Quantification of water exchange across the blood-brain barrier using noncontrast MR fingerprinting.

PURPOSE: A method is proposed to quantify cerebral blood volume ( v b $$ {v}_b $$ ) and intravascular water residence time ( τ b $$ {\tau}_b $$ ) using MR fingerprinting (MRF), applied using a spoiled gradient echo sequence without the need for contrast agent. METHODS: An in silico study optimized an acquisition protocol to maximize the sensitivity of the measurement to v b $$ {v}_b $$ and τ b $$ {\tau}_b $$ changes. Its accuracy in the presence of variations in T 1 , t $$ {\mathrm{T}}_{1,t} $$ , T 1 , b $$ {\mathrm{T}}_{1,b} $$ , and B 1 $$ {\mathrm{B}}_1 $$ was evaluated. The optimized protocol (scan time of 19 min) was then tested in a exploratory healthy volunteer study (10 volunteers, mean age 24 ± $$ \pm $$ 3, six males) at 3 T with a repeat scan taken after repositioning to allow estimation of repeatability. RESULTS: Simulations show that assuming literature values for T 1 , b $$ {\mathrm{T}}_{1,b} $$ and T 1 , t $$ {\mathrm{T}}_{1,t} $$ , no variation in B 1 $$ {\mathrm{B}}_1 $$ , while fitting only v b $$ {v}_b $$ and τ b $$ {\tau}_b $$ , leads to large errors in quantification of v b $$ {v}_b $$ and τ b $$ {\tau}_b $$ , regardless of noise levels. However, simulations also show that matching T 1 , t $$ {\mathrm{T}}_{1,t} $$ , T 1 , b $$ {\mathrm{T}}_{1,b} $$ , B 1 + $$ {\mathrm{B}}_1^{+} $$ , v b $$ {v}_b $$ and τ b $$ {\tau}_b $$ , simultaneously is feasible at clinically achievable noise levels. Across the healthy volunteers, all parameter quantifications fell within the expected literature range. In addition, the maps show good agreement between hemispheres suggesting physiologically relevant information is being extracted. Expected differences between white and gray matter T 1 , t $$ {\mathrm{T}}_{1,t} $$ (p < 0.0001) and v b $$ {v}_b $$ (p < 0.0001) are observed, T 1 , b $$ {\mathrm{T}}_{1,b} $$ and τ b $$ {\tau}_b $$ show no significant differences, p = 0.4 and p = 0.6, respectively. Moderate to excellent repeatability was seen between repeat scans: mean intra-class correlation coefficient of T 1 , t : 0 . 91 $$ {\mathrm{T}}_{1,t}:0.91 $$ , T 1 , b : 0 . 58 $$ {\mathrm{T}}_{1,b}:0.58 $$ , v b : 0 . 90 $$ {v}_b:0.90 $$ , and τ b : 0 . 96 $$ {\tau}_b:0.96 $$ . CONCLUSION: We demonstrate that regional simultaneous quantification of v b $$ {v}_b $$ , τ b $$ {\tau}_b $$ , T 1 , b , T 1 , t $$ {\mathrm{T}}_{1,b},{T}_{1,t} $$ , and B 1 + $$ {\mathrm{B}}_1^{+} $$ using MRF is feasible in vivo.

Independent component analysis (ICA) applied to dynamic oxygen-enhanced MRI (OE-MRI) for robust functional lung imaging at 3 T.

