Journal: J Cereb Blood Flow Metab

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Abstract

Dynamic cerebral autoregulation estimates derived from near infrared spectroscopy and transcranial Doppler are similar after correction for transit time and blood flow and blood volume oscillations.

Elting JWJ, Tas J, Aries MJ, Czosnyka M, Maurits NM

We analysed mean arterial blood pressure, cerebral blood flow velocity, oxygenated haemoglobin and deoxygenated haemoglobin signals to estimate dynamic cerebral autoregulation. We compared macrovascular (mean arterial blood pressure-cerebral blood flow velocity) and microvascular (oxygenated haemoglobin-deoxygenated haemoglobin) dynamic cerebral autoregulation estimates during three different conditions: rest, mild hypocapnia and hypercapnia. Microvascular dynamic cerebral autoregulation estimates were created by introducing the constant time lag plus constant phase shift model, which enables correction for transit time, blood flow and blood volume oscillations (TT-BF/BV correction). After TT-BF/BV correction, a significant agreement between mean arterial blood pressure-cerebral blood flow velocity and oxygenated haemoglobin-deoxygenated haemoglobin phase differences in the low frequency band was found during rest (left: intraclass correlation=0.6, median phase difference 29.5° vs. 30.7°, right: intraclass correlation=0.56, median phase difference 32.6° vs. 39.8°) and mild hypocapnia (left: intraclass correlation=0.73, median phase difference 48.6° vs. 43.3°, right: intraclass correlation=0.70, median phase difference 52.1° vs. 61.8°). During hypercapnia, the mean transit time decreased and blood volume oscillations became much more prominent, except for very low frequencies. The transit time related to blood flow oscillations was remarkably stable during all conditions. We conclude that non-invasive microvascular dynamic cerebral autoregulation estimates are similar to macrovascular dynamic cerebral autoregulation estimates, after TT-BF/BV correction is applied. These findings may increase the feasibility of non-invasive continuous autoregulation monitoring and guided therapy in clinical situations.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:135-149
Elting JWJ, Tas J, Aries MJ, Czosnyka M, Maurits NM
J Cereb Blood Flow Metab: 30 Dec 2019; 40:135-149 | PMID: 30353763
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Abstract

Limited benefit of slow rewarming after cerebral hypothermia for global cerebral ischemia in near-term fetal sheep.

Davidson JO, Wassink G, Draghi V, Dhillon SK, Bennet L, Gunn AJ

The optimal rate of rewarming after therapeutic hypothermia for neonatal hypoxic-ischemic encephalopathy is unknown, although it is widely suggested that slow rewarming is beneficial. Some preclinical studies suggest better outcomes with slower rewarming, but did not control for the duration of hypothermia. In this study, near-term fetal sheep (0.85 gestation) received 30 min cerebral ischemia followed by normothermia, 48 h hypothermia with rapid rewarming over 1 h, 48-h hypothermia with slow rewarming over 24 h, or 72-h hypothermia with rapid rewarming. Slow rewarming after 48 h of hypothermia improved recovery of EEG power compared with rapid rewarming ( < 0.05), but was not different from rapid rewarming after 72 h of hypothermia. At seven days recovery, neuronal survival was partially improved by both fast and slow rewarming after 48-h hypothermia, but less than 72-h hypothermia in the cortex and CA4 ( < 0.05). In conclusion, although electrographic recovery was partially improved by slow rewarming over 24 h following cerebral hypothermia for 48 h, optimal neuroprotection was seen with hypothermia for 72 h with rapid rewarming, suggesting that the overall duration of cooling was the critical determinant of outcomes after therapeutic hypothermia.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2246-2257
Davidson JO, Wassink G, Draghi V, Dhillon SK, Bennet L, Gunn AJ
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2246-2257 | PMID: 30092709
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Abstract

Endothelial cells are critical regulators of iron transport in a model of the human blood-brain barrier.

Chiou B, Neal EH, Bowman AB, Lippmann ES, Simpson IA, Connor JR

Iron delivery to the brain is essential for multiple neurological processes such as myelination, neurotransmitter synthesis, and energy production. Loss of brain iron homeostasis is a significant factor in multiple neurological disorders. Understanding the mechanism by which the transport of iron across the blood-brain barrier (BBB) is regulated is crucial to address the impact of iron deficiency on brain development and excessive accumulation of iron in neurodegenerative diseases. Using induced pluripotent stem cell (iPSC)-derived brain endothelial cells (huECs) as a human BBB model, we demonstrate the ability of transferrin, hepcidin, and DMT1 to impact iron transport and release. Our model reveals a new function for H-ferritin to transport iron across the BBB by binding to the T-cell immunoglobulin and mucin receptor 1. We show that huECs secrete both transferrin and H-ferritin, which can serve as iron sources for the brain. Based on our data, brain iron status can exert control of iron transport across the endothelial cells that constitute the BBB. These data address a number of pertinent questions such as how brain iron uptake is regulated at the regional level, the source of iron delivery to the brain, and the clinical strategies for attempting to treat brain iron deficiency.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2117-2131
Chiou B, Neal EH, Bowman AB, Lippmann ES, Simpson IA, Connor JR
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2117-2131 | PMID: 29911470
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Abstract

Non-invasive optical neuromonitoring of the temperature-dependence of cerebral oxygen metabolism during deep hypothermic cardiopulmonary bypass in neonatal swine.

Ko TS, Mavroudis CD, Baker WB, Morano VC, ... Kilbaugh TJ, Licht DJ

Management of deep hypothermic (DH) cardiopulmonary bypass (CPB), a critical neuroprotective strategy, currently relies on non-invasive temperature to guide cerebral metabolic suppression during complex cardiac surgery in neonates. Considerable inter-subject variability in temperature response and residual metabolism may contribute to the persisting risk for postoperative neurological injury. To characterize and mitigate this variability, we assess the sufficiency of conventional nasopharyngeal temperature (NPT) guidance, and in the process, validate combined non-invasive frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) for direct measurement of cerebral metabolic rate of oxygen (). During CPB,  = 8 neonatal swine underwent cooling from normothermia to 18℃, sustained DH perfusion for 40 min, and then rewarming to simulate cardiac surgery. Continuous non-invasive and invasive measurements of intracranial temperature (ICT) andwere acquired. Significant hysteresis ( < 0.001) between cooling and rewarming periods in the NPT versus ICT and NPT versusrelationships were found. Resolution of this hysteresis in the ICT versusrelationship identified a crucial insufficiency of conventional NPT guidance. Non-invasivetemperature coefficients with respect to NPT ( = 2.0) and ICT ( = 2.5) are consistent with previous reports and provide further validation of FD-DOS/DCSmonitoring during DH CPB to optimize management.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:187-203
Ko TS, Mavroudis CD, Baker WB, Morano VC, ... Kilbaugh TJ, Licht DJ
J Cereb Blood Flow Metab: 30 Dec 2019; 40:187-203 | PMID: 30375917
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Abstract

Molecular switching from ubiquitin-proteasome to autophagy pathways in mice stroke model.

Liu X, Yamashita T, Shang J, Shi X, ... Ohta Y, Abe K

The ubiquitin-proteasome system (UPS) and autophagy are two major pathways to degrade misfolded proteins that accumulate under pathological conditions. When UPS is overloaded, the degeneration pathway may switch to autophagy to remove excessive misfolded proteins. However, it is still unclear whether and how this switch occurs during cerebral ischemia. In the present study, transient middle cerebral artery occlusion (tMCAO) resulted in accelerated ubiquitin-positive protein aggregation from 0.5 h of reperfusion in mice brain after 10, 30 or 60 min of tMCAO. In contrast, significant reduction of p62 and induction of LC3-II were observed, peaking at 24 h of reperfusion after 30 and 60 min tMCAO. Western blot analyses showed an increase of BAG3 and HDAC6 at 1 or 24 h of reperfusion that was dependent on the ischemic period. In contract, BAG1 decreased at 24 h of reperfusion after 10, 30 or 60 min of tMCAO after double immunofluorescent colocalization of ubiquitin, HSP70, p62 and BAG3. These data suggest that a switch from UPS to autophagy occurred between 10 and 30 min of cerebral ischemia depending on the BAG1/BAG3 ratio and level of HDAC6.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:214-224
Liu X, Yamashita T, Shang J, Shi X, ... Ohta Y, Abe K
J Cereb Blood Flow Metab: 30 Dec 2019; 40:214-224 | PMID: 30375939
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Abstract

Experimental ischemic stroke induces long-term T cell activation in the brain.

Xie L, Li W, Hersh J, Liu R, Yang SH

Mounting evidence has demonstrated that both innate and adaptive immune cells infiltrate into the brain after ischemic stroke. T cell invasion has been found in the ischemic region up to one month post experimental ischemic stroke and has been shown to persist for years in stroke patients. However, the function and phenotypic characteristics of the brain invading T cells after ischemic stroke have not been investigated. In the current study, we determined the function of brain invading T cells in the acute and chronic phase following experimental ischemic stroke induced by transient middle cerebral artery occlusion. We observed a significant increase of CD4 and CD8 T cells presented in the peri-infarct area at up to one month after experimental ischemic stroke. The brain invading T cells after ischemic stroke demonstrated close interaction with active astrocytes and a progressive proinflammatory phenotype as evidenced by the increased expression of T cell activation markers CD44 and CD25, proinflammatory cytokines INF-γ, IL-17, IL-10, TNF-α, and perforin, with corresponding transcriptional factors T-bet and RORc. Our results indicated a prolonged activation of brain invading CD4 and CD8 T cells after ischemic stroke which may play a role in the neural repair process after stroke.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2268-2276
Xie L, Li W, Hersh J, Liu R, Yang SH
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2268-2276 | PMID: 30092705
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Abstract

Neuroprotective effects of microglial P2Y receptors against ischemic neuronal injury.

Fukumoto Y, Tanaka KF, Parajuli B, Shibata K, ... Koizumi S, Kinouchi H

Extracellular ATP, which is released from damaged cells after ischemia, activates P2 receptors. P2Y receptors (P2YR) have received considerable attention, especially in astrocytes, because their activation plays a central role in the regulation of neuron-to-glia communication. However, the functions or even existence of P2YR in microglia remain unknown, despite the fact that many microglial P2 receptors are involved in several brain diseases. Herein, we demonstrate the presence and functional capability of microglial P2YR to provide neuroprotective effects following ischemic stress. Cerebral ischemia resulted in increased microglial P2YR expression. The number of injured hippocampal neurons was significantly higher in P2Y R knockout (KO) mice than wildtype mice after forebrain ischemia. Propidium iodide (PI) uptake, a marker for dying cells, was significantly higher in P2YR KO hippocampal slices compared with wildtype hippocampal slices at 48 h after 40-min oxygen-glucose deprivation (OGD). Furthermore, increased PI uptake following OGD was rescued by ectopic overexpression of P2YR in microglia. In summary, these data suggest that microglial P2YR mediate neuroprotective effects against ischemic stress and OGD insult.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2144-2156
Fukumoto Y, Tanaka KF, Parajuli B, Shibata K, ... Koizumi S, Kinouchi H
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2144-2156 | PMID: 30334687
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Abstract

Sustaining cerebral perfusion in intracranial atherosclerotic stenosis: The roles of antegrade residual flow and leptomeningeal collateral flow.

Lan L, Leng X, Ip V, Soo Y, ... Wong KS, Leung TW

We aimed to investigate the roles of antegrade residual flow and leptomeningeal collateral flow in sustaining cerebral perfusion distal to an intracranial atherosclerotic stenosis (ICAS). Patients with apparently normal cerebral perfusion distal to a symptomatic middle cerebral artery (MCA)-M1 stenosis were enrolled. Computational fluid dynamics models were built based on CT angiography to obtain a translesional pressure ratio (PR) to gauge the residual antegrade flow. Leptomeningeal collaterals (LMCs) were scaled on CT angiography. Cerebral perfusion metrics were obtained in CT perfusion maps. Among 83 patients, linear regression analyses revealed that both translesional PR and LMC scale were independently associated with relative ipsilesional mean transit time (rMTT). Subgroup analyses showed that ipsilesional rMTT was significantly associated with translesional PR ( < 0.001) rather than LMC scale in those with a moderate (50-69%) MCA stenosis, which, however, was only significantly associated with LMC scale ( = 0.051) in those with a severe (70-99%) stenosis. Antegrade residual flow and leptomeningeal collateral flow have complementary effects in sustaining cerebral perfusion distal to an ICAS, while cerebral perfusion may rely more on the collateral circulation in those with a severe stenosis.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:126-134
Lan L, Leng X, Ip V, Soo Y, ... Wong KS, Leung TW
J Cereb Blood Flow Metab: 30 Dec 2019; 40:126-134 | PMID: 30351176
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Abstract

Non-invasive monitoring of longitudinal changes in cerebral hemodynamics in acute ischemic stroke using BOLD signal delay.

