Water-exchange MRI detects subtle blood-brain barrier breakdown in Alzheimer's disease rats

Blood-brain barrier (BBB) breakdown has been hypothesized to play a key role in the onset and progression of Alzheimer's disease (AD). However, the question of whether AD itself contributes to loss of BBB integrity is still uncertain, as many in-vivo studies have failed to detect signs of AD-related BBB breakdown. We hypothesize AD-related BBB damage is subtle, and that these negative results arise from a lack of measurement sensitivity. With the aim of developing a more sensitive measure of BBB breakdown, we have designed a novel MRI scanning protocol to quantify the trans-BBB exchange of endogenous water. Using this method, we detect increased BBB water permeability in a rat model of AD that is associated with reduced expression of the tight junction protein occludin. BBB permeability to MRI contrast agent, assessed using dynamic contrast-enhanced (DCE)-MRI, did not differ between transgenic and wild-type animals and was uncorrelated with occludin expression. Our data supports the occurrence of AD-related BBB breakdown, and indicates that such BBB pathology is subtle and may be undetectable using existing ‘tracer leakage’ methods. Our validated water-exchange MRI method provides a new powerful tool with which to study BBB damage in-vivo

Blood-brain barrier water exchange measurements using FEXI: Impact of modeling paradigm and relaxation time effects

PURPOSE: To evaluate potential modeling paradigms and the impact of relaxation time effects on human blood-brain barrier (BBB) water exchange measurements using FEXI (BBB-FEXI), and to quantify the accuracy, precision, and repeatability of BBB-FEXI exchange rate estimates at 3 T. METHODS: Three modeling paradigms were evaluated: (i) the apparent exchange rate (AXR) model; (ii) a two-compartment model (2CM) explicitly representing intra- and extravascular signal components, and (iii) a two-compartment model additionally accounting for finite compartmental T1 and T2 relaxation times (2CMr). Each model had three free parameters. Simulations quantified biases introduced by the assumption of infinite relaxation times in the AXR and 2CM models, as well as the accuracy and precision of all three models. The scan–rescan repeatability of all paradigms was quantified for the first time in vivo in 10 healthy volunteers (age range 23–52 years; five female) RESULTS: The assumption of infinite relaxation times yielded exchange rate errors in simulations up to 42%/14% in the AXR/2CM models, respectively. Accuracy was highest in the compartmental models; precision was best in the AXR model. Scan–rescan repeatability in vivo was good for all models, with negligible bias and repeatability coefficients in grey matter of RCAXR = 0.43 s −1, RC2CM = 0.51 s −1, and RC2CMr = 0.61 s −1. CONCLUSION: Compartmental modelling of BBB-FEXI signals can provide accurate and repeatable measurements of BBB water exchange; however, relaxation time and partial volume effects may cause model-dependent biases

Alzheimer's disease pathology is associated with earlier alterations to blood–brain barrier water permeability compared with healthy ageing in TgF344‐AD rats

From Wiley via Jisc Publications RouterHistory: received 2020-11-05, rev-recd 2021-02-06, accepted 2021-02-26, pub-electronic 2021-03-15, pub-print 2021-07Article version: VoRPublication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/F011350Funder: Engineering and Physical Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000266; Grant(s): EP/M005909/1Funder: European Union’s Seventh Framework Programme; Grant(s): FP7/2007‐2013, HEALTH‐F2‐2011‐278850, HEALTH‐F2‐2011‐278850The effects of Alzheimer's disease (AD) and ageing on blood–brain barrier (BBB) breakdown are investigated in TgF344‐AD and wild‐type rats aged 13, 18 and 21 months. Permeability surface area products of the BBB to water (PSw) and gadolinium‐based contrast agent (PSg) were measured in grey matter using multiflip angle multiecho dynamic contrast‐enhanced MRI. At 13 months of age, there was no significant difference in PSw between TgF344‐AD and wild‐types (p = 0.82). Between 13 and 18 months, PSw increased in TgF344‐AD rats (p = 0.027), but not in wild‐types (p = 0.99), leading to significantly higher PSw in TgF344‐AD rats at 18 months, as previously reported (p = 0.012). Between 18 and 21 months, PSw values increased in wild‐types (p = 0.050), but not in TgF344‐AD rats (p = 0.50). These results indicate that BBB water permeability is affected by both AD pathology and ageing, but that changes occur earlier in the presence of AD pathology. There were no significant genotype or ageing effects on PSg (p > 0.05). In conclusion, we detected increases in BBB water permeability with age in TgF344‐AD and wild‐type rats, and found that changes occurred at an earlier age in rats with AD pathology

A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-01-12, accepted 2021-04-22, epub 2021-05-20Publication status: PublishedIntroduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD

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

Characterisation of microvessel blood velocity and segment length in the brain using multi-diffusion-time diffusion-weighted MRI

From SAGE Publishing via Jisc Publications RouterHistory: received 2020-05-13, rev-recd 2020-10-24, accepted 2020-10-27, epub 2020-12-16Publication status: PublishedMulti-diffusion-time diffusion-weighted MRI can probe tissue microstructure, but the method has not been widely applied to the microvasculature. At long diffusion-times, blood flow in capillaries is in the diffusive regime, and signal attenuation is dependent on blood velocity (v) and capillary segment length (l). It is described by the pseudo-diffusion coefficient (D*=vl/6) of intravoxel incoherent motion (IVIM). At shorter diffusion-times, blood flow is in the ballistic regime, and signal attenuation depends on v, and not l. In theory, l could be estimated using D* and v. In this study, we compare the accuracy and repeatability of three approaches to estimating v, and therefore l: the IVIM ballistic model, the velocity autocorrelation model, and the ballistic approximation to the velocity autocorrelation model. Twenty-nine rat datasets from two strains were acquired at 7 T, with b-values between 0 and 1000 smm−2 and diffusion times between 11.6 and 50 ms. Five rats were scanned twice to assess scan-rescan repeatability. Measurements of l were validated using corrosion casting and micro-CT imaging. The ballistic approximation of the velocity autocorrelation model had lowest bias relative to corrosion cast estimates of l, and had highest repeatability