PURPOSE: Dynamic lung oxygen-enhanced MRI (OE-MRI) is challenging due to the presence of confounding signals and poor signal-to-noise ratio, particularly at 3 T. We have created a robust pipeline utilizing independent component analysis (ICA) to automatically extract the oxygen-induced signal change from confounding factors to improve the accuracy and sensitivity of lung OE-MRI. METHODS: Dynamic OE-MRI was performed on healthy participants using a dual-echo multi-slice spoiled gradient echo sequence at 3 T and cyclical gas delivery. ICA was applied to each echo within a thoracic mask. The ICA component relating to the oxygen-enhancement signal was automatically identified using correlation analysis. The oxygen-enhancement component was reconstructed, and the percentage signal enhancement (PSE) was calculated. The lung PSE of current smokers was compared with nonsmokers; scan-rescan repeatability, ICA pipeline repeatability, and reproducibility between two vendors were assessed. RESULTS: ICA successfully extracted a consistent oxygen-enhancement component for all participants. Lung tissue and oxygenated blood displayed the opposite oxygen-induced signal enhancements. A significant difference in PSE was observed between the lungs of current smokers and nonsmokers. The scan-rescan repeatability and the ICA pipeline repeatability were good. CONCLUSION: The developed pipeline demonstrated sensitivity to the signal enhancements of the lung tissue and oxygenated blood at 3 T. The difference in lung PSE between current smokers and nonsmokers indicates a likely sensitivity to lung function alterations that may be seen in mild pathology, supporting future use of our methods in patient studies.

Feasibility of dynamic T2 *-based oxygen-enhanced lung MRI at 3T.

PURPOSE: To demonstrate proof-of-concept of a T2 *-sensitized oxygen-enhanced MRI (OE-MRI) method at 3T by assessing signal characteristics, repeatability, and reproducibility of dynamic lung OE-MRI metrics in healthy volunteers. METHODS: We performed sequence-specific simulations for protocol optimisation and acquired free-breathing OE-MRI data from 16 healthy subjects using a dual-echo RF-spoiled gradient echo approach at 3T across two institutions. Non-linear registration and tissue density correction were applied. Derived metrics included percent signal enhancement (PSE), ∆R2 * and wash-in time normalized for breathing rate (τ-nBR). Inter-scanner reproducibility and intra-scanner repeatability were evaluated using intra-class correlation coefficient (ICC), repeatability coefficient, reproducibility coefficient, and Bland-Altman analysis. RESULTS: Simulations and experimental data show negative contrast upon oxygen inhalation, due to substantial dominance of ∆R2 * at TE > 0.2 ms. Density correction improved signal fluctuations. Density-corrected mean PSE values, aligned with simulations, display TE-dependence, and an anterior-to-posterior PSE reduction trend at TE1 . ∆R2 * maps exhibit spatial heterogeneity in oxygen delivery, featuring anterior-to-posterior R2 * increase. Mean T2 * values across 32 scans were 0.68 and 0.62 ms for pre- and post-O2 inhalation, respectively. Excellent or good agreement emerged from all intra-, inter-scanner and inter-rater variability tests for PSE and ∆R2 *. However, ICC values for τ-nBR demonstrated limited agreement between repeated measures. CONCLUSION: Our results demonstrate the feasibility of a T2 *-weighted method utilizing a dual-echo RF-spoiled gradient echo approach, simultaneously capturing PSE, ∆R2 * changes, and oxygen wash-in during free-breathing. The excellent or good repeatability and reproducibility on intra- and inter-scanner PSE and ∆R2 * suggest potential utility in multi-center clinical applications.

The ISMRM Open Science Initiative for Perfusion Imaging (OSIPI): Results from the OSIPI-Dynamic Contrast-Enhanced challenge.

