Journal: J Cereb Blood Flow Metab

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Abstract

Measurement of CMRO and its relationship with CBF in hypoxia with an extended calibrated BOLD method.

Zhang Y, Yin Y, Li H, Gao JH

Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO) are physiological parameters that not only reflect brain health and disease but also jointly contribute to blood oxygen level-dependent (BOLD) signals. Nevertheless, unsolved issues remain concerning the CBF-CMRO relationship in the working brain under various oxygen conditions. In particular, the CMRO responses to functional tasks in hypoxia are less studied. We extended the calibrated BOLD model to incorporate CMRO measurements in hypoxia. The extended model, which was cross-validated with a multicompartment BOLD model, considers the influences of the reduced arterial saturation level and increased baseline cerebral blood volume (CBV) and deoxyhemoglobin concentration on the changes of BOLD signals in hypoxia. By implementing a pulse sequence to simultaneously acquire the CBV-, CBF- and BOLD-weighted signals, we investigated the effects of mild hypoxia on the CBF and CMRO responses to graded visual stimuli. Compared with normoxia, mild hypoxia caused significant alterations in both the amplitude and the trend of the CMRO responses but did not impact the corresponding CBF responses. Our observations suggested that the flow-metabolism coupling strategies in the brain during mild hypoxia were different from those during normoxia.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2066-2080
Zhang Y, Yin Y, Li H, Gao JH
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2066-2080 | PMID: 31665954
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Abstract

Validation of diffuse correlation spectroscopy against O-water PET for regional cerebral blood flow measurement in neonatal piglets.

Giovannella M, Andresen B, Andersen JB, El-Mahdaoui S, ... Weigel UM, Law I

Diffuse correlation spectroscopy (DCS) can non-invasively and continuously asses regional cerebral blood flow (rCBF) at the cot-side by measuring a blood flow index (BFI) in non-traditional units of cm/s. We have validated DCS against positron emission tomography using O-labeled water (O-water PET) in a piglet model allowing us to derive a conversion formula for BFI to rCBF in conventional units (ml/100g/min). Neonatal piglets were continuously monitored by the BabyLux device integrating DCS and time resolved near infrared spectroscopy (TRS) while acquiring O-water PET scans at baseline, after injection of acetazolamide and during induced hypoxic episodes. BFI by DCS was highly correlated with rCBF (R = 0.94,  < 0.001) by PET. A scaling factor of 0.89 (limits of agreement for individual measurement: 0.56, 1.39)×10× (ml/100g/min)/(cm/s) was used to derive baseline rCBF from baseline BFI measurements of another group of piglets and of healthy newborn infants showing an agreement with expected values. These results pave the way towards non-invasive, cot-side absolute CBF measurements by DCS on neonates.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2055-2065
Giovannella M, Andresen B, Andersen JB, El-Mahdaoui S, ... Weigel UM, Law I
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2055-2065 | PMID: 31665953
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Abstract

Circulating tPA contributes to neurovascular coupling by a mechanism involving the endothelial NMDA receptors.

Anfray A, Drieu A, Hingot V, Hommet Y, ... Orset C, Vivien D

The increase of cerebral blood flow evoked by neuronal activity is essential to ensure enough energy supply to the brain. In the neurovascular unit, endothelial cells are ideally placed to regulate key neurovascular functions of the brain. Nevertheless, some outstanding questions remain about their exact role neurovascular coupling (NVC). Here, we postulated that the tissue-type plasminogen activator (tPA) present in the circulation might contribute to NVC by a mechanism dependent of its interaction with endothelial N-Methyl-D-Aspartate Receptor (NMDAR). To address this question, we used pharmacological and genetic approaches to interfere with vascular tPA-dependent NMDAR signaling, combined with laser speckle flowmetry, intravital microscopy and ultrafast functional ultrasound in vivo imaging. We found that the tPA present in the blood circulation is capable of potentiating the cerebral blood flow increase induced by the activation of the mouse somatosensorial cortex, and that this effect is mediated by a tPA-dependent activation of NMDAR expressed at the luminal part of endothelial cells of arteries. Although blood molecules, such as acetylcholine, bradykinin or ATP are known to regulate vascular tone and induce vessel dilation, our present data provide the first evidence that circulating tPA is capable of influencing neurovascular coupling (NVC).



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2038-2054
Anfray A, Drieu A, Hingot V, Hommet Y, ... Orset C, Vivien D
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2038-2054 | PMID: 31665952
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Abstract

Hyaluronidase reduced edema after experimental traumatic brain injury.

Washington PM, Lee C, Dwyer MKR, Konofagou EE, Kernie SG, Morrison B

Cerebral edema and the subsequent increased intracranial pressure are associated with mortality and poor outcome following traumatic brain injury. Previous in vitro studies have shown that the Gibbs-Donnan effect, which describes the tendency of a porous, negatively charged matrix to attract positive ions and water, applies to brain tissue and that enzymatic reduction of the fixed charge density can prevent tissue swelling. We tested whether hyaluronidase, an enzyme that degrades the large, negatively charged glycosaminoglycan hyaluronan, could reduce brain edema after traumatic brain injury. In vivo, intracerebroventricular injection of hyaluronidase after controlled cortical impact in mice reduced edema in the ipsilateral hippocampus at 24 h by both the wet-weight/dry-weight method (78.15 ± 0.65% vs. 80.4 ± 0.46%; p < 0.01) and T-weighted magnetic resonance imaging (13.88 ± 3.09% vs. 29.23 ± 6.14%; p < 0.01). Hyaluronidase did not adversely affect blood-brain-barrier-integrity measured by dynamic contrast-enhanced magnetic resonance imaging, nor did hyaluronidase negatively affect functional recovery after controlled cortical impact measured with the rotarod or Morris water maze tasks. Reduction of fixed charge density by hyaluronidase was confirmed in cortical explants in vitro (5.46 ± 1.15 µg/mg vs. 7.76 ± 1.87 µg/mg; p < 0.05). These data demonstrate that targeting the fixed charge density with hyaluronidase reduced edema in an in vivo mouse model of traumatic brain injury.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2026-2037
Washington PM, Lee C, Dwyer MKR, Konofagou EE, Kernie SG, Morrison B
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2026-2037 | PMID: 31648593
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Abstract

Modification of oxygen consumption and blood flow in mouse somatosensory cortex by cell-type-specific neuronal activity.

Dahlqvist MK, Thomsen KJ, Postnov DD, Lauritzen MJ

Gamma activity arising from the interplay between pyramidal neurons and fast-spiking parvalbumin (PV) interneurons is an integral part of higher cognitive functions and is assumed to contribute significantly to brain metabolic responses. Cerebral metabolic rate of oxygen (CMRO) responses were evoked by optogenetic stimulation of cortical PV interneurons and pyramidal neurons. We found that CMRO responses depended on neuronal activation, but not on the power of gamma activity induced by optogenetic stimulation. This implies that evoked gamma activity per se is not energy demanding. Optogenetic stimulation of PV interneurons during somatosensory stimulation reduced excitatory neuronal activity but did not potentiate O consumption as previously hypothesized. In conclusion, our data suggest that activity-driven CMRO responses depend on neuronal excitation rather than the cerebral rhythmic activity they induce. Excitation of both excitatory and inhibitory neurons requires energy, but inhibition of cortical excitatory neurons by interneurons does not potentiate activity-driven energy consumption.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2010-2025
Dahlqvist MK, Thomsen KJ, Postnov DD, Lauritzen MJ
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2010-2025 | PMID: 31645177
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Abstract

Early-stage C-Flumazenil PET predicts day-14 selective neuronal loss in a rodent model of transient focal cerebral ischemia.

Hughes JL, Beech JS, Jones PS, Wang D, ... Fryer TD, Baron JC

Predicting tissue outcome early after stroke is an important goal. MRI >3 h accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Previous studies suggest that chronic-stage C-flumazenil PET (FMZ-PET) is a validated marker of SNL in rats, while early-stage FMZ-PET may predict infarction. Whether early FMZ-PET also predicts SNL is unknown. Following 45-min distal MCA occlusion, adult rats underwent FMZ-PET at 1 h and 48 h post-reperfusion to map distribution volume (V), which reflects GABA- receptor binding. NeuN immunohistochemistry was performed at Day 14. In each rat, V and %NeuN loss were determined in 44 ROIs spanning the hemisphere. NeuN revealed isolated SNL and cortical infarction in five and one rats, respectively. In the SNL subgroup, V-1 h was mildly reduced and only weakly predicted SNL, while V-48 h was significantly increased and predicted SNL both individually ( < 0.01, Kendall) and across the group ( < 0.001), i.e. the higher the V, the stronger the SNL. Similar correlations were found in the rat with infarction. Our findings suggest GABA- receptors are still present on injured neurons at the 48 h timepoint, and the increased 48 h V observed here is consistent with earlier rat studies showing early GABA- receptor upregulation. That FMZ binding at 48 h was predictive of SNL may have clinical implications.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:1997-2009
Hughes JL, Beech JS, Jones PS, Wang D, ... Fryer TD, Baron JC
J Cereb Blood Flow Metab: 29 Sep 2020; 40:1997-2009 | PMID: 31637947
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Abstract

Role of deep medullary veins in pathogenesis of lacunes: Longitudinal observations from the CIRCLE study.

Zhou Y, Li Q, Zhang R, Zhang W, ... Zhang M, Lou M

Our purpose is to assess the role of deep medullary veins in pathogenesis of lacunes in patients with cerebral small vessel disease (cSVD). We included patients with baseline and 2.5-year follow-up MRI in CIRCLE study. Susceptibility Weighted Imaging-Phase images were used to evaluate deep medullary veins based on a brain region-based visual score, and T2-Fluid-Attenuated-Inversion-Recovery images were used to evaluate lacunes. Cerebral blood flow and microstructural parameters in white matter hyperintensities and normal appearing white matter were also analyzed. A total of 203 cSVD patients were analyzed and 101 (49.8%) patients had baseline lacunes. Among them, 64 patients had follow-up MRI, including 16 (25.0%) with new lacunes. The patients\' deep medullary veins median score was 9 (7-12). At baseline, high deep medullary veins score was independently associated with the presence of lacunes after adjusting for age, diabetes mellitus, white matter hyperintensities volume and cerebral blood flow or white matter microstructural parameters (all <0.001). Longitudinally, high deep medullary veins score was independently associated with new lacunes after adjusting for gender (<0.001). The association was also independent of white matter hyperintensities volumes, cerebral blood flow or white matter microstructural parameters (all <0.05). Our results suggest that deep medullary veins disruption might be involved in pathogenesis of lacunes.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1797-1805
Zhou Y, Li Q, Zhang R, Zhang W, ... Zhang M, Lou M
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1797-1805 | PMID: 31619117
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Abstract

miR-98 reduces endothelial dysfunction by protecting blood-brain barrier (BBB) and improves neurological outcomes in mouse ischemia/reperfusion stroke model.

Bernstein DL, Zuluaga-Ramirez V, Gajghate S, Reichenbach NL, ... Persidsky Y, Rom S

Most neurological diseases, including stroke, lead to some degree of blood-brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB. However, miRNAs\' role during cerebral ischemia/reperfusion is still underexplored. Endothelial levels of miR-98 were significantly altered following ischemia/reperfusion insults, bothand , transient middle cerebral artery occlusion (tMCAO), and oxygen-glucose deprivation (OGD), respectively. Overexpression of miR-98 reduced the mouse\'s infarct size after tMCAO. Further, miR-98 lessened infiltration of proinflammatory Ly6C leukocytes into the brain following stroke and diminished the prevalence of M1 (activated) microglia within the impacted area. miR-98 attenuated BBB permeability, as demonstrated by changes to fluorescently-labeled dextran penetrationand improved transendothelial electrical resistance (TEER) . Treatment with miR-98 improved significantly the locomotor impairment. Our study provides identification and functional assessment of miRNAs in brain endothelium and lays the groundwork for improving therapeutic approaches for patients suffering from ischemic attacks.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:1953-1965
Bernstein DL, Zuluaga-Ramirez V, Gajghate S, Reichenbach NL, ... Persidsky Y, Rom S
J Cereb Blood Flow Metab: 29 Sep 2020; 40:1953-1965 | PMID: 31601141
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Abstract

Vasodilator effects of sulforaphane in cerebral circulation: A critical role of endogenously produced hydrogen sulfide and arteriolar smooth muscle K and BK channels in the brain.

Parfenova H, Liu J, Hoover DT, Fedinec AL

We investigated the effects of sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, in the regulation of cerebral blood flow using cranial windows in newborn pigs. SFN administered topically (10 µM-1 mM) or systemically (0.4 mg/kg ip) caused immediate and sustained dilation of pial arterioles concomitantly with elevated HS in periarachnoid cortical cerebrospinal fluid. HS is a potent vasodilator of cerebral arterioles. SFN is not a HS donor but it acts via stimulating HS generation in the brain catalyzed by cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS). CSE/CBS inhibitors propargylglycine, β-cyano-L-alanine, and aminooxyacetic acid blocked brain HS generation and cerebral vasodilation caused by SFN. The SFN-elicited vasodilation requires activation of potassium channels in cerebral arterioles. The inhibitors of K and BK channels glibenclamide, paxilline, and iberiotoxin blocked the vasodilator effects of topical and systemic SFN, supporting the concept that HS is the mediator of the vasodilator properties of SFN in cerebral circulation. Overall, we provide first evidence that SFN is a brain permeable compound that increases cerebral blood flow via a non-genomic mechanism that is mediated via activation of CSE/CBS-catalyzed HS formation in neurovascular cells followed by HS-induced activation of K and BK channels in arteriolar smooth muscle.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:1987-1996
Parfenova H, Liu J, Hoover DT, Fedinec AL
J Cereb Blood Flow Metab: 29 Sep 2020; 40:1987-1996 | PMID: 31594422
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Abstract

Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke.

Edwards DN, Salmeron K, Lukins DE, Trout AL, Fraser JF, Bix GJ

Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell β integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by β1 integrins. Following tandem transient common carotid artery/middle cerebral artery occlusion on wild-type mice, we administered the integrin a5b1 inhibitor, ATN-161, intraperitoneal (IP) injection at 1 mg/kg acutely after reperfusion, on post-stroke day (PSD)1 and PSD2. Systemic changes (heart rate, pulse distension, and body temperature) were determined. Additionally, infarct volume and edema were determined by 2,3-triphenyltetrazolium chloride and magnetic resonance imaging, while neurological changes were evaluated using an 11-point Neuroscore. Brain immunohistochemistry was performed for claudin-5, α5β1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1β, collagen IV, and CXCL12. ATN-161 significantly reduced integrin α5β1 expression in the surrounding peri-infarct region with no systemic changes. Infarct volume, edema, and functional deficit were significantly reduced in ATN-161-treated mice. Furthermore, ATN-161 treatment reduced IgG extravasation into the parenchyma through conserved claudin-5, collagen IV, CXCL12 while reducing MMP-9 transcription. Additionally, IL-1β and CD45 + cells were reduced in the ipsilateral cortex following ATN-161 administration. Collectively, ATN-161 may be a promising novel stroke therapy by reducing post-stroke inflammation and BBB permeability.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1695-1708
Edwards DN, Salmeron K, Lukins DE, Trout AL, Fraser JF, Bix GJ
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1695-1708 | PMID: 31575337
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Abstract

Different preprocessing strategies lead to different conclusions: A [C]DASB-PET reproducibility study.

