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

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 opti-mal 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 mi

Welfare and Revenue Guarantees for Competitive Bundling Equilibrium

We study equilibria of markets with $m$ heterogeneous indivisible goods and $n$ consumers with combinatorial preferences. It is well known that a competitive equilibrium is not guaranteed to exist when valuations are not gross substitutes. Given the widespread use of bundling in real-life markets, we study its role as a stabilizing and coordinating device by considering the notion of \emph{competitive bundling equilibrium}: a competitive equilibrium over the market induced by partitioning the goods for sale into fixed bundles. Compared to other equilibrium concepts involving bundles, this notion has the advantage of simulatneous succinctness ($O(m)$ prices) and market clearance. Our first set of results concern welfare guarantees. We show that in markets where consumers care only about the number of goods they receive (known as multi-unit or homogeneous markets), even in the presence of complementarities, there always exists a competitive bundling equilibrium that guarantees a logarithmic fraction of the optimal welfare, and this guarantee is tight. We also establish non-trivial welfare guarantees for general markets, two-consumer markets, and markets where the consumer valuations are additive up to a fixed budget (budget-additive). Our second set of results concern revenue guarantees. Motivated by the fact that the revenue extracted in a standard competitive equilibrium may be zero (even with simple unit-demand consumers), we show that for natural subclasses of gross substitutes valuations, there always exists a competitive bundling equilibrium that extracts a logarithmic fraction of the optimal welfare, and this guarantee is tight. The notion of competitive bundling equilibrium can thus be useful even in markets which possess a standard competitive equilibrium

Validation of High-Resolution Tractography Against In Vivo Tracing in the Macaque Visual Cortex

Diffusion magnetic resonance imaging (MRI) allows for the noninvasive in vivo examination of anatomical connections in the human brain, which has an important role in understanding brain function. Validation of this technique is vital, but has proved difficult due to the lack of an adequate gold standard. In this work, the macaque visual system was used as a model as an extensive body of literature of in vivo and postmortem tracer studies has established a detailed understanding of the underlying connections. We performed probabilistic tractography on high angular resolution diffusion imaging data of 2 ex vivo, in vitro macaque brains. Comparisons were made between identified connections at different thresholds of probabilistic connection “strength,” and with various tracking optimization strategies previously proposed in the literature, and known connections from the detailed visual system wiring map described by Felleman and Van Essen (1991; FVE91). On average, 74% of connections that were identified by FVE91 were reproduced by performing the most successfully optimized probabilistic diffusion MRI tractography. Further comparison with the results of a more recent tracer study ( Markov et al. 2012) suggests that the fidelity of tractography in estimating the presence or absence of interareal connections may be greater than this

Assessing Inflammation in Acute Intracerebral Hemorrhage with PK11195 PET and Dynamic Contrast-Enhanced MRI

BACKGROUND AND PURPOSE: Studies in animal models suggest that inflammation is a major contributor to secondary injury after intracerebral hemorrhage (ICH). Direct, noninvasive monitoring of inflammation in the human brain after ICH will facilitate early-phase development of anti-inflammatory treatments. We sought to investigate the feasibility of multimodality brain imaging in subacute ICH. METHODS: Acute ICH patients were recruited to undergo multiparametric MRI (including dynamic contrast-enhanced measurement of blood-brain barrier transfer constant (Ktrans ) and PET with [11 C]-(R)-PK11195). [11 C]-(R)-PK11195 binds to the translocator protein 18 kDa (TSPO), which is rapidly upregulated in activated microglia. Circulating inflammatory markers were measured at the time of PET. RESULTS: Five patients were recruited to this feasibility study with imaging between 5 and 16 days after onset. Etiologies included hypertension-related small vessel disease, cerebral amyloid angiopathy (CAA), cavernoma, and arteriovenous malformation (AVM). [11 C]-(R)-PK11195 binding was low in all hematomas and 2 (patient 2 [probable CAA] and 4 [AVM]) cases showed widespread increase in binding in the perihematomal region versus contralateral. All had increased Ktrans in the perihematomal region (mean difference = 2.2 × 10-3 minute-1 ; SD = 1.6 × 10-3 minute-1 ) versus contralateral. Two cases (patients 1 [cavernoma] and 4 [AVM]) had delayed surgery (3 and 12 months post-onset, respectively) with biopsies showing intense microglial activation in perilesional tissue. CONCLUSIONS: Our study demonstrates for the first time the feasibility of performing complex multimodality brain imaging for noninvasive monitoring of neuroinflammation for this severe stroke subtype