PURPOSE: K trans $$ {K}^{\mathrm{trans}} $$ has often been proposed as a quantitative imaging biomarker for diagnosis, prognosis, and treatment response assessment for various tumors. None of the many software tools for K trans $$ {K}^{\mathrm{trans}} $$ quantification are standardized. The ISMRM Open Science Initiative for Perfusion Imaging-Dynamic Contrast-Enhanced (OSIPI-DCE) challenge was designed to benchmark methods to better help the efforts to standardize K trans $$ {K}^{\mathrm{trans}} $$ measurement. METHODS: A framework was created to evaluate K trans $$ {K}^{\mathrm{trans}} $$ values produced by DCE-MRI analysis pipelines to enable benchmarking. The perfusion MRI community was invited to apply their pipelines for K trans $$ {K}^{\mathrm{trans}} $$ quantification in glioblastoma from clinical and synthetic patients. Submissions were required to include the entrants' K trans $$ {K}^{\mathrm{trans}} $$ values, the applied software, and a standard operating procedure. These were evaluated using the proposed OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score defined with accuracy, repeatability, and reproducibility components. RESULTS: Across the 10 received submissions, the OSIP I gold $$ \mathrm{OSIP}{\mathrm{I}}_{\mathrm{gold}} $$ score ranged from 28% to 78% with a 59% median. The accuracy, repeatability, and reproducibility scores ranged from 0.54 to 0.92, 0.64 to 0.86, and 0.65 to 1.00, respectively (0-1 = lowest-highest). Manual arterial input function selection markedly affected the reproducibility and showed greater variability in K trans $$ {K}^{\mathrm{trans}} $$ analysis than automated methods. Furthermore, provision of a detailed standard operating procedure was critical for higher reproducibility. CONCLUSIONS: This study reports results from the OSIPI-DCE challenge and highlights the high inter-software variability within K trans $$ {K}^{\mathrm{trans}} $$ estimation, providing a framework for ongoing benchmarking against the scores presented. Through this challenge, the participating teams were ranked based on the performance of their software tools in the particular setting of this challenge. In a real-world clinical setting, many of these tools may perform differently with different benchmarking methodology.

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 $$ \mathrm{T} $$ . METHODS: Three modeling paradigms were evaluated: (i) the apparent exchange rate (AXR) model; (ii) a two-compartment model ( 2 CM $$ 2\mathrm{CM} $$ ) explicitly representing intra- and extravascular signal components, and (iii) a two-compartment model additionally accounting for finite compartmental T 1 $$ {\mathrm{T}}_1 $$ and T 2 $$ {\mathrm{T}}_2 $$ relaxation times ( 2 CM r $$ 2{\mathrm{CM}}_r $$ ). Each model had three free parameters. Simulations quantified biases introduced by the assumption of infinite relaxation times in the AXR and 2 CM $$ 2\mathrm{CM} $$ 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/ 2 CM $$ 2\mathrm{CM} $$ 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 RC AXR = 0 . 43 $$ {\mathrm{RC}}_{\mathrm{AXR}}=0.43 $$ s - 1 $$ {\mathrm{s}}^{-1} $$ , RC 2 CM = 0 . 51 $$ {\mathrm{RC}}_{2\mathrm{CM}}=0.51 $$ s - 1 $$ {\mathrm{s}}^{-1} $$ , and RC 2 CM r = 0 . 61 $$ {\mathrm{RC}}_{2{\mathrm{CM}}_r}=0.61 $$ s - 1 $$ {\mathrm{s}}^{-1} $$ . 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.

Cardiac q-space trajectory imaging by motion-compensated tensor-valued diffusion encoding in human heart in vivo.

PURPOSE: Tensor-valued diffusion encoding can probe more specific features of tissue microstructure than what is available by conventional diffusion weighting. In this work, we investigate the technical feasibility of tensor-valued diffusion encoding at high b-values with q-space trajectory imaging (QTI) analysis, in the human heart in vivo. METHODS: Ten healthy volunteers were scanned on a 3T scanner. We designed time-optimal gradient waveforms for tensor-valued diffusion encoding (linear and planar) with second-order motion compensation. Data were analyzed with QTI. Normal values and repeatability were investigated for the mean diffusivity (MD), fractional anisotropy (FA), microscopic FA (µFA), isotropic, anisotropic and total mean kurtosis (MKi, MKa, and MKt), and orientation coherence (Cc ). A phantom, consisting of two fiber blocks at adjustable angles, was used to evaluate sensitivity of parameters to orientation dispersion and diffusion time. RESULTS: QTI data in the left ventricular myocardium were MD = 1.62 ± 0.07 µm2 /ms, FA = 0.31 ± 0.03, µFA = 0.43 ± 0.07, MKa = 0.20 ± 0.07, MKi = 0.13 ± 0.03, MKt = 0.33 ± 0.09, and Cc  = 0.56 ± 0.22 (mean ± SD across subjects). Phantom experiments showed that FA depends on orientation dispersion, whereas µFA was insensitive to this effect. CONCLUSION: We demonstrated the first tensor-valued diffusion encoding and QTI analysis in the heart in vivo, along with first measurements of myocardial µFA, MKi, MKa, and Cc . The methodology is technically feasible and provides promising novel biomarkers for myocardial tissue characterization.