Nørgaard M, Ganz M, Svarer C, Frokjaer VG, ... Strother SC, Knudsen GM

Positron emission tomography (PET) neuroimaging provides unique possibilities to study biological processes in vivo under basal and interventional conditions. For quantification of PET data, researchers commonly apply different arrays of sequential data analytic methods (\"preprocessing pipeline\"), but it is often unknown how the choice of preprocessing affects the final outcome. Here, we use an available data set from a double-blind, randomized, placebo-controlled [C]DASB-PET study as a case to evaluate how the choice of preprocessing affects the outcome of the study. We tested the impact of 384 commonly used preprocessing strategies on a previously reported positive association between the change from baseline in neocortical serotonin transporter binding determined with [C]DASB-PET, and change in depressive symptoms, following a pharmacological sex hormone manipulation intervention in 30 women. The two preprocessing steps that were most critical for the outcome were motion correction and kinetic modeling of the dynamic PET data. We found that 36% of the applied preprocessing strategies replicated the originally reported finding ( < 0.05). For preprocessing strategies with motion correction, the replication percentage was 72%, whereas it was 0% for strategies without motion correction. In conclusion, the choice of preprocessing strategy can have a major impact on a study outcome.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1902-1911
Nørgaard M, Ganz M, Svarer C, Frokjaer VG, ... Strother SC, Knudsen GM
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1902-1911 | PMID: 31575336
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Abstract

Assessment of a white matter reference region for C-UCB-J PET quantification.

Rossano S, Toyonaga T, Finnema SJ, Naganawa M, ... Maguire RP, Carson RE

C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution () to nondisplaceable uptake in gray matter, . Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CSand . However, even with these corrections, CSoverestimatedby ∼35-40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1890-1901
Rossano S, Toyonaga T, Finnema SJ, Naganawa M, ... Maguire RP, Carson RE
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1890-1901 | PMID: 31570041
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Abstract

Cardiorespiratory fitness is associated with increased middle cerebral arterial compliance and decreased cerebral blood flow in young healthy adults: A pulsed ASL MRI study.

Furby HV, Warnert EA, Marley CJ, Bailey DM, Wise RG

Cardiorespiratory fitness is thought to have beneficial effects on systemic vascular health, in part, by decreasing arterial stiffness. However, in the absence of non-invasive methods, it remains unknown whether this effect extends to the cerebrovasculature. The present study uses a novel pulsed arterial spin labelling (pASL) technique to explore the relationship between cardiorespiratory fitness and arterial compliance of the middle cerebral arteries (MCAC). Other markers of cerebrovascular health, including resting cerebral blood flow (CBF) and cerebrovascular reactivity to CO (CVR) were also investigated. Eleven healthy males aged 21 ± 2 years with varying levels of cardiorespiratory fitness (maximal oxygen uptake (O) 38-76 ml/min/kg) underwent MRI scanning at 3 Tesla. Higher O was associated with greater MCAC (R= 0.64,  < 0.01) and lower resting grey matter CBF (R= 0.75,  < 0.01). However, O was not predictive of global grey matter BOLD-based CVR (R= 0.47,  = 0.17) or CBF-based CVR (R= 0.19,  = 0.21). The current experiment builds upon the established benefits of exercise on arterial compliance in the systemic vasculature, by showing that increased cardiorespiratory fitness is associated with greater cerebral arterial compliance in early adulthood.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1879-1889
Furby HV, Warnert EA, Marley CJ, Bailey DM, Wise RG
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1879-1889 | PMID: 31564194
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Abstract

Experimental cortical stroke induces aberrant increase of sharp-wave-associated ripples in the hippocampus and disrupts cortico-hippocampal communication.

He JW, Rabiller G, Nishijima Y, Akamatsu Y, ... Yazdan-Shahmorad A, Liu J

The functional consequences of ischemic stroke in the remote brain regions are not well characterized. The current study sought to determine changes in hippocampal oscillatory activity that may underlie the cognitive impairment observed following distal middle cerebral artery occlusion (dMCAO) without causing hippocampal structural damage. Local field potentials were recorded from the dorsal hippocampus and cortex in urethane-anesthetized rats with multichannel silicon probes during dMCAO and reperfusion, or mild ischemia induced by bilateral common carotid artery occlusion (CCAO). Bilateral change of brain state was evidenced by reduced theta/delta amplitude ratio and shortened high theta duration following acute dMCAO but not CCAO. An aberrant increase in the occurrence of sharp-wave-associated ripples (150-250 Hz), crucial for memory consolidation, was only detected after dMCAO reperfusion, coinciding with an increased occurrence of high-frequency discharges (250-450 Hz). dMCAO also significantly affected the modulation of gamma amplitude in the cortex coupled to hippocampal theta phase, although both hippocampal theta and gamma power were temporarily decreased during dMCAO. Our results suggest that MCAO may disrupt the balance between excitatory and inhibitory circuits in the hippocampus and alter the function of cortico-hippocampal network, providing a novel insight in how cortical stroke affects function in remote brain regions.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1778-1796
He JW, Rabiller G, Nishijima Y, Akamatsu Y, ... Yazdan-Shahmorad A, Liu J
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1778-1796 | PMID: 31558106
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Abstract

Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis.

Quandt F, Fischer F, Schröder J, Heinze M, ... Gerloff C, Thomalla G

Internal carotid artery stenosis is a risk factor for ischemic stroke. Even in the absence of visible structural brain changes, patients with asymptomatic stenosis are prone to cognitive impairment. On a neuronal level, it was suggested that stenosis may lead to disturbed functional brain connectivity. If so, carotid revascularization should have an effect on hypothesized brain network disturbances. We studied functional connectivity in a motor network by resting-state electroencephalography in 12 patients with high grade asymptomatic carotid stenosis before and after interventional or surgical revascularization as compared to 23 controls. In patients with stenosis, functional connectivity of neural oscillations was significantly decreased prior and improved returning to normal connectivity after revascularization. In a subgroup of patients, also studied by contrast perfusion magnetic resonance imaging, reduced connectivity was associated with decreased regional brain perfusion reflected by increased mean transit time in the middle cerebral artery borderzone. Cognitive testing revealed only minor differences between patients and controls. In summary, we identified oscillatory connectivity changes in patients with asymptomatic carotid stenosis correlating with regional hypoperfusion, which both normalized after revascularization. Hence, electrophysiological changes might be a reversible precursor preceding macroscopic structural brain damage and behavioral impairment in patients with asymptomatic carotid stenosis.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1838-1848
Quandt F, Fischer F, Schröder J, Heinze M, ... Gerloff C, Thomalla G
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1838-1848 | PMID: 31510853
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Abstract

Urinary ketone body loss leads to degeneration of brain white matter in elderly SLC5A8-deficient mice.

Suissa L, Flachon V, Guigonis JM, Olivieri CV, ... Pourcher T, Lindenthal S

SLC5A8 is a sodium-coupled monocarboxylate and ketone transporter expressed in various epithelial cells. A putative role of SLC5A8 in neuroenergetics has been also hypothesized. To clarify this issue, we studied the cerebral phenotype of SLC5A8-deficient mice during aging. Elderly SLC5A8-deficient mice presented diffuse leukoencephalopathy characterized by intramyelinic oedema without demyelination suggesting chronic energetic crisis. Hypo-metabolism in the white matter of elderly SLC5A8-deficient mice was found using Tc-hexamethylpropyleneamine oxime (HMPAO) single-photon emission CT (SPECT). Since the SLC5A8 protein could not be detected in the mouse brain, it was hypothesized that the leukoencephalopathy of aging SLC5A8-deficient mice was caused by the absence of slc5a8 expression in a peripheral organ, i.e. the kidney, where SLC5A8 is strongly expressed. A hyper-excretion of the ketone β-hydroxybutyrate (BHB) in the urine of SLC5A8-deficient mice was observed and showed that SLC5A8-deficient mice suffered a cerebral BHB insufficiency. Elderly SLC5A8-deficient mice also presented altered glucose metabolism. We propose that the continuous renal loss of BHB leads to a chronic energetic deficiency in the brain of elderly SLC5A8-deficient mice who are unable to counterbalance their glucose deficit. This study highlights the importance of alternative energetic substrates in neuroenergetics especially under conditions of restricted glucose availability.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1709-1723
Suissa L, Flachon V, Guigonis JM, Olivieri CV, ... Pourcher T, Lindenthal S
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1709-1723 | PMID: 31506013
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Abstract

Vasomotor influences on glymphatic-lymphatic coupling and solute trafficking in the central nervous system.

Goodman JR, Iliff JJ

Despite the recent description of meningeal lymphatic vessels draining solutes from the brain interstitium and cerebrospinal fluid (CSF), the physiological factors governing cranial lymphatic efflux remain largely unexplored. In agreement with recent findings, cervical lymphatic drainage of 70 kD and 2000 kD fluorescent tracers injected into the adult mouse cortex was significantly impaired in the anesthetized compared to waking animals (tracer distribution across 2.1 ± 4.5% and 23.7 ± 15.8% of deep cervical lymph nodes, respectively); however, free-breathing anesthetized mice were markedly hypercapnic and acidemic (paCO = 64 ± 8 mmHg; pH = 7.22 ± 0.05). Mechanical ventilation normalized arterial blood gases in anesthetized animals, and rescued lymphatic efflux of interstitial solutes in anesthetized mice. Experimental hypercapnia blocked cervical lymphatic efflux of intraparenchymal tracers. When tracers were injected into the subarachnoid CSF compartment, glymphatic influx into brain tissue was virtually abolished by hypercapnia, while lymphatic drainage was not appreciably altered. These findings demonstrate that cervical lymphatic drainage of interstitial solutes is, in part, regulated by upstream changes in glymphatic CSF-interstitial fluid exchange. Further, they suggest that maintaining physiological blood gas values in studies of glymphatic exchange and meningeal lymphatic drainage may be critical to defining the physiological regulation of these processes.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1724-1734
Goodman JR, Iliff JJ
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1724-1734 | PMID: 31506012
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Abstract

High long-term test-retest reliability for extrastriatal C-raclopride binding in healthy older adults.

Karalija N, Jonassson L, Johansson J, Papenberg G, ... Nyberg L, Boraxbekk CJ

In vivo dopamine D2-receptor availability is frequently assessed with C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for C-raclopride in areas with low D2 receptor densities, the ligand has been considered unreliable for measurements outside the dopamine-dense striatum. Intriguingly, recent studies show that extrastriatal C-raclopride binding potential (BP) values are (i) reliably higher than in the cerebellum (where D2-receptor levels are negligible), (ii) correlate with behavior in the expected direction, and (iii) showed good test-retest reliability in a sample of younger adults. The present work demonstrates high seven-month test-retest reliability of striatal and extrastriatal C-raclopride BP values in healthy, older adults (n = 27, age: 64-78 years). Mean C-raclopride BP values were stable between test sessions in subcortical nuclei, and in frontal and temporal cortices (p > 0.05). Across all structures analyzed, intraclass correlation coefficients were high (0.85-0.96), absolute variability was low (mean: 4-8%), and coefficients of variance ranged between 9 and 25%. Furthermore, regional C-raclopride BP values correlated with previously determined F-fallypride BP values (ρ = 0.97 and 0.92 in correlations with and without striatal values, respectively, p < 0.01) and postmortem determined D2-receptor densities (including striatum: ρ = 0.92; p < 0.001; excluding striatum: ρ = 0.75; p = 0.067). These observations suggest that extrastriatal C-raclopride measurements represent a true D2 signal.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1859-1868
Karalija N, Jonassson L, Johansson J, Papenberg G, ... Nyberg L, Boraxbekk CJ
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1859-1868 | PMID: 31506011
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Abstract

Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers.

Hougaard A, Younis S, Iljazi A, Haanes KA, ... Ayata C, Ashina M

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1685-1694
Hougaard A, Younis S, Iljazi A, Haanes KA, ... Ayata C, Ashina M
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1685-1694 | PMID: 31500524
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Abstract

Choroid plexus perfusion and intracranial cerebrospinal fluid changes after angiogenesis.

Johnson SE, McKnight CD, Lants SK, Juttukonda MR, ... Claassen DO, Donahue MJ

Recent studies have provided evidence that cortical brain ischemia may influence choroid plexus function, and such communication may be mediated by either traditional CSF circulation pathways and/or a possible glymphatic pathway. Here we investigated the hypothesis that improvements in arterial health following neoangiogenesis alter (i) intracranial CSF volume and (ii) choroid plexus perfusion in humans. CSF and tissue volume measurements were obtained from -weighted MRI, and cortical and choroid plexus perfusion were obtained from perfusion-weighted arterial spin labeling MRI, in patients with non-atherosclerotic intracranial stenosis (e.g. Moyamoya). Measurements were repeated after indirect surgical revascularization, which elicits cortical neoangiogenesis near the revascularization site ( = 23; age = 41.8 ± 13.4 years), or in a cohort of participants at two time points without interval surgeries ( = 10; age = 41.7 ± 10.7 years). Regression analyses were used to evaluate dependence of perfusion and volume on state (time 1 vs. 2). Post-surgery, neither CSF nor tissue volumes changed significantly. In surgical patients, cortical perfusion increased and choroid plexus perfusion decreased after surgery; in participants without surgeries, cortical perfusion reduced and choroid plexus perfusion increased between time points. Findings are discussed in the context of a homeostatic mechanism, whereby arterial health, paravascular flow, and/or ischemia can affect choroid plexus perfusion.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1658-1671
Johnson SE, McKnight CD, Lants SK, Juttukonda MR, ... Claassen DO, Donahue MJ
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1658-1671 | PMID: 31500523
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Abstract

Quantification of cerebral blood flow in adults by contrast-enhanced near-infrared spectroscopy: Validation against MRI.

Milej D, He L, Abdalmalak A, Baker WB, ... Yodh AG, St Lawrence K

The purpose of this study was to assess the accuracy of absolute cerebral blood flow (CBF) measurements obtained by dynamic contrast-enhanced (DCE) near-infrared spectroscopy (NIRS) using indocyanine green as a perfusion contrast agent. For validation, CBF was measured independently using the MRI perfusion method arterial spin labeling (ASL). Data were acquired at two sites and under two flow conditions (normocapnia and hypercapnia). Depth sensitivity was enhanced using time-resolved detection, which was demonstrated in a separate set of experiments using a tourniquet to temporally impede scalp blood flow. A strong correlation between CBF measurements from ASL and DCE-NIRS was observed (slope = 0.99 ± 0.08, y-intercept = -1.7 ± 7.4 mL/100 g/min, and  = 0.88). Mean difference between the two techniques was 1.9 mL/100 g/min (95% confidence interval ranged from -15 to 19 mL/100g/min and the mean ASL CBF was 75.4 mL/100 g/min). Error analysis showed that structural information and baseline absorption coefficient were needed for optimal CBF reconstruction with DCE-NIRS. This study demonstrated that DCE-NIRS is sensitive to blood flow in the adult brain and can provide accurate CBF measurements with the appropriate modeling techniques.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1672-1684
Milej D, He L, Abdalmalak A, Baker WB, ... Yodh AG, St Lawrence K
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1672-1684 | PMID: 31500522
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Abstract

Comparison of simultaneous arterial spin labeling MRI and O-HO PET measurements of regional cerebral blood flow in rest and altered perfusion states.

