The Larmor frequency shift of a white matter magnetic microstructure model with multiple sources.

Magnetic susceptibility imaging may provide valuable information about chemical composition and microstructural organization of tissue. However, its estimation from the MRI signal phase is particularly difficult as it is sensitive to magnetic tissue properties ranging from the molecular to the macroscopic scale. The MRI Larmor frequency shift measured in white matter (WM) tissue depends on the myelinated axons and other magnetizable sources such as iron-filled ferritin. We have previously derived the Larmor frequency shift arising from a dense medium of cylinders with scalar susceptibility and arbitrary orientation dispersion. Here, we extend our model to include microscopic WM susceptibility anisotropy as well as spherical inclusions with scalar susceptibility to represent subcellular structures, biologically stored iron, and so forth. We validate our analytical results with computer simulations and investigate the feasibility of estimating susceptibility using simple iterative linear least squares without regularization or preconditioning. This is done in a digital brain phantom synthesized from diffusion MRI measurements of an ex vivo mouse brain at ultra-high field.

Exploring vascular contributions to cognitive impairment and dementia (ENIGMA): protocol for a prospective observational study.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is common. However, the underlying pathophysiology remains largely unknown. Understanding the role of microvascular changes and finding markers that can predict PSCI, could be a first step towards better screening and management of PSCI. Capillary dysfunction is a pathological feature of cerebral small vessel disease and may play a role in the mechanisms underlying PSCI. Extracellular vesicles (EVs) are secreted from cells and may act as disease biomarkers. We aim to investigate the role of capillary dysfunction in PSCI and the associations between EV characteristics and cognitive function one year after acute ischemic stroke (AIS) and transient ischemic attack (TIA). METHODS: The ENIGMA study is a single-centre prospective clinical observational study conducted at Aarhus University Hospital, Denmark. Consecutive patients with AIS and TIA are included and followed for one year with follow-up visits at three and 12 months. An MRI is performed at 24 h and 12 months follow-up. EV characteristics will be characterised from blood samples drawn at 24 h and three months follow-up. Cognitive function is assessed three and 12 months after AIS and TIA using the Repeatable Battery for the Assessment of Neuropsychological Status. DISCUSSION: Using novel imaging and molecular biological techniques the ENIGMA study will provide new knowledge about the vascular contributions to cognitive decline and dementia. TRIAL REGISTRATION: The study is retrospectively registered as an ongoing observational study at ClinicalTrials.gov with the identifier NCT06257823.

Capillary dysfunction in healthy elderly APOE ε4 carriers with raised brain Aß deposition.

INTRODUCTION: Capillary dysfunction, characterized by disturbances in capillary blood flow distribution, might be an overlooked factor in the development of Alzheimer's disease (AD). This study investigated microvascular blood flow in preclinical and prodromal AD individuals. METHODS: Using dynamic susceptibility contrast magnetic resonance imaging and positron emission tomography, we examined alterations in microvascular circulation and levels of Aß deposition in two independent cohorts of APOE ε4 carriers. RESULTS: Capillary dysfunction was elevated in both prodromal and preclinical AD individuals compared to age-matched controls. Additionally, the prodromal group exhibited higher levels of capillary dysfunction compared to the preclinical group. DISCUSSION: These findings suggest that capillary dysfunction can be detected at the preclinical stage of AD and indicates a worsening of capillary dysfunction throughout the AD continuum. Understanding the interaction between capillary dysfunction and Aß could provide insights into the relationship between cardiovascular risk factors and the development of AD. HIGHLIGHTS: Alzheimer's disease (AD) is associated with disturbances in microvascular circulation. Capillary dysfunction can be detected in preclinical AD. As cognitive symptoms progress in prodromal AD, capillary dysfunction worsens. Capillary dysfunction may impede the clearance of beta-amyloid (Aß). Capillary dysfunction might contribute to the development of AD.

Deletion of aquaporin-4 improves capillary blood flow distribution in brain edema.