Khalil AA, Villringer K, Filleböck V, Hu JY, ... Fiebach JB, Villringer A

Relative delays in blood-oxygen-level-dependent (BOLD) signal oscillations can be used to assess cerebral perfusion without using contrast agents. However, little is currently known about the utility of this method in detecting clinically relevant perfusion changes over time. We investigated the relationship between longitudinal BOLD delay changes, vessel recanalization, and reperfusion in 15 acute stroke patients with vessel occlusion examined within 24 h of symptom onset (D0) and one day later (D1). We created BOLD delay maps using time shift analysis of resting-state functional MRI data and quantified perfusion lesion volume changes (using the D1/D0 volume ratio) and severity changes (using a linear mixed model) over time. Between baseline and follow-up, BOLD delay lesions shrank (median D1/D0 ratio = 0.2, IQR = 0.03-0.7) and BOLD delay severity decreased (b = -4.4 s) in patients with recanalization, whereas they grew (median D1/D0 ratio = 1.47, IQR = 1.1-1.7) and became more severe (b = 4.3 s) in patients with persistent vessel occlusion. Clinically relevant changes in cerebral perfusion in early stroke can be detected using BOLD delay, making this non-invasive method a promising option for detecting tissue at risk of infarction and monitoring stroke patients following recanalization therapy.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:23-34
Khalil AA, Villringer K, Filleböck V, Hu JY, ... Fiebach JB, Villringer A
J Cereb Blood Flow Metab: 30 Dec 2019; 40:23-34 | PMID: 30334657
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Abstract

Involvement of caveolin-1 in neurovascular unit remodeling after stroke: Effects on neovascularization and astrogliosis.

Blochet C, Buscemi L, Clément T, Gehri S, Badaut J, Hirt L

Complex cellular and molecular events occur in the neurovascular unit after stroke, such as blood-brain barrier (BBB) dysfunction and inflammation that contribute to neuronal death, neurological deterioration and mortality. Caveolin-1 (Cav-1) has distinct physiological functions such as caveolae formation associated with endocytosis and transcytosis as well as in signaling pathways. Cav-1 has been proposed to be involved in BBB dysfunction after brain injury; however, its precise role is poorly understood. The goal of this study was to characterize the expression and effect of Cav-1 deletion on outcome in the first week in a transient Middle Cerebral Artery Occlusion stroke model. We found increased Cav-1 expression in new blood vessels in the lesion and in reactive astrocytes in the peri-lesion areas. In Cav-1 KO mice, the lesion volume was larger and the behavioral outcome worse than in WT mice. Cav-1 KO mice exhibited reduced neovascularization and modified astrogliosis, without formation of a proper glial scar around the lesion at three days post injury, coinciding with aggravated outcomes. Altogether, these results point towards a potential protective role of endogenous Cav-1 in the first days after ischemia by promoting neovascularization, astrogliosis and scar formation.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:163-176
Blochet C, Buscemi L, Clément T, Gehri S, Badaut J, Hirt L
J Cereb Blood Flow Metab: 30 Dec 2019; 40:163-176 | PMID: 30354902
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Abstract

Elevated brain oxygen extraction fraction measured by MRI susceptibility relates to perfusion status in acute ischemic stroke.

Fan AP, Khalil AA, Fiebach JB, Zaharchuk G, ... Villringer K, Gauthier CJ

Recent clinical trials of new revascularization therapies in acute ischemic stroke have highlighted the importance of physiological imaging to identify optimal treatments for patients. Oxygen extraction fraction (OEF) is a hallmark of at-risk tissue in stroke, and can be quantified from the susceptibility effect of deoxyhemoglobin molecules in venous blood on MRI phase scans. We measured OEF within cerebral veins using advanced quantitative susceptibility mapping (QSM) MRI reconstructions in 20 acute stroke patients. Absolute OEF was elevated in the affected (29.3 ± 3.4%) versus the contralateral hemisphere (25.5 ± 3.1%) of patients with large diffusion-perfusion lesion mismatch ( = 0.032). In these patients, OEF negatively correlated with relative CBF measured by dynamic susceptibility contrast MRI ( = 0.004), suggesting compensation for reduced flow. Patients with perfusion-diffusion match or no hypo-perfusion showed less OEF difference between hemispheres. Nine patients received longitudinal assessment and showed OEF ratio (affected to contralateral) of 1.2 ± 0.1 at baseline that normalized (decreased) to 1.0 ± 0.1 at follow-up three days later ( = 0.03). Our feasibility study demonstrates that QSM MRI can non-invasively quantify OEF in stroke patients, relates to perfusion status, and is sensitive to OEF changes over time.Longitudinal MRI examinations of patients with brain ischemia and blood brain barrier permeability; .



J Cereb Blood Flow Metab: 28 Feb 2020; 40:539-551
Fan AP, Khalil AA, Fiebach JB, Zaharchuk G, ... Villringer K, Gauthier CJ
J Cereb Blood Flow Metab: 28 Feb 2020; 40:539-551 | PMID: 30732551
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Abstract

Flow-metabolism uncoupling in patients with asymptomatic unilateral carotid artery stenosis assessed by multi-modal magnetic resonance imaging.

Göttler J, Kaczmarz S, Kallmayer M, Wustrow I, ... Preibisch C, Hyder F

Oxygen extraction (OEF), oxidative metabolism (CMRO), and blood flow (CBF) in the brain, as well as the coupling between CMRO and CBF due to cerebral autoregulation are fundamental to brain\'s health. We used a clinically feasible MRI protocol to assess impairments of these parameters in the perfusion territories of stenosed carotid arteries. Twenty-nine patients with unilateral high-grade carotid stenosis and thirty age-matched healthy controls underwent multi-modal MRI scans. Pseudo-continuous arterial spin labeling (pCASL) yielded absolute CBF, whereas multi-parametric quantitative blood oxygenation level dependent (mqBOLD) modeling allowed imaging of relative OEF and CMRO. Both CBF and CMRO were significantly reduced in the stenosed territory compared to the contralateral side, while OEF was evenly distributed across both hemispheres similarly in patients and controls. The CMRO-CBF coupling was significantly different between both hemispheres in patients, i.e. significant interhemispheric flow-metabolism uncoupling was observed in patients compared to controls. Given that CBF and CMRO are intimately linked to brain function in health and disease, the proposed easily applicable MRI protocol of pCASL and mqBOLD imaging might serve as a valuable tool for early diagnosis of potentially harmful cerebral hemodynamic and metabolic states with the final aim to select clinically asymptomatic patients who would benefit from carotid revascularization therapy.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2132-2143
Göttler J, Kaczmarz S, Kallmayer M, Wustrow I, ... Preibisch C, Hyder F
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2132-2143 | PMID: 29968499
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Abstract

Divergent metabolic substrate utilization in brain during epileptogenesis precedes chronic hypometabolism.

Bascuñana P, Brackhan M, Leiter I, Keller H, ... Bankstahl M, Bankstahl JP

Alterations in metabolism during epileptogenesis may be a therapy target. Recently, an increase in amino acid transport into the brain was proposed to play a role in epileptogenesis. We aimed to characterize alterations of substrate utilization during epileptogenesis and in chronic epilepsy. The lithium-pilocarpine post status epilepticus (SE) rat model was used. We performed longitudinal O-(2-[(18)F]fluoroethyl)-l-tyrosine (F-FET) and F-fluorodeoxyglucose (F-FDG) positron emission tomography (PET) and calculated F-FET volume of distribution (V) and F-FDG uptake. Correlation analyses were performed with translocator protein-PET defined neuroinflammation from previously acquired data. We found reduced F-FET V at 48 h after SE (amygdala: -30.2%,  = 0.014), whereas F-FDG showed increased glucose uptake 4 and 24 h after SE (hippocampus: + 43.6% and +42.5%, respectively;  < 0.001) returning to baseline levels thereafter. In chronic epileptic animals, we found a reduction in F-FET and F-FDG in the hippocampus. No correlation was found for F-FET or F-FDG to microglial activation at seven days post SE. Whereas metabolic alterations do not reflect higher metabolism associated to activated microglia, they might be partially driven by chronic neuronal loss. However, both metabolisms diverge during early epileptogenesis, pointing to amino acid turnover as a possible biomarker and/or therapeutic target for epileptogenesis.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:204-213
Bascuñana P, Brackhan M, Leiter I, Keller H, ... Bankstahl M, Bankstahl JP
J Cereb Blood Flow Metab: 30 Dec 2019; 40:204-213 | PMID: 30375913
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Abstract

Age dependency of cerebral P-glycoprotein function in wild-type and APPPS1 mice measured with PET.

Zoufal V, Wanek T, Krohn M, Mairinger S, ... Pahnke J, Langer O

P-glycoprotein (P-gp, ABCB1) is an efflux transporter at the blood-brain barrier (BBB), which mediates clearance of beta-amyloid (Aβ) from brain into blood. We used ()-[C]verapamil PET in combination with partial P-gp inhibition with tariquidar to measure cerebral P-gp function in a beta-amyloidosis mouse model (APPtg) and in control mice at three different ages (50, 200 and 380 days). Following tariquidar pre-treatment (4 mg/kg), whole brain-to-plasma radioactivity concentration ratios () were significantly higher in APPtg than in wild-type mice aged 50 days, pointing to decreased cerebral P-gp function. Moreover, we found an age-dependent decrease in cerebral P-gp function in both wild-type and APPtg mice of up to -50%. Alterations in P-gp function were more pronounced in Aβ-rich brain regions (hippocampus, cortex) than in a control region with negligible Aβ load (cerebellum). PET results were confirmed by immunohistochemical staining of P-gp in brain microvessels. Our results confirm previous findings of reduced P-gp function in Alzheimer\'s disease mouse models and show that our PET protocol possesses adequate sensitivity to measure these functional changes in vivo. Our PET protocol may find use in clinical studies to test the efficacy of drugs to induce P-gp function at the human BBB to enhance Aβ clearance.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:150-162
Zoufal V, Wanek T, Krohn M, Mairinger S, ... Pahnke J, Langer O
J Cereb Blood Flow Metab: 30 Dec 2019; 40:150-162 | PMID: 30354871
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Abstract

Modulation of cerebral ketone metabolism following traumatic brain injury in humans.

Bernini A, Masoodi M, Solari D, Miroz JP, ... Cuenoud B, Oddo M

Adaptive metabolic response to injury includes the utilization of alternative energy substrates - such as ketone bodies (KB) - to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI;  = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and β-hydroxybutyrate). Nutrition - from fasting vs. stable nutrition state - was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] µmol/L vs. 13.1 [6.5-64.3] µmol/L,  < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] µmol/L,  < 0.01). Blood KB correlated with brain KB (Spearman\'s rho 0.56,  = 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:177-186
Bernini A, Masoodi M, Solari D, Miroz JP, ... Cuenoud B, Oddo M
J Cereb Blood Flow Metab: 30 Dec 2019; 40:177-186 | PMID: 30353770
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Abstract

Urokinase-type plasminogen activator (uPA) protects the tripartite synapse in the ischemic brain via ezrin-mediated formation of peripheral astrocytic processes.

Diaz A, Merino P, Manrique LG, Cheng L, Yepes M

Cerebral ischemia has a harmful effect on the synapse associated with neurological impairment. The \"tripartite synapse\" is assembled by the pre- and postsynaptic terminals, embraced by astrocytic elongations known as peripheral astrocytic processes (PAPs). Ischemic stroke induces the detachment of PAPs from the synapse, leading to synaptic dysfunction and neuronal death. Ezrin is a membrane-associated protein, required for the formation of PAPs, that links the cell surface to the actin cytoskeleton. Urokinase-type plasminogen activator (uPA) is a serine proteinase that upon binding to its receptor (uPAR) promotes neurite growth during development. In the adult brain, neurons release uPA and astrocytes recruit uPAR to the plasma membrane during the recovery phase from an ischemic stroke, and uPA/uPAR binding promotes functional improvement following an ischemic injury. We found that uPA induces the synthesis of ezrin in astrocytes, with the subsequent formation of PAPs that enter in direct contact with the synapse. Furthermore, either the release of neuronal uPA or intravenous treatment with recombinant uPA (ruPA) induces the formation of PAPs in the ischemic brain, and the interaction of these PAPs with the pre- and postsynaptic terminals protects the integrity of the \"tripartite synapse\" from the harmful effects of the ischemic injury.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2157-2171
Diaz A, Merino P, Manrique LG, Cheng L, Yepes M
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2157-2171 | PMID: 29890880
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Abstract

Repetitive head injury in adolescent mice: A role for vascular inflammation.