Puig O, Henriksen OM, Vestergaard MB, Hansen AE, ... Lindberg U, Law I

Arterial spin labelling (ASL) is a non-invasive magnetic resonance imaging (MRI) technique that may provide fully quantitative regional cerebral blood flow (rCBF) images. However, before its application in clinical routine, ASL needs to be validated against the clinical gold standard, O-HO positron emission tomography (PET). We aimed to compare the two techniques by performing simultaneous quantitative ASL-MRI and O-HO-PET examinations in a hybrid PET/MRI scanner. Duplicate rCBF measurements were performed in healthy young subjects ( = 14) in rest, during hyperventilation, and after acetazolamide (post-ACZ), yielding 63 combined PET/MRI datasets in total. Average global CBF by ASL-MRI and O-HO-PET was not significantly different in any state (40.0 ± 6.5 and 40.6 ± 4.1 mL/100 g/min, respectively in rest, 24.5 ± 5.1 and 23.4 ± 4.8 mL/100 g/min, respectively, during hyperventilation, and 59.1 ± 10.4 and 64.7 ± 10.0 mL/100 g/min, respectively, post-ACZ). Overall, strong correlation between the two methods was found across all states (slope = 1.01, R= 0.82), while the correlations within individual states and of reactivity measures were weaker, in particular in rest (R= 0.05,  = 0.03). Regional distribution was similar, although ASL yielded higher perfusion and absolute reactivity in highly vascularized areas. In conclusion, ASL-MRI and O-HO-PET measurements of rCBF are highly correlated across different perfusion states, but with variable correlation within and between hemodynamic states, and systematic differences in regional distribution.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1621-1633
Puig O, Henriksen OM, Vestergaard MB, Hansen AE, ... Lindberg U, Law I
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1621-1633 | PMID: 31500521
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Abstract

Mannose-binding lectin has a direct deleterious effect on ischemic brain microvascular endothelial cells.

Neglia L, Fumagalli S, Orsini F, Zanetti A, Perego C, De Simoni MG

Mannose-binding lectin (MBL), an initiator of the lectin pathway, is detrimental in ischemic stroke. MBL deposition on the ischemic endothelium indicates the beginning of its actions, but downstream mechanisms are not clear yet.We investigated MBL interactions with the ischemic endothelium by exposing human brain microvascular endothelial cells (hBMECs) to protocols of ischemia. Cells were exposed to hypoxia or oxygen-glucose deprivation (OGD), and re-oxygenated with human serum (HS) or recombinant MBL (rhMBL). Hypoxic hBMECs re-oxygenated with HS showed increased complement system activation (C3c deposition, +59%) and MBL deposition (+93%) than normoxic cells. Super-resolution microscopy showed MBL internalization in hypoxic cells and altered cytoskeletal organization, indicating a potential MBL action on the endothelial structure. To isolate MBL effect, hBMECs were re-oxygenated with rhMBL after hypoxia/OGD. In both conditions, MBL reduced viability (hypoxia: -25%, OGD: -34%) compared to conditions without MBL, showing a direct toxic effect. Ischemic cells also showed greater MBL deposition (hypoxia: +143%, OGD: +126%) than normoxic cells. These results were confirmed with primary hBMECs exposed to OGD (increased MBL-induced cell death: +226%, and MBL deposition: +104%). The present findings demonstrate that MBL can exert a direct deleterious effect on ischemic brain endothelial cells in vitro, independently from complement activation.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1608-1620
Neglia L, Fumagalli S, Orsini F, Zanetti A, Perego C, De Simoni MG
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1608-1620 | PMID: 31495300
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Abstract

Delayed clearance of cerebrospinal fluid tracer from choroid plexus in idiopathic normal pressure hydrocephalus.

Eide PK, Valnes LM, Pripp AH, Mardal KA, Ringstad G

Impaired clearance of amyloid-β from choroid plexus is one proposed mechanism behind amyloid deposition in Alzheimer\'s disease. The present study examined whether clearance from choroid plexus of a cerebrospinal fluid tracer, serving as a surrogate marker of a metabolic waste product, is altered in idiopathic normal pressure hydrocephalus (iNPH), one sub-type of dementia. In a prospective observational study of close to healthy individuals (reference cohort; REF) and individuals with iNPH, we performed standardized T1-weighted magnetic resonance imaging scans before and through 24 h after intrathecal administration of a cerebrospinal fluid tracer (the magnetic resonance imaging contrast agent gadobutrol). Changes in normalized T1 signal within the choroid plexus and cerebrospinal fluid of lateral ventricles were quantified using FreeSurfer. The normalized T1 signal increased to maximum within choroid plexus and cerebrospinal fluid of lateral ventricles 6-9 h after intrathecal gadobutrol in both the REF and iNPH cohorts (enrichment phase). Peak difference in normalized T1 signals between REF and iNPH individuals occurred after 24 h (clearance phase). The results gave evidence for gadobutrol resorption from cerebrospinal fluid by choroid plexus, but with delay in iNPH patients. Whether choroid plexus has a role in iNPH pathogenesis in terms of delayed clearance of amyloid-β remains to be shown.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1849-1858
Eide PK, Valnes LM, Pripp AH, Mardal KA, Ringstad G
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1849-1858 | PMID: 31495299
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Abstract

Clinical relevance of asymptomatic intracerebral hemorrhage post thrombectomy depends on angiographic collateral score.

Nawabi J, Kniep H, Broocks G, Faizy TD, ... Fiehler J, Hanning U

Asymptomatic intracerebral hemorrhage (aICH) is a common phenomenon in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (ET). However, the impact of aICH on the functional outcome remains widely unclear. In this study, we aimed at identifying predictors for aICH and analyzing its impact on functional outcome. Patients with AIS due to large artery occlusion in the anterior circulation treated with successful ET were enrolled in a tertiary stroke center. Patients with aICH or without intracerebral hemorrhage were included according to post-treatment CT performed within 72 h; 100 consecutive patients fulfilled the inclusion criteria and 30% classified with aICH. In logistic regression analysis, lower collateral score (OR 0.24; 95% CI 0.12-0.46,  < 0.0001) was significantly associated with aICH. Less patients with aICH achieved an independent outcome (mRS 0-2, 16.7% vs. 44.3%,  = 0.007). Poor outcome (mRS 4-6) was significantly higher in patients with aICH (41.4% vs. 70%,  = 0.021). Patients with aICH had a lower ratio of independent outcome (OR 0.23, 95% CI 0.05-0.1.05,  = 0.041) than without ICH. There were no differences concerning poor outcome ( = 0.5). Lower collateral status was a strong independent predictor for aICH. aICH after successful ET may decrease the likelihood of an independent functional outcome without influencing poor outcome.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1599-1607
Nawabi J, Kniep H, Broocks G, Faizy TD, ... Fiehler J, Hanning U
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1599-1607 | PMID: 31433715
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Abstract

Dynamics of the cerebral blood flow response to brief neural activity in human visual cortex.

Kim JH, Taylor AJ, Wang DJ, Zou X, Ress D

The blood oxygen-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal depends on an interplay of cerebral blood flow (CBF), oxygen metabolism, and cerebral blood volume. Despite wide usage of BOLD fMRI, it is not clear how these physiological components create the BOLD signal. Here, baseline CBF and its dynamics evoked by a brief stimulus (2 s) in human visual cortex were measured at 3T. We found a stereotypical CBF response: immediate increase, rising to a peak a few second after the stimulus, followed by a significant undershoot. The BOLD hemodynamic response function (HRF) was also measured in the same session. Strong correlations between HRF and CBF peak responses indicate that the flow responses evoked by neural activation in nearby gray matter drive the early HRF. Remarkably, peak CBF and HRF were also strongly modulated by baseline perfusion. The CBF undershoot was reliable and significantly correlated with the HRF undershoot. However, late-time dynamics of the HRF and CBF suggest that oxygen metabolism can also contribute to the HRF undershoot. Combined measurement of the CBF and HRF for brief neural activation is a useful tool to understand the temporal dynamics of neurovascular and neurometabolic coupling.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1823-1837
Kim JH, Taylor AJ, Wang DJ, Zou X, Ress D
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1823-1837 | PMID: 31429358
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Abstract

Neurovascular coupling and cerebral autoregulation in atrial fibrillation.

Junejo RT, Braz ID, Lucas SJ, van Lieshout JJ, ... Lip GY, Fisher JP

The risk of cognitive decline and stroke is increased by atrial fibrillation (AF). We sought to determine whether neurovascular coupling and cerebral autoregulation are blunted in people with AF in comparison with age-matched, patients with hypertension and healthy controls. Neurovascular coupling was assessed using five cycles of visual stimulation for 30 s followed by 30 s with both eyes-closed. Cerebral autoregulation was examined using a sit-stand test, and a repeated squat-to-stand (0.1 Hz) manoeuvre with transfer function analysis of mean arterial pressure (MAP; input) and middle cerebral artery mean blood flow velocity (MCA V; output) relationships at 0.1 Hz. Visual stimulation increased posterior cerebral artery conductance, but the magnitude of the response was blunted in patients with AF (18 [8] %; mean [SD]) and hypertension (17 [8] %), in comparison with healthy controls (26 [9] %) ( < 0.05). In contrast, transmission of MAP to MCA V was greater in AF patients compared to hypertension and healthy controls, indicating diminished cerebral autoregulation. We have shown for the first time that AF patients have impaired neurovascular coupling responses to visual stimulation and diminished cerebral autoregulation. Such deficits in cerebrovascular regulation may contribute to the increased risk of cerebral dysfunction in people with AF.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1647-1657
Junejo RT, Braz ID, Lucas SJ, van Lieshout JJ, ... Lip GY, Fisher JP
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1647-1657 | PMID: 31426699
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Abstract

The mass transfer coefficient for oxygen transport from blood to tissue in cerebral cortex.

Secomb TW, Bullock KV, Boas DA, Sakadžić S

The functioning of cerebral cortex depends on adequate tissue oxygenation. MRI-based techniques allow estimation of blood oxygen levels, tissue perfusion, and oxygen consumption rate (CMRO), but do not directly measure partial pressure of oxygen (PO) in tissue. To address the estimation of tissue PO, the oxygen mass transfer coefficient (KTO) is here defined as the CMRO divided by the difference in spatially averaged PO between blood and tissue, and is estimated by analyzing Krogh-cylinder type models. Resistance to radial diffusion of oxygen from microvessels to tissue is distributed within vessels and in the extravascular tissue. The value of KTO is shown to depend strongly on vascular length density and also on microvessel tube hematocrits and diameters, but to be insensitive to blood flow rate and to transient changes in flow or oxygen consumption. Estimated values of KTO are higher than implied by previous studies, implying smaller declines in PO from blood to tissue. Average tissue PO can be estimated from MRI-based measurements as average blood PO minus the product of KTO and CMRO. For oxygen consumption rates and vascular densities typical of mouse cortex, the predicted difference between average blood and tissue PO is about 10 mmHg.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1634-1646
Secomb TW, Bullock KV, Boas DA, Sakadžić S
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1634-1646 | PMID: 31423930
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Abstract

HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage.

Formisano L, Laudati G, Guida N, Mascolo L, ... Pignataro G, Annunziato L

The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na/Ca exchanger isoform 3 () after stroke are still unknown. Overexpression or knocking-down of HDAC4/HDAC5 down-regulates or increases, respectively, NCX3 mRNA and protein. Likewise, MC1568 (class IIa HDACs inhibitor), but not MS-275 (class I HDACs inhibitor) increased NCX3 promoter activity, gene and protein expression. Furthermore, HDAC4 and HDAC5 physically interacted with the transcription factor downstream regulatory element antagonist modulator (DREAM). As MC1568, DREAM knocking-down prevented HDAC4 and HDAC5 recruitment to thepromoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to thegene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation ofpromoter. Conversely, the tMCAO-induced NCX3 reduction was prevented by intracerebroventricular injection of siDREAM, siHDAC4, and siHDAC5. Notably, MC1568 prevented oxygen glucose deprivation plus reoxygenation and tMCAO-induced neuronal damage, whereas its neuroprotective effect was abolished byknockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulatesgene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2081-2097
Formisano L, Laudati G, Guida N, Mascolo L, ... Pignataro G, Annunziato L
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2081-2097 | PMID: 31696766
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Abstract

High spatiotemporal vessel-specific hemodynamic mapping with multi-echo single-vessel fMRI.

He Y, Wang M, Yu X

High-resolution fMRI enables noninvasive mapping of the hemodynamic responses from individual penetrating vessels in animal brains. Here, a 2D multi-echo single-vessel fMRI (MESV-fMRI) method has been developed to map the fMRI signal from arterioles and venules with a 100 ms sampling rate at multiple echo times (TE, 3-30 ms) and short acquisition windows (<1 ms). The T*-weighted signal shows the increased extravascular effect on venule voxels as a function of TE. In contrast, the arteriole voxels show an increased fMRI signal with earlier onset than venules voxels at the short TE (3 ms) with increased blood inflow and volume effects. MESV-fMRI enables vessel-specific T2* mapping and presents T2*-based fMRI time courses with higher contrast-to-noise ratios (CNRs) than the T2*-weighted fMRI signal at a given TE. The vessel-specific T2* mapping also allows semi-quantitative estimation of the oxygen saturation levels (Y) and their changes (ΔY) at a given blood volume fraction upon neuronal activation. The MESV-fMRI method enables vessel-specific T2* measurements with high spatiotemporal resolution for better modeling of the fMRI signal based on the hemodynamic parameters.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2098-2114
He Y, Wang M, Yu X
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2098-2114 | PMID: 31696765
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Abstract

Microvessel occlusions alter amyloid-beta plaque morphology in a mouse model of Alzheimer\'s disease.

Zhang Y, Bander ED, Lee Y, Muoser C, Schaffer CB, Nishimura N

Vascular dysfunction is correlated to the incidence and severity of Alzheimer\'s disease. In a mouse model of Alzheimer\'s disease (APP/PS1) using in vivo, time-lapse, multiphoton microscopy, we found that occlusions of the microvasculature alter amyloid-beta (Aβ) plaques. We used several models of vascular injury that varied in severity. Femtosecond laser-induced occlusions in single capillaries generated a transient increase in small, cell-sized, Aβ deposits visualized with methoxy-X04, a label of fibrillar Aβ. After occlusions of penetrating arterioles, some plaques changed morphology, while others disappeared, and some new plaques appeared within a week after the lesion. Antibody labeling of Aβ revealed a transient increase in non-fibrillar Aβ one day after the occlusion that coincided with the disappearance of methoxy-X04-labeled plaques. Four days after the lesion, anti-Aβ labeling decreased and only remained in patches unlabeled by methoxy-X04 near microglia. Histology in two additional models, sparse embolic occlusions from intracarotid injections of beads and infarction from photothrombosis, demonstrated increased labeling intensity in plaques after injury. These results suggest that microvascular lesions can alter the deposition and clearance of Aβ and confirm that Aβ plaques are dynamic structures, complicating the interpretation of plaque burden as a marker of Alzheimer\'s disease progression.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:2115-2131
Zhang Y, Bander ED, Lee Y, Muoser C, Schaffer CB, Nishimura N
J Cereb Blood Flow Metab: 29 Sep 2020; 40:2115-2131 | PMID: 31744388
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Abstract

Guidelines for the content and format of PET brain data in publications and archives: A consensus paper.

