to tissue, (Formula presented.), but to estimate (Formula presented.) in practice it is necessary to separate the intra- and extravascular signals. This is challenging in standard ASL data owing to the small difference in (Formula presented.) values. Here, a gadolinium-based contrast agent is used to increase this (Formula presented.) difference and enable the signal components to be disentangled. The optimal post-contrast blood (Formula presented.) ((Formula presented.)) at 3 T was determined in a sensitivity analysis, and the accuracy and precision of the method quantified using Monte Carlo simulations. Proof-of-concept data were acquired in six healthy volunteers (five female, age range 24–46 years). The sensitivity analysis identified the optimal (Formula presented.) at 3 T as 0.8 s. Simulations showed that (Formula presented.) could be estimated in individual cortical regions with a relative error (Formula presented.) % and coefficient of variation (Formula presented.) %; however, a high dependence on blood (Formula presented.) was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit time (Formula presented.) s, cerebral blood flow (Formula presented.) mL blood/min/100 mL tissue and water exchange rate (Formula presented.) s−1. CE-ASL can provide regional BBB water exchange rate estimates; however, the clinical utility of the technique is dependent on the achievable accuracy of measured (Formula presented.) values

Water Exchange Rate across the Blood-Brain Barrier Is Associated with CSF Amyloid-β 42 in Healthy Older Adults

INTRODUCTION: We tested if water exchange across the blood-brain barrier (BBB), estimated with a noninvasive magnetic resonance imaging (MRI) technique, is associated with cerebrospinal fluid (CSF) biomarkers of Alzheimer\u27s disease (AD) and neuropsychological function. METHODS: Forty cognitively normal older adults (67–86 years old) were scanned with diffusion‐prepared, arterial spin labeling (DP‐ASL), which estimates water exchange rate across the BBB (kw). Participants also underwent CSF draw and neuropsychological testing. Multiple linear regression models were run with kw as a predictor of CSF concentrations and neuropsychological scores. RESULTS: In multiple brain regions, BBB kw was positively associated with CSF amyloid beta (Aβ)42 concentration levels. BBB kw was only moderately associated with neuropsychological performance. DISCUSSION: Our results suggest that low water exchange rate across the BBB is associated with low CSF Aβ42 concentration. These findings suggest that kw may be a promising noninvasive indicator of BBB Aβ clearance functions, a possibility which should be further tested in future research

Development of non-invasive MRI to measure water permeability across the blood-brain interface

The blood-brain interface (BBI) is a physical and biochemical barrier that protects and maintains healthy brain function. Disruption of the BBI is indicative of the early stages of certain neurodegenerative diseases, such as Alzheimer’s Disease. However, there is currently a lack of sensitive tools available to accurately quantify the early alterations to the integrity of the BBI. This thesis describes the development and implementation of multiple echo time arterial spin labelling (multi-TE ASL) MRI technique in the mouse brain to measure vascular water permeability across the BBI. The technique was implemented in two high-field MRI system to demonstrate the consistency of the imaging protocols and the sensitivity of the measures of BBI water permeability. The multi-TE ASL technique was used to probe the function of aquaporin-4 (AQP4) water channels, which play a key role in the clearance of the deleterious proteins from the brain. This non-invasive technique was able to demonstrate its sensitivity to targeting AQP4 by measuring a 31% slowing of cortical BBI water permeability with the removal of the AQP4 water channels. The technique also measured a 34% slowing in the BBI water permeability in the cerebellum brain region with a reduction of AQP4 channels at the BBI. Finally, the technique measured a 32% increase in cortical BBI permeability to water in a mouse model of ageing. The non-invasive imaging measurements were 7 associated with a 2-fold increase in mRNA expression of pericytes, while other BBI markers such as tight junction proteins were maintained. Overall, this work has demonstrated the scope of novel MRI technique to target changes to BBI water permeability, with potential for clinical translation for the early detection and understanding of neurodegenerative disease

Novel mechanisms of DC and kilohertz electrical stimulation

Transcranial electrical stimulation is a promising technique where a weak electrical current is applied to the scalp with the goal of modulating brain activity. Understanding the cellular mechanism of direct current (DC) and kilohertz (kHz) electrical stimulation is of broad interest in neuromodulation. More specifically, there is a large mismatch between enthusiasm for clinical applications of the method and understanding of DC and kHz novel mechanisms of action. This dissertation is centered around two main fundamental aims: 1) systematic study of the acute and long-term effects of kilohertz electrical stimulation and amplitude-modulated waveform with kHz carrier frequency using a well-established animal model, hippocampal brain slice, 2) study the effect of tDCS on water exchange rate across the blood-brain barrier using an advanced MRI imaging technique in a healthy population to investigate effect of tDCS stimulation on neurovascular units. The neuronal membrane has a well-established low pass filtering characteristic. This feature attenuates the sensitivity of the nervous system to any waveforms with high-frequency components. On the contrary, kilohertz stimulation has recently revolutionized spinal cord stimulation and even generated promising results in transcranial electrical stimulation. Investigating the effect of low kilohertz stimulation for neuromodulation is of huge interest. In chapters 2 and 3, several experimental designs are used to systematically investigate the frequency and dose-response of neuronal activity to unmodulated and amplitude modulated waveforms in low kilohertz range. The results support the theory of membrane attenuation of high-frequency stimulation. This dissertation provides the first direct in vitro evidence on acute effects of kilohertz electrical stimulation on modulating gamma oscillation using both unmodulated and Amplitude-modulated waveforms. While supported by membrane characteristics of neurons, we uncovered that using low kilohertz stimulation diminishes the sensitivity of hippocampal neurons to electrical stimulation. Moreover, Amplitude-Modulated waveforms can generate a different pattern of modulation with even higher sensitivity to stimulation. However, the required electric field, in this case, is still significantly higher than low-frequency stimulation methods such as tACS. Effects of DC stimulation have been studied in neuronal depolarization/hyperpolarization, synaptic plasticity, and neuronal network modulation. Recent evidence suggests that DC stimulation can induce polarity-dependent water exchange rate across the blood-brain barrier (BBB) in cell culture experiments through a mechanism called electroosmosis. Modulating water exchange rate across BBB is of broad interest in neurological diseases such as dementia, Alzheimer’s, and stroke where the brain clearance system is disrupted. Investigating the effect of electrical stimulation on water exchange across BBB can potentially lead to complimentary treatment options. In chapter 4, an advanced MRI technique was used to investigate induced changes in cerebral blood flow (CBF) and water exchange rate across BBB during stimulation in areas under electrodes. Contrary to our hypothesis, we could not resolve an effect in the water exchange rate across BBB. In conclusion, in our efforts to investigate effects of high frequency stimulation we found that sensitivity of neuronal networks to oscillating electrical stimulation is governed by time constant of neuronal membrane. Moreover, neuronal networks are selective to different kilohertz waveforms (i.e., amplitude modulated) and this is governed by a nonlinear adaptive mechanism present in the network. For the effect of DC stimulation on neurovascular units, we hypothesized that stimulation affects water exchange rate across BBB through a mechanism known as electroosmosis which is a very small portion of a large water exchange across BBB in active transport. We believe that this may be the answer to our negative results in experiments

Washington University Senior Undergraduate Research Digest (WUURD), Spring 2018

From the Washington University Office of Undergraduate Research Digest (WUURD), Vol. 13, 05-01-2018. Published by the Office of Undergraduate Research. Joy Zalis Kiefer, Director of Undergraduate Research and Associate Dean in the College of Arts & Scien