Wu L, Chung JY, Saith S, Tozzi L, ... Kaplan D, Whalen MJ

Repetitive mild traumatic brain injury during adolescence can induce neurological dysfunction through undefined mechanisms. Interleukin-1 (IL-1) contributes to experimental adult diffuse and contusion TBI models, and IL-1 antagonists have entered clinical trials for severe TBI in adults; however, no such data exist for adolescent TBI. We developed an adolescent mouse repetitive closed head injury (rCHI) model to test the role of IL-1 family members in post-injury neurological outcome. Compared to one CHI, three daily injuries (3HD) produced acute and chronic learning deficits and emergence of hyperactivity, without detectable gliosis, neurodegeneration, brain atrophy, and white matter loss at one year. Mature IL-1β and IL-18 were induced in brain endothelium in 3HD but not 1HD, three hit weekly, or sham animals. IL-1β processing was induced cell-autonomously in three-dimensional human endothelial cell cultures subjected to in vitro concussive trauma. Mice deficient in IL-1 receptor-1 or caspase-1 had improved post-injury Morris water maze performance. Repetitive mild CHI in adolescent mice may induce behavioral deficits in the absence of significant histopathology. The endothelium is a potential source of IL-1β and IL-18 in rCHI, and IL-1 family members may be therapeutic targets to reduce or prevent neurological dysfunction after repetitive mild TBI in adolescents.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2196-2209
Wu L, Chung JY, Saith S, Tozzi L, ... Kaplan D, Whalen MJ
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2196-2209 | PMID: 30001646
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Abstract

Physiologic MR imaging of the tumor microenvironment revealed switching of metabolic phenotype upon recurrence of glioblastoma in humans.

Stadlbauer A, Oberndorfer S, Zimmermann M, Renner B, ... Kleindienst A, Roessler K

Treating recurrent glioblastoma (GB) is one of the challenges in modern neurooncology. Hypoxia, neovascularization, and energy metabolism are of crucial importance for therapy failure and recurrence. Twenty-one patients with initially untreated GB who developed recurrence were examined with a novel MRI approach for noninvasive visualization of the tumor microenvironment (TME). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of five different TME compartments: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation, and glycolysis. Volume percentages of these TME compartments were compared between untreated and recurrent GB. At initial diagnosis, all 21 GB showed either the features of a glycolytic dominant phenotype with a high percentage of functional neovasculature (N = 12) or those of a necrotic/hypoxic dominant phenotype with a high percentage of defective tumor neovasculature (N = 9). At recurrence, all 21 GB revealed switching of the initial metabolic phenotype: either from the glycolytic to the necrotic/hypoxic dominant phenotype or vice-versa. A necrotic/hypoxic phenotype at recurrence was associated with a higher rate of multifocality of the recurrent lesions. Our MRI approach may be helpful for a better understanding of treatment-induced metabolic phenotype switching and for future studies developing targeted therapeutic strategies for recurrent GB.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:528-538
Stadlbauer A, Oberndorfer S, Zimmermann M, Renner B, ... Kleindienst A, Roessler K
J Cereb Blood Flow Metab: 28 Feb 2020; 40:528-538 | PMID: 30732550
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Abstract

Characterizing ipsilateral thalamic diaschisis in symptomatic cerebrovascular steno-occlusive patients.

Hendrik Bas van Niftrik C, Sebök M, Muscas G, Piccirelli M, ... Regli L, Fierstra J

The clinical significance of ipsilateral thalamic diaschisis (ITD) occurring after stroke is unknown. To characterize ITD, we investigate its hemodynamic, structural, and clinical implications. A single-institution prospective cross-sectional study was conducted using 28 symptomatic cerebrovascular steno-occlusive patients undergoing both BOLD-CVR and Diamox-challenged (O)-HO-PET. Follow-up was at least three months. In addition, 15 age-matched healthy subjects were included. ITD was diagnosed based on a BOLD-CVR thalamic asymmetry index (TAI) > +2 standard deviations from healthy subjects. Cerebral blood flow differences were assessed using a PET-based TAI before and after Diamox challenge. Thalamic volume masks were determined using Freesurfer. Neurological status at symptom onset and after three months was determined with NIHSS and mRS scores. ITD was diagnosed in 15 of 28 (57%) patients. PET-TAI before and after Diamox challenge were increased in patients with ITD, indicating an ipsilateral thalamic blood flow decrease. Patients with ITD exhibited a marked ipsilateral thalamic volume decrease as compared to patients without ITD and healthy subjects. Furthermore, patients with ITD had worse NIHSS and mRS at symptom onset and after three months follow-up, even after adjustment for stroke volume. The presence of ITD is characterized by thalamic volume reduction, reduced thalamic blood flow, and worse neurological performance unrelated to stroke volume.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:563-573
Hendrik Bas van Niftrik C, Sebök M, Muscas G, Piccirelli M, ... Regli L, Fierstra J
J Cereb Blood Flow Metab: 28 Feb 2020; 40:563-573 | PMID: 30755133
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Abstract

Plasma osteopontin may predict neuroinflammation and the severity of pediatric traumatic brain injury.

Gao N, Zhang-Brotzge X, Wali B, Sayeed I, ... Kuan CY, Reisner A

Traumatic brain injury (TBI) is the leading cause of death in children and adolescents in developed countries, but there are no blood-based biomarkers to support the diagnosis or prognosis of pediatric TBI to-date. Here we report that the plasma levels of osteopontin (OPN), a phosphoprotein chiefly secreted by macrophages and/or activated microglia, may contribute to this goal. In animal models of TBI, while OPN, fibrillary acidic protein (GFAP), and matrix metalloproteinase 9 (MMP-9) were all readily induced by controlled cortical impact in the brains of one-month-old mice, only OPN and GFAP ascended in the blood in correlation with high neurological severity scores (NSS). In children with TBI (three to nine years of age,  = 66), the plasma levels of OPN, but not GFAP, correlated with severe TBI (Glasgow Coma Score ≤ 8) and intracranial lesions at emergency department. In addition, the plasma OPN levels in severe pediatric TBI patients continued to ascend for 72 h and correlated with mortality and the days requiring ventilator or intensive care unit support, whereas the plasma GFAP levels lacked these properties. Together, these results suggest that plasma OPN outperforms GFAP and may be a neuroinflammation-based diagnostic and prognostic biomarker in pediatric TBI.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:35-43
Gao N, Zhang-Brotzge X, Wali B, Sayeed I, ... Kuan CY, Reisner A
J Cereb Blood Flow Metab: 30 Dec 2019; 40:35-43 | PMID: 30866741
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Abstract

Metabolite concentration changes associated with positive and negative BOLD responses in the human visual cortex: A functional MRS study at 7 Tesla.

Boillat Y, Xin L, van der Zwaag W, Gruetter R

Negative blood oxygenation-level dependent (BOLD) signal observed during task execution in functional magnetic resonance imaging (fMRI) can be caused by different mechanisms, such as a blood-stealing effect or neuronal deactivation. Electrophysiological recordings showed that neuronal deactivation underlies the negative BOLD observed in the occipital lobe during visual stimulation. In this study, the metabolic demand of such a response was studied by measuring local metabolite concentration changes during a visual checkerboard stimulation using functional magnetic resonance spectroscopy (fMRS) at 7 Tesla. The results showed increases of glutamate and lactate concentrations during the positive BOLD response, consistent with previous fMRS studies. In contrast, during the negative BOLD response, decreasing concentrations of glutamate, lactate and gamma-aminobutyric acid (GABA) were found, suggesting a reduction of glycolytic and oxidative metabolic demand below the baseline. Additionally, the respective changes of the BOLD signal, glutamate and lactate concentrations of both groups suggest that a local increase of inhibitory activity might occur during the negative BOLD response.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:488-500
Boillat Y, Xin L, van der Zwaag W, Gruetter R
J Cereb Blood Flow Metab: 28 Feb 2020; 40:488-500 | PMID: 30755134
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Abstract

Mechanisms of glutathione-conjugate efflux from the brain into blood: Involvement of multiple transporters in the course.

Okamura T, Okada M, Kikuchi T, Wakizaka H, Zhang MR

Accumulation of detrimental glutathione-conjugated metabolites in the brain potentially causes neurological disorders, and must therefore be exported from the brain. However, in vivo mechanisms of glutathione-conjugates efflux from the brain remain unknown. We investigated the involvement of transporters in glutathione-conjugates efflux using 6-bromo-7-[C]methylpurine ([C]), which enters the brain and is converted into its glutathione conjugate, -(7-[C]methylpurin-6-yl)glutathione ([C]). In mice of control and knockout of P-glycoprotein/breast cancer resistance protein and multidrug resistance-associated protein 2 ([]), [C] formed in the brain was rapidly cleared, with no significant difference in efflux rate. In contrast, [C] formed in the brain of 1 mice was slowly cleared, whereas [C] microinjected into the brain of control andmice was 75% cleared within 60 min, with no significant difference in efflux rate. These suggest that Mrp1 contributes to [C] efflux across cell membranes, but not BBB. Efflux rate of [C] formed in the brain was significantly lower inand organic anion transporter 3 () mice compared with control mice. In conclusion, Mrp1, Oat3, and Mrp4 mediate [C] efflux from the brain. Mrp1 may contribute to [C] efflux from brain parenchymal cells, while extracellular [C] is likely cleared across the BBB, partly by Oat3 and Mrp4.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:116-125
Okamura T, Okada M, Kikuchi T, Wakizaka H, Zhang MR
J Cereb Blood Flow Metab: 30 Dec 2019; 40:116-125 | PMID: 30346895
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Abstract

Correlations between dopaminergic dysfunction and abnormal metabolic network activity in REM sleep behavior disorder.

Huang Z, Jiang C, Li L, Xu Q, ... Yu H, Wu P

Striatal dopamine transporter (DAT) deficiency and abnormal expression of Parkinson\'s disease (PD)-related pattern (PDRP) have been observed in patients with idiopathic REM sleep behavior disorder (IRBD). This study aimed to investigate the correlations between these two measures with comparison to PD using a dual tracer imaging design. Age-matched 37 IRBD patients, 86 PD patients, and 15 control subjects underwent concurrent PET scans with C-CFT to quantify dopaminergic dysfunction and F-FDG to quantify PDRP expression. IRBD patients were divided into two subgroups: those with relatively normal (IRBD-RN) or abnormal (IRBD-AB) striatal DAT binding. Significantly decreased DAT binding and increased PDRP scores were present in all patient groups, except for IRBD-RN, relative to the controls. There was a significant effect of hemisphere and hemisphere × group interaction for DAT binding but not for PDRP expression. Significant correlations were observed between DAT binding and PDRP expression in the IRBD-AB and PD groups but not in the IRBD-RN group. IRBD patients present with an intermediate state in striatal DAT distribution and PDRP activity between PD and normal controls. The modest correlations between the two measures in both IRBD and PD suggest that differences in network activity cannot be fully explained by nigrostriatal dopaminergic denervation.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:552-562
Huang Z, Jiang C, Li L, Xu Q, ... Yu H, Wu P
J Cereb Blood Flow Metab: 28 Feb 2020; 40:552-562 | PMID: 30741074
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Abstract

Brain ischemic insult induces cofilin rod formation leading to synaptic dysfunction in neurons.

Shu L, Chen B, Chen B, Xu H, ... Liu X, Wang Y

Ischemic stroke not only induces neuron death in the infarct area but also structural and functional damage of the surviving neurons in the surrounding peri-infarct area. In the present study, we first identified cofilin rod, a pathological rod-like aggregation, formed in neurons of in vivo ischemic stroke animal model and induced neuronal impairment. Cofilin rods formed only on the ipsilateral side of the middle cerebral artery occlusion and reperfusion (MCAO-R) rat brain and showed the highest density in peri-infarct area. Our real-time live cell imaging, immunostaining and patch clamp studies showed that cofilin rod formation in neurons led to dendritic mitochondrial transportation failure, as well as impairment of synaptic structure and functions. Overexpression of LIM kinase or activation of its upstream regulator Rho, suppressed ischemia-induced cofilin rod formation and showed protective effect on synaptic function and structure impairment in both cultured neurons and MCAO-R rat model. In summary, our results demonstrate a novel mechanism of ischemic stroke-induced neuron injury in peri-infarct area and provide a potential target for the protection of neuronal structure and function against brain ischemia insult.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2181-2195
Shu L, Chen B, Chen B, Xu H, ... Liu X, Wang Y
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2181-2195 | PMID: 29932353
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Abstract

Altered hemodynamics contribute to local but not remote functional connectivity disruption due to glioma growth.