Knudsen GM, Ganz M, Appelhoff S, Boellaard R, ... Zoghbi S, Innis RB

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1576-1585
Knudsen GM, Ganz M, Appelhoff S, Boellaard R, ... Zoghbi S, Innis RB
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1576-1585 | PMID: 32065076
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Abstract

Microvascular platelet aggregation and thrombosis after subarachnoid hemorrhage: A review and synthesis.

Clarke JV, Suggs JM, Diwan D, Lee JV, ... Vellimana AK, Zipfel GJ

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (SAH) has been associated with numerous pathophysiological sequelae, including large artery vasospasm and microvascular thrombosis. The focus of this review is to provide an overview of experimental animal model studies and human autopsy studies that explore the temporal-spatial characterization and mechanism of microvascular platelet aggregation and thrombosis following SAH, as well as to critically assess experimental studies and clinical trials highlighting preventative therapeutic options against this highly morbid pathophysiological process. Upon review of the literature, we discovered that microvascular platelet aggregation and thrombosis occur after experimental SAH across multiple species and SAH induction techniques in a similar time frame to other components of DCI, occurring in the cerebral cortex and hippocampus across both hemispheres. We discuss the relationship of these findings to human autopsy studies. In the final section of this review, we highlight the important therapeutic options for targeting microvascular platelet aggregation and thrombosis, and emphasize why therapeutic targeting of this neurovascular pathology may improve patient care. We encourage ongoing research into the pathophysiology of SAH and DCI, especially in regard to microvascular platelet aggregation and thrombosis and the translation to randomized clinical trials.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1565-1575
Clarke JV, Suggs JM, Diwan D, Lee JV, ... Vellimana AK, Zipfel GJ
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1565-1575 | PMID: 32345104
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Abstract

Cerebral perfusion and blood-brain barrier assessment in brain trauma using contrast-enhanced near-infrared spectroscopy with indocyanine green: A review.

Forcione M, Chiarelli AM, Davies DJ, Perpetuini D, ... Merla A, Belli A

Contrast-enhanced near-infrared spectroscopy (NIRS) with indocyanine green (ICG) can be a valid non-invasive, continuous, bedside neuromonitoring tool. However, its usage in moderate and severe traumatic brain injury (TBI) patients can be unprecise due to their clinical status. This review is targeted at researchers and clinicians involved in the development and application of contrast-enhanced NIRS for the care of TBI patients and can be used to design future studies. This review describes the methods developed to monitor the brain perfusion and the blood-brain barrier integrity using the changes of diffuse reflectance during the ICG passage and the results on studies in animals and humans. The limitations in accuracy of these methods when applied on TBI patients and the proposed solutions to overcome them are discussed. Finally, the analysis of relative parameters is proposed as a valid alternative over absolute values to address some current clinical needs in brain trauma care. In conclusion, care should be taken in the translation of the optical signal into absolute physiological parameters of TBI patients, as their clinical status must be taken into consideration. Discussion on where and how future studies should be directed to effectively incorporate contrast-enhanced NIRS into brain trauma care is given.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1586-1598
Forcione M, Chiarelli AM, Davies DJ, Perpetuini D, ... Merla A, Belli A
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1586-1598 | PMID: 32345103
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Abstract

Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update.

Ren H, Han R, Chen X, Liu X, ... Yang X, Wang J

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality and disability but no specific or effective treatment. In the last two decades, much has been learned about the pathologic mechanisms of ICH. It is now known that after ICH onset, immune and inflammatory responses contribute to blood-brain barrier disruption, edema development, and cell death processes, jointly resulting in secondary brain injury. However, the translation of potential therapies from preclinical to clinical success has been disappointing. With the development of new laboratory technology, recent progress has been made in the understanding of ICH pathomechanisms, and promising therapeutic targets have been identified. This review provides an update of recent progress on ICH and describes the prospects for further preclinical studies in this field. Our goal is to discuss new therapeutic targets and directions for the treatment of ICH and promote the effective transformation from preclinical to clinical trials.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1752-1768
Ren H, Han R, Chen X, Liu X, ... Yang X, Wang J
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1752-1768 | PMID: 32423330
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Abstract

Collateral status contributes to differences between observed and predicted 24-h infarct volumes in DEFUSE 3.

Rao VL, Mlynash M, Christensen S, Yennu A, ... Lansberg MG, Albers GW

We previously demonstrated that in the DEFUSE 3 trial, the union of the baseline core and the 24-h Tmax > 6 s perfusion lesion predicts the infarct volume at 24 h. Presently, we assessed if collateral robustness measured by the hypoperfusion intensity ratio (HIR) and cerebral blood volume (CBV) index accounts for the variance in these predictions. DEFUSE 3 patients underwent MRI/CT perfusion imaging at baseline and 24 h post-randomization. We compared baseline and follow-up HIR and CBV index across subgroups stratified by differences between predicted and observed 24-h infarct volumes. Of 123 eligible patients, 34 with 24-h infarcts larger than predicted had less favorable collaterals at baseline (HIR 0.43 vs. 0.32,  = 0.006; CBV Index 0.78 vs. 0.85,  = 0.001) and 24 h (HIR 0.56 vs. 0.07,  = 0.004; CBV Index 0.47 vs. 0.73,  = 0.006) compared to 71 patients with more accurate infarct volume prediction. Eighteen patients with 24-h infarcts smaller than predicted had similar baseline collateral scores but more favorable 24-h CBV indices (0.81 vs. 0.73,  = 0.040). Overall, patients with 24-h infarcts larger than predicted had evidence of less favorable baseline collaterals that fail within 24 h, while patients with 24-h infarcts smaller than predicted typically had favorable collaterals that persisted for 24 h.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:1966-1974
Rao VL, Mlynash M, Christensen S, Yennu A, ... Lansberg MG, Albers GW
J Cereb Blood Flow Metab: 29 Sep 2020; 40:1966-1974 | PMID: 32423329
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Abstract

From in vitro to in vivo reprogramming for neural transdifferentiation: An approach for CNS tissue remodeling using stem cell technology.

Egawa N, Suzuki H, Takahashi R, Hayakawa K, ... Arai K, Inoue H

Advances in stem cell technology have provided three approaches to address the demanding issue of the treatment of intractable neurological disease. One of the approaches is the screening of compounds attenuating pathological phenotypes in stem-cell based models. A second approach consists of exogenous-targeted cell supplementation to the lesion with stem cell-derived differentiated cells. A third approach involves in vivo direct programming to transdifferentiate endogenous somatic cells and to boost CNS tissue remodeling. In this review, we outline research advances in stem cell technology of direct reprogramming in vitro and in vivo and discuss the future challenge of tissue remodeling by neural transdifferentiation.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1739-1751
Egawa N, Suzuki H, Takahashi R, Hayakawa K, ... Arai K, Inoue H
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1739-1751 | PMID: 32423328
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Impact:
Abstract

Hypoxia induces de novo formation of cerebral collaterals and lessens the severity of ischemic stroke.

Zhang H, Rzechorzek W, Aghajanian A, Faber JE

Pial collaterals provide protection in stroke. Evidence suggests their formation late during gestation (collaterogenesis) is driven by reduced oxygen levels in the cerebral watersheds. The purpose of this study was to determine if collaterogenesis can be re-activated in the adult to induce formation of additional collaterals (\"neo-collateral formation\", NCF). Mice were gradually acclimated to reduced inspired oxygen (FIO) and maintained at 12, 10, 8.5 or 7% for two-to-eight weeks. Hypoxemia induced \"dose\"-dependent NCF and remodeling of native collaterals, and decreased infarct volume after permanent MCA occlusion. In contrast, no formation occurred of addition collateral-like intra-tree anastomoses, PComs, or branches within the MCA tree. Hypoxic NCF, remodeling and infarct protection were durable, i.e. retained for at least six weeks after return to normoxia. Hypoxia increased expression ofand . Neo-collateral formation was abolished in mice lackinga novel gene involved in VEGFA→Flk1 signaling and required for formation of collaterals during development, and inhibited by knockdown of ,and . -dependent NCF was also induced by permanent MCA occlusion. This is the first report that hypoxia induces new pial collaterals to form. Hypoxia- and occlusion-induced neo-collateral formation provide models to study collaterogenesis in the adult.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1806-1822
Zhang H, Rzechorzek W, Aghajanian A, Faber JE
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1806-1822 | PMID: 32423327
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Impact:
Abstract

Light sheet fluorescence microscopy of optically cleared brains for studying the glymphatic system.

Bèchet NB, Kylkilahti TM, Mattsson B, Petrasova M, Shanbhag NC, Lundgaard I

Fluid transport in the perivascular space by the glia-lymphatic (glymphatic) system is important for the removal of solutes from the brain parenchyma, including peptides such as amyloid-beta which are implicated in the pathogenesis of Alzheimer\'s disease. The glymphatic system is highly active in the sleep state and under the influence of certain of anaesthetics, while it is suppressed in the awake state and by other anaesthetics. Here we investigated whether light sheet fluorescence microscopy of whole optically cleared murine brains was capable of detecting glymphatic differences in sleep- and awake-mimicking anaesthesia, respectively. Using light-sheet imaging of whole brains, we found anaesthetic-dependent cerebrospinal fluid (CSF) influx differences, including reduced tracer influx along tertiary branches of the middle cerebral artery and reduced influx along dorsal and anterior penetrating arterioles, in the awake-mimicking anaesthesia. This study establishes that light sheet microscopy of optically cleared brains is feasible for quantitative analyses and can provide images of the entire glymphatic system in whole brains.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:1975-1986
Bèchet NB, Kylkilahti TM, Mattsson B, Petrasova M, Shanbhag NC, Lundgaard I
J Cereb Blood Flow Metab: 29 Sep 2020; 40:1975-1986 | PMID: 32525440
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Impact:
Abstract

Mechanisms of the negative potential associated with Leão\'s spreading depolarization: A history of brain electrogenesis.

Herreras O, Makarova J

Spreading depolarization (SD) is a self-propagated wave that provokes transient disorder of numerous cell and tissue functions, and that may kill neurons in metabolically compromised tissue. We examined the mechanisms underlying the main hallmark of SD, a giant extracellular potential (ΔV) for which multiple electromotive forces have been proposed. The end-point is that neurons and not glia, dendritic channels and not spatial currents, and increased sodium conductance rather than potassium gradients, appear to be the main actors in the generation of the negative ΔV. Neuronal currents are established by two mechanisms, a voltage independent dendritic current, and the differential polarization along the neuron membranes. Notably, despite of a marked drop of ion gradients, these evolve significantly during SD, and yet the membrane potential remains clamped at zero no matter how much inward current is present. There may be substantial inward current or none in function of the evolving portion of the neuron dendrites with SD-activated channels. We propose that the ΔV promotes swelling-induced dendritic damage. Understanding SD electrogenesis requires all elements relevant for membrane potential, action currents, field potentials and volume conduction to be jointly considered, and it has already encouraged the search for new targets to limit SD-related pathology.



J Cereb Blood Flow Metab: 29 Sep 2020; 40:1934-1952
Herreras O, Makarova J
J Cereb Blood Flow Metab: 29 Sep 2020; 40:1934-1952 | PMID: 32580670
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Impact:
Abstract

Leaky memories: Impact of on blood-brain barrier and dementia.

Li W, Lo EH

A new study suggests that the leading genetic risk factor for Alzheimer\'s disease, apolipoprotein E4 (), is linked to blood-brain barrier breakdown and subsequent cognitive decline. These findings broaden our understanding of how cerebrovascular mechanisms contribute to cognitive impairment and should stimulate new directions for pursuing therapeutic approaches for Alzheimer\'s disease and related dementias.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1912-1914
Li W, Lo EH
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1912-1914 | PMID: 32600092
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Abstract

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

Percie du Sert N, Hurst V, Ahluwalia A, Alam S, ... Steckler T, Würbel H

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the \"ARRIVE Essential 10,\" which constitutes the minimum requirement, and the \"Recommended Set,\" which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.



J Cereb Blood Flow Metab: 30 Aug 2020; 40:1769-1777
Percie du Sert N, Hurst V, Ahluwalia A, Alam S, ... Steckler T, Würbel H
J Cereb Blood Flow Metab: 30 Aug 2020; 40:1769-1777 | PMID: 32663096
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Impact:
Abstract

Can oligodendrocyte precursor cells be a therapeutic target for mitigating cognitive decline in cerebrovascular disease?

Arai K

Oligodendrocyte precursor cells (OPCs) give rise to mature myelin-forming oligodendrocytes during white matter development. In adult brains, some populations of OPCs remain to renew oligodendrocyte pools and myelin. Two recent studies highlight the importance of OPCs in white matter homeostasis. Genetic tracing studies suggest that age-related decline in OPCs may contribute to diminished myelin renewal and memory deficits in mouse models. Single cell transcriptomics and imaging may now define specific subsets of OPCs involved in process elaboration, motility and myelination. These advances raise the possibility of pursuing OPCs as novel therapeutic targets for vascular cognitive impairment.



J Cereb Blood Flow Metab: 30 Jul 2020; 40:1735-1736
Arai K
J Cereb Blood Flow Metab: 30 Jul 2020; 40:1735-1736 | PMID: 32674700
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Impact:
Abstract

A glucose-stimulated BOLD fMRI study of hypothalamic dysfunction in mice fed a high-fat and high-sucrose diet.

Mohr AA, Garcia-Serrano AM, Vieira JP, Skoug C, Davidsson H, Duarte JM

The hypothalamus is the central regulator of energy homeostasis. Hypothalamic neuronal circuits are disrupted upon overfeeding, and play a role in the development of metabolic disorders. While mouse models have been extensively employed for understanding the mechanisms of hypothalamic dysfunction, functional magnetic resonance imaging (fMRI) on hypothalamic nuclei has been challenging. We implemented a robust glucose-induced fMRI paradigm that allows to repeatedly investigate hypothalamic responses to glucose. This approach was used to test the hypothesis that hypothalamic nuclei functioning is impaired in mice exposed to a high-fat and high-sucrose diet (HFHSD) for seven days. The blood oxygen level-dependent (BOLD) fMRI signal was measured from brains of mice under light isoflurane anaesthesia, during which a 2.6 g/kg glucose load was administered. The mouse hypothalamus responded to glucose but not saline administration with a biphasic BOLD fMRI signal reduction. Relative to controls, HFHSD-fed mice showed attenuated or blunted responses in arcuate nucleus, lateral hypothalamus, ventromedial nucleus and dorsomedial nucleus, but not in paraventricular nucleus. In sum, we have developed an fMRI paradigm that is able to determine dysfunction of glucose-sensing neuronal circuits within the mouse hypothalamus in a non-invasive manner.



J Cereb Blood Flow Metab: 04 Aug 2020:271678X20942397; epub ahead of print
Mohr AA, Garcia-Serrano AM, Vieira JP, Skoug C, Davidsson H, Duarte JM
J Cereb Blood Flow Metab: 04 Aug 2020:271678X20942397; epub ahead of print | PMID: 32757742
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Impact:
Abstract

Binding of the synaptic vesicle radiotracer [C]UCB-J is unchanged during functional brain activation using a visual stimulation task.