Brain edema is a feared complication to disorders and insults affecting the brain. It can be fatal if the increase in intracranial pressure is sufficiently large to cause brain herniation. Moreover, accruing evidence suggests that even slight elevations of intracranial pressure have adverse effects, for instance on brain perfusion. The water channel aquaporin-4 (AQP4), densely expressed in perivascular astrocytic endfeet, plays a key role in brain edema formation. Using two-photon microscopy, we have studied AQP4-mediated swelling of astrocytes affects capillary blood flow and intracranial pressure (ICP) in unanesthetized mice using a mild brain edema model. We found improved regulation of capillary blood flow in mice devoid of AQP4, independently of the severity of ICP increase. Furthermore, we found brisk AQP4-dependent astrocytic Ca2+ signals in perivascular endfeet during edema that may play a role in the perturbed capillary blood flow dynamics. The study suggests that astrocytic endfoot swelling and pathological signaling disrupts microvascular flow regulation during brain edema formation.

Tensor denoising of multidimensional MRI data.

PURPOSE: To develop a denoising strategy leveraging redundancy in high-dimensional data. THEORY AND METHODS: The SNR fundamentally limits the information accessible by MRI. This limitation has been addressed by a host of denoising techniques, recently including the so-called MPPCA: principal component analysis of the signal followed by automated rank estimation, exploiting the Marchenko-Pastur distribution of noise singular values. Operating on matrices comprised of data patches, this popular approach objectively identifies noise components and, ideally, allows noise to be removed without introducing artifacts such as image blurring, or nonlocal averaging. The MPPCA rank estimation, however, relies on a large number of noise singular values relative to the number of signal components to avoid such ill effects. This condition is unlikely to be met when data patches and therefore matrices are small, for example due to spatially varying noise. Here, we introduce tensor MPPCA (tMPPCA) for the purpose of denoising multidimensional data, such as from multicontrast acquisitions. Rather than combining dimensions in matrices, tMPPCA uses each dimension of the multidimensional data's inherent tensor-structure to better characterize noise, and to recursively estimate signal components. RESULTS: Relative to matrix-based MPPCA, tMPPCA requires no additional assumptions, and comparing the two in a numerical phantom and a multi-TE diffusion MRI data set, tMPPCA dramatically improves denoising performance. This is particularly true for small data patches, suggesting that tMPPCA can be especially beneficial in such cases. CONCLUSIONS: The MPPCA denoising technique can be extended to high-dimensional data with improved performance for smaller patch sizes.

Anesthesia-related brain microstructure modulations detected by diffusion magnetic resonance imaging.

Recent studies have shown significant changes to brain microstructure during sleep and anesthesia. In vivo optical microscopy and magnetic resonance imaging (MRI) studies have attributed these changes to anesthesia and sleep-related modulation of the brain's extracellular space (ECS). Isoflurane anesthesia is widely used in preclinical diffusion MRI (dMRI) and it is therefore important to investigate if the brain's microstructure is affected by anesthesia to an extent detectable with dMRI. Here, we employ diffusion kurtosis imaging (DKI) to assess brain microstructure in the awake and anesthetized mouse brain (n = 22). We find both mean diffusivity (MD) and mean kurtosis (MK) to be significantly decreased in the anesthetized mouse brain compared with the awake state (p < 0.001 for both). This effect is observed in both gray matter and white matter. To further investigate the time course of these changes we introduce a method for time-resolved fast DKI. With this, we show the time course of the microstructural alterations in mice (n = 5) as they transition between states in an awake-anesthesia-awake paradigm. We find that the decrease in MD and MK occurs rapidly after delivery of gas isoflurane anesthesia and that values normalize only slowly when the animals return to the awake state. Finally, time-resolved fast DKI is employed in an experimental mouse model of brain edema (n = 4), where cell swelling causes the ECS volume to decrease. Our results show that isoflurane affects DKI parameters and metrics of brain microstructure and point to isoflurane causing a reduction in the ECS volume. The demonstrated DKI methods are suitable for in-bore perturbation studies, for example, for investigating microstructural modulations related to sleep/wake-dependent functions of the glymphatic system. Importantly, our study shows an effect of isoflurane anesthesia on rodent brain microstructure that has broad relevance to preclinical dMRI.

FDA-approved carbonic anhydrase inhibitors reduce amyloid ß pathology and improve cognition, by ameliorating cerebrovascular health and glial fitness.