Orukari IE, Siegel JS, Warrington NM, Baxter GA, ... Rubin JB, Culver JP

Glioma growth can cause pervasive changes in the functional connectivity (FC) of brain networks, which has been associated with re-organization of brain functions and development of functional deficits in patients. Mechanisms underlying functional re-organization in brain networks are not understood and efforts to utilize functional imaging for surgical planning, or as a biomarker of functional outcomes are confounded by the heterogeneity in available human data. Here we apply multiple imaging modalities in a well-controlled murine model of glioma with extensive validation using human data to explore mechanisms of FC disruption due to glioma growth. We find gliomas cause both local and distal changes in FC. FC changes in networks proximal to the tumor occur secondary to hemodynamic alterations but surprisingly, remote FC changes are independent of hemodynamic mechanisms. Our data strongly implicate hemodynamic alterations as the main driver of local changes in measurements of FC in patients with glioma.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:100-115
Orukari IE, Siegel JS, Warrington NM, Baxter GA, ... Rubin JB, Culver JP
J Cereb Blood Flow Metab: 30 Dec 2019; 40:100-115 | PMID: 30334672
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Abstract

Reduction of spike generation frequency by cooling in brain slices from rats and from patients with epilepsy.

Nomura S, Kida H, Hirayama Y, Imoto H, ... Mitsushima D, Suzuki M

This study aimed to understand the mechanism by which brain cooling terminates epileptic discharge. Cortical slices were prepared from rat brains (n = 19) and samples from patients with intractable epilepsy that had undergone temporal lobectomy (n = 7). We performed whole cell current clamp recordings at approximately physiological brain temperature (35℃) and at cooler temperatures (25℃ and 15℃). The firing threshold in human neurons was lower at 25℃ (-32.6 mV) than at 35℃ (-27.0 mV). The resting potential and spike frequency were similar at 25℃ and 35℃. Cooling from 25℃ to 15℃ did not change the firing threshold, but the resting potential increased from -65.5 to -54.0 mV and the waveform broadened from 1.85 to 6.55 ms, due to delayed repolarization. These changes enhanced the initial spike appearance and reduced spike frequency; moreover, spike frequency was insensitive to increased levels of current injections. Similar results were obtained in rat brain studies. We concluded that the reduction in spike frequency at 15℃, due to delayed repolarization, might be a key mechanism by which brain cooling terminates epileptic discharge. On the other hand, spike frequency was not influenced by the reduced firing threshold or the elevated resting potential caused by cooling.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2286-2294
Nomura S, Kida H, Hirayama Y, Imoto H, ... Mitsushima D, Suzuki M
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2286-2294 | PMID: 30117752
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Abstract

Cortical cerebral microinfarcts predict cognitive decline in memory clinic patients.

Hilal S, Tan CS, van Veluw SJ, Xu X, ... Biessels GJ, Chen C

Cortical cerebral microinfarcts (CMIs) - a novel MRI marker of cerebral vascular pathology have been linked with dementia and impaired cognition in cross-sectional studies. However, it is unknown if cortical CMIs are an indicator of further cognitive decline. We sought to examine whether baseline cortical CMIs predict cognitive decline in a prospective memory-clinic setting. A total of 313 patients with baseline 3T MRI scans and at least two neuropsychological assessments obtained a minimum of one year apart were recruited. Cortical CMIs were graded on baseline MRI according to a validated protocol. The Montreal Cognitive Assessment (MoCA) and a detailed neuropsychological battery were used to assess cognition. Patients with increased cortical CMIs showed greater decline in MoCA and global cognition per year. Patients with > 2 cortical CMIs decline on average by 2 scores on MoCA and 0.5 on global cognition at year two which corresponds to 109.8% and 184.5% greater decline when compared to those without CMIs. Furthermore, cortical CMIs at baseline were associated with accelerated decline in memory and language domains. Similar associations were observed when analysis was restricted to demented patients. Cortical CMIs together with other cerebrovascular disease markers can be used to design clinical trials in vascular cognitive impairment.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:44-53
Hilal S, Tan CS, van Veluw SJ, Xu X, ... Biessels GJ, Chen C
J Cereb Blood Flow Metab: 30 Dec 2019; 40:44-53 | PMID: 30890075
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Abstract

Increased ASL-CBF in the right amygdala predicts the first onset of depression in healthy young first-degree relatives of patients with major depression.

Zhang N, Qin J, Yan J, Zhu Y, ... Ju S, Li Y

Healthy first-degree relatives of patients with major depression are at an elevated risk of developing depression, and regional cerebral blood flow (CBF) alterations are observed in patients with depression. Therefore, in a 33-month follow-up study, we used arterial spin labeling-magnetic resonance imaging (ASL-MRI) to investigate quantitative CBF before and after the diagnosis of depression in healthy young adults with and without first-degree relatives with major depression (FH + and FH-, respectively). In cross-sectional and longitudinal CBF comparisons, CBF in the right amygdala was increased or decreased. Additionally, a significant correlation was observed between the altered CBF in the right amygdala and the scores on the 17-item Hamilton Depression Rating Scale (HDRS) in the FH + group. Furthermore, logistic regression and receiver operating characteristic curve analyses showed that increased CBF in the right amygdala at baseline predicted the subsequent onset of depression in the FH + group. Our results suggest that among healthy young adults with a familial risk of depression, those who exhibit increased CBF in the amygdala are susceptible to developing this disease.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:54-66
Zhang N, Qin J, Yan J, Zhu Y, ... Ju S, Li Y
J Cereb Blood Flow Metab: 30 Dec 2019; 40:54-66 | PMID: 31272311
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Abstract

Assessment of cerebral autoregulation in stroke: A systematic review and meta-analysis of studies at rest.

Intharakham K, Beishon L, Panerai RB, Haunton VJ, Robinson TG

Dynamic cerebral autoregulation (dCA) has been shown to be impaired in cerebrovascular diseases, but there is a lack of consistency across different studies and the different metrics that have been proposed for assessment. We performed a systematic review and meta-analyses involving assessment of dCA in ischemic and hemorrhagic stroke. Thirty-three articles describing assessment of dCA with transfer function analysis (TFA) were included, with meta-analyses performed for derived parameters of gain, phase and autoregulation index (ARI). A total of 1233 patients were pooled from 12 studies on acute ischemic stroke (AIS) and two studies on intracerebral hemorrhage (ICH). In comparison with controls, TFA phase of AIS was significantly reduced (nine studies), in both hemispheres ( < 0.0001). TFA gain provided inconsistent results, with reduced values in relation to controls, for both hemispheres. The ARI (six studies) was reduced compared to controls, in both hemispheres ( < 0.005). In ICH, gain showed higher values compared to controls for the unaffected ( = 0.01), but not for the affected hemisphere. Meta-analyses in AIS have demonstrated that phase and the ARI index can show highly significant differences in comparison with healthy controls, while ICH have been limited by the scarcity of studies and the diversity of units adopted for gain.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2105-2116
Intharakham K, Beishon L, Panerai RB, Haunton VJ, Robinson TG
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2105-2116 | PMID: 31433714
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Abstract

Small vessel disease is associated with altered cerebrovascular pulsatility but not resting cerebral blood flow.

Shi Y, Thrippleton MJ, Blair GW, Dickie DA, ... Chappell F, Wardlaw JM

Cerebral small vessel disease (SVD) contributes to 25% of ischemic strokes and 45% of dementias. We aimed to investigate the role of cerebral blood flow (CBF) and intracranial pulsatility in SVD. We scanned 60 patients with minor ischemic stroke, representing a range of white matter hyperintensities (WMH). We rated WMH and perivascular spaces (PVS) using semi-quantitative scales and measured WMH volume. We measured flow and pulsatility in the main cerebral vessels and cerebrospinal fluid (CSF) using phase-contrast MRI. We investigated the association between flow, pulsatility and SVD features. In 56/60 patients (40 male, 67.8±8.3 years) with complete data, median WMH volume was 10.7 mL (range 1.4-75.0 mL), representing median 0.77% (0.11-5.17%) of intracranial volume. Greater pulsatility index (PI) in venous sinuses was associated with larger WMH volume (e.g. superior sagittal sinus, β = 1.29,  < 0.01) and more basal ganglia PVS (e.g. odds ratio = 1.38, 95% confidence interval 1.06, 1.79, per 0.1 increase in superior sagittal sinus PI) independently of age, sex and blood pressure. CSF pulsatility and CBF were not associated with SVD features. Our results support a close association of SVD features with increased intracranial pulsatility rather than with low global CBF, and provide potential targets for mechanistic research, treatment and prevention of SVD.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:85-99
Shi Y, Thrippleton MJ, Blair GW, Dickie DA, ... Chappell F, Wardlaw JM
J Cereb Blood Flow Metab: 30 Dec 2019; 40:85-99 | PMID: 30295558
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Abstract

Dynamic metabolic changes in human visual cortex in regions with positive and negative blood oxygenation level-dependent response.

Martínez-Maestro M, Labadie C, Möller HE

Dynamic metabolic changes were investigated by functional magnetic resonance spectroscopy (fMRS) during sustained stimulation of human primary visual cortex. Two established paradigms, consisting of either a full-field or a small-circle flickering checkerboard, were employed to generate wide-spread areas of positive or negative blood oxygenation level-dependent (BOLD) responses, respectively. Compared to baseline, the glutamate concentration increased by 5.3% ( = 0.007) during activation and decreased by -3.8% ( = 0.017) during deactivation. These changes were positively correlated with the amplitude of the BOLD response ( = 0.60,  = 0.002) and probably reflect changes of tricarboxylic acid cycle activity. During deactivation, the glucose concentration decreased by -7.9% ( = 0.025) presumably suggesting increased consumption or reduced glucose supply. Other findings included an increased concentration of glutathione (4.2%,  = 0.023) during deactivation and a negative correlation of glutathione and BOLD signal changes ( = -0.49,  = 0.012) as well as positive correlations of aspartate ( = 0.44,  = 0.035) and -acetylaspartylglutamate ( = 0.42,  = 0.035) baseline concentrations with the BOLD response. It remains to be shown in future work if the observed effects on glutamate and glucose levels deviate from the assumption of a direct link between glucose utilization and regulation of blood flow or support previous suggestions that the hemodynamic response is mainly driven by feedforward release of vasoactive messengers.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2295-2307
Martínez-Maestro M, Labadie C, Möller HE
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2295-2307 | PMID: 30117749
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Abstract

Single-cell, high-throughput analysis of cell docking to vessel wall.

Andrzejewska A, Nowakowski A, Grygorowicz T, Dabrowska S, ... Lukomska B, Janowski M

Therapeutic potential of mesenchymal stem cells (MSCs) has been reported consistently in animal models of stroke, with mechanism mainly through immunomodulation and paracrine activity. Intravenous injection has been a prevailing route for MSCs administration, but cell quantities needed when scaling-up from mouse to human are extremely high putting into question feasibility of that approach. Intra-arterial delivery directly routes the cells to the brain thus lowering the required dose. Cell engineering may additionally improve cell homing, further potentiating the value of intra-arterial route. Therefore, our goal was to create microfluidic platform for screening and fast selection of molecules that enhance the docking of stem cells to vessel wall. We hypothesized that our software will be capable of detecting distinct docking properties of naïve and ITGA4-engineered MSCs. Indeed, the cell flow tracker analysis revealed positive effect of cell engineering on docking frequency of MSCs (42% vs. 9%, engineered vs. control cells,  < 0.001). These observations were then confirmed in an animal model of focal brain injury where cell engineering resulted in improved homing to the brain. To conclude, we developed a platform to study the docking of cells to the vessel wall which is highly relevant for intraarterial cell targeting or studies on neuroinflammation.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2308-2320
Andrzejewska A, Nowakowski A, Grygorowicz T, Dabrowska S, ... Lukomska B, Janowski M
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2308-2320 | PMID: 30362860
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Abstract

Regional times to equilibria and their impact on semi-quantification of [F]AV-1451 uptake.