Smart K, Liu H, Matuskey D, Chen MK, ... Huang Y, Carson RE

The positron emission tomography radioligand [C]UCB-J binds to synaptic vesicle glycoprotein 2 A (SV2A), a regulator of vesicle release. Increased neuronal firing could potentially affect tracer concentrations if binding site availability is altered during vesicle exocytosis. This study assessed whether physiological brain activation induces changes in [C]UCB-J tissue influx (), volume of distribution (), or binding potential (). Healthy volunteers ( = 7) underwent 60-min [C]UCB-J PET scans at baseline and during intermittent presentation of 8-Hz checkerboard visual stimulation. Sensitivity to intermittent changes in kinetic parameters was assessed in simulations, and visual stimulation was repeated using functional magnetic resonance imaging to characterize neural responses. andwere determined using the one-tissue compartment model andusing the simplified reference tissue model. In primary visual cortex,increased 34.3 ± 15.5% ( = 0.001) during stimulation, with no change in other regions (s>0.12).change was correlated with fMRI BOLD response (r = 0.77,  = 0.043). There was no change in(-3.9 ± 8.8%, =0.33) or(-0.2 ± 9.6%, =0.94) in visual cortex nor other regions (s>0.19). Therefore, despite robust increases in regional tracer influx due to blood flow increases, binding measures were unchanged during stimulation. [C]UCB-Jandare likely to be stable in vivo measures of synaptic density.



J Cereb Blood Flow Metab: 04 Aug 2020:271678X20946198; epub ahead of print
Smart K, Liu H, Matuskey D, Chen MK, ... Huang Y, Carson RE
J Cereb Blood Flow Metab: 04 Aug 2020:271678X20946198; epub ahead of print | PMID: 32757741
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Impact:
Abstract

Interleukin-4 improves white matter integrity and functional recovery after murine traumatic brain injury via oligodendroglial PPARγ.

Pu H, Zheng X, Jiang X, Mu H, ... Bennett MV, Chen J

Long-term neurological recovery after severe traumatic brain injury (TBI) is strongly linked to the repair and functional restoration of injured white matter. Emerging evidence suggests that the anti-inflammatory cytokine interleukin-4 (IL-4) plays an important role in promoting white matter integrity after cerebral ischemic injury. Here, we report that delayed intranasal delivery of nanoparticle-packed IL-4 boosted sensorimotor neurological recovery in a murine model of controlled cortical impact, as assessed by a battery of neurobehavioral tests for up to five weeks. Post-injury IL-4 treatment failed to reduce macroscopic brain lesions after TBI, but preserved the structural and functional integrity of white matter, at least in part through oligodendrogenesis. IL-4 directly facilitated the differentiation of oligodendrocyte progenitor cells (OPCs) into mature myelin-producing oligodendrocytes in primary cultures, an effect that was attenuated by selective PPARγ inhibition. IL-4 treatment after TBI in vivo also failed to stimulate oligodendrogenesis or improve white matter integrity in OPC-specific PPARγ conditional knockout (cKO) mice. Accordingly, IL-4-afforded improvements in sensorimotor neurological recovery after TBI were markedly impaired in the PPARγ cKO mice compared to wildtype controls. These results support IL-4 as a potential novel neurorestorative therapy to improve white matter functionality and mitigate the long-term neurological consequences of TBI.



J Cereb Blood Flow Metab: 04 Aug 2020:271678X20941393; epub ahead of print
Pu H, Zheng X, Jiang X, Mu H, ... Bennett MV, Chen J
J Cereb Blood Flow Metab: 04 Aug 2020:271678X20941393; epub ahead of print | PMID: 32757740
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Impact:
Abstract

Cardiac arrest and resuscitation activates the hypothalamic-pituitary-adrenal axis and results in severe immunosuppression.

Zhao Q, Shen Y, Li R, Wu J, ... Zhang W, Yang W

In patients who are successfully resuscitated after initial cardiac arrest (CA), mortality and morbidity rates are high, due to ischemia/reperfusion injury to the whole body including the nervous and immune systems. How the interactions between these two critical systems contribute to post-CA outcome remains largely unknown. Using a mouse model of CA and cardiopulmonary resuscitation (CA/CPR), we demonstrate that CA/CPR induced neuroinflammation in the brain, in particular, a marked increase in pro-inflammatory cytokines, which subsequently activated the hypothalamic-pituitary-adrenal (HPA) axis. Importantly, this activation was associated with a severe immunosuppression phenotype after CA. The phenotype was characterized by a striking reduction in size of lymphoid organs accompanied by a massive loss of immune cells and reduced immune function of splenic lymphocytes. The mechanistic link between post-CA immunosuppression and the HPA axis was substantiated, as we discovered that glucocorticoid treatment, which mimics effects of the activated HPA axis, exacerbated post-CA immunosuppression, while RU486 treatment, which suppresses its effects, significantly mitigated lymphopenia and lymphoid organ atrophy and improved CA outcome. Taken together, targeting the HPA axis could be a viable immunomodulatory therapeutic to preserve immune homeostasis after CA/CPR and thus improve prognosis of post-resuscitation CA patients.



J Cereb Blood Flow Metab: 11 Aug 2020:271678X20948612; epub ahead of print
Zhao Q, Shen Y, Li R, Wu J, ... Zhang W, Yang W
J Cereb Blood Flow Metab: 11 Aug 2020:271678X20948612; epub ahead of print | PMID: 32787543
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Impact:
Abstract

Association between tissue hypoxia, perfusion restrictions, and microvascular architecture alterations with lesion-induced impairment of neurovascular coupling.

Stadlbauer A, Kinfe TM, Zimmermann M, Eyüpoglu I, ... Dörfler A, Brandner S

Functional magnetic resonance imaging (fMRI) has been mainly utilized for the preoperative localization of eloquent cortical areas. However, lesion-induced impairment of neurovascular coupling (NVC) in the lesion border zone may lead to false-negative fMRI results. The purpose of this study was to determine physiological factors impacting the NVC. Twenty patients suffering from brain lesions were preoperatively examined using multimodal neuroimaging including fMRI, magnetoencephalography (MEG) during language or sensorimotor tasks (depending on lesion location), and a novel physiologic MRI approach for the combined quantification of oxygen metabolism, perfusion state, and microvascular architecture. Congruence of brain activity patterns between fMRI and MEG were found in 13 patients. In contrast, we observed missing fMRI activity in perilesional cortex that demonstrated MEG activity in seven patients, which was interpreted as lesion-induced impairment of NVC. In these brain regions with impaired NVC, physiologic MRI revealed significant brain tissue hypoxia, as well as significantly decreased macro- and microvascular perfusion and microvascular architecture. We demonstrated that perilesional hypoxia with reduced vascular perfusion and architecture is associated with lesion-induced impairment of NVC. Our physiologic MRI approach is a clinically applicable method for preoperative risk assessment for the presence of false-negative fMRI results and may prevent severe postoperative functional deficits.



J Cereb Blood Flow Metab: 11 Aug 2020:271678X20947546; epub ahead of print
Stadlbauer A, Kinfe TM, Zimmermann M, Eyüpoglu I, ... Dörfler A, Brandner S
J Cereb Blood Flow Metab: 11 Aug 2020:271678X20947546; epub ahead of print | PMID: 32787542
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Impact:
Abstract

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.

Lee H, Xu F, Liu X, Koundal S, ... Van Nostrand WE, Benveniste H

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer\'s disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aβ deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.



J Cereb Blood Flow Metab: 12 Aug 2020:271678X20944226; epub ahead of print
Lee H, Xu F, Liu X, Koundal S, ... Van Nostrand WE, Benveniste H
J Cereb Blood Flow Metab: 12 Aug 2020:271678X20944226; epub ahead of print | PMID: 32791876
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Impact:
Abstract

Impaired response of cerebral oxygen metabolism to visual stimulation in Huntington\'s disease.

Klinkmueller P, Kronenbuerger M, Miao X, Bang J, ... Ross CA, Hua J

Huntington\'s disease (HD) is a neurodegenerative disease caused by a CAG triplet repeat expansion in the Huntingtin gene. Metabolic and microvascular abnormalities in the brain may contribute to early physiological changes that subserve the functional impairments in HD. This study is intended to investigate potential abnormality in dynamic changes in cerebral blood volume (CBV) and cerebral blood flow (CBF), and cerebral metabolic rate of oxygen (CMRO) in the brain in response to functional stimulation in premanifest and early manifest HD patients. A recently developed 3-D-TRiple-acquisition-after-Inversion-Preparation magnetic resonance imaging (MRI) approach was used to measure dynamic responses in CBV, CBF, and CMRO during visual stimulation in one single MRI scan. Experiments were conducted in 23 HD patients and 16 healthy controls. Decreased occipital cortex CMRO responses were observed in premanifest and early manifest HD patients compared to controls ( < 0.001), correlating with the CAG-Age Product scores in these patients ( = 0.4,  = 0.001). The results suggest the potential value of this reduced CMRO response during visual stimulation as a biomarker for HD and may illuminate the role of metabolic alterations in the pathophysiology of HD.



J Cereb Blood Flow Metab: 16 Aug 2020:271678X20949286; epub ahead of print
Klinkmueller P, Kronenbuerger M, Miao X, Bang J, ... Ross CA, Hua J
J Cereb Blood Flow Metab: 16 Aug 2020:271678X20949286; epub ahead of print | PMID: 32807001
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Abstract

Reduced parenchymal cerebral blood flow is associated with greater progression of brain atrophy: The SMART-MR study.

Ghaznawi R, Zwartbol MH, Zuithoff NP, Bresser J, ... Geerlings MI,

Global cerebral hypoperfusion may be involved in the aetiology of brain atrophy; however, long-term longitudinal studies on this relationship are lacking. We examined whether reduced cerebral blood flow was associated with greater progression of brain atrophy. Data of 1165 patients (61 ± 10 years) from the SMART-MR study, a prospective cohort study of patients with arterial disease, were used of whom 689 participated after 4 years and 297 again after 12 years. Attrition was substantial. Total brain volume and total cerebral blood flow were obtained from magnetic resonance imaging scans and expressed as brain parenchymal fraction (BPF) and parenchymal cerebral blood flow (pCBF). Mean decrease in BPF per year was 0.22% total intracranial volume (95% CI: -0.23 to -0.21). Mean decrease in pCBF per year was 0.24 ml/min per 100 ml brain volume (95% CI: -0.29 to -0.20). Using linear mixed models, lower pCBF at baseline was associated with a greater decrease in BPF over time (=0.01). Lower baseline BPF, however, was not associated with a greater decrease in pCBF (=0.43). These findings indicate that reduced cerebral blood flow is associated with greater progression of brain atrophy and provide further support for a role of cerebral blood flow in the process of neurodegeneration.



J Cereb Blood Flow Metab: 16 Aug 2020:271678X20948614; epub ahead of print
Ghaznawi R, Zwartbol MH, Zuithoff NP, Bresser J, ... Geerlings MI,
J Cereb Blood Flow Metab: 16 Aug 2020:271678X20948614; epub ahead of print | PMID: 32807000
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Impact:
Abstract

MiR-17-92 enriched exosomes derived from multipotent mesenchymal stromal cells enhance axon-myelin remodeling and motor electrophysiological recovery after stroke.

Xin H, Liu Z, Buller B, Li Y, ... Zhang ZG, Chopp M

MiR-17-92 cluster enriched exosomes derived from multipotent mesenchymal stromal cells (MSCs) increase functional recovery after stroke. Here, we investigate the mechanisms underlying this recovery. At 24 h (h) post transient middle cerebral artery occlusion, rats received control liposomes or exosomes derived from MSCs infected with pre-miR-17-92 expression lentivirus (Exo-miR-17-92) or control lentivirus (Exo-Con) intravenously. Compared to the liposomes, exosomes significantly reduced the intracortical microstimulation threshold current of the contralateral cortex for evoking impaired forelimb movements (day 21), increased the neurite and myelin density in the ischemic boundary area, and contralesional axonal sprouting into the caudal forelimb area of ipsilateral side and in the denervated spinal cord (day 28), respectively. The Exo-miR-17-92 further enhanced axon-myelin remodeling and electrophysiological recovery compared with the EXO-Con. Ex vivo cultured rat brain slice data showed that myelin and neuronal fiber density were significantly increased by Exo-miR-17-92, while significantly inhibited by application of the PI3K/Akt/mTOR pathway inhibitors. Our studies suggest that the miR-17-92 cluster enriched MSC exosomes enhanced neuro-functional recovery of stroke may be attributed to an increase of axonal extension and myelination, and this enhanced axon-myelin remodeling may be mediated in part via the activation of the PI3K/Akt/mTOR pathway induced by the downregulation of PTEN.



J Cereb Blood Flow Metab: 17 Aug 2020:271678X20950489; epub ahead of print
Xin H, Liu Z, Buller B, Li Y, ... Zhang ZG, Chopp M
J Cereb Blood Flow Metab: 17 Aug 2020:271678X20950489; epub ahead of print | PMID: 32811262
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Abstract

Feasibility of oscillating and pulsed gradient diffusion MRI to assess neonatal hypoxia-ischemia on clinical systems.

Gao F, Shen X, Zhang H, Ba R, ... Zhang Y, Wu D

Diffusion-time- () dependent diffusion MRI (dMRI) extends our ability to characterize brain microstructure by measuring dMRI signals at varying . The use of oscillating gradient (OG) is essential for accessing shortbut is technically challenging on clinical MRI systems. This study aims to investigate the clinical feasibility and value of -dependent dMRI in neonatal hypoxic-ischemic encephalopathy (HIE). Eighteen HIE neonates and six normal term-born neonates were scanned on a 3 T scanner, with OG-dMRI at an oscillating frequency of 33 Hz (equivalent  ≈ 7.5 ms) and pulsed gradient (PG)-dMRI at aof 82.8 ms and b-value of 700 s/mm. The -dependence, as quantified by the difference in apparent diffusivity coefficients between OG- and PG-dMRI (ΔADC), was observed in the normal neonatal brains, and the ΔADC was higher in the subcortical white matter than the deep grey matter. In HIE neonates with severe and moderate injury, ΔADC significantly increased in the basal ganglia (BG) compared to the controls (23.7% and 10.6%, respectively). In contrast, the conventional PG-ADC showed a 12.6% reduction only in the severe HIE group. White matter edema regions also demonstrated increased ΔADC, where PG-ADC did not show apparent changes. Our result demonstrated that -dependent dMRI provided high sensitivity in detecting moderate-to-severe HIE.



J Cereb Blood Flow Metab: 17 Aug 2020:271678X20944353; epub ahead of print
Gao F, Shen X, Zhang H, Ba R, ... Zhang Y, Wu D
J Cereb Blood Flow Metab: 17 Aug 2020:271678X20944353; epub ahead of print | PMID: 32811261
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Abstract

4D flow MRI for non-invasive measurement of blood flow in the brain: A systematic review.