INTRODUCTION: Cerebrovascular pathology is an early and causal hallmark of Alzheimer's disease (AD), in need of effective therapies. METHODS: Based on the success of our previous in vitro studies, we tested for the first time in a model of AD and cerebral amyloid angiopathy (CAA), the carbonic anhydrase inhibitors (CAIs) methazolamide and acetazolamide, Food and Drug Administration-approved against glaucoma and high-altitude sickness. RESULTS: Both CAIs reduced cerebral, vascular, and glial amyloid beta (Aß) accumulation and caspase activation, diminished gliosis, and ameliorated cognition in TgSwDI mice. The CAIs also improved microvascular fitness and induced protective glial pro-clearance pathways, resulting in the reduction of Aß deposition. Notably, we unveiled that the mitochondrial carbonic anhydrase-VB (CA-VB) is upregulated in TgSwDI brains, CAA and AD+CAA human subjects, and in endothelial cells upon Aß treatment. Strikingly, CA-VB silencing specifically reduces Aß-mediated endothelial apoptosis. DISCUSSION: This work substantiates the potential application of CAIs in clinical trials for AD and CAA.

Diffusion time dependence, power-law scaling, and exchange in gray matter.

Characterizing neural tissue microstructure is a critical goal for future neuroimaging. Diffusion MRI (dMRI) provides contrasts that reflect diffusing spins' interactions with myriad microstructural features of biological systems. However, the specificity of dMRI remains limited due to the ambiguity of its signals vis-à-vis the underlying microstructure. To improve specificity, biophysical models of white matter (WM) typically express dMRI signals according to the Standard Model (SM) and have more recently in gray matter (GM) taken spherical compartments into account (the SANDI model) in attempts to represent cell soma. The validity of the assumptions underlying these models, however, remains largely undetermined, especially in GM. To validate these assumptions experimentally, observing their unique, functional properties, such as the b-1/2 power-law associated with one-dimensional diffusion, has emerged as a fruitful strategy. The absence of this signature in GM, in turn, has been explained by neurite water exchange, non-linear morphology, and/or by obscuring soma signal contributions. Here, we present diffusion simulations in realistic neurons demonstrating that curvature and branching does not destroy the stick power-law behavior in impermeable neurites, but also that their signal is drowned by the soma signal under typical experimental conditions. Nevertheless, by studying the GM dMRI signal's behavior as a function of diffusion weighting as well as time, we identify an attainable experimental regime in which the neurite signal dominates. Furthermore, we find that exchange-driven time dependence produces a signal behavior opposite to that which would be expected from restricted diffusion, thereby providing a functional signature that disambiguates the two effects. We present data from dMRI experiments in ex vivo rat brain at ultrahigh field of 16.4T and observe a time dependence that is consistent with substantial exchange but also with a GM stick power-law. The first finding suggests significant water exchange between neurites and the extracellular space while the second suggests a small sub-population of impermeable neurites. To quantify these observations, we harness the Kärger exchange model and incorporate the corresponding signal time dependence in the SM and SANDI models.

Impaired cerebral microcirculation in isolated REM sleep behaviour disorder.

During the prodromal period of Parkinson's disease and other α-synucleinopathy-related parkinsonisms, neurodegeneration is thought to progressively affect deep brain nuclei, such as the locus coeruleus, caudal raphe nucleus, substantia nigra, and the forebrain nucleus basalis of Meynert. Besides their involvement in the regulation of mood, sleep, behaviour, and memory functions, these nuclei also innervate parenchymal arterioles and capillaries throughout the cortex, possibly to ensure that oxygen supplies are adjusted according to the needs of neural activity. The aim of this study was to examine whether patients with isolated REM sleep behaviour disorder, a parasomnia considered to be a prodromal phenotype of α-synucleinopathies, reveal microvascular flow disturbances consistent with disrupted central blood flow control. We applied dynamic susceptibility contrast MRI to characterize the microscopic distribution of cerebral blood flow in the cortex of 20 polysomnographic-confirmed patients with isolated REM sleep behaviour disorder (17 males, age range: 54-77 years) and 25 healthy matched controls (25 males, age range: 58-76 years). Patients and controls were cognitively tested by Montreal Cognitive Assessment and Mini Mental State Examination. Results revealed profound hypoperfusion and microvascular flow disturbances throughout the cortex in patients compared to controls. In patients, the microvascular flow disturbances were seen in cortical areas associated with language comprehension, visual processing and recognition and were associated with impaired cognitive performance. We conclude that cortical blood flow abnormalities, possibly related to impaired neurogenic control, are present in patients with isolated REM sleep behaviour disorder and associated with cognitive dysfunction. We hypothesize that pharmacological restoration of perivascular neurotransmitter levels could help maintain cognitive function in patients with this prodromal phenotype of parkinsonism.

The Ambibaric Brain: Pathophysiological and Clinical Implications.