Heurling K, Smith R, Strandberg OT, Schain M, ... Hansson O, Schöll M

The semi-quantitative estimate standardised uptake value ratios (SUVR) correlate well with specific binding of the tracer expressed as distribution volume ratios (DVR) for the tau positron emission tomography tracer [F]AV-1451 uptake and are therefore widely used as proxy for tracer binding. With regard to tracer kinetic modelling, there exists a time point when SUVR deviates minimally from DVR, occurring when the specific binding reaches a transient equilibrium Here, we have investigated whether the time to equilibrium affects the agreement between SUVR and DVR across different brain regions. We show that the time required to reach equilibrium differs across brain regions, resulting in region-specific biases. However, even though the 80-100 min post-injection time window did not show the smallest bias numerically, the disagreement between SUVR and DVR varied least between regions during this time. In conclusion, our findings suggest a regional component to the bias of SUVR related to the time to transient equilibrium of the specific binding. [F]AV-1451 uptake should consequently be interpreted with some caution when compared across brain regions using this method of quantification. The commonly used time window 80-100 min post-injection shows the most consistent bias across regions and is recommended for semi-quantification of [F]AV-1451.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2223-2232
Heurling K, Smith R, Strandberg OT, Schain M, ... Hansson O, Schöll M
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2223-2232 | PMID: 30073880
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Abstract

Impaired meningeal lymphatic vessel development worsens stroke outcome.

Yanev P, Poinsatte K, Hominick D, Khurana N, ... Dellinger MT, Stowe AM

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show thatmice develop significantly fewer meningeal LVs thanmice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke inmice. Interestingly,mice develop larger stroke volumes thanmice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:263-275
Yanev P, Poinsatte K, Hominick D, Khurana N, ... Dellinger MT, Stowe AM
J Cereb Blood Flow Metab: 30 Jan 2020; 40:263-275 | PMID: 30621519
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Abstract

Impaired cerebral autoregulation and neurovascular coupling in middle cerebral artery stroke: Influence of severity?

Salinet AS, Silva NC, Caldas J, de Azevedo DS, ... Panerai RB, Bor-Seng-Shu E

We aimed to assess cerebral autoregulation (CA) and neurovascular coupling (NVC) in stroke patients of differing severity comparing responses to healthy controls and explore the association between CA and NVC with functional outcome. Patients admitted with middle cerebral artery (MCA) stroke and healthy controls were recruited. Stroke severity was defined by the National Institutes of Health Stroke Scale (NIHSS) scores: ≤4 mild, 5-15 moderate and ≥16 severe. Transcranial Doppler ultrasound and Finometer recorded MCA cerebral blood flow velocity (CBFv) and blood pressure, respectively, over 5 min baseline and 1 min passive movement of the elbow to calculate the autoregulation index (ARI) and CBFv amplitude responses to movement. All participants were followed up for three months. A total of 87 participants enrolled in the study, including 15 mild, 27 moderate and 13 severe stroke patients, and 32 control subjects. ARI was lower in the affected hemisphere (AH) of moderate and severe stroke groups. Decreased NVC was seen bilaterally in all stroke groups. CA and NVC correlated with stroke severity and functional outcome. CBFv regulation is significantly impaired in acute stroke, and further compromised with increasing stroke severity. Preserved CA and NVC in the acute period were associated with improved three-month functional outcome.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2277-2285
Salinet AS, Silva NC, Caldas J, de Azevedo DS, ... Panerai RB, Bor-Seng-Shu E
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2277-2285 | PMID: 30117360
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Abstract

Cerebral vasomotor reactivity during hypo- and hypercapnia across the adult lifespan.

Tomoto T, Riley J, Turner M, Zhang R, Tarumi T

Age is the strongest risk factor for cerebrovascular disease; however, age-related changes in cerebrovascular function are still not well understood. The objective of this study was to measure cerebral vasomotor reactivity (CVMR) during hypo- and hypercapnia across the adult lifespan. One hundred fifty-three healthy participants (21-80 years) underwent measurements of cerebral blood flow velocity (CBFV) via transcranial Doppler, mean arterial pressure (MAP) via plethysmograph, and end-tidal CO (EtCO) via capnography during hyperventilation (hypocapnia) and a modified rebreathing protocol (hypercapnia). Cerebrovascular conductance (CVCi) and resistance (CVRi) indices were calculated from the ratios of CBFV and MAP. CVMRs were assessed by the slopes of CBFV and CVCi in response to changes in EtCO. The baseline CBFV and CVCi decreased and CVRi increased with age. Advanced age was associated with progressive declines in CVMR during hypocapnia indicating reduced cerebral vasoconstriction, but increases in CVMR during hypercapnia indicating increased vasodilation. A negative correlation between hypo- and hypercapnic CVMRs was observed across all subjects (CBFV%/ EtCO:  = -0.419, CVCi%/ EtCO:  = -0.442,  < 0.0001). Collectively, these findings suggest that aging is associated with decreases in CBFV, increases in cerebrovascular resistance, reduced vasoconstriction during hypocapnia, but increased vasodilatory responsiveness during hypercapnia.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:600-610
Tomoto T, Riley J, Turner M, Zhang R, Tarumi T
J Cereb Blood Flow Metab: 28 Feb 2020; 40:600-610 | PMID: 30764704
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Abstract

Experimental pediatric stroke shows age-specific recovery of cognition and role of hippocampal Nogo-A receptor signaling.

Orfila JE, Dietz RM, Rodgers KM, Dingman A, ... Schroeder C, Herson PS

Ischemic stroke is a leading cause of death worldwide and clinical data suggest that children may recover from stroke better than adults; however, supporting experimental data are lacking. We used our novel mouse model of experimental juvenile ischemic stroke (MCAO) to characterize age-specific cognitive dysfunction following ischemia. Juvenile and adult mice subjected to 45-min MCAO, and extracellular field recordings of CA1 neurons were performed to assess hippocampal synaptic plasticity changes after MCAO, and contextual fear conditioning was performed to evaluate memory and biochemistry used to analyze Nogo-A expression. Juvenile mice showed impaired synaptic plasticity seven days after MCAO, followed by full recovery by 30 days. Memory behavior was consistent with synaptic impairments and recovery after juvenile MCAO. Nogo-A expression increased in ipsilateral hippocampus seven days after MCAO compared to contralateral and sham hippocampus. Further, inhibition of Nogo-A receptors reversed MCAO-induced synaptic impairment in slices obtained seven days after juvenile MCAO. Adult MCAO-induced impairment of LTP was not associated with increased Nogo-A. This study demonstrates that stroke causes functional impairment in the hippocampus and recovery of behavioral and synaptic function is more robust in the young brain. Nogo-A receptor activity may account for the impairments seen following juvenile ischemic injury.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:588-599
Orfila JE, Dietz RM, Rodgers KM, Dingman A, ... Schroeder C, Herson PS
J Cereb Blood Flow Metab: 28 Feb 2020; 40:588-599 | PMID: 30762478
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Abstract

Phosphorus spectroscopy in acute TBI demonstrates metabolic changes that relate to outcome in the presence of normal structural MRI.

Stovell MG, Mada MO, Carpenter TA, Yan JL, ... Hutchinson PJ, Carpenter KL

Metabolic dysfunction is a key pathophysiological process in the acute phase of traumatic brain injury (TBI). Although changes in brain glucose metabolism and extracellular lactate/pyruvate ratio are well known, it was hitherto unknown whether these translate to downstream changes in ATP metabolism and intracellular pH. We have performed the first clinical voxel-basedphosphorus magnetic resonance spectroscopy (P MRS) in 13 acute-phase major TBI patients versus 10 healthy controls (HCs), at 3T, focusing on eight central 2.5 × 2.5 × 2.5 cm voxels per subject. PCr/γATP ratio (a measure of energy status) in TBI patients was significantly higher (median = 1.09) than that of HCs (median = 0.93) (p < 0.0001), due to changes in both PCr and ATP. There was no significant difference in PCr/γATP between TBI patients with favourable and unfavourable outcome. Cerebral intracellular pH of TBI patients was significantly higher (median = 7.04) than that of HCs (median = 7.00) (p = 0.04). Alkalosis was limited to patients with unfavourable outcome (median = 7.07) (p < 0.0001). These changes persisted after excluding voxels with > 5% radiologically visible injury. This is the first clinical demonstration of brain alkalosis and elevated PCr/γATP ratio acutely after major TBI. P MRS has potential for non-invasively assessing brain injury in the absence of structural injury, predicting outcome and monitoring therapy response.



J Cereb Blood Flow Metab: 30 Dec 2019; 40:67-84
Stovell MG, Mada MO, Carpenter TA, Yan JL, ... Hutchinson PJ, Carpenter KL
J Cereb Blood Flow Metab: 30 Dec 2019; 40:67-84 | PMID: 30226401
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Abstract

Oxidative stress-induced activation of Abl and Src kinases rapidly induces P-glycoprotein internalization via phosphorylation of caveolin-1 on tyrosine-14, decreasing cortisol efflux at the blood-brain barrier.

Hoshi Y, Uchida Y, Tachikawa M, Ohtsuki S, ... Suzuki T, Terasaki T

Exposure of the brain to high levels of glucocorticoids during ischemia-reperfusion induces neuronal cell death. Oxidative stress alters blood-brain barrier (BBB) function during ischemia-reperfusion, and so we hypothesized that it might impair P-glycoprotein (P-gp)-mediated efflux transport of glucocorticoids at the BBB. Therefore, the purpose of this study was to clarify the molecular mechanism of this putative decrease of P-gp-mediated efflux function. First, we established that HO treatment of a human in vitro BBB model (hCMEC/D3) reduced both P-gp efflux transport activity and protein expression on the plasma membrane within 20 min. These results suggested that the rapid decrease of efflux function might be due to internalization of P-gp. Furthermore, HO treatment markedly increased tyrosine-14-phosphorylated caveolin-1, which is involved in P-gp internalization. A brain perfusion study in rats showed that cortisol efflux at the BBB was markedly decreased by HO administration, and inhibitors of Abl kinase and Src kinase, which phosphorylate tyrosine-14 in caveolin-1, suppressed this decrease. Overall, these findings support the idea that oxidative stress-induced activation of Abl kinase and Src kinase induces internalization of P-gp via the phosphorylation of tyrosine-14 in caveolin-1, leading to a rapid decrease of P-gp-mediated cortisol efflux at the BBB.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:420-436
Hoshi Y, Uchida Y, Tachikawa M, Ohtsuki S, ... Suzuki T, Terasaki T
J Cereb Blood Flow Metab: 30 Jan 2020; 40:420-436 | PMID: 30621530
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Abstract

Quantification of [F]florbetapir: A test-retest tracer kinetic modelling study.

Golla SS, Verfaillie SC, Boellaard R, Adriaanse SM, ... van Berckel BN, Lammertsma AA

Accumulation of amyloid beta can be visualized using [F]florbetapir positron emission tomography. The aim of this study was to identify the optimal model for quantifying [F]florbetapir uptake and to assess test-retest reliability of corresponding outcome measures. Eight Alzheimer\'s disease patients (age: 67 ± 6 years, Mini-Mental State Examination (MMSE): 23 ± 3) and eight controls (age: 63 ± 4 years, MMSE: 30 ± 0) were included. Ninety-minute dynamic positron emission tomography scans, together with arterial blood sampling, were acquired immediately following a bolus injection of 294 ± 32 MBq [F]florbetapir. Several plasma input models and the simplified reference tissue model (SRTM) were evaluated. The Akaike information criterion was used to identify the preferred kinetic model. Compared to controls, Alzheimer\'s disease patients had lower MMSE scores and evidence for cortical Aβ pathology. A reversible two-tissue compartment model with fitted blood volume fraction (2T4k_V) was the preferred model for describing [F]florbetapir kinetics. SRTM-derived non-displaceable binding potential (BP) correlated well (r= 0.83, slope = 0.86) with plasma input-derived distribution volume ratio. Test-retest reliability for plasma input-derived distribution volume ratio, SRTM-derived BP and SUVr were  = 0.88, 0.91 and 0.86, respectively. In vivo kinetics of [F]florbetapir could best be described by a reversible two-tissue compartmental model and [F]florbetapir BP can be reliably estimated using an SRTM.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2172-2180
Golla SS, Verfaillie SC, Boellaard R, Adriaanse SM, ... van Berckel BN, Lammertsma AA
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2172-2180 | PMID: 29897009
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Abstract

Effects of traumatic brain injury on sleep and enlarged perivascular spaces.

Opel RA, Christy A, Boespflug EL, Weymann KB, ... Silbert LC, Lim MM

Clearance of perivascular wastes in the brain may be critical to the pathogenesis of amyloidopathies. Enlarged perivascular spaces (ePVS) on MRI have also been associated with amyloidopathies, suggesting that there may be a mechanistic link between ePVS and impaired clearance. Sleep and traumatic brain injury (TBI) both modulate clearance of amyloid-beta through glymphatic function. Therefore, we sought to evaluate the relationship between sleep, TBI, and ePVS on brain MRI. A retrospective study was performed in individuals with overnight polysomnography and 3T brain MRI consented from a single site ( = 38). Thirteen of these individuals had a medically confirmed history of TBI. ePVS were visually assessed by blinded experimenters and analyzed in conjunction with sleep metrics and TBI status. Overall, individuals with shorter total sleep time had significantly higher ePVS burden. Furthermore, individuals with TBI showed a stronger relationship between sleep and ePVS compared to the non-TBI group. These results support the hypothesis that ePVS may be modulated by sleep and TBI, and may have implications for the role of the glymphatic system in ePVS.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2258-2267
Opel RA, Christy A, Boespflug EL, Weymann KB, ... Silbert LC, Lim MM
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2258-2267 | PMID: 30092696
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Abstract

Deleterious role of endothelial lectin-like oxidized low-density lipoprotein receptor-1 in ischaemia/reperfusion cerebral injury.

Akhmedov A, Bonetti NR, Reiner MF, Spescha RD, ... Liberale L, Camici GG

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is implicated in cardiovascular disease by modulating apoptosis and oxidative stress. We hypothesized that LOX-1 may be involved in pathophysiology of stroke by mediating ischaemia/reperfusion (I/R)-dependent cell death. Transient middle cerebral artery occlusion (tMCAO) was performed in wild-type (WT) mice, endothelial-specific LOX-1 transgenic mice (eLOX-1TG) and WT animals treated with LOX-1 silencing RNA (siRNA). In WT mice exposed to tMCAO, LOX-1 expression and function were increased in the MCA. Compared to WT animals, eLOX-1TG mice displayed increased stroke volumes and worsened outcome after I/R. Conversely, LOX-1-silencing decreased both stroke volume and neurological impairment. Similarly, in HBMVECs, hypoxia/reoxygenation increased LOX-1 expression, while LOX-1 overexpressing cells showed increased death following hypoxia reoxygenation. Increased caspase-3 activation was observed following LOX-1 overexpression both in vivo and in vitro, thus representing a likely mediator. Finally, monocytes from ischaemic stroke patients exhibited increased LOX-1 expression which also correlated with disease severity. Our data unequivocally demonstrate a key role for LOX-1 in determining outcome following I/R brain damage. Our findings could be corroborated in human brain endothelial cells and monocytes from patients, underscoring their translational relevance and suggesting siRNA-mediated LOX-1 knockdown as a novel therapeutic strategy for stroke patients.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2233-2245
Akhmedov A, Bonetti NR, Reiner MF, Spescha RD, ... Liberale L, Camici GG
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2233-2245 | PMID: 30073881
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Abstract

Human non-REM sleep and the mean global BOLD signal.

McAvoy MP, Tagliazucchi E, Laufs H, Raichle ME

A hallmark of non-rapid eye movement (REM) sleep is the decreased brain activity as measured by global reductions in cerebral blood flow, oxygen metabolism, and glucose metabolism. It is unknown whether the blood oxygen level dependent (BOLD) signal undergoes similar changes. Here we show that, in contrast to the decreases in blood flow and metabolism, the mean global BOLD signal increases with sleep depth in a regionally non-uniform manner throughout gray matter. We relate our findings to the circulatory and metabolic processes influencing the BOLD signal and conclude that because oxygen consumption decreases proportionately more than blood flow in sleep, the resulting decrease in paramagnetic deoxyhemoglobin accounts for the increase in mean global BOLD signal.



J Cereb Blood Flow Metab: 30 Oct 2019; 39:2210-2222
McAvoy MP, Tagliazucchi E, Laufs H, Raichle ME
J Cereb Blood Flow Metab: 30 Oct 2019; 39:2210-2222 | PMID: 30073858
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Abstract

Fracture shortly before stroke in mice leads to hippocampus inflammation and long-lasting memory dysfunction.

Li Z, Wei M, Lyu H, Huo K, ... Zhang M, Su H

Cognitive impairment occurs in stroke and hip fracture patients. In mice, bone fracture (BF) exacerbates stroke-related neuronal damage and sensorimotor dysfunction. We hypothesize that BF exacerbates post-stroke cognitive impairment. Adult mice were randomly assigned into BF, stroke, BF+stroke (BF 6 h before stroke), and control (sham operated) groups. Memory function was evaluated weekly for eight weeks by Y maze test and at eight weeks post-surgeries by novel object recognition (NOR) test. The neuronal damage and inflammation in hippocampus were analyzed three days and eight weeks after the surgeries. In Y maze test, BF+stroke mice started making fewer alternations than controls two weeks after the surgeries. Significant difference between BF+stroke and stroke groups started at five weeks post-injury and continued to the end of the experiment. In NOR test, BF+stroke group spent less time on novel objective than that of other groups. Cx3cr1 cells and CD68 cells accumulated in the stratum lacunosum moleculare (SLM) on the ipsilateral side of stroke injury in stroke and BF+stroke mice. BF+stroke mice had a higher ratio of ipsilateral/contralateral Cx3cr1 cell-density than that of stroke mice. Therefore, BF shortly before stroke exacerbates hippocampal inflammation and causes long-lasting memory dysfunction.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:446-455
Li Z, Wei M, Lyu H, Huo K, ... Zhang M, Su H
J Cereb Blood Flow Metab: 30 Jan 2020; 40:446-455 | PMID: 30667320
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Abstract

Partial loss of endothelial nitric oxide leads to increased cerebrovascular beta amyloid.

Austin SA, Katusic ZS

Cerebral amyloid angiopathy (CAA) is present in over half of the elderly population and in 80-90% of Alzheimer\'s disease (AD) patients. CAA is defined by the deposition of beta amyloid (Aβ) in small cerebral arteries and capillaries. Cardiovascular risk factors are associated with an increased incidence of CAA. We utilized 18-month-old endothelial nitric oxide synthase (eNOS) heterozygous knockout () mice, a clinically relevant model of endothelial dysfunction, to examine the role of endothelial nitric oxide (NO) in vascular Aβ accumulation. eNOS mice had significantly higher vascular levels of Aβ40 ( < 0.05). Aβ42 was not detected. There was no difference in Aβ in brain tissue. Amyloid precursor protein and β-site APP cleavage enzyme 1 protein levels were unaltered, while levels of the α-secretase enzyme, a disintegrin and metalloproteinase 10, were significantly lower in eNOS  microvascular tissue ( < 0.05). Insulin degrading enzyme and low-density lipoprotein receptor-related protein 1 were significantly increased in eNOS microvascular tissue, most likely an adaptive response to locally higher Aβ concentrations. Lastly, catalase and CuZn superoxide dismutase were significantly elevated in eNOS microvascular tissue ( < 0.05). These data demonstrate decreased availability of endothelial NO leads to increased cerebrovascular concentration of Aβ along with compensatory mechanisms to protect the vasculature.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:392-403
Austin SA, Katusic ZS
J Cereb Blood Flow Metab: 30 Jan 2020; 40:392-403 | PMID: 30614363
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Abstract

Differential effects of anesthetics on resting state functional connectivity in the mouse.

Xie H, Chung DY, Kura S, Sugimoto K, ... Boas DA, Ayata C

Blood oxygen level-dependent (BOLD) functional MRI (fMRI) is a standard approach to examine resting state functional connectivity (RSFC), but fMRI in animal models is challenging. Recently, functional optical intrinsic signal imaging-which relies on the same hemodynamic signal underlying BOLD fMRI-has been developed as a complementary approach to assess RSFC in mice. Since it is difficult to ensure that an animal is in a truly resting state while awake, RSFC measurements under anesthesia remain an important approach. Therefore, we systematically examined measures of RSFC using non-invasive, widefield optical intrinsic signal imaging under five different anesthetics in male C57BL/6J mice. We find excellent seed-based, global, and interhemispheric connectivity using tribromoethanol (Avertin) and ketamine-xylazine, comparable to results in the literature including awake animals. Urethane anesthesia yielded intermediate results, while chloral hydrate and isoflurane were both associated with poor RSFC. Furthermore, we found a correspondence between the strength of RSFC and the power of low-frequency hemodynamic fluctuations. In conclusion, Avertin and ketamine-xylazine provide robust and reproducible measures of RSFC in mice, whereas chloral hydrate and isoflurane do not.



J Cereb Blood Flow Metab: 30 Mar 2020; 40:875-884
Xie H, Chung DY, Kura S, Sugimoto K, ... Boas DA, Ayata C
J Cereb Blood Flow Metab: 30 Mar 2020; 40:875-884 | PMID: 31092086
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Abstract

An exploratory investigation of brain collateral circulation plasticity after cerebral ischemia in two experimental C57BL/6 mouse models.

Foddis M, Winek K, Bentele K, Mueller S, ... Dirnagl U, Sassi C

Brain collateral circulation is an essential compensatory mechanism in response to acute brain ischemia. To study the temporal evolution of brain macro and microcollateral recruitment and their reciprocal interactions in response to different ischemic conditions, we applied a combination of complementary techniques (T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) in two different mouse models. Hypoperfusion was either induced by permanent bilateral common carotid artery stenosis (BCCAS) or 60-min transient unilateral middle cerebral artery occlusion (MCAO). In both models, collateralization is a very dynamic phenomenon with a global effect affecting both hemispheres. Patency of ipsilateral posterior communicating artery (PcomA) represents the main variable survival mechanism and the main determinant of stroke lesion volume and recovery in MCAO, whereas the promptness of external carotid artery retrograde flow recruitment together with PcomA patency, critically influence survival, brain ischemic lesion volume and retinopathy in BCCAS mice. Finally, different ischemic gradients shape microcollateral density and size.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:276-287
Foddis M, Winek K, Bentele K, Mueller S, ... Dirnagl U, Sassi C
J Cereb Blood Flow Metab: 30 Jan 2020; 40:276-287 | PMID: 31549895
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Abstract

Signal variance-based collateral index in DSC perfusion: A novel method to assess leptomeningeal collateralization in acute ischaemic stroke.

Seiler A, Lauer A, Deichmann R, Nöth U, ... Klein JC, Wagner M

As a determinant of the progression rate of the ischaemic process in acute large-vessel stroke, the degree of collateralization is a strong predictor of the clinical outcome after reperfusion therapy and may influence clinical decision-making. Therefore, the assessment of leptomeningeal collateralization is of major importance. The purpose of this study was to develop and evaluate a quantitative and observer-independent method for assessing leptomeningeal collateralization in acute large-vessel stroke based on signal variance characteristics in T2*-weighted dynamic susceptibility contrast (DSC) perfusion-weighted MR imaging (PWI). Voxels representing leptomeningeal collateral vessels were extracted according to the magnitude of signal variance in the PWI raw data time series in 55 patients with proximal large-artery occlusion and an intra-individual collateral vessel index (CVI) was calculated. CVI correlated significantly with the initial ischaemic core volume (rho = -0.459, p = 0.0001) and the PWI/DWI mismatch ratio (rho = 0.494, p = 0.0001) as an indicator of the amount of salvageable tissue. Furthermore, CVI was significantly negatively correlated with NIHSS and mRS at discharge (rho = -0.341, p = 0.015 and rho = -0.305, p = 0.023). In multivariate logistic regression, CVI was an independent predictor of favourable functional outcome (mRS 0-2) (OR = 16.39, 95% CI 1.42-188.7, p = 0.025). CVI provides useful rater-independent information on the leptomeningeal collateral supply in acute stroke.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:574-587
Seiler A, Lauer A, Deichmann R, Nöth U, ... Klein JC, Wagner M
J Cereb Blood Flow Metab: 28 Feb 2020; 40:574-587 | PMID: 30755069
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Abstract

Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia.

Marushima A, Nieminen M, Kremenetskaia I, Gianni-Barrera R, ... Vajkoczy P, Hecht N

The myoblast-mediated delivery of angiogenic genes represents a cell-based approach for targeted induction of therapeutic collateralization. Here, we tested the superiority of myoblast-mediated co-delivery of vascular endothelial growth factor-A (VEGF) together with platelet-derived growth factor-BB (PDGF-BB) on transpial collateralization of an indirect encephalomyosynangiosis (EMS) in a model of chronic cerebral ischemia. Mouse myoblasts expressing a reporter gene alone (empty vector), VEGF, PDGF-BB or VEGF and PDGF-BB through a single bi-cistronic vector (VIP) were implanted into the temporalis muscle of an EMS following permanent ipsilateral internal carotid artery occlusion in adult, male C57BL/6N mice. Over 84 days, myoblast engraftment and gene product expression, hemodynamic impairment, transpial collateralization, angiogenesis, pericyte recruitment and post-ischemic neuroprotection were assessed. By day 42, animals that received PDGF-BB in combination with VEGF (VIP) showed superior hemodynamic recovery, EMS collateralization and ischemic protection with improved pericyte recruitment around the parenchymal vessels and EMS collaterals. Also, supplementation of PDGF-BB resulted in a striking astrocytic activation with intrinsic VEGF mobilization in the cortex below the EMS. Our findings suggest that EMS surgery together with myoblast-mediated co-delivery of VEGF/PDGF-BB may have the potential to serve as a novel treatment strategy for augmentation of collateral flow in the chronically hypoperfused brain.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:404-419
Marushima A, Nieminen M, Kremenetskaia I, Gianni-Barrera R, ... Vajkoczy P, Hecht N
J Cereb Blood Flow Metab: 30 Jan 2020; 40:404-419 | PMID: 30621518
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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: 09 Oct 2019:271678X19882264; epub ahead of print
Bernstein DL, Zuluaga-Ramirez V, Gajghate S, Reichenbach NL, ... Persidsky Y, Rom S
J Cereb Blood Flow Metab: 09 Oct 2019:271678X19882264; epub ahead of print | PMID: 31601141
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Abstract

The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: A meta-analysis.

Moxon JV, Trollope AF, Dewdney B, de Hollander C, ... Maguire JM, Golledge J

Clinical studies report that low circulating angiopoietin-1 concentration at presentation predicts worse outcomes after ischaemic stroke. Upregulating angiopoietin-1 may therefore have therapeutic benefit for ischaemic stroke. This systematic review assessed whether upregulating angiopoietin-1 improved outcomes in rodent models of ischaemic stroke. Random-effects models quantified the effect of angiopoietin-1 upregulation on stroke severity in terms of the size of cerebral infarction and the extent of blood-brain barrier permeability. Eleven studies utilising rat and mouse models of ischaemic stroke fulfilled the inclusion criteria. Meta-analyses demonstrated that angiopoietin-1 upregulation significantly reduced cerebral infarction size (standardised mean difference: -3.02; 95% confidence intervals: -4.41, -1.63;  < 0.001;  = 171 animals) and improved blood-brain barrier integrity (standardized mean difference: -2.02; 95% confidence intervals: -3.27, -0.77;  = 0.002;  = 129 animals). Subgroup analyses demonstrated that angiopoietin-1 upregulation improved outcomes in models of transient, not permanent cerebral ischaemia. Six studies assessed the effect of angiopoietin-1 upregulation on neurological function; however, inter-study heterogeneity prevented meta-analysis. In conclusion, published rodent data suggest that angiopoietin-1 upregulation improves outcome following temporary cerebral ischaemia by reducing cerebral infarction size and improving blood-brain barrier integrity. Additional research is required to examine the effect of angiopoietin-1 upregulation on neurological function during stroke recovery and investigate the benefit and risks in patients.



J Cereb Blood Flow Metab: 03 Oct 2019:271678X19876876; epub ahead of print
Moxon JV, Trollope AF, Dewdney B, de Hollander C, ... Maguire JM, Golledge J
J Cereb Blood Flow Metab: 03 Oct 2019:271678X19876876; epub ahead of print | PMID: 31581897
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Abstract

Chronic kidney disease in the pathogenesis of acute ischemic stroke.

Chelluboina B, Vemuganti R

Chronic kidney disease has a graded and independent inverse impact on cerebrovascular health. Both thrombotic and hemorrhagic complications are highly prevalent in chronic kidney disease patients. Growing evidence suggests that in chronic kidney disease patients, ischemic strokes are more common than hemorrhagic strokes. Chronic kidney disease is asymptomatic until an advanced stage, but mild to moderate chronic kidney disease incites various pathogenic mechanisms such as inflammation, oxidative stress, neurohormonal imbalance, formation of uremic toxins and vascular calcification which damage the endothelium and blood vessels. Cognitive dysfunction, dementia, transient infarcts, and white matter lesions are widespread in mild to moderate chronic kidney disease patients. Uremic toxins produced after chronic kidney disease can pass through the blood-brain barrier and mediate cognitive dysfunction and neurodegeneration. Furthermore, chronic kidney disease precipitates vascular risk factors that can lead to atherosclerosis, hypertension, atrial fibrillation, and diabetes. Chronic kidney disease also exacerbates stroke pathogenesis, worsens recovery outcomes, and limits the eligibility of stroke patients to receive available stroke therapeutics. This review highlights the mechanisms involved in the advancement of chronic kidney disease and its possible association with stroke.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1893-1905
Chelluboina B, Vemuganti R
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1893-1905 | PMID: 31366298
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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: 08 Oct 2019:271678X19878284; epub ahead of print
Parfenova H, Liu J, Hoover DT, Fedinec AL
J Cereb Blood Flow Metab: 08 Oct 2019:271678X19878284; epub ahead of print | PMID: 31594422
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Abstract

Delayed recanalization in acute ischemic stroke patients: Late is better than never?

Pang J, Zhang JH, Jiang Y

Successful recanalization of the occluded vessel as early as possible has been widely accepted as the key principle of acute ischemic stroke (AIS) treatment. Unfortunately, for many years, the vast majority of AIS patients were prevented from receiving effective recanalization therapy because of a narrow therapeutic window. Recently, a series of inspiring clinical trials have indicated that more patients may benefit from delayed recanalization during an expanded therapeutic window, even up to 24 h after symptom onset. However, could potentially salvageable brain tissue (penumbra) in patients who do not receive medication within 24 h still possible to be saved?



J Cereb Blood Flow Metab: 07 Oct 2019:271678X19881449; epub ahead of print
Pang J, Zhang JH, Jiang Y
J Cereb Blood Flow Metab: 07 Oct 2019:271678X19881449; epub ahead of print | PMID: 31594437
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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 Sep 2019:271678X19880450; epub ahead of print
Nørgaard M, Ganz M, Svarer C, Frokjaer VG, ... Strother SC, Knudsen GM
J Cereb Blood Flow Metab: 30 Sep 2019:271678X19880450; epub ahead of print | PMID: 31575336
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Abstract

Reducing myeloperoxidase activity decreases inflammation and increases cellular protection in ischemic stroke.

Kim HJ, Wei Y, Wojtkiewicz GR, Lee JY, Moskowitz MA, Chen JW

Myeloperoxidase (MPO) is a pro-inflammatory enzyme abundantly secreted by activated myeloid cells after stroke. We show that when MPO activity is either blocked by the specific inhibitor 4-aminobenzoic acid hydrazide (ABAH) in wildtype (WT) mice or congenitally absent (MPO), there was decreased cell loss, including degenerating neurons and oligodendrocytes, in the ischemic brains compared to vehicle-treated WT mice after stroke. MPO inhibition also reduced the number of activated myeloid cells after ischemia. MPO inhibition increased cytoprotective heat shock protein 70 (Hsp70) by 70% and p-Akt by 60%, while decreased the apoptotic marker p53 level by 62%, compared to vehicle-treated mice after ischemia. Similarly, MPO inhibition increased the number of Hsp70/NeuN cells after stroke by 60%. Notably, MPO inhibition significantly improved neurological outcome compared with the vehicle-treated group after stroke. We further found longer treatment periods resulted in larger reduction of infarct size and greater neurobehavioral improvement from MPO inhibition, even when given days after stroke. Therefore, MPO inhibition with ABAH or MPO deficiency creates a protective environment that decreased inflammatory cell recruitment and increased expression of survival factors to improve functional outcome. MPO inhibition may represent a promising therapeutic target for stroke therapy, possibly even days after stroke has occurred.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1864-1877
Kim HJ, Wei Y, Wojtkiewicz GR, Lee JY, Moskowitz MA, Chen JW
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1864-1877 | PMID: 29673284
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Impact:
Abstract

Inflammatory pathways are central to posterior cerebrovascular artery remodelling prior to the onset of congenital hypertension.

Walas D, Nowicki-Osuch K, Alibhai D, von Linstow Roloff E, ... Waterfall C, Paton JF

Cerebral artery hypoperfusion may provide the basis for linking ischemic stroke with hypertension. Brain hypoperfusion may induce hypertension that may serve as an auto-protective mechanism to prevent ischemic stroke. We hypothesised that hypertension is caused by remodelling of the cerebral arteries, which is triggered by inflammation. We used a congenital rat model of hypertension and examined age-related changes in gene expression of the cerebral arteries using RNA sequencing. Prior to hypertension, we found changes in signalling pathways associated with the immune system and fibrosis. Validation studies using second harmonics generation microscopy revealed upregulation of collagen type I and IV in both tunica externa and media. These changes in the extracellular matrix of cerebral arteries pre-empted hypertension accounting for their increased stiffness and resistance, both potentially conducive to stroke. These data indicate that inflammatory driven cerebral artery remodelling occurs prior to the onset of hypertension and may be a trigger elevating systemic blood pressure in genetically programmed hypertension.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1803-1817
Walas D, Nowicki-Osuch K, Alibhai D, von Linstow Roloff E, ... Waterfall C, Paton JF
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1803-1817 | PMID: 29651914
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Abstract

Effects of minocycline on epiplexus macrophage activation, choroid plexus injury and hydrocephalus development in spontaneous hypertensive rats.

Gu C, Hao X, Li J, Hua Y, Keep RF, Xi G

Hydrocephalus has been reported to occur in spontaneous hypertensive rats (SHRs). The purposes of this study were (1) to use T2 magnetic resonance imaging to examine time of onset, (2) to elucidate potential underlying mechanisms and (3) to determine whether minocycline could prevent hydrocephalus development. Ventriculomegaly was evaluated by T2 imaging in SHRs and Wistar-Kyoto rats from weeks 4 to 7 after birth. Brain histology and transmission electron microscopy were used to assess the periventricular and choroid plexus damage. SHRs were also treated with either vehicle or minocycline. We found that hydrocephalus was observed in SHRs but not in Wistar-Kyoto rats. It occurred at seven weeks of age but was not present at four and five weeks. The hydrocephalus was associated with epiplexus cell (macrophage) activation, choroid plexus cell death and damage to the ventricle wall. Treatment with minocycline from week 5 attenuated hydrocephalus development and pathological changes in choroid plexus and ventricular wall at week 7. The current study found that spontaneous hydrocephalus arises at ∼7 weeks in male SHRs. The early development of hydrocephalus (persistent ventricular dilatation) may result from epiplexus cell activation, choroid plexus cell death and periventricular damage, which can be ameliorated by treatment with minocycline.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1936-1948
Gu C, Hao X, Li J, Hua Y, Keep RF, Xi G
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1936-1948 | PMID: 30862302
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Abstract

Test-retest repeatability of [F]Flortaucipir PET in Alzheimer\'s disease and cognitively normal individuals.

Timmers T, Ossenkoppele R, Visser D, Tuncel H, ... Golla SS, van Berckel BN

The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer\'s disease and six cognitively normal subjects. All underwent two 130-min dynamic [F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr: 3.05% (1.28-5.52),  < 0.001. Furthermore, for SUVr and SUVr, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.



J Cereb Blood Flow Metab: 30 Sep 2019:271678X19879226; epub ahead of print
Timmers T, Ossenkoppele R, Visser D, Tuncel H, ... Golla SS, van Berckel BN
J Cereb Blood Flow Metab: 30 Sep 2019:271678X19879226; epub ahead of print | PMID: 31575335
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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: 29 Sep 2019:271678X19879230; epub ahead of print
Rossano S, Toyonaga T, Finnema SJ, Naganawa M, ... Maguire RP, Carson RE
J Cereb Blood Flow Metab: 29 Sep 2019:271678X19879230; epub ahead of print | PMID: 31570041
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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 Sep 2019:271678X19880161; epub ahead of print
Edwards DN, Salmeron K, Lukins DE, Trout AL, Fraser JF, Bix GJ
J Cereb Blood Flow Metab: 30 Sep 2019:271678X19880161; epub ahead of print | PMID: 31575337
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Abstract

Na/K-ATPase α isoform deficiency results in distinct spreading depolarization phenotypes.

Reiffurth C, Alam M, Zahedi-Khorasani M, Major S, Dreier JP

Compromised Na/K-ATPase function is associated with the occurrence of spreading depolarization (SD). Mutations in ATP1A2, the gene encoding the α2 isoform of the Na/K-ATPase, were identified in patients with familial hemiplegic migraine type 2 (FHM2), a Mendelian model disease for SD. This suggests a distinct role for the α2 isoform in modulating SD susceptibility and raises questions about underlying mechanisms including the roles of other Na/K-ATPase α isoforms. Here, we investigated the effects of genetic ablation and pharmacological inhibition of α1, α2, and α3 on SD using heterozygous knock-out mice. We found that only α2 heterozygous mice displayed higher SD susceptibility when challenged with prolonged extracellular high potassium concentration ([K]), a pronounced post SD oligemia and higher SD speed in-vivo. By contrast, under physiological [K], α2 heterozygous mice showed similar SD susceptibility compared to wild-type littermates. Deficiency of α3 resulted in increased resistance against electrically induced SD in-vivo, whereas α1 deficiency did not affect SD. The results support important roles of the α2 isoform in SD. Moreover, they suggest that specific experimental conditions can be necessary to reveal an inherent SD phenotype by driving a (meta-) stable system into decompensation, reminiscent of the episodic nature of SDs in various diseases.



J Cereb Blood Flow Metab: 28 Feb 2020; 40:622-638
Reiffurth C, Alam M, Zahedi-Khorasani M, Major S, Dreier JP
J Cereb Blood Flow Metab: 28 Feb 2020; 40:622-638 | PMID: 30819023
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Abstract

Robust RBM3 and β-klotho expression in developing neurons in the human brain.

Jackson TC, Janesko-Feldman K, Carlson SW, Kotermanski SE, Kochanek PM

RNA binding motif 3 (RBM3) is a powerful neuroprotectant that inhibits neurodegenerative cell death in vivo and is a promising therapeutic target in brain ischemia. RBM3 is increased by the hormone fibroblast growth factor 21 (FGF21) in an age- and temperature-dependent manner in rat cortical neurons. FGF21 receptor binding is controlled by the transmembrane protein β-klotho, which is mostly absent in the adult brain. We discovered that RBM3/β-klotho is unexpectedly high in the human infant vs. adult brain (hippocampus/prefrontal cortex). The use of tissue homogenates in that study precluded a comparison of RBM3/β-klotho expression among different CNS cell-types, thus, omitted key evidence (i.e. confirmation of neuronal expression) that would otherwise provide a critical link to support their possible direct neuroprotective effects in humans. This report addresses that knowledge gap. High-quality fixed human hippocampus, cortex, and hypothalamic tissues were acquired from the NIH Neurobiobank (<1 yr (premature born) infants, 1 yr, 4 yr, and 34 yr). Dual labeling of cell-type markers vs. RBM3/β-klotho revealed enriched staining of targets in neurons in the developing brain. Identifying that RBM3/β-klotho is abundant in neurons in the immature brain is fundamentally important to guide protocol design and conceptual frameworks germane to future testing of these neuroprotective pathways in humans.



J Cereb Blood Flow Metab: 28 Sep 2019:271678X19878889; epub ahead of print
Jackson TC, Janesko-Feldman K, Carlson SW, Kotermanski SE, Kochanek PM
J Cereb Blood Flow Metab: 28 Sep 2019:271678X19878889; epub ahead of print | PMID: 31566073
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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: 09 Sep 2019:271678X19873662; epub ahead of print
Suissa L, Flachon V, Guigonis JM, Olivieri CV, ... Pourcher T, Lindenthal S
J Cereb Blood Flow Metab: 09 Sep 2019:271678X19873662; epub ahead of print | PMID: 31506013
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Abstract

CX3CR1-CCR2-dependent monocyte-microglial signaling modulates neurovascular leakage and acute injury in a mouse model of childhood stroke.

Faustino J, Chip S, Derugin N, Jullienne A, ... Obenaus A, Vexler ZS

Stroke is among the top 10 causes of death in children. The developmental stage of the brain is central to stroke pathophysiology. The incidence of childhood arterial ischemic stroke (CAIS) is lower than of perinatal arterial ischemic stroke but the rate of recurrence is strikingly high. Vascular inflammation is seen as major contributor to CAIS but the mechanisms that govern structural-functional basis of vascular abnormalities remain poorly understood. To identify the contribution of immune-neurovascular interactions to CAIS, we established stroke model in postnatal day 21 (P21) mice. We demonstrate acute functional deficits and histological injury and chronic MRI-identifiable injury, brain atrophy and marked derangements in the vascular network. In contrast to negligible albumin leakage and neutrophil infiltration following acute perinatal stroke, CAIS leads to significantly increased albumin leakage and neutrophil infiltration in injured regions of wild type mice and mice with functional CX3CR1-CCR2 receptors. In mice with dysfunctional CX3CR1-CCR2 signaling, extravascular albumin leakage is significantly attenuated, infiltration of injurious Ccr2-monocytes essentially aborted, accumulation of Ly6G+ neutrophils reduced and acute injury attenuated. Unique identifiers of microglia and monocytes revealed phenotypic changes in each cell subtype of the monocyte lineage after CAIS. Taken together, CX3CR1-CCR2-dependent microglia-monocyte signaling contributes to cerebrovascular leakage, inflammation and CAIS injury.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1919-1935
Faustino J, Chip S, Derugin N, Jullienne A, ... Obenaus A, Vexler ZS
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1919-1935 | PMID: 30628839
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Abstract

Annexin A2 is a Robo4 ligand that modulates ARF6 activation-associated cerebral trans-endothelial permeability.

Li W, Chen Z, Yuan J, Yu Z, ... Dai H, Wang X

Blood-brain barrier (BBB) disruption in neurological disorders remains an intractable problem with limited therapeutic options. Here, we investigate whether the endothelial cell membrane protein annexin A2 (ANXA2) may play a role in reducing trans-endothelial permeability and maintaining cerebrovascular integrity after injury. Compared with wild-type mice, the expression of cerebral endothelial junctional proteins was reduced in E15.5 and adult ANXA2 knockout mice, along with increased leakage of small molecule tracers. In human brain endothelial cells that were damaged by hypoxia plus IL-1β, treatment with recombinant ANXA2 (rA2) rescued the expression of junctional proteins and decreased trans-endothelial permeability. These protective effects were mediated in part by interactions with F-actin and VE-cadherin, and the ability of rA2 to modulate signaling via the roundabout guidance receptor 4 (Robo4)-paxillin-ADP-ribosylation factor 6 (ARF6) pathway. Taken together, these observations suggest that ANXA2 may be associated with the maintenance of endothelial tightness after cerebrovascular injury. ANXA2-mediated pathways should be further explored as potential therapeutic targets for protecting the BBB in neurological disorders.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2048-2060
Li W, Chen Z, Yuan J, Yu Z, ... Dai H, Wang X
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2048-2060 | PMID: 29786451
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Abstract

Triggering receptor expressed on myeloid cells-2 expression in the brain is required for maximal phagocytic activity and improved neurological outcomes following experimental stroke.

Kurisu K, Zheng Z, Kim JY, Shi J, ... Hsieh CL, Yenari MA

Triggering receptor expressed on myeloid cells-2 (TREM2) is an innate immune receptor that promotes phagocytosis by myeloid cells such as microglia and macrophages. We previously showed that TREM2 deficiency worsened outcomes from experimental stroke and impeded phagocytosis. However, myeloid cells participating in stroke pathology include both brain resident microglia and circulating macrophages. We now clarify whether TREM2 on brain microglia or circulating macrophages contribute to its beneficial role in ischemic stroke by generating bone marrow (BM) chimeric mice. BM chimera mice from TREM2 knockout (KO) or wild type (Wt) mice were used as donor and recipient mice. Mice were subjected to experimental stroke, and neurological function and infarct volume were assessed. Mice with intact TREM2 in brain microglia showed better neurological recovery and reduced infarct volumes, compared with mice lacking microglial TREM2. Myeloid cell activation and numbers of phagocytes were decreased in mice lacking brain TREM2, compared with mice with intact brain TREM2. These results suggest that TREM2 expression is important for post-stroke recovery, and that TREM2 expression on brain resident microglia is more essential to this recovery, than that of circulating macrophages. These findings might suggest a new therapeutic target for cerebrovascular diseases.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1906-1918
Kurisu K, Zheng Z, Kim JY, Shi J, ... Hsieh CL, Yenari MA
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1906-1918 | PMID: 30523715
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Abstract

A critical role for the ATP-sensitive potassium channel subunit K6.1 in the control of cerebral blood flow.

Hosford PS, Christie IN, Niranjan A, Aziz Q, ... Tinker A, Gourine AV

K6.1 (KCNJ8) is a subunit of ATP sensitive potassium channel (K) that plays an important role in the control of peripheral vascular tone and is highly expressed in brain contractile cells (vascular smooth muscle cells and pericytes). This study determined the effect of global deletion of the K6.1 subunit on cerebral blood flow, neurovascular coupling and cerebral oxygenation in mice. In K6.1 deficient mice resting cerebral blood flow and brain parenchymal partial pressure of oxygen (O) were found to be markedly lower compared to that in their wildtype littermates. However, cortical blood oxygen level dependent responses triggered by visual stimuli were not affected in conditions of K6.1 deficiency. These data suggest that K channels containing K6.1 subunit are critically important for the maintenance of normal cerebral perfusion and parenchymal O but play no significant role in the mechanisms underlying functional changes in brain blood flow.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2089-2095
Hosford PS, Christie IN, Niranjan A, Aziz Q, ... Tinker A, Gourine AV
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2089-2095 | PMID: 29862863
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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: 09 Sep 2019:271678X19874770; epub ahead of print
Karalija N, Jonassson L, Johansson J, Papenberg G, ... Nyberg L, Boraxbekk CJ
J Cereb Blood Flow Metab: 09 Sep 2019:271678X19874770; epub ahead of print | PMID: 31506011
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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: 09 Sep 2019:271678X19874134; epub ahead of print
Goodman JR, Iliff JJ
J Cereb Blood Flow Metab: 09 Sep 2019:271678X19874134; epub ahead of print | PMID: 31506012
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Abstract

The intracerebral hemorrhage blood transcriptome in humans differs from the ischemic stroke and vascular risk factor control blood transcriptomes.

Stamova B, Ander BP, Jickling G, Hamade F, ... Shroff N, Sharp FR

Understanding how the blood transcriptome of human intracerebral hemorrhage (ICH) differs from ischemic stroke (IS) and matched controls (CTRL) will improve understanding of immune and coagulation pathways in both disorders. This study examined RNA from 99 human whole-blood samples using GeneChip® HTA 2.0 arrays to assess differentially expressed transcripts of alternatively spliced genes between ICH, IS and CTRL. We used a mixed regression model with FDR-corrected (Dx) < 0.2 and  < 0.005 and |FC| > 1.2 for individual comparisons. For time-dependent analyses, subjects were divided into four time-points: 0(CTRL), <24 h, 24-48 h, >48 h; 489 transcripts were differentially expressed between ICH and CTRL, and 63 between IS and CTRL. ICH had differentially expressed T-cell receptor and CD36 genes, and iNOS, TLR, macrophage, and T-helper pathways. IS had more non-coding RNA. ICH and IS both had angiogenesis, CTLA4 in T lymphocytes, CD28 in T helper cells, NFAT regulation of immune response, and glucocorticoid receptor signaling pathways. Self-organizing maps revealed 4357 transcripts changing expression over time in ICH, and 1136 in IS. Understanding ICH and IS transcriptomes will be useful for biomarker development, treatment and prevention strategies, and for evaluating how well animal models recapitulate human ICH and IS.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1818-1835
Stamova B, Ander BP, Jickling G, Hamade F, ... Shroff N, Sharp FR
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1818-1835 | PMID: 29651892
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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: 29 Sep 2019:271678X19865449; epub ahead of print
Furby HV, Warnert EA, Marley CJ, Bailey DM, Wise RG
J Cereb Blood Flow Metab: 29 Sep 2019:271678X19865449; epub ahead of print | PMID: 31564194
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Abstract

Spontaneous BOLD waves - A novel hemodynamic activity in Sprague-Dawley rat brain detected by functional magnetic resonance imaging.

Shatillo A, Lipponen A, Salo RA, Tanila H, ... Giniatullin R, Gröhn OH

We report spontaneous hemodynamic activity termed \"Spontaneous BOLD Waves\" (SBWs) detected by BOLD fMRI in Sprague-Dawley rats under medetomidine anesthesia. These SBWs, which lasted several minutes, were observed in cortex, thalamus and hippocampus. The SBWs\' correlates were undetectable in electrophysiological recordings, suggesting an exclusive gliovascular phenomenon dissociated from neuronal activity. SBWs were insensitive to the NMDA receptors antagonist MK-801 but were inhibited by the α1-adrenoceptor blocker prazