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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 (Formula presented.). Methods: Three modeling paradigms were evaluated: (i) the apparent exchange rate (AXR) model; (ii) a two-compartment model ((Formula presented.)) explicitly representing intra- and extravascular signal components, and (iii) a two-compartment model additionally accounting for finite compartmental (Formula presented.) and (Formula presented.) relaxation times ((Formula presented.)). Each model had three free parameters. Simulations quantified biases introduced by the assumption of infinite relaxation times in the AXR and (Formula presented.) 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/ (Formula presented.) 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 (Formula presented.) (Formula presented.), (Formula presented.) (Formula presented.), and (Formula presented.) (Formula presented.). 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.

Chemical-exchange spin-lock (CESL) MRI can map regional uptake and utilisation of glucose in the brain at high spatial resolution (i.e sub 0.2 mm3 voxels). We propose two quantitative kinetic models to describe glucose-induced changes in tissue R1ρ and apply them to glucoCESL MRI data acquired in tumour-bearing and healthy rats. When assuming glucose transport is saturable, the maximal transport capacity ( Tmax) measured in normal tissue was 3.2 ± 0.6 µmol/min/mL, the half saturation constant ( Kt) was 8.8 ± 2.2 mM, the metabolic rate of glucose consumption ( MRglc) was 0.21 ± 0.13 µmol/min/mL, and the cerebral blood volume ( vb) was 0.006 ± 0.005 mL/mL. Values in tumour were: Tmax = 7.1 ± 2.7 µmol/min/mL, Kt = 14 ± 1.7 mM, MRglc = 0.22 ± 0.09 µmol/min/mL, vb = 0.030 ± 0.035 mL/mL. Tmax and Kt were significantly higher in tumour tissue than normal tissue (p = 0.006 and p = 0.011, respectively). When assuming glucose uptake also occurs via free diffusion, the free diffusion rate ( kd) was 0.061 ± 0.017 mL/min/mL in normal tissue and 0.12 ± 0.042 mL/min/mL in tumour. These parameter estimates agree well with literature values obtained using other approaches (e.g. NMR spectroscopy).

The recent revolution in tissue-resident macrophage biology has resulted largely from murine studies performed in C57BL/6 mice. Here, using both C57BL/6 and BALB/c mice, we analyze immune cells in the pleural cavity. Unlike C57BL/6 mice, naive tissue-resident large-cavity macrophages (LCMs) of BALB/c mice failed to fully implement the tissue-residency program. Following infection with a pleural-dwelling nematode, these pre-existing differences were accentuated with LCM expansion occurring in C57BL/6, but not in BALB/c mice. While infection drove monocyte recruitment in both strains, only in C57BL/6 mice were monocytes able to efficiently integrate into the resident pool. Monocyte-to-macrophage conversion required both T cells and interleukin-4 receptor alpha (IL-4Rα) signaling. The transition to tissue residency altered macrophage function, and GATA6+ tissue-resident macrophages were required for host resistance to nematode infection. Therefore, during tissue nematode infection, T helper 2 (Th2) cells control the differentiation pathway of resident macrophages, which determines infection outcome.

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,kb, but to estimatekbin practice it is necessary to separate the intra- and extravascular signals. This is challenging in standard ASL data owing to the small difference inT1values. Here, a gadolinium-based contrast agent is used to increase thisT1difference and enable the signal components to be disentangled. The optimal post-contrast bloodT1at 3T 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 optimalat 3T as 0.8 s. Simulations showedkbcould be estimated in individual cortical regions with a relative errorϵ< 1% and coefficient of variation CoV = 30 %; however, a high dependence on bloodT1was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit timetA= 1.15±0.49 s, cerebral blood flowf= 58.0±14.3 ml blood / min / 100 ml tissue, water exchange ratekb= 2.32 ± 2.49 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 measuredT1values.

Multi-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 ([Formula: see text]) and capillary segment length ([Formula: see text]). It is described by the pseudo-diffusion coefficient ([Formula: see text]) of intravoxel incoherent motion (IVIM). At shorter diffusion-times, blood flow is in the ballistic regime, and signal attenuation depends on [Formula: see text], and not [Formula: see text]. In theory, [Formula: see text] could be estimated using [Formula: see text] and [Formula: see text]. In this study, we compare the accuracy and repeatability of three approaches to estimating [Formula: see text], and therefore [Formula: see text]: 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 [Formula: see text]-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 [Formula: see text] 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 [Formula: see text], and had highest repeatability.