A Secular Trend toward Earlier Male Sexual Maturity: Evidence from Shifting Ages of Male Young Adult Mortality

This paper shows new evidence of a steady long-term decline in age of male sexual maturity since at least the mid-eighteenth century. A method for measuring the timing of male maturity is developed based on the age at which male young adult mortality accelerates. The method is applied to mortality data from Sweden, Denmark, Norway, the United Kingdom, and Italy. The secular trend toward earlier male sexual maturity parallels the trend toward earlier menarche for females, suggesting that common environmental cues influence the speed of both males' and females' sexual maturation

Fast spin echo sequences for BOLD functional MRI

At higher field strengths, spin echo (SE) functional MRI (fMRI) is an attractive alternative to gradient echo (GE) as the increased weighting towards the microvasculature results in intrinsically better localization of the BOLD signal. Images are free of signal voids but the commonly used echo planar imaging (EPI) sampling scheme causes geometric distortions, and T2* effects often contribute considerably to the signal changes measured upon brain activation. Multiply refocused SE sequences such as fast spin echo (FSE) are essentially artifact free but their application to fast fMRI is usually hindered due to high energy deposition, and long sampling times. In the work presented here, a combination of parallel imaging and partial Fourier acquisition is used to shorten FSE acquisition times to near those of conventional SE-EPI, permitting sampling of eight slices (matrix 64  ×  64) per second. Signal acquisition is preceded by a preparation experiment that aims at increasing the relative contribution of extravascular dynamic averaging to the BOLD signal. Comparisons are made with conventional SE-EPI using a visual stimulation paradigm. While the observed signal changes are approximately 30% lower, most likely due to the absence of T2* contamination, activation size and t-scores are comparable for both methods, suggesting that HASTE fMRI is a viable alternative, particularly if distortion free images are required. Our data also indicate that the BOLD post-stimulus undershoot is most probably attributable to persistent elevated oxygen metabolism rather than to delayed vascular compliance

Common polygenic variation in coeliac disease and confirmation of ZNF335 and NIFA as disease susceptibility loci

Coeliac disease (CD) is a chronic immune-mediated disease triggered by the ingestion of gluten. It has an estimated prevalence of approximately 1% in European populations. Specific HLA-DQA1 and HLA-DQB1 alleles are established coeliac susceptibility genes and are required for the presentation of gliadin to the immune system resulting in damage to the intestinal mucosa. In the largest association analysis of CD to date, 39 non-HLA risk loci were identified, 13 of which were new, in a sample of 12 014 individuals with CD and 12 228 controls using the Immunochip genotyping platform. Including the HLA, this brings the total number of known CD loci to 40. We have replicated this study in an independent Irish CD case–control population of 425 CD and 453 controls using the Immunochip platform. Using a binomial sign test, we show that the direction of the effects of previously described risk alleles were highly correlated with those reported in the Irish population, (P=2.2 × 10−16). Using the Polygene Risk Score (PRS) approach, we estimated that up to 35% of the genetic variance could be explained by loci present on the Immunochip (P=9 × 10−75). When this is limited to non-HLA loci, we explain a maximum of 4.5% of the genetic variance (P=3.6 × 10−18). Finally, we performed a meta-analysis of our data with the previous reports, identifying two further loci harbouring the ZNF335 and NIFA genes which now exceed genome-wide significance, taking the total number of CD susceptibility loci to 42