We propose a new evolutionary interpretation of the brain's circulation that has physiological, pathophysiological, and clinical implications. We review the evidence for the concept, discuss clinical implications, and suggest techniques to address outstanding questions. We conclude that the brain circulation contains complementary low-pressure and high-pressure system that must be kept in balance for optimal brain health.

Beyond the diffusion standard model in fixed rat spinal cord with combined linear and planar encoding.

Information about tissue on the microscopic and mesoscopic scales can be accessed by modelling diffusion MRI signals, with the aim of extracting microstructure-specific biomarkers. The standard model (SM) of diffusion, currently the most broadly adopted microstructural model, describes diffusion in white matter (WM) tissues by two Gaussian components, one of which has zero radial diffusivity, to represent diffusion in intra- and extra-axonal water, respectively. Here, we reappraise these SM assumptions by collecting comprehensive double diffusion encoded (DDE) MRI data with both linear and planar encodings, which was recently shown to substantially enhance the ability to estimate SM parameters. We find however, that the SM is unable to account for data recorded in fixed rat spinal cord at an ultrahigh field of 16.4 T, suggesting that its underlying assumptions are violated in our experimental data. We offer three model extensions to mitigate this problem: first, we generalize the SM to accommodate finite radii (axons) by releasing the constraint of zero radial diffusivity in the intra-axonal compartment. Second, we include intracompartmental kurtosis to account for non-Gaussian behaviour. Third, we introduce an additional (third) compartment. The ability of these models to account for our experimental data are compared based on parameter feasibility and Bayesian information criterion. Our analysis identifies the three-compartment description as the optimal model. The third compartment exhibits slow diffusion with a minor but non-negligible signal fraction (∼12%). We demonstrate how failure to take the presence of such a compartment into account severely misguides inferences about WM microstructure. Our findings bear significance for microstructural modelling at large and can impact the interpretation of biomarkers extracted from the standard model of diffusion.

Microstructural changes in the brain after long-term post-concussion symptoms: A randomized trial.

A recent randomized controlled trial in young patients with long-term post-concussion symptoms showed that a novel behavioral intervention "Get going After concussIoN" is superior to enhanced usual care in terms of symptom reduction. It is unknown whether these interventional effects are associated with microstructural brain changes. The aim of this study was to examine whether diffusion-weighted MRI indices, which are sensitive to the interactions between cellular structures and water molecules' Brownian motion, respond differently to the interventions of the above-mentioned trial and whether such differences correlate with the improvement of post-concussion symptoms. Twenty-three patients from the intervention group (mean age 22.8, 18 females) and 19 patients from the control group (enhanced usual care) (mean age 23.9, 14 females) were enrolled. The primary outcome measure was the mean kurtosis tensor, which is sensitive to the microscopic complexity of brain tissue. The mean kurtosis tensor was significantly increased in the intervention group (p = 0.003) in the corpus callosum but not in the thalamus (p = 0.78) and the hippocampus (p = 0.34). An increase in mean kurtosis tensor in the corpus callosum tended to be associated with a reduction in symptoms, but this association did not reach significance (p = 0.059). Changes in diffusion tensor imaging metrics did not differ between intervention groups and were not associated with symptoms. The current study found different diffusion-weighted MRI responses from the microscopic cellular structures of the corpus callosum between patients receiving a novel behavioral intervention and patients receiving enhanced usual care. Correlations with improvement of post-concussion symptoms were not evident.

Cerebral Macro- and Microcirculation during Ephedrine versus Phenylephrine Treatment in Anesthetized Brain Tumor Patients: A Randomized Clinical Trial Using Magnetic Resonance Imaging.