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, k b , but to estimate k b 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 T 1 values. Here, a gadolinium-based contrast agent is used to increase this T 1 difference and enable the signal components to be disentangled. The optimal post-contrast blood T 1 ( T 1 , b post ) 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 T 1 , b post at 3 T as 0.8 s. Simulations showed that k b could be estimated in individual cortical regions with a relative error ϵ < 1 % and coefficient of variation CoV = 30 %; however, a high dependence on blood T 1 was also observed. In volunteer data, mean parameter values in grey matter were: arterial transit time t A = 1 . 15 ± 0 . 49 s, cerebral blood flow f = 58 . 0 ± 14 . 3 mL blood/min/100 mL tissue and water exchange rate k b = 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 measured T 1 values.

Mitochondrial uniparental inheritance achieved after fertilization challenges the nuclear-cytoplasmic conflict hypothesis for anisogamy evolution.

In eukaryotes, a fundamental phenomenon underlying sexual selection is the evolution of gamete size dimorphism between the sexes (anisogamy) from an ancestral gametic system with gametes of the same size in both mating types (isogamy). The nuclear-cytoplasmic conflict hypothesis has been one of the major theoretical hypotheses for the evolution of anisogamy. It proposes that anisogamy evolved as an adaptation for preventing nuclear-cytoplasmic conflict by minimizing male gamete size to inherit organelles uniparentally. In ulvophycean green algae, biparental inheritance of organelles is observed in isogamous species, as the hypothesis assumes. So we tested the hypothesis by examining whether cytoplasmic inheritance is biparental in Monostroma angicava, a slightly anisogamous ulvophycean that produces large male gametes. We tracked the fates of mitochondria in intraspecific crosses with PCR-RFLP markers. We confirmed that mitochondria are maternally inherited. However, paternal mitochondria enter the zygote, where their DNA can be detected for over 14 days. This indicates that uniparental inheritance is enforced by eliminating paternal mitochondrial DNA in the zygote, rather than by decreasing male gamete size to the minimum. Thus, uniparental cytoplasmic inheritance is achieved by an entirely different mechanism, and is unlikely to drive the evolution of anisogamy in ulvophyceans.

Comparative analysis of signal models for microscopic fractional anisotropy estimation using q-space trajectory encoding.

Microscopic diffusion anisotropy imaging using diffusion-weighted MRI and multidimensional diffusion encoding is a promising method for quantifying clinically and scientifically relevant microstructural properties of neural tissue. Several methods for estimating microscopic fractional anisotropy (µFA), a normalized measure of microscopic diffusion anisotropy, have been introduced but the differences between the methods have received little attention thus far. In this study, the accuracy and precision of µFA estimation using q-space trajectory encoding and different signal models were assessed using imaging experiments and simulations. Three healthy volunteers and a microfibre phantom were imaged with five non-zero b-values and gradient waveforms encoding linear and spherical b-tensors. Since the ground-truth µFA was unknown in the imaging experiments, Monte Carlo random walk simulations were performed using axon-mimicking fibres for which the ground truth was known. Furthermore, parameter bias due to time-dependent diffusion was quantified by repeating the simulations with tuned waveforms, which have similar power spectra, and with triple diffusion encoding, which, unlike q-space trajectory encoding, is not based on the assumption of time-independent diffusion. The truncated cumulant expansion of the powder-averaged signal, gamma-distributed diffusivities assumption, and q-space trajectory imaging, a generalization of the truncated cumulant expansion to individual signals, were used to estimate µFA. The gamma-distributed diffusivities assumption consistently resulted in greater µFA values than the second order cumulant expansion, 0.1 greater when averaged over the whole brain. In the simulations, the generalized cumulant expansion provided the most accurate estimates. Importantly, although time-dependent diffusion caused significant overestimation of µFA using all the studied methods, the simulations suggest that the resulting bias in µFA is less than 0.1 in human white matter.