Morgan AG, Thrippleton MJ, Wardlaw JM, Marshall I

The brain\'s vasculature is essential for brain health and its dysfunction contributes to the onset and development of many dementias and neurological disorders. While numerous in vivo imaging techniques exist to investigate cerebral haemodynamics in humans, phase-contrast magnetic resonance imaging (MRI) has emerged as a reliable, non-invasive method of quantifying blood flow within intracranial vessels. In recent years, an advanced form of this method, known as 4D flow, has been developed and utilised in patient studies, where its ability to capture complex blood flow dynamics within any major vessel across the acquired volume has proved effective in collecting large amounts of information in a single scan. While extremely promising as a method of examining the vascular system\'s role in brain-related diseases, the collection of 4D data can be time-consuming, meaning data quality has to be traded off against the acquisition time. Here, we review the available literature to examine 4D flow\'s capabilities in assessing physiological and pathological features of the cerebrovascular system. Emerging techniques such as dynamic velocity-encoding and advanced undersampling methods, combined with increasingly high-field MRI scanners, are likely to bring 4D flow to the forefront of cerebrovascular imaging studies in the years to come.



J Cereb Blood Flow Metab: 15 Sep 2020:271678X20952014; epub ahead of print
Morgan AG, Thrippleton MJ, Wardlaw JM, Marshall I
J Cereb Blood Flow Metab: 15 Sep 2020:271678X20952014; epub ahead of print | PMID: 32936731
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Abstract

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage.

Fischer P, Sugimoto K, Chung DY, Tamim I, ... Sakadzic S, Ayata C

Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0-4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8-52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.



J Cereb Blood Flow Metab: 15 Sep 2020:271678X20951993; epub ahead of print
Fischer P, Sugimoto K, Chung DY, Tamim I, ... Sakadzic S, Ayata C
J Cereb Blood Flow Metab: 15 Sep 2020:271678X20951993; epub ahead of print | PMID: 32936730
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Abstract

Hippocampal blood-brain barrier permeability is related to the APOE4 mutation status of elderly individuals without dementia.

Moon WJ, Lim C, Ha IH, Kim Y, ... Kim HJ, Han SH

Blood-brain barrier (BBB) disruption, modulated by APOE4 mutation, is implicated in the pathogenesis of cognitive decline. We determined whether BBB permeability differed according to cognitive functioning and APOE4 status in elderly subjects without dementia. In this prospective study, 33 subjects with mild cognitive impairment (MCI) and 33 age-matched controls (normal cognition [NC]) underwent 3 T brain magnetic resonance imaging. The Patlak model was used to calculate tissue permeability (K). A region-of interest analysis of K was performed to compare relevant brain regions. Effects of K on cognitive functioning were evaluated with linear regression analysis adjusted for confounding factors. NC and MCI groups did not differ in terms of vascular risk factors or hippocampal K except for hippocampal volume. Hippocampal K was significantly higher in APOE4 carriers than in non-carriers ( = 0.007). Factors which predicted cognitive functioning included hippocampal volume (beta=-0.445, standard error [SE]=0.137,  = 0.003) and hippocampal BBB permeability (beta = 0.142, SE = 0.050,  = 0.008) after correcting for age, education, and APOE4 status. This suggests that hippocampal BBB permeability is associated with APOE4 mutation, and may predict cognitive functioning. BBB permeability imaging represents a distinct imaging biomarker for APOE4 mutations in NC and MCI subjects and for determining the degree of APOE4-related pathology.



J Cereb Blood Flow Metab: 15 Sep 2020:271678X20952012; epub ahead of print
Moon WJ, Lim C, Ha IH, Kim Y, ... Kim HJ, Han SH
J Cereb Blood Flow Metab: 15 Sep 2020:271678X20952012; epub ahead of print | PMID: 32936729
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Abstract

Subarachnoid hemorrhage leads to early and persistent functional connectivity and behavioral changes in mice.

Chung DY, Oka F, Jin G, Harriott A, ... Whalen MJ, Ayata C

Aneurysmal subarachnoid hemorrhage (SAH) leads to significant long-term cognitive deficits, which can be associated with alterations in resting state functional connectivity (RSFC). However, modalities such as fMRI-which is commonly used to assess RSFC in humans-have practical limitations in small animals. Therefore, we used non-invasive optical intrinsic signal imaging to determine the effect of SAH on RSFC in mice up to three months after prechiasmatic blood injection. We assessed Morris water maze (MWM), open field test (OFT), Y-maze, and rotarod performance from approximately two weeks to three months after SAH. Compared to sham, we found that SAH reduced motor, retrosplenial, and visual seed-based connectivity indices. These deficits persisted in retrosplenial and visual cortex seeds at three months. Seed-to-seed analysis confirmed early attenuation of correlation coefficients in SAH mice, which persisted in predominantly posterior network connections at later time points. Seed-independent global and interhemispheric indices of connectivity revealed decreased correlations following SAH for at least one month. SAH led to MWM hidden platform and OFT deficits at two weeks, and Y-maze deficits for at least three months, without altering rotarod performance. In conclusion, experimental SAH leads to early and persistent alterations both in hemodynamically derived measures of RSFC and in cognitive performance.



J Cereb Blood Flow Metab: 15 Sep 2020:271678X20940152; epub ahead of print
Chung DY, Oka F, Jin G, Harriott A, ... Whalen MJ, Ayata C
J Cereb Blood Flow Metab: 15 Sep 2020:271678X20940152; epub ahead of print | PMID: 32936728
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Abstract

Remote ischemic conditioning enhances oxygen supply to ischemic brain tissue in a mouse model of stroke: Role of elevated 2,3-biphosphoglycerate in erythrocytes.

Wang L, Ren C, Li Y, Gao C, ... Xia C, Ji X

Oxygen supply for ischemic brain tissue during stroke is critical to neuroprotection. Remote ischemic conditioning (RIC) treatment is effective for stroke. However, it is not known whether RIC can improve brain tissue oxygen supply. In current study, we employed a mouse model of stroke created by middle cerebral artery occlusion (MCAO) to investigate the effect of RIC on oxygen supply to the ischemic brain tissue using a hypoxyprobe system. Erythrocyte oxygen-carrying capacity and tissue oxygen exchange were assessed by measuring oxygenated hemoglobin and oxygen dissociation curve. We found that RIC significantly mitigated hypoxic signals and decreased neural cell death, thereby preserving neurological functions. The tissue oxygen exchange was markedly enhanced, along with the elevated hemoglobin P50 and right-shifted oxygen dissociation curve. Intriguingly, RIC markedly elevated 2,3-biphosphoglycerate (2,3-BPG) levels in erythrocyte, and the erythrocyte 2,3-BPG levels were highly negatively correlated with the hypoxia in the ischemic brain tissue. Further, adoptive transfusion of 2,3-BPG-rich erythrocytes prepared from RIC-treated mice significantly enhanced the oxygen supply to the ischemic tissue in MCAO mouse model. Collectively, RIC protects against ischemic stroke through improving oxygen supply to the ischemic brain tissue where the enhanced tissue oxygen delivery and exchange by RIC-induced 2,3-BPG-rich erythrocytes may play a role.



J Cereb Blood Flow Metab: 14 Sep 2020:271678X20952264; epub ahead of print
Wang L, Ren C, Li Y, Gao C, ... Xia C, Ji X
J Cereb Blood Flow Metab: 14 Sep 2020:271678X20952264; epub ahead of print | PMID: 32933360
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Abstract

Regulation of blood-brain barrier integrity by microglia in health and disease: A therapeutic opportunity.

Ronaldson PT, Davis TP

The blood-brain barrier (BBB) is a critical regulator of CNS homeostasis. It possesses physical and biochemical characteristics (i.e. tight junction protein complexes, transporters) that are necessary for the BBB to perform this physiological role. Microvascular endothelial cells require support from astrocytes, pericytes, microglia, neurons, and constituents of the extracellular matrix. This intricate relationship implies the existence of a neurovascular unit (NVU). NVU cellular components can be activated in disease and contribute to dynamic remodeling of the BBB. This is especially true of microglia, the resident immune cells of the brain, which polarize into distinct proinflammatory (M1) or anti-inflammatory (M2) phenotypes. Current data indicate that M1 pro-inflammatory microglia contribute to BBB dysfunction and vascular \"leak\", while M2 anti-inflammatory microglia play a protective role at the BBB. Understanding biological mechanisms involved in microglia activation provides a unique opportunity to develop novel treatment approaches for neurological diseases. In this review, we highlight characteristics of M1 proinflammatory and M2 anti-inflammatory microglia and describe how these distinct phenotypes modulate BBB physiology. Additionally, we outline the role of other NVU cell types in regulating microglial activation and highlight how microglia can be targeted for treatment of disease with a focus on ischemic stroke and Alzheimer\'s disease.



J Cereb Blood Flow Metab: 13 Sep 2020:271678X20951995; epub ahead of print
Ronaldson PT, Davis TP
J Cereb Blood Flow Metab: 13 Sep 2020:271678X20951995; epub ahead of print | PMID: 32928017
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Abstract

Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

Pålhaugen L, Sudre CH, Tecelao S, Nakling A, ... Selnes P, Fladby T

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer\'s disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/-) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH ( = 0.001) and occipital DWMH ( = 0.003) loads were increased in SCD-Aβ+ compared with Aβ- controls. In MCI-Aβ+ compared with Aβ- controls, there were differences in global WMH ( = 0.003), as well as occipital DWMH ( = 0.001) and temporal DWMH ( = 0.002) loads. FRS-CVD was associated with frontal PWMHs ( = 0.003) and frontal DWMHs ( = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology.



J Cereb Blood Flow Metab: 20 Sep 2020:271678X20957604; epub ahead of print
Pålhaugen L, Sudre CH, Tecelao S, Nakling A, ... Selnes P, Fladby T
J Cereb Blood Flow Metab: 20 Sep 2020:271678X20957604; epub ahead of print | PMID: 32955960
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Abstract

Long-term outcome of endovascular therapy for acute basilar artery occlusion.

Wu L, Zhang D, Chen J, Sun C, ... Wu D, Ji X

The long-term functional outcome of acute basilar artery occlusion (BAO) patients who received modern endovascular therapy (EVT) is unclear. We sought to assess the long-term functional outcome of BAO patients treated with EVT and determine the prognostic factors associated with favorable outcome. We enrolled consecutive BAO patients who received EVT between December 2012 and December 2018 in this observational study. Baseline characteristics and outcomes were presented. Multivariable logistic regression analysis was performed to identify the prognostic factors associated with long-term outcome. Among the 177 BAO patients included in this study, 80 patients (45.2%) obtained favorable outcome and 97 patients (54.8%) had unfavorable outcome at long-term follow-up with a median observation time of 12 months (interquartile range, 3-19). A total of 67 patients (37.9%) died. National Institutes of Health Stroke Scale (NIHSS), posterior circulation Alberta Stroke Program Early Computed Tomography Score (pc-ASPECTS), time from stroke onset to recanalization, and recanalization condition were identified as independent predictors for long-term outcome. Over 40% of BAO patients who were treated with modern EVT achieved favorable outcome at long-term follow-up. NIHSS, pc-ASPECTS, time from stroke onset to recanalization, and recanalization condition were identified as independent prognostic factors of long-term outcome.



J Cereb Blood Flow Metab: 20 Sep 2020:271678X20958587; epub ahead of print
Wu L, Zhang D, Chen J, Sun C, ... Wu D, Ji X
J Cereb Blood Flow Metab: 20 Sep 2020:271678X20958587; epub ahead of print | PMID: 32955959
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Abstract

The rise of pericytes in neurovascular research.

Beard DJ, Brown LS, Sutherland BA

The popularity of pericyte research is increasing, and this was not more evident than at the recent 2019 Brain meeting in Yokohama which featured a large number of presentations focused on brain pericyte research, including the Presidential Symposium. In this article, we will provide a history of brain pericyte research, present the results of our analysis showing a substantial increase in brain pericyte research presented at Brain meetings since 2005, suggest reasons for their increased popularity, and comment on what the future holds for brain pericyte research.



J Cereb Blood Flow Metab: 20 Sep 2020:271678X20958497; epub ahead of print
Beard DJ, Brown LS, Sutherland BA
J Cereb Blood Flow Metab: 20 Sep 2020:271678X20958497; epub ahead of print | PMID: 32955956
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Abstract

Simplified quantification of [F]FE-PE2I PET in Parkinson\'s disease: Discriminative power, test-retest reliability and longitudinal validity during early peak and late pseudo-equilibrium.

Brumberg J, Kerstens V, Cselényi Z, Svenningsson P, ... Fazio P, Varrone A

Quantification of dopamine transporter (DAT) availability with [F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium. Receiver operating characteristics area under the curve (PD vs. controls) was high for early (0.996) and late (0.991) SBR. Early SBR provided more favourable effect size, absolute variability, and standard error of measurement than late SBR (caudate: 1.29 vs. 1.23; 6.9% vs. 9.8%; 0.09 vs. 0.20; putamen: 1.75 vs. 1.67; 7.7% vs. 14.0%; 0.08 vs. 0.17). The annual percentage change was comparable for both time windows (-7.2%-8.5%), but decline was significant only for early SBR. Whereas early and late [F]FE-PE2I PET acquisitions have similar discriminative power to separate PD patients and controls, the early peak equilibrium acquisition can be recommended if [F]FE-PE2I is used to measure longitudinal changes of DAT availability.



J Cereb Blood Flow Metab: 20 Sep 2020:271678X20958755; epub ahead of print
Brumberg J, Kerstens V, Cselényi Z, Svenningsson P, ... Fazio P, Varrone A
J Cereb Blood Flow Metab: 20 Sep 2020:271678X20958755; epub ahead of print | PMID: 32955955
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Abstract

Benefits of exercise training on cerebrovascular and cognitive function in ageing.

Bliss ES, Wong RH, Howe PR, Mills DE

Derangements in cerebrovascular structure and function can impair cognitive performance throughout ageing and in cardiometabolic disease states, thus increasing dementia risk. Modifiable lifestyle factors that cause a decline in cardiometabolic health, such as physical inactivity, exacerbate these changes beyond those that are associated with normal ageing. The purpose of this review was to examine cerebrovascular, cognitive and neuroanatomical adaptations to ageing and the potential benefits of exercise training on these outcomes in adults 50 years or older. We systematically searched for cross-sectional or intervention studies that included exercise (aerobic, resistance or multimodal) and its effect on cerebrovascular function, cognition and neuroanatomical adaptations in this age demographic. The included studies were tabulated and described narratively. Aerobic exercise training was the predominant focus of the studies identified; there were limited studies exploring the effects of resistance exercise training and multimodal training on cerebrovascular function and cognition. Collectively, the evidence indicated that exercise can improve cerebrovascular function, cognition and neuroplasticity through areas of the brain associated with executive function and memory in adults 50 years or older, irrespective of their health status. However, more research is required to ascertain the mechanisms of action.



J Cereb Blood Flow Metab: 19 Sep 2020:271678X20957807; epub ahead of print
Bliss ES, Wong RH, Howe PR, Mills DE
J Cereb Blood Flow Metab: 19 Sep 2020:271678X20957807; epub ahead of print | PMID: 32954902
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Abstract

Glucagon like peptide-1 receptor agonists as neuroprotective agents for ischemic stroke: a systematic scoping review.