BACKGROUND: This study compared ephedrine versus phenylephrine treatment on cerebral macro- and microcirculation, measured by cerebral blood flow, and capillary transit time heterogeneity, in anesthetized brain tumor patients. The hypothesis was that capillary transit time heterogeneity in selected brain regions is greater during phenylephrine than during ephedrine, thus reducing cerebral oxygen tension. METHODS: In this single-center, double-blinded, randomized clinical trial, 24 anesthetized brain tumor patients were randomly assigned to ephedrine or phenylephrine. Magnetic resonance imaging of peritumoral and contralateral hemispheres was performed before and during vasopressor infusion. The primary endpoint was between-group difference in capillary transit time heterogeneity. Secondary endpoints included changes in cerebral blood flow, estimated oxygen extraction fraction, and brain tissue oxygen tension. RESULTS: Data from 20 patients showed that mean (± SD) capillary transit time heterogeneity in the contralateral hemisphere increased during phenylephrine from 3.0 ± 0.5 to 3.2 ± 0.7 s and decreased during ephedrine from 3.1 ± 0.8 to 2.7 ± 0.7 s (difference phenylephrine versus difference ephedrine [95% CI], -0.6 [-0.9 to -0.2] s; P = 0.004). In the peritumoral region, the mean capillary transit time heterogeneity increased during phenylephrine from 4.1 ± 0.7 to 4.3 ± 0.8 s and decreased during ephedrine from 3.5 ± 0.9 to 3.3 ± 0.9 s (difference phenylephrine versus difference ephedrine [95%CI], -0.4[-0.9 to 0.1] s; P = 0.130). Cerebral blood flow (contralateral hemisphere ratio difference [95% CI], 0.3 [0.06 to 0.54]; P = 0.018; and peritumoral ratio difference [95% CI], 0.3 [0.06 to 0.54; P = 0.018) and estimated brain tissue oxygen tension (contralateral hemisphere ratio difference [95% CI], 0.34 [0.09 to 0.59]; P = 0.001; and peritumoral ratio difference [95% CI], 0.33 [0.09 to 0.57]; P = 0.010) were greater during ephedrine than phenylephrine in both regions. CONCLUSIONS: Phenylephrine caused microcirculation in contralateral tissue, measured by the change in capillary transit time heterogeneity, to deteriorate compared with ephedrine, despite reaching similar mean arterial pressure endpoints. Ephedrine improved cerebral blood flow and tissue oxygenation in both brain regions and may be superior to phenylephrine in improving cerebral macro- and microscopic hemodynamics and oxygenation.

August Krogh's theory of muscle microvascular control and oxygen delivery: a paradigm shift based on new data.

August Krogh twice won the prestigious international Steegen Prize, for nitrogen metabolism (1906) and overturning the concept of active transport of gases across the pulmonary epithelium (1910). Despite this, at the beginning of 1920, the consummate experimentalist was relatively unknown worldwide and even among his own University of Copenhagen faculty. But, in early 1919, he had submitted three papers to Dr Langley, then editor of The Journal of Physiology in England. These papers coalesced anatomical observations of skeletal muscle capillary numbers with O2 diffusion theory to propose a novel active role for capillaries that explained the prodigious increase in blood-muscle O2 flux from rest to exercise. Despite his own appraisal of the first two papers as "rather dull" to his friend, the eminent Cambridge respiratory physiologist, Joseph Barcroft, Krogh believed that the third one, dealing with O2 supply and capillary regulation, was"interesting". These papers, which won Krogh an unopposed Nobel Prize for Physiology or Medicine in 1920, form the foundation for this review. They single-handedly transformed the role of capillaries from passive conduit and exchange vessels, functioning at the mercy of their upstream arterioles, into independent contractile units that were predominantly closed at rest and opened actively during muscle contractions in a process he termed 'capillary recruitment'. Herein we examine Krogh's findings and some of the experimental difficulties he faced. In particular, the boundary conditions selected for his model (e.g. heavily anaesthetized animals, negligible intramyocyte O2 partial pressure, binary open-closed capillary function) have not withstood the test of time. Subsequently, we update the reader with intervening discoveries that underpin our current understanding of muscle microcirculatory control and place a retrospectroscope on Krogh's discoveries. The perspective is presented that the imprimatur of the Nobel Prize, in this instance, may have led scientists to discount compelling evidence. Much as he and Marie Krogh demonstrated that active transport of gases across the blood-gas barrier was unnecessary in the lung, capillaries in skeletal muscle do not open and close spontaneously or actively, nor is this necessary to account for the increase in blood-muscle O2 flux during exercise. Thus, a contemporary model of capillary function features most muscle capillaries supporting blood flow at rest, and, rather than capillaries actively vasodilating from rest to exercise, increased blood-myocyte O2 flux occurs predominantly via elevating red blood cell and plasma flux in already flowing capillaries. Krogh is lauded for his brilliance as an experimentalist and for raising scientific questions that led to fertile avenues of investigation, including the study of microvascular function.

Theophylline as an Add-On to Thrombolytic Therapy in Acute Ischemic Stroke: A Randomized Placebo-Controlled Trial.