Haemorrhagic stroke represents a significant public health burden, yet our knowledge and ability to treat this type of stroke are lacking. Previously we showed that we can target ischaemic-stroke lesions by selective translocation of lipid nanoparticles through the site of blood-brain barrier (BBB) disruption. The data we presented in this study provide compelling evidence that haemorrhagic stroke in mice induces BBB injury that mimics key features of the human pathology and, more importantly, provides a gate for entry of lipid nanoparticles-based therapeutics selectively to the bleeding site. [Methods] Haemorrhagic stroke was induced in mice by intra-striatal collagenase injection. lipid nanoparticles were injected intravenously at 3 h, 24 h & 48 h post-haemorrhagic stroke and accumulation in the brain studied using in-vivo optical imaging and histology. BBB integrity, brain water content and iron accumulation were characterised using dynamic contrast-enhanced MRI, quantitative T1 mapping, and gradient echo MRI. [Results] Using in-vivo SPECT/CT imaging and optical imaging revealed biphasic lipid nanoparticles entry into the bleeding site, with an early phase of increased uptake at 3-24 h post-haemorrhagic stroke, followed by a second phase at 48-72 h. Lipid nanoparticles entry into the brain post-haemorrhage showed an identical entry pattern to the trans-BBB leakage rate (K [min]) of Gd-DOTA, a biomarker for BBB disruption, measured using dynamic contrast-enhanced MRI. [Discussion] Our findings suggest that selective accumulation of liposomes into the lesion site is linked to a biphasic pattern of BBB hyper-permeability. This approach provides a unique opportunity to selectively and efficiently deliver therapeutic molecules across the BBB, an approach that has not been utilised for haemorrhagic stroke therapy and is not achievable using free small drug molecules., The authors acknowledge Lipoid Co. (Germany) for the lipid sample gifts, the staff at the bioimaging facility at the University of Manchester and NTU for advice on confocal imaging and data analysis. The authors also would like to acknowledge the access to the Leica Thunder Imager 3D Cell Culture system funded by the Office for Students at NTU. They also wish to thank the Biological Services Facility at the University of Manchester for the excellent animal husbandry. The cost of this study has been covered by: a) Dr Z Al-Ahmady research fellowship (School of Pharmacy and Optometry, University of Manchester), b) QR fund and Vice-Chancellor PhD studentship awarded for Dr Zahraa Al-Ahmady and Satinderdeep Kaur, Nottingham Trent University, c) BBSRC DTP Studentship awarded to Jessica Bates, Nottingham Trent University, d) MRC DTP studentship to Jack Barrington at University of Manchester. Jack Barrington also received support from the Natalie Kate Moss Trust, e) MRC grant (MR/N003586/1) for Eloise Lemarchand at University of Manchester, and f) EPSRC grant for Dr Ben Dickie at the University of Manchester (EP/S021510). Graphical abstract and schematic graphes were performed using Biorender.

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.

Amyloid plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

Purpose: Dynamic contrast-enhanced (DCE) -MRI with Patlak model analysis is increasingly used to quantify low-level blood-brain barrier (BBB) leakage in studies of pathophysiology. We aimed to investigate systematic errors due to physiological, experimental, and modeling factors influencing quantification of the permeability-surface area product PS and blood plasma volume v p, and to propose modifications to reduce the errors so that subtle differences in BBB permeability can be accurately measured. Methods: Simulations were performed to predict the effects of potential sources of systematic error on conventional PS and v p quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and (Formula presented.) error. The impact of targeted modifications to the acquisition and processing were evaluated, including: assumption of fast versus no BBB water exchange, bolus versus slow injection of contrast agent, exclusion of early data from model fitting and (Formula presented.) correction. The optimal protocol was applied in a cohort of recent mild ischaemic stroke patients. Results: Simulation results demonstrated substantial systematic errors due to the factors investigated (absolute PS error ≤ 4.48 × 10 −4 min −1). However, these were reduced (≤0.56 × 10 −4 min −1) by applying modifications to the acquisition and processing pipeline. Processing modifications also had substantial effects on in-vivo normal-appearing white matter PS estimation (absolute change ≤ 0.45 × 10 −4 min −1). Conclusion: Measuring subtle BBB leakage with DCE-MRI presents unique challenges and is affected by several confounds that should be considered when acquiring or interpreting such data. The evaluated modifications should improve accuracy in studies of neurodegenerative diseases involving subtle BBB breakdown.