Trade-Offs with Growth Limit Host Range in Complex Life-Cycle Helminths.

AbstractParasitic worms with complex life cycles have several developmental stages, with each stage creating opportunities to infect additional host species. Using a data set for 973 species of trophically transmitted acanthocephalans, cestodes, and nematodes, we confirmed that worms with longer life cycles (i.e., more successive hosts) infect a greater diversity of host species and taxa (after controlling for study effort). Generalism at the stage level was highest for middle life stages, the second and third intermediate hosts of long life cycles. By simulating life cycles in real food webs, we found that middle stages had more potential host species to infect, suggesting that opportunity constrains generalism. However, parasites usually infected fewer host species than expected from simulated cycles, suggesting that generalism has costs. There was no trade-off in generalism from one stage to the next, but worms spent less time growing and developing in stages where they infected more taxonomically diverse hosts. Our results demonstrate that life-cycle complexity favors high generalism and that host use across life stages is determined by both ecological opportunity and life-history trade-offs.

Evolution of Anisogamy in Organisms with Parthenogenetic Gametes.

AbstractThe two sexes are defined by the sizes of the gametes they produce, anisogamy being the state with two differing gamete sizes (hence, females and males). The origin of this divergence has received much research interest, both theoretically and empirically. The gamete dynamics (GD) theory is a widely accepted theoretical explanation for anisogamy, and green algae have been an important empirical testing ground for the theory. However, some green and brown algae produce parthenogenetic gametes (gametes that can develop without fusing with another gamete), in contrast to an assumption in GD theory that unfused gametes do not develop. Here, we construct a GD model accounting for parthenogenetic gametes. We find that under conditions of panmixia and highly efficient fertilization (i.e., conditions of classical GD models from 1972 onward), the results remain largely unaltered by parthenogametes. However, under gamete-limited conditions anisogamy evolves less easily in the new model, and a novel result emerges: whereas previous models typically predict the evolution of either anisogamy or small isogamy, the current model shows that large isogamy can evolve when parthenogenetic gametes evolve under conditions of inefficient fertilization. Our analyses uncover unexplored complications relating to sex ratios under this relatively uncharted gametic system. We discuss limitations these complications impose on our models and suggest avenues for future research. We compare model results to algae with parthenogenetic gametes in nature.

Optimization of quantitative susceptibility mapping for regional estimation of oxygen extraction fraction in the brain.

PURPOSE: We sought to determine the degree to which oxygen extraction fraction (OEF) estimated using quantitative susceptibility mapping (QSM) depends on two critical acquisition parameters that have a significant impact on acquisition time: voxel size and final echo time. METHODS: Four healthy volunteers were imaged using a range of isotropic voxel sizes and final echo times. The 0.7 mm data were downsampled at different stages of QSM processing by a factor of 2 (to 1.4 mm), 3 (2.1 mm), or 4 (2.8 mm) to determine the impact of voxel size on each analysis step. OEF was estimated from 11 veins of varying diameter. Inter- and intra-session repeatability were estimated for the optimal protocol by repeat scanning in 10 participants. RESULTS: Final echo time was found to have no significant effect on OEF. The effect of voxel size was significant, with larger voxel sizes underestimating OEF, depending on the proximity of the vein to the superficial surface of the brain and on vein diameter. The last analysis step of estimating vein OEF values from susceptibility images had the largest dependency on voxel size. Inter-session coefficients of variation on OEF estimates of between 5.2% and 8.7% are reported, depending on the vein. CONCLUSION: QSM acquisition times can be minimized by reducing the final echo time but an isotropic voxel size no larger than 1 mm is needed to accurately estimate OEF in most medium/large veins in the brain. Such acquisitions can be achieved in under 4 min.

A model selection framework to quantify microvascular liver function in gadoxetate-enhanced MRI: Application to healthy liver, diseased tissue, and hepatocellular carcinoma.

PURPOSE: We introduce a novel, generalized tracer kinetic model selection framework to quantify microvascular characteristics of liver and tumor tissue in gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI). METHODS: Our framework includes a hierarchy of nested models, from which physiological parameters are derived in 2 regimes, corresponding to the active transport and free diffusion of gadoxetate. We use simulations to show the sensitivity of model selection and parameter estimation to temporal resolution, time-series duration, and noise. We apply the framework in 8 healthy volunteers (time-series duration up to 24 minutes) and 10 patients with hepatocellular carcinoma (6 minutes). RESULTS: The active transport regime is preferred in 98.6% of voxels in volunteers, 82.1% of patients' non-tumorous liver, and 32.2% of tumor voxels. Interpatient variations correspond to known co-morbidities. Simulations suggest both datasets have sufficient temporal resolution and signal-to-noise ratio, while patient data would be improved by using a time-series duration of at least 12 minutes. CONCLUSIONS: In patient data, gadoxetate exhibits different kinetics: (a) between liver and tumor regions and (b) within regions due to liver disease and/or tumor heterogeneity. Our generalized framework selects a physiological interpretation at each voxel, without preselecting a model for each region or duplicating time-consuming optimizations for models with identical functional forms.

Validating pore size estimates in a complex microfiber environment on a human MRI system.

PURPOSE: Recent advances in diffusion-weighted MRI provide "restricted diffusion signal fraction" and restricting pore size estimates. Materials based on co-electrospun oriented hollow cylinders have been introduced to provide validation for such methods. This study extends this work, exploring accuracy and repeatability using an extended acquisition on a 300 mT/m gradient human MRI scanner, in substrates closely mimicking tissue, that is, non-circular cross-sections, intra-voxel fiber crossing, intra-voxel distributions of pore-sizes, and smaller pore-sizes overall. METHODS: In a single-blind experiment, diffusion-weighted data were collected from a biomimetic phantom on a 3T Connectom system using multiple gradient directions/diffusion times. Repeated scans established short-term and long-term repeatability. The total scan time (54 min) matched similar protocols used in human studies. The number of distinct fiber populations was estimated using spherical deconvolution, and median pore size estimated through the combination of CHARMED and AxCaliber3D framework. Diffusion-based estimates were compared with measurements derived from scanning electron microscopy. RESULTS: The phantom contained substrates with different orientations, fiber configurations, and pore size distributions. Irrespective of one or two populations within the voxel, the pore-size estimates (~5 µm) and orientation-estimates showed excellent agreement with the median values of pore-size derived from scanning electron microscope and phantom configuration. Measurement repeatability depended on substrate complexity, with lower values seen in samples containing crossing-fibers. Sample-level repeatability was found to be good. CONCLUSION: While no phantom mimics tissue completely, this study takes a step closer to validating diffusion microstructure measurements for use in vivo by demonstrating the ability to quantify microgeometry in relatively complex configurations.

Sources of systematic error in DCE-MRI estimation of low-level blood-brain barrier leakage.

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 vp , 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 vp quantification: restricted BBB water exchange, reduced cerebral blood flow, arterial input function (AIF) delay and B1+ 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 B1+ 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.

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

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.

Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study.

BACKGROUND: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. METHODS: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). CONCLUSIONS: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Dynamic contrast-enhanced MRI of synovitis in knee osteoarthritis: repeatability, discrimination and sensitivity to change in a prospective experimental study.