BACKGROUND AND PURPOSE: Delayed recanalization increases the risk of infarct growth and poor clinical outcome in acute ischemic stroke. The vasoactive agent theophylline has shown neuroprotective effects in animal stroke models but inconclusive results in case series and randomized clinical trials. The primary objective of this study was to evaluate whether theophylline, as an add-on to thrombolytic therapy, is safe and effective in acute ischemic stroke patients. METHODS: The TEA-Stroke trial (The Theophylline in Acute Ischemic Stroke) was an investigator-initiated 2-center, proof-of-concept, phase II clinical study with a randomized, double-blinded, placebo-controlled design. The main inclusion criteria were magnetic resonance imaging-verified acute ischemic stroke, moderate to severe neurological deficit (National Institutes of Health Stroke Scale score of ≥4), and treatment with thrombolysis within 4.5 hours of onset. Participants were randomly assigned in the ratio 1:1 to either 220 mg of intravenous theophylline or placebo. The co-primary outcomes were early clinical improvement on the National Institutes of Health Stroke Scale score and infarct growth on magnetic resonance imaging at 24-hour follow-up. RESULTS: Theophylline as an add-on to thrombolytic therapy improved the National Institutes of Health Stroke Scale score at 24 hours by mean 4.7 points (SD, 5.6) compared with an improvement of 1.3 points (SD, 7.5) in the control group (P=0.044). Mean infarct growth was 141.6% (SD, 126.5) and 104.1% (SD, 62.5) in the theophylline and control groups, respectively (P=0.146). Functional independence at 90 days was 61% in the theophylline group and 58% in the control group (P=0.802). CONCLUSIONS: This proof-of-concept trial investigated theophylline administration as an add-on to thrombolytic therapy in acute ischemic stroke. The co-primary end points early clinical improvement and infarct growth at 24-hour follow-up were not significantly different after post hoc correction for multiplicity (Bonferroni technique). The small study size precludes a conclusion as to whether theophylline has a neuroprotective effect but provides a promising clinical signal that may support a future clinical trial. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: EudraCT number 2013-001989-42.

Krogh's capillary recruitment hypothesis, 100 years on: Is the opening of previously closed capillaries necessary to ensure muscle oxygenation during exercise?

In 1919, August Krogh published his seminal work on skeletal muscle oxygenation. Krogh's observations indicated that muscle capillary diameter is actively regulated, rather than a passive result of arterial blood flow regulation. Indeed, combining a mathematical model with the number of ink-filled capillaries he observed in muscle cross sections taken at different workloads, Krogh was able to account for muscle tissue's remarkably efficient oxygen extraction during exercise in terms of passive diffusion from nearby capillaries. Krogh was awarded the 1920 Nobel Prize for his account of muscle oxygenation. Today, his observations are engrained in the notion of capillary recruitment: the opening of previously closed capillaries. While the binary distinction between "closed" and "open" was key to Krogh's model argument, he did in fact report a continuum of capillary diameters, degrees of erythrocyte deformation, and perfusion states. Indeed, modern observations question the presence of closed muscle capillaries. We therefore examined whether changes in capillary flow patterns and hematocrit among open capillaries can account for oxygen extraction in muscle across orders-of-magnitude changes in blood flow. Our four-compartment model of oxygen extraction in muscle confirms this notion and provides a framework for quantifying the impact of changes in microvascular function on muscle oxygenation in health and disease. Our results underscore the importance of capillary function for oxygen extraction in muscle tissue as first proposed by Krogh. While Krogh's model calculations still hold, our model predictions support that capillary recruitment can be viewed in the context of continuous, rather than binary, erythrocyte distributions among capillaries.NEW & NOTEWORTHY Oxygen extraction in working muscle is extremely efficient in view of single capillaries properties. The underlying mechanisms have been widely debated. Here, we develop a four-compartment model to quantify the influence of each of the hypothesized mechanisms on muscle oxygenation. Our results show that changes in capillary flow pattern and hematocrit can account for the high oxygen extraction observed in working muscle, while capillary recruitment is not required to account for these extraction properties.

Noninvasive Characterization of Tumor Angiogenesis and Oxygenation in Bevacizumab-treated Recurrent Glioblastoma by Using Dynamic Susceptibility MRI: Secondary Analysis of the European Organization for Research and Treatment of Cancer 26101 Trial.