Maskery MP, Holscher C, Jones SP, Price CI, ... Werring DJ, Emsley HCA

Stroke mortality and morbidity is expected to rise. Despite considerable recent advances within acute ischemic stroke treatment, scope remains for development of widely applicable neuroprotective agents. Glucagon like peptide-1 receptor agonists (GLP-1RAs), originally licensed for the management of Type 2 Diabetes Mellitus, have demonstrated pre-clinical neuroprotective efficacy in a range of neurodegenerative conditions. This systematic scoping review reports the pre-clinical basis of GLP-1RAs as neuroprotective agents in acute ischemic stroke and their translation into clinical trials. We included 35 pre-clinical studies, 11 retrospective database studies, 7 cardiovascular outcome trials and 4 prospective clinical studies. Pre-clinical neuroprotection was demonstrated in normoglycemic models when administration was delayed by up to 24 h following stroke induction. Outcomes included reduced infarct volume, apoptosis, oxidative stress and inflammation alongside increased neurogenesis, angiogenesis and cerebral blood flow. Improved neurological function and a trend towards increased survival were also reported. Cardiovascular outcomes trials reported a significant reduction in stroke incidence with semaglutide and dulaglutide. Retrospective database studies show a trend towards neuroprotection. Prospective interventional clinical trials are on-going, but initial indicators of safety and tolerability are favourable. Ultimately, we propose that repurposing GLP-1RAs is potentially advantageous but appropriately designed trials are needed to determine clinical efficacy and cost-effectiveness.



J Cereb Blood Flow Metab: 19 Sep 2020:271678X20952011; epub ahead of print
Maskery MP, Holscher C, Jones SP, Price CI, ... Werring DJ, Emsley HCA
J Cereb Blood Flow Metab: 19 Sep 2020:271678X20952011; epub ahead of print | PMID: 32954901
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Abstract

Longitudinal monitoring of microglial/macrophage activation in ischemic rat brain using Iba-1-specific nanoparticle-enhanced magnetic resonance imaging.

Sillerud LO, Yang Y, Yang LY, Duval KB, Thompson J, Yang Y

Microglial/macrophage activation plays a dual role in response to brain injury after a stroke, promoting early neuroinflammation and benefit for neurovascular recovery. Therefore, the dynamics of stroke-induced cerebral microglial/macrophage activation are of substantial interest. This study used novel anti-Iba-1-targeted superparamagnetic iron-platinum (FePt) nanoparticles in conjunction with magnetic resonance imaging (MRI) to measure the spatiotemporal changes of the microglial/macrophage activation in living rat brain for four weeks post-stroke. Ischemic lesion areas were identified and measured using T-weighted MR images. After injection of the FePt-nanoparticles, T*-weighted MR images showed that the nanoparticles were seen solely in brain regions that coincided with areas of active microglia/macrophages detected by post-mortem immunohistochemistry. Good agreement in morphological and distributive dynamic changes was also observed between the Fe-cells and the Iba-1-microglia/macrophages. The spatiotemporal changes of nanoparticle detected by T*-weighted images paralleled the changes of microglial/macrophage activation and phenotypes measured by post-mortem immunohistochemistry over the four weeks post-stroke. Maximum microglial/macrophage activation occurred seven days post-stroke for both measures, and the diminished activation found after two weeks continued to four weeks. Our results suggest that nanoparticle-enhanced MRI may constitute a novel approach for monitoring the dynamic development of neuroinflammation in living animals during the progression and treatment of stroke.



J Cereb Blood Flow Metab: 21 Sep 2020:271678X20953913; epub ahead of print
Sillerud LO, Yang Y, Yang LY, Duval KB, Thompson J, Yang Y
J Cereb Blood Flow Metab: 21 Sep 2020:271678X20953913; epub ahead of print | PMID: 32960690
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Abstract

Distinct peripheral blood monocyte and neutrophil transcriptional programs following intracerebral hemorrhage and different etiologies of ischemic stroke.

Carmona-Mora P, Ander BP, Jickling GC, Dykstra-Aiello C, ... Sharp FR, Stamova B

Understanding cell-specific transcriptome responses following intracerebral hemorrhage (ICH) and ischemic stroke (IS) will improve knowledge of the immune response to brain injury. Transcriptomic profiles of 141 samples from 48 subjects with ICH, different IS etiologies, and vascular risk factor controls were characterized using RNA-seq in isolated neutrophils, monocytes and whole blood. In both IS and ICH, monocyte genes were down-regulated, whereas neutrophil gene expression changes were generally up-regulated. The monocyte down-regulated response to ICH included innate, adaptive immune, dendritic, NK cell and atherosclerosis signaling. Neutrophil responses to ICH included tRNA charging, mitochondrial dysfunction, and ER stress pathways. Common monocyte and neutrophil responses to ICH included interferon signaling, neuroinflammation, death receptor signaling, and NFAT pathways. Suppressed monocyte responses to IS included interferon and dendritic cell maturation signaling, phagosome formation, and IL-15 signaling. Activated neutrophil responses to IS included oxidative phosphorylation, mTOR, BMP, growth factor signaling, and calpain proteases-mediated blood-brain barrier (BBB) dysfunction. Common monocyte and neutrophil responses to IS included JAK1, JAK3, STAT3, and thrombopoietin signaling. Cell-type and cause-specific approaches will assist the search for future IS and ICH biomarkers and treatments.



J Cereb Blood Flow Metab: 21 Sep 2020:271678X20953912; epub ahead of print
Carmona-Mora P, Ander BP, Jickling GC, Dykstra-Aiello C, ... Sharp FR, Stamova B
J Cereb Blood Flow Metab: 21 Sep 2020:271678X20953912; epub ahead of print | PMID: 32960689
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Abstract

Tissue despite full recanalization following thrombectomy for anterior circulation stroke with proximal occlusion: A clinical study.

Schiphorst AT, Charron S, Hassen WB, Provost C, ... Baron JC, Oppenheim C

Despite early thrombectomy, a sizeable fraction of acute stroke patients with large vessel occlusion have poor outcome. Thephenomenon, i.e. impaired microvascular reperfusion despite complete recanalization, may contribute to such \"futile recanalizations\". Although well reported in animal models,is still poorly characterized in man. From a large prospective thrombectomy database, we included all patients with intracranial proximal occlusion, complete recanalization (modified thrombolysis in cerebral infarction score 2c-3), and availability of both baseline and 24 h follow-up MRI including arterial spin labeling perfusion mapping.was operationally defined as i) hypoperfusion ≥40% relative to contralateral homologous region, assessed with both visual (two independent investigators) and automatic image analysis, and ii) infarction on follow-up MRI. Thirty-three patients were eligible (median age: 70 years, NIHSS: 18, and stroke onset-to-recanalization delay: 208 min). The operational criteria were met in one patient only, consistently with the visual and automatic analyses. This patient recanalized 160 min after stroke onset and had excellent functional outcome. In our cohort of patients with complete and stable recanalization following thrombectomy for intracranial proximal occlusion, severe ipsilateral hypoperfusion on follow-up imaging associated with newly developed infarction was a rare occurrence. Thus,may be infrequent in human stroke and may not substantially contribute to futile recanalizations.



J Cereb Blood Flow Metab: 21 Sep 2020:271678X20954929; epub ahead of print
Schiphorst AT, Charron S, Hassen WB, Provost C, ... Baron JC, Oppenheim C
J Cereb Blood Flow Metab: 21 Sep 2020:271678X20954929; epub ahead of print | PMID: 32960688
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Abstract

NMDA receptor ion channel activation detected in vivo with [F]GE-179 PET after electrical stimulation of rat hippocampus.

Vibholm AK, Landau AM, Møller A, Jacobsen J, ... Sørensen JC, Brooks DJ

The positron emission tomography (PET) tracer [F]GE-179 binds to the phencyclidine (PCP) site in the open -methyl-D-aspartate receptor ion channel (NMDAR-IC). To demonstrate that PET can visualise increased [F]GE-179 uptake by active NMDAR-ICs and that this can be blocked by the PCP antagonist S-ketamine, 15 rats had an electrode unilaterally implanted in their ventral hippocampus. Seven rats had no stimulation, five received pulsed 400 µA supra-threshold 60 Hz stimulation alone, and three received intravenous S-ketamine injection prior to stimulation. Six other rats were not implanted. Each rat had a 90 min [F]GE-179 PET scan. Stimulated rats had simultaneous depth-EEG recordings of induced seizure activity. [F]GE-179 uptake (volume of distribution, V) was compared between hemispheres and between groups. Electrical stimulation induced a significant increase in [F]GE-179 uptake at the electrode site compared to the contralateral hippocampus (mean 22% increase in V, =0.0014) and to non-stimulated comparator groups. Rats injected with S-ketamine prior to stimulation maintained non-stimulated levels of [F]GE-179 uptake during stimulation. In conclusion, PET visualisation of focal [F]GE-179 uptake during electrically activated NMDAR-ICs and the demonstration of specificity for PCP sites by blockade with S-ketamine support the in vivo utility of [F]GE-179 PET as a use-dependent marker of NMDAR-IC activation.



J Cereb Blood Flow Metab: 21 Sep 2020:271678X20954928; epub ahead of print
Vibholm AK, Landau AM, Møller A, Jacobsen J, ... Sørensen JC, Brooks DJ
J Cereb Blood Flow Metab: 21 Sep 2020:271678X20954928; epub ahead of print | PMID: 32960687
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Abstract

Epitranscriptomic regulation by mA RNA methylation in brain development and diseases.

Chokkalla AK, Mehta SL, Vemuganti R

Cellular RNAs are pervasively tagged with diverse chemical moieties, collectively called epitranscriptomic modifications. The methylation of adenosine at N position generates N-methyladenosine (mA), which is the most abundant and reversible epitranscriptomic modification in mammals. The mA signaling is mediated by a dedicated set of proteins comprised of writers, erasers, and readers. Contrary to the activation-repression binary view of gene regulation, emerging evidence suggests that the mA methylation controls multiple aspects of mRNA metabolism, such as splicing, export, stability, translation, and degradation, culminating in the fine-tuning of gene expression. Brain shows the highest abundance of mA methylation in the body, which is developmentally altered. Within the brain, mA methylation is biased toward neuronal transcripts and sensitive to neuronal activity. In a healthy brain, mA maintains several developmental and physiological processes such as neurogenesis, axonal growth, synaptic plasticity, circadian rhythm, cognitive function, and stress response. The mA imbalance contributes to the pathogenesis of acute and chronic CNS insults, brain cancer, and neuropsychiatric disorders. This review discussed the molecular mechanisms of mA regulation and its implication in the developmental, physiological, and pathological processes of the brain.



J Cereb Blood Flow Metab: 22 Sep 2020:271678X20960033; epub ahead of print
Chokkalla AK, Mehta SL, Vemuganti R
J Cereb Blood Flow Metab: 22 Sep 2020:271678X20960033; epub ahead of print | PMID: 32967524
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Abstract

Large-scale characterization of the microvascular geometry in development and disease by tissue clearing and quantitative ultramicroscopy.

Hahn A, Bode J, Alexander A, Karimian-Jazi K, ... Kurz FT, Breckwoldt MO

Three-dimensional assessment of optically cleared, entire organs and organisms has recently become possible by tissue clearing and selective plane illumination microscopy (\"ultramicroscopy\"). Resulting datasets can be highly complex, encompass over a thousand images with millions of objects and data of several gigabytes per acquisition. This constitutes a major challenge for quantitative analysis. We have developed post-processing tools to quantify millions of microvessels and their distribution in three-dimensional datasets from ultramicroscopy and demonstrate the capabilities of our pipeline within entire mouse brains and embryos. Using our developed acquisition, segmentation, and analysis platform, we quantify physiological vascular networks in development and the healthy brain. We compare various geometric vessel parameters (e.g. vessel density, radius, tortuosity) in the embryonic spinal cord and brain as well as in different brain regions (basal ganglia, corpus callosum, cortex). White matter tract structures (corpus callosum, spinal cord) showed lower microvascular branch densities and longer vessel branch length compared to grey matter (cortex, basal ganglia). Furthermore, we assess tumor neoangiogenesis in a mouse glioma model to compare tumor core and tumor border. The developed methodology allows rapid quantification of three-dimensional datasets by semi-automated segmentation of fluorescently labeled objects with conventional computer hardware. Our approach can aid preclinical investigations and paves the way towards \"quantitative ultramicroscopy\".



J Cereb Blood Flow Metab: 11 Oct 2020:271678X20961854; epub ahead of print
Hahn A, Bode J, Alexander A, Karimian-Jazi K, ... Kurz FT, Breckwoldt MO
J Cereb Blood Flow Metab: 11 Oct 2020:271678X20961854; epub ahead of print | PMID: 33043767
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Abstract

Microglia/macrophage polarization: Fantasy or evidence of functional diversity?

Hu X

Microglia and non-parenchymal macrophages are increasingly recognized to play critical roles in the central nervous system (CNS) health and disease. Accumulating evidence suggests that these mononuclear phagocytes do not constitute stereotypical cell populations, but rather polarize into a variety of phenotypes at different stages of CNS development, stresses, and diseases. This commentary aims to discuss our current consensus and controversy on microglia/macrophage phenotypes. Collective single-cell level evidence validates the concept of microglia/macrophage polarization, while suggests multi-polarity instead of dichotomic polarization. Characterizing the functions of a specific microglia/macrophage phenotype is challenging yet essential to translate our scientific discoveries into clinical application.



J Cereb Blood Flow Metab: 05 Oct 2020:271678X20963405; epub ahead of print
Hu X
J Cereb Blood Flow Metab: 05 Oct 2020:271678X20963405; epub ahead of print | PMID: 33023387
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Abstract

Intracranial vessel wall lesions on 7T MRI and MRI features of cerebral small vessel disease-The SMART-MR study.

Zwartbol MH, van der Kolk AG, Kuijf HJ, Witkamp TD, ... Geerlings MI,

The etiology of cerebral small vessel disease (CSVD) is the subject of ongoing research. Although intracranial atherosclerosis (ICAS) has been proposed as a possible cause, studies on their relationship remain sparse. We used 7 T vessel wall magnetic resonance imaging (MRI) to study the association between intracranial vessel wall lesions-a neuroimaging marker of ICAS-and MRI features of CSVD. Within the SMART-MR study, cross-sectional analyses were performed in 130 patients (68 ± 9 years; 88% male). ICAS burden-defined as the number of vessel wall lesions-was determined on 7 T vessel wall MRI. CSVD features were determined on 1.5 T and 7 T MRI. Associations between ICAS burden and CSVD features were estimated with linear or modified Poisson regression, adjusted for age, sex, vascular risk factors, and medication use. In 125 patients, ≥1 vessel wall lesions were found (mean 8.5 ± 5.7 lesions). ICAS burden (per + 1 SD) was associated with presence of large subcortical and/or cortical infarcts (RR = 1.65; 95%CI: 1.12-2.43), lacunes (RR = 1.45; 95% CI: 1.14-1.86), cortical microinfarcts (RR = 1.48; 95%CI: 1.13-1.94), and total white matter hyperintensity volume ( = 0.24; 95%CI: 0.02-0.46). Concluding, patients with a higher ICAS burden had more CSVD features, although no evidence of co-location was observed. Further longitudinal studies are required to determine if ICAS precedes development of CSVD.



J Cereb Blood Flow Metab: 05 Oct 2020:271678X20958517; epub ahead of print
Zwartbol MH, van der Kolk AG, Kuijf HJ, Witkamp TD, ... Geerlings MI,
J Cereb Blood Flow Metab: 05 Oct 2020:271678X20958517; epub ahead of print | PMID: 33023386
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Abstract

Cerebrovascular effects of glibenclamide investigated using high-resolution magnetic resonance imaging in healthy volunteers.

Al-Karagholi MA, Ghanizada H, Nielsen CAW, Ansari A, ... Amin FM, Ashina M

Glibenclamide inhibits sulfonylurea receptor (SUR), which regulates several ion channels including SUR1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel and ATP-sensitive potassium (K) channel. Stroke upregulates SURl-TRPM4 channel, which causes a rapid edema formation and brain swelling. Glibenclamide may antagonize the formation of cerebral edema during stroke. Preclinical studies showed that glibenclamide inhibits K channel-induced vasodilation without altering the basal vascular tone. The in vivo human cerebrovascular effects of glibenclamide have not previously been investigated.In a randomized, double-blind, placebo-controlled, three-way cross-over study, we used advanced 3 T MRI methods to investigate the effects of glibenclamide and K channel opener levcromakalim on mean global cerebral blood flow (CBF) and intra- and extracranial artery circumferences in 15 healthy volunteers. Glibenclamide administration did not alter the mean global CBF and the basal vascular tone. Following levcromakalim infusion, we observed a 14% increase of the mean global CBF and an 8% increase of middle cerebral artery (MCA) circumference, and glibenclamide did not attenuate levcromakalim-induced vascular changes. Collectively, the findings demonstrate the vital role of K channels in cerebrovascular hemodynamic and indicate that glibenclamide does not inhibit the protective effects of K channel activation during hypoxia and ischemia-induced brain injury.



J Cereb Blood Flow Metab: 06 Oct 2020:271678X20959294; epub ahead of print
Al-Karagholi MA, Ghanizada H, Nielsen CAW, Ansari A, ... Amin FM, Ashina M
J Cereb Blood Flow Metab: 06 Oct 2020:271678X20959294; epub ahead of print | PMID: 33028147
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Abstract

A local-neighborhood Lassen plot filter for creating occupancy and non-displaceable binding images.

de Laat B, Morris ED

For radioligands without a reference region, the Lassen plot can be used to estimate receptor occupancy by an exogenous drug (). However, the Lassen plot is not well-suited for spatial variation in . To overcome this limitation, we introduce a Lassen plot filter, i.e. a Lassen plot applied to local neighborhoods in PET images. Image data were simulated with regional variation in , , both, or neither and analyzed using the change in binding potential (), the conventional Lassen plot, and the Lassen plot filter at the region of interest (ROI) and voxel level. All methods were also applied to a human [C]flumazenil occupancy study using PF-06372865. This combination of a non-selective radioligand and selective drug should lead to varying provided the distribution of subtypes varies spatially. In contrast withand the conventional Lassen plot, ROI-level and voxel-level Lassen plot filter estimates remained unbiased in the presence of regional variation inor . In the [C]flumazenil data-set,was shown to vary regionally in accordance with the distribution of binding sites for [C]flumazenil and PF-06372865. We demonstrate that a local-neighborhood Lassen plot filter provides robust and unbiased estimates ofandwithout the need for any user intervention.



J Cereb Blood Flow Metab: 12 Oct 2020:271678X20950486; epub ahead of print
de Laat B, Morris ED
J Cereb Blood Flow Metab: 12 Oct 2020:271678X20950486; epub ahead of print | PMID: 33050827
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Abstract

Impaired capillary-to-arteriolar electrical signaling after traumatic brain injury.

Mughal A, Sackheim AM, Sancho M, Longden TA, ... Nelson MT, Freeman K

Traumatic brain injury (TBI) acutely impairs dynamic regulation of local cerebral blood flow, but long-term (>72 h) effects on functional hyperemia are unknown. Functional hyperemia depends on capillary endothelial cell inward rectifier potassium channels (Kir2.1) responding to potassium (K) released during neuronal activity to produce a regenerative, hyperpolarizing electrical signal that propagates from capillaries to dilate upstream penetrating arterioles. We hypothesized that TBI causes widespread disruption of electrical signaling from capillaries-to-arterioles through impairment of Kir2.1 channel function. We randomized mice to TBI or control groups and allowed them to recover for 4 to 7 days post-injury. We measured in vivo cerebral hemodynamics and arteriolar responses to local stimulation of capillaries with 10 mM K using multiphoton laser scanning microscopy through a cranial window under urethane and α-chloralose anesthesia. Capillary angio-architecture was not significantly affected following injury. However, K-induced hyperemia was significantly impaired. Electrophysiology recordings in freshly isolated capillary endothelial cells revealed diminished Ba-sensitive Kir2.1 currents, consistent with a reduction in channel function. In pressurized cerebral arteries isolated from TBI mice, K failed to elicit the vasodilation seen in controls. We conclude that disruption of endothelial Kir2.1 channel function impairs capillary-to-arteriole electrical signaling, contributing to altered cerebral hemodynamics after TBI.



J Cereb Blood Flow Metab: 12 Oct 2020:271678X20962594; epub ahead of print
Mughal A, Sackheim AM, Sancho M, Longden TA, ... Nelson MT, Freeman K
J Cereb Blood Flow Metab: 12 Oct 2020:271678X20962594; epub ahead of print | PMID: 33050826
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Abstract

Impairment of cerebrovascular reactivity in response to hypercapnic challenge in a mouse model of repetitive mild traumatic brain injury.

Lynch CE, Eisenbaum M, Algamal M, Balbi M, ... Crawford F, Bachmeier C

Incidences of repetitive mild TBI (r-mTBI), like those sustained by contact sports athletes and military personnel, are thought to be a risk factor for development of neurodegenerative disorders. Those suffering from chronic TBI-related illness demonstrate deficits in cerebrovascular reactivity (CVR), the ability of the cerebral vasculature to respond to a vasoactive stimulus. CVR is thus an important measure of traumatic cerebral vascular injury (TCVI), and a possible in vivo endophenotype of TBI-related neuropathogenesis. We combined laser speckle imaging of CVR in response to hypercapnic challenge with neurobehavioral assessment of learning and memory, to investigate if decreased cerebrovascular responsiveness underlies impaired cognitive function in our mouse model of chronic r-mTBI. We demonstrate a profile of blunted hypercapnia-evoked CVR in the cortices of r-mTBI mice like that of human TBI, alongside sustained memory and learning impairment, without biochemical or immunohistopathological signs of cerebral vessel laminar or endothelium constituent loss. Transient decreased expression of alpha smooth muscle actin and platelet-derived growth factor receptor β, indicative of TCVI, is obvious only at the time of the most pronounced CVR deficit. These findings implicate CVR as a valid preclinical measure of TCVI, perhaps useful for developing therapies targeting TCVI after recurrent mild head trauma.



J Cereb Blood Flow Metab: 12 Oct 2020:271678X20954015; epub ahead of print
Lynch CE, Eisenbaum M, Algamal M, Balbi M, ... Crawford F, Bachmeier C
J Cereb Blood Flow Metab: 12 Oct 2020:271678X20954015; epub ahead of print | PMID: 33050825
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Abstract

Complete inhibition of ABCB1 and ABCG2 at the blood-brain barrier by co-infusion of erlotinib and tariquidar to improve brain delivery of the model ABCB1/ABCG2 substrate [C]erlotinib.

Tournier N, Goutal S, Mairinger S, Lozano IH, ... Wanek T, Langer O

P-glycoprotein (ABCB1) and breast cancer resistance protein (ABCG2) restrict at the blood-brain barrier (BBB) the brain distribution of the majority of currently known molecularly targeted anticancer drugs. To improve brain delivery of dual ABCB1/ABCG2 substrates, both ABCB1 and ABCG2 need to be inhibited simultaneously at the BBB. We examined the feasibility of simultaneous ABCB1/ABCG2 inhibition with i.v. co-infusion of erlotinib and tariquidar by studying brain distribution of the model ABCB1/ABCG2 substrate [C]erlotinib in mice and rhesus macaques with PET. Tolerability of the erlotinib/tariquidar combination was assessed in human embryonic stem cell-derived cerebral organoids. In mice and macaques, baseline brain distribution of [C]erlotinib was low (brain distribution volume,  < 0.3 mL/cm). Co-infusion of erlotinib and tariquidar increasedin mice by 3.0-fold and in macaques by 3.4- to 5.0-fold, while infusion of erlotinib alone or tariquidar alone led to less pronouncedincreases in both species. Treatment of cerebral organoids with erlotinib/tariquidar led to an induction of Caspase-3-dependent apoptosis. Co-infusion of erlotinib/tariquidar may potentially allow for complete ABCB1/ABCG2 inhibition at the BBB, while simultaneously achieving brain-targeted EGFR inhibition. Our protocol may be applicable to enhance brain delivery of molecularly targeted anticancer drugs for a more effective treatment of brain tumors.



J Cereb Blood Flow Metab: 19 Oct 2020:271678X20965500; epub ahead of print
Tournier N, Goutal S, Mairinger S, Lozano IH, ... Wanek T, Langer O
J Cereb Blood Flow Metab: 19 Oct 2020:271678X20965500; epub ahead of print | PMID: 33081568
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Abstract

Arterial elasticity, endothelial function and intracranial vascular health: A multimodal MRI study.

Liu W, Chen Z, Ortega D, Liu X, ... Li H, Yang J

Vascular dysfunctions, including arterial stiffness and endothelial dysfunction, are prevalent in hypertensive subjects. We aimed to study their relations to subclinical intracranial vascular health in this study. A total of 200 older hypertensive males without overt cardiovascular or cerebrovascular diseases were recruited. Arterial elasticity was measured as carotid-femoral pulse wave velocity (cfPWV) and endothelial function was measured as digital reactive hyperemia index (RHI). Cerebrovascular health was evaluated using MRI in four aspects: intracranial atherosclerosis, brain perfusion as cerebral blood flow (CBF), vascular rarefaction analyzed as visible arterial branches on angiography using a custom-developed analysis technique and small vessel disease measured as white matter hyperintensity (WMH). There was a significant negative association between cfPWV and CBF, suggesting a link between arterial stiffness and CBF decline. Higher cfPWV was also associated with presence of intracranial stenotic plaque and greater WMH volume. RHI was positively related to CBF, indicating that endothelial dysfunction was associated with reduced CBF. All the associations remained significant after adjustment for confounding variables. Arterial stiffness and endothelial dysfunction are associated with reduced brain perfusion in older hypertensive males. Arterial stiffness is also associated with global cerebral vascular injury, affecting both small and medium-to-large arteries.



J Cereb Blood Flow Metab: 19 Oct 2020:271678X20956950; epub ahead of print
Liu W, Chen Z, Ortega D, Liu X, ... Li H, Yang J
J Cereb Blood Flow Metab: 19 Oct 2020:271678X20956950; epub ahead of print | PMID: 33081567
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Abstract

Evaluation of the potassium channel tracer [F]3F4AP in rhesus macaques.

Guehl NJ, Ramos-Torres KM, Linnman C, Moon SH, ... Normandin MD, Brugarolas P

Demyelination causes slowed or failed neuronal conduction and is a driver of disability in multiple sclerosis and other neurological diseases. Currently, the gold standard for imaging demyelination is MRI, but despite its high spatial resolution and sensitivity to demyelinated lesions, it remains challenging to obtain specific and quantitative measures of molecular changes involved in demyelination. To understand the contribution of demyelination in different diseases and to assess the efficacy of myelin-repair therapies, it is critical to develop new in vivo imaging tools sensitive to changes induced by demyelination. Upon demyelination, axonal K channels, normally located underneath the myelin sheath, become exposed and increase in expression, causing impaired conduction. Here, we investigate the properties of the K channel PET tracer [F]3F4AP in primates and its sensitivity to a focal brain injury that occurred three years prior to imaging. [F]3F4AP exhibited favorable properties for brain imaging including high brain penetration, high metabolic stability, high plasma availability, high reproducibility, high specificity, and fast kinetics. [F]3F4AP showed preferential binding in areas of low myelin content as well as in the previously injured area. Sensitivity of [F]3F4AP for the focal brain injury was higher than [F]FDG, [C]PiB, and [C]PBR28, and compared favorably to currently used MRI methods.



J Cereb Blood Flow Metab: 21 Oct 2020:271678X20963404; epub ahead of print
Guehl NJ, Ramos-Torres KM, Linnman C, Moon SH, ... Normandin MD, Brugarolas P
J Cereb Blood Flow Metab: 21 Oct 2020:271678X20963404; epub ahead of print | PMID: 33090071
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Abstract

Neuroinflammatory responses of microglia in central nervous system trauma.

Shields DC, Haque A, Banik NL

Although relatively few in number compared to astrocytes and neurons, microglia demonstrate multiple, varied neuroimmunological functions in the central nervous system during normal and pathological states. After injury to the brain or spinal cord, microglia express beneficial pro- and anti-inflammatory phenotypes at various stages of recovery. However, prolonged microglial activation following injury has been linked to impaired parenchymal healing and functional restoration. The nature and magnitude of microglial response to injury relates in part to peripheral immune cell invasion, extent of tissue damage, and the local microenvironment.



J Cereb Blood Flow Metab: 21 Oct 2020:271678X20965786; epub ahead of print
Shields DC, Haque A, Banik NL
J Cereb Blood Flow Metab: 21 Oct 2020:271678X20965786; epub ahead of print | PMID: 33086921
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Abstract

Profiling cerebrovascular function in migraine: A systematic review and meta-analysis.

Dzator JS, Howe PR, Wong RH

Previous studies have investigated whether migraine is a circulatory disorder, as migraineurs are at heightened risk of cerebrovascular disease. However, in most cases, systemic vascular function was evaluated, which may not reflect abnormalities in the cerebral circulation. Therefore, we aimed to determine whether cerebrovascular function differs between migraineurs and controls. A systematic literature search was conducted across three electronic databases to search for studies that compared cerebrovascular function in migraineurs to controls. Where applicable, meta-analyses were used to determine standardised mean differences (SMD) between migraineurs and controls. Seventy articles were identified, 40 of which contained quantitative data. Meta-analyses showed pulsatility index (PI) was higher (SMD = 0.23; 95%CI = 0.05 to 0.42,  = 0.01) and cerebrovascular responsiveness (CVR) to hypercapnia was lower (SMD=-0.34; 95%CI=-0.67 to -0.01,  = 0.04) in the posterior circulation of migraineurs, particularly those without aura. The meta-analyses also indicated that migraineurs have higher resting mean blood flow velocity in both anterior (SMD = 0.14; 95%CI = 0.05 to 0.23,  = 0.003) and posterior circulations (SMD = 0.20; 95%CI = 0.05 to 0.34,  = 0.007). Compared to healthy controls, migraineurs have altered cerebrovascular function, evidenced by elevated PI (representing arterial stiffness) and impaired CVR to hypercapnia (representing cerebral vasodilator function). Future studies should investigate whether improvement of cerebrovascular function is able to alleviate migraine.



J Cereb Blood Flow Metab: 21 Oct 2020:271678X20964344; epub ahead of print
Dzator JS, Howe PR, Wong RH
J Cereb Blood Flow Metab: 21 Oct 2020:271678X20964344; epub ahead of print | PMID: 33086920
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This program is still in alpha version.