The 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.

Senile plaques are a hallmark of Alzheimer’s disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats.Fourteen mice (eight transgenic, six wild-type) and eight rats (four transgenic, four wild-type) were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4T Bruker scanner. Susceptibility-weighted images, transverse relaxation rate (R2*) maps, and quantitative susceptibility maps were derived from high-resolution 3D multi-gradient-echo (MGE) data to directly visualize plaques. Longitudinal relaxation rate (R1) maps were derived from MP2RAGE data to measure regional manganese uptake. After scanning, the brains were processed for histology and stained for beta-amyloid (4G8 antibody), iron (Perl’s), and calcium/manganese (Alizarin Red).MnCl2 improved signal-to-noise ratio (1.55±0.39-fold increase in MGE images) as expected, although this was not necessary for detection of plaques in the high-resolution images. Plaques were visible in susceptibility-weighted images, R2* maps, and quantitative susceptibility maps, with increased R2* and more positive magnetic susceptibility compared to surrounding tissue.In the 5xFAD mice, most MR-visible plaques were in the hippocampus, though histology confirmed plaques in the cortex and thalamus as well. In the TgF344-AD rats, many more plaques were MR-visible throughout the hippocampus and cortex. Beta-amyloid and iron staining indicate that, in both models, MR visibility was driven by plaque size and iron load.Voxel-wise comparison of R1 maps revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. Interestingly, in contrast to plaque visibility in the high-resolution images, the increased manganese uptake was limited to the rhinencephalon in the TgF344-AD rats (family-wise error (FWE)-corrected p < 0.05) while it was most significantly increased in the cortex of the 5xFAD mice (FWE-corrected p < 0.3). Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats.Multi-parametric MEMRI is a simple, viable method for detecting senile plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.HighlightsThis is the first study to use manganese-enhanced MRI (MEMRI) for direct visualization of senile plaques in rodent models of Alzheimer’s disease, in vivo.Manganese enhancement is not necessary to detect plaques but improves image contrast and signal-to-noise ratio.Manganese binds to plaques in 5xFAD mice but not in TgF344-AD rats, demonstrating potential as a targeted contrast agent for imaging plaques in certain models of AD.

BackgroundPhysiological brain function depends on tight glucose regulation, including transport and phosphorylation, the first step in its metabolism. Impaired glucose regulation is increasingly implicated in the pathophysiology of Alzheimer's disease (AD). Glucose hypometabolism in AD may be at least partly due to impaired glucose transport at the blood-brain barrier (BBB). Glucose transporters (GLUTs) are an integral component of the BBB. There is evidence of a significant reduction in vascular and non-vascular forms of GLUT1 and GLUT3 in AD brains compared to age-matched controls. Glucose transport, as well as phosphorylation, appears to be a rate limiting step for glucose metabolism in the brain. We have reviewed the literature on glucose transport abnormalities in AD and the effect such abnormalities have on the brain.MethodPublished literature between 1st January 1946 and 1st November 2019 was identified using EMBASE and MEDLINE databases and titles and abstracts were scanned. Human studies (autopsy and imaging) and data from animal models were included while reviews, letters and cellular or molecular studies were excluded from the search.ResultAutopsy studies in AD patients show significant reductions in GLUT3 in areas of the brain closely associated with AD pathology. Patients with AD and diabetes showed greater reductions of GLUT1 and GLUT3. A longitudinal study showed significant reductions in GLUT3 levels which correlated with greater amyloid-β (Aβ) and neurofibrillary tangle pathological burden in participants with AD pathology at post-mortem but without evidence of cognitive dysfunction in their lifetime. Some studies showed increased GLUT1, with others showing reduced GLUT1, levels in AD brain. A newly recognised GLUT12 appears to be increased in AD. Animal studies showed similar results with GLUT1 and GLUT3 knockout animal models exhibiting AD pathology, while overexpression of GLUT1 or treatment with metformin decreased Aβ toxicity in a Drosophila model of AD. GLUT2 levels were increased in both human AD brain and in an animal model of AD. Imaging studies using fluorodeoxyglucose [18F]FDG with positron emission tomography (FDG-PET) in AD subjects show reductions in glucose transport and glucose metabolism in areas most affected in AD. A small randomised control trial showed anti-diabetic medications improved the glucose transport in AD subjects.ConclusionGLUTs play a significant role in AD pathology with evidence suggesting that GLUT3 reductions may precede the onset of clinical symptoms, while GLUT2 and GLUT12 may have a compensatory role. Repurposing anti-diabetic drugs shows promising results in both animal and human studies of AD.

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.

Purpose To improve the accuracy and precision of tracer kinetic model parameter estimates for use in dynamic contrast enhanced (DCE) MRI studies of solid tumors. Theory Quantitative DCE-MRI requires an estimate of precontrast T1, which is obtained prior to fitting a tracer kinetic model. As T1 mapping and tracer kinetic signal models are both a function of precontrast T1 it was hypothesized that its joint estimation would improve the accuracy and precision of both precontrast T1 and tracer kinetic model parameters. Methods Accuracy and/or precision of two-compartment exchange model (2CXM) parameters were evaluated for standard and joint fitting methods in well-controlled synthetic data and for 36 bladder cancer patients. Methods were compared under a number of experimental conditions. Results In synthetic data, joint estimation led to statistically significant improvements in the accuracy of estimated parameters in 30 of 42 conditions (improvements between 1.8% and 49%). Reduced accuracy was observed in 7 of the remaining 12 conditions. Significant improvements in precision were observed in 35 of 42 conditions (between 4.7% and 50%). In clinical data, significant improvements in precision were observed in 18 of 21 conditions (between 4.6% and 38%). Conclusion Accuracy and precision of DCE-MRI parameter estimates are improved when signal models are fit jointly rather than sequentially. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Background: The microvascular contrast agent transfer constant Ktrans has shown prognostic value in cervical cancer patients treated with chemoradiotherapy. This study aims to determine whether this is explained by the contribution to Ktrans of plasma flow (Fp), vessel permeability surface-area product (PS), or a combination of both.Methods: Pre-treatment dynamic contrast-enhanced MRI (DCE-MRI) data from 36 patients were analysed using the two-compartment exchange model. Estimates of Fp, PS, Ktrans, and fractional plasma and interstitial volumes (vp and ve) were made and used in univariate and multivariate survival analyses adjusting for clinicopathologic variables tumour stage, nodal status, histological subtype, patient age, tumour volume, and treatment type (chemoradiotherapy vs radiotherapy alone). Results: In univariate analyses, Fp (HR=0.25, P=0.0095) and Ktrans (HR=0.20, P=0.032) were significantly associated with disease-free survival while PS, vp and ve were not. In multivariate analyses adjusting for clinicopathologic variables, Fp and Ktrans significantly increased the accuracy of survival predictions (P=0.0089).Conclusions: The prognostic value of Ktrans in cervical cancer patients treated with chemoradiotherapy is explained by microvascular plasma flow (Fp) rather than vessel permeability surface-area product (PS).

To improve the accuracy and precision of tracer kinetic model parameter estimates for use in dynamic contrast enhanced (DCE) MRI studies of solid tumors.Quantitative DCE-MRI requires an estimate of precontrast T1 , which is obtained prior to fitting a tracer kinetic model. As T1 mapping and tracer kinetic signal models are both a function of precontrast T1 it was hypothesized that its joint estimation would improve the accuracy and precision of both precontrast T1 and tracer kinetic model parameters.Accuracy and/or precision of two-compartment exchange model (2CXM) parameters were evaluated for standard and joint fitting methods in well-controlled synthetic data and for 36 bladder cancer patients. Methods were compared under a number of experimental conditions.In synthetic data, joint estimation led to statistically significant improvements in the accuracy of estimated parameters in 30 of 42 conditions (improvements between 1.8% and 49%). Reduced accuracy was observed in 7 of the remaining 12 conditions. Significant improvements in precision were observed in 35 of 42 conditions (between 4.7% and 50%). In clinical data, significant improvements in precision were observed in 18 of 21 conditions (between 4.6% and 38%).Accuracy and precision of DCE-MRI parameter estimates are improved when signal models are fit jointly rather than sequentially. Magn Reson Med 76:1270-1281, 2016. © 2015 Wiley Periodicals, Inc.