Background Relevance of antiangiogenic treatment with bevacizumab in patients with glioblastoma is controversial because progression-free survival benefit did not translate into an overall survival (OS) benefit in randomized phase III trials. Purpose To perform longitudinal characterization of intratumoral angiogenesis and oxygenation by using dynamic susceptibility contrast agent-enhanced (DSC) MRI and evaluate its potential for predicting outcome from administration of bevacizumab. Materials and Methods In this secondary analysis of the prospective randomized phase II/III European Organization for Research and Treatment of Cancer 26101 trial conducted between October 2011 and December 2015 in 596 patients with first recurrence of glioblastoma, the subset of patients with availability of anatomic MRI and DSC MRI at baseline and first follow-up was analyzed. Patients were allocated into those administered bevacizumab (hereafter, the BEV group; either bevacizumab monotherapy or bevacizumab with lomustine) and those not administered bevacizumab (hereafter, the non-BEV group with lomustine monotherapy). Contrast-enhanced tumor volume, noncontrast-enhanced T2 fluid-attenuated inversion recovery (FLAIR) signal abnormality volume, Gaussian-normalized relative cerebral blood volume (nrCBV), Gaussian-normalized relative blood flow (nrCBF), and tumor metabolic rate of oxygen (nTMRO2) was quantified. The predictive ability of these imaging parameters was assessed with multivariable Cox regression and formal interaction testing. Results A total of 254 of 596 patients were evaluated (mean age, 57 years ± 11; 155 men; 161 in the BEV group and 93 in non-BEV group). Progression-free survival was longer in the BEV group (3.7 months; 95% confidence interval [CI]: 3.0, 4.2) compared with the non-BEV group (2.5 months; 95% CI: 1.5, 2.9; P = .01), whereas OS was not different (P = .15). The nrCBV decreased for the BEV group (-16.3%; interquartile range [IQR], -39.5% to 12.0%; P = .01), but not for the non-BEV group (1.2%; IQR, -17.9% to 23.3%; P = .19) between baseline and first follow-up. An identical pattern was observed for both nrCBF and nTMRO2 values. Contrast-enhanced tumor and noncontrast-enhanced T2 FLAIR signal abnormality volumes decreased for the BEV group (-66% [IQR, -83% to -35%] and -33% [IQR, -71% to -5%], respectively; P < .001 for both), whereas they increased for the non-BEV group (30% [IQR, -17% to 98%], P = .001; and 10% [IQR, -13% to 82%], P = .02, respectively) between baseline and first follow-up. None of the assessed MRI parameters were predictive for OS in the BEV group. Conclusion Bevacizumab treatment decreased tumor volumes, angiogenesis, and oxygenation, thereby reflecting its effectiveness for extending progression-free survival; however, these parameters were not predictive of overall survival (OS), which highlighted the challenges of identifying patients that derive an OS benefit from bevacizumab. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Dillon in this issue.

Ephedrine versus Phenylephrine Effect on Cerebral Blood Flow and Oxygen Consumption in Anesthetized Brain Tumor Patients: A Randomized Clinical Trial.

BACKGROUND: Studies in anesthetized patients suggest that phenylephrine reduces regional cerebral oxygen saturation compared with ephedrine. The present study aimed to quantify the effects of phenylephrine and ephedrine on cerebral blood flow and cerebral metabolic rate of oxygen in brain tumor patients. The authors hypothesized that phenylephrine reduces cerebral metabolic rate of oxygen in selected brain regions compared with ephedrine. METHODS: In this double-blinded, randomized clinical trial, 24 anesthetized patients with brain tumors were randomly assigned to ephedrine or phenylephrine treatment. Positron emission tomography measurements of cerebral blood flow and cerebral metabolic rate of oxygen in peritumoral and normal contralateral regions were performed before and during vasopressor infusion. The primary endpoint was between-group difference in cerebral metabolic rate of oxygen. Secondary endpoints included changes in cerebral blood flow, oxygen extraction fraction, and regional cerebral oxygen saturation. RESULTS: Peritumoral mean ± SD cerebral metabolic rate of oxygen values before and after vasopressor (ephedrine, 67.0 ± 11.3 and 67.8 ± 25.7 µmol · 100 g · min; phenylephrine, 68.2 ± 15.2 and 67.6 ± 18.0 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 1.5 [-13.3 to 16.3] µmol · 100 g · min [P = 0.839]). Corresponding contralateral hemisphere cerebral metabolic rate of oxygen values (ephedrine, 90.8 ± 15.9 and 94.6 ± 16.9 µmol · 100 g · min; phenylephrine, 100.8 ± 20.7 and 96.4 ± 17.7 µmol · 100 g · min) showed no intergroup difference (difference [95% CI], 8.2 [-2.0 to 18.5] µmol · 100 g · min [P = 0.118]). Ephedrine significantly increased cerebral blood flow (difference [95% CI], 3.9 [0.7 to 7.0] ml · 100 g · min [P = 0.019]) and regional cerebral oxygen saturation (difference [95% CI], 4 [1 to 8]% [P = 0.024]) in the contralateral hemisphere compared to phenylephrine. The change in oxygen extraction fraction in both regions (peritumoral difference [95% CI], -0.6 [-14.7 to 13.6]% [P = 0.934]; contralateral hemisphere difference [95% CI], -0.1 [- 12.1 to 12.0]% [P = 0.989]) were comparable between groups. CONCLUSIONS: The cerebral metabolic rate of oxygen changes in peritumoral and normal contralateral regions were similar between ephedrine- and phenylephrine-treated patients. In the normal contralateral region, ephedrine was associated with an increase in cerebral blood flow and regional cerebral oxygen saturation compared with phenylephrine.

The evidence for the physiological effects of lactate on the cerebral microcirculation: a systematic review.

Lactate's role in the brain is understood as a contributor to brain energy metabolism, but it may also regulate the cerebral microcirculation. The purpose of this systematic review was to evaluate evidence of lactate as a physiological effector within the normal cerebral microcirculation in reports ranging from in vitro experiments to in vivo studies in animals and humans. Following pre-registration of a review protocol, we systematically searched the PubMed, EMBASE, and Cochrane databases for literature covering themes of 'lactate', 'the brain', and 'microcirculation'. Abstracts were screened, and data extracted independently by two individuals. We excluded studies evaluating lactate in disease models. Twenty-eight papers were identified, 18 of which were in vivo animal experiments (65%), four on human studies (14%), and six on in vitro or ex vivo experiments (21%). Approximately half of the papers identified lactate as an augmenter of the hyperemic response to functional activation by a visual stimulus or as an instigator of hyperemia in a dose-dependent manner, without external stimulation. The mechanisms are likely to be coupled to NAD+ /NADH redox state influencing the production of nitric oxide. Unfortunately, only 38% of these studies demonstrated any control for bias, which makes reliable generalizations of the conclusions insecure. This systematic review identifies that lactate may act as a dose-dependent regulator of cerebral microcirculation by augmenting the hyperemic response to functional activation below 5 mmol/kg, and by initiating a hyperemic response above 5 mmol/kg. OPEN SCIENCE BADGES: This article has received a badge for *Pre-registration* because it made the data publicly available. The data can be accessed at www.radboudumc.nl/getmedia/53625326-d1df-432c-980f-27c7c80d1a90/THollyer_lactate_protocol.aspx. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Individualized quantification of the benefit from reperfusion therapy using stroke predictive models.

PURPOSE: Recent imaging developments have shown the potential of voxel-based models in assessing infarct growth after stroke. Many models have been proposed but their relevance in predicting the benefit of a reperfusion therapy remains unclear. We searched for a predictive model whose volumetric predictions would identify stroke patients who are to benefit from tissue plasminogen activator (t-PA)-induced reperfusion. MATERIAL AND METHODS: Forty-five cases were used to study retrospectively stroke progression from admission to end of follow-up. Predictive approaches based on various statistical models, predictive variables and spatial filtering methods were compared. The optimal approach was chosen according to the area under the precision-recall curve (AUPRC). The final lesion volume was then predicted assuming that the patient would or would not reperfuse. Patients, with an acute lesion of ≤50 ml and a predicted reduction in the presence of reperfusion >6 ml and >25% of the acute lesion, were classified as responders. RESULTS: The optimal model was a logistic regression using the voxel distance to the acute lesion, the volume of the acute lesion and Gaussian-filtered MRI contrast parameters as predictive variables. The predictions gave a median AUPRC of 0.655, a median AUC of 0.976 and a median volumetric error of 8.29 ml. Nineteen patients matched the responder profile. A non-significant trend of improved reduction in NIHSS score (-42.8%, p = .09) and in lesion volume (-78.1%, p = 0.21) following reperfusion was observed for responder patients. CONCLUSION: Despite limited volumetric accuracy, predictive stroke models can be used to quantify the benefit of reperfusion therapies.