OBJECTIVES: Evaluate test-retest repeatability, ability to discriminate between osteoarthritic and healthy participants, and sensitivity to change over 6 months, of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarkers in knee OA. METHODS: Fourteen individuals aged 40-60 with mild-moderate knee OA and 6 age-matched healthy volunteers (HV) underwent DCE-MRI at 3 T at baseline, 1 month and 6 months. Voxelwise pharmacokinetic modelling of dynamic data was used to calculate DCE-MRI biomarkers including Ktrans and IAUC60. Median DCE-MRI biomarker values were extracted for each participant at each study visit. Synovial segmentation was performed using both manual and semiautomatic methods with calculation of an additional biomarker, the volume of enhancing pannus (VEP). Test-retest repeatability was assessed using intraclass correlation coefficients (ICC). Smallest detectable differences (SDDs) were calculated from test-retest data. Discrimination between OA and HV was assessed via calculation of between-group standardised mean differences (SMD). Responsiveness was assessed via the number of OA participants with changes greater than the SDD at 6 months. RESULTS: Ktrans demonstrated the best test-retest repeatability (Ktrans/IAUC60/VEP ICCs 0.90/0.84/0.40, SDDs as % of OA mean 33/71/76%), discrimination between OA and HV (SMDs 0.94/0.54/0.50) and responsiveness (5/1/1 out of 12 OA participants with 6-month change > SDD) when compared to IAUC60 and VEP. Biomarkers derived from semiautomatic segmentation outperformed those derived from manual segmentation across all domains. CONCLUSIONS: Ktrans demonstrated the best repeatability, discrimination and sensitivity to change suggesting that it is the optimal DCE-MRI biomarker for use in experimental medicine studies. KEY POINTS: • Dynamic contrast-enhanced MRI (DCE-MRI) provides quantitative measures of synovitis in knee osteoarthritis which may permit early assessment of efficacy in experimental medicine studies. • This prospective observational study compared DCE-MRI biomarkers across domains relevant to experimental medicine: test-retest repeatability, discriminative validity and sensitivity to change. • The DCE-MRI biomarker Ktrans demonstrated the best performance across all three domains, suggesting that it is the optimal biomarker for use in future interventional studies.

A tutorial and tool for exploring feature similarity gradients with MRI data.

There has been an increasing interest in examining organisational principles of the cerebral cortex (and subcortical regions) using different MRI features such as structural or functional connectivity. Despite the widespread interest, introductory tutorials on the underlying technique targeted for the novice neuroimager are sparse in the literature. Articles that investigate various "neural gradients" (for example based on region studied "cortical gradients," "cerebellar gradients," "hippocampal gradients" etc … or feature of interest "functional gradients," "cytoarchitectural gradients," "myeloarchitectural gradients" etc …) have increased in popularity. Thus, we believe that it is opportune to discuss what is generally meant by "gradient analysis". We introduce basics concepts in graph theory, such as graphs themselves, the degree matrix, and the adjacency matrix. We discuss how one can think about gradients of feature similarity (the similarity between timeseries in fMRI, or streamline in tractography) using graph theory and we extend this to explore such gradients across the whole MRI scale; from the voxel level to the whole brain level. We proceed to introduce a measure for quantifying the level of similarity in regions of interest. We propose the term "the Vogt-Bailey index" for such quantification to pay homage to our history as a brain mapping community. We run through the techniques on sample datasets including a brain MRI as an example of the application of the techniques on real data and we provide several appendices that expand upon details. To maximise intuition, the appendices contain a didactic example describing how one could use these techniques to solve a particularly pernicious problem that one may encounter at a wedding. Accompanying the article is a tool, available in both MATLAB and Python, that enables readers to perform the analysis described in this article on their own data. We refer readers to the graphical abstract as an overview of the analysis pipeline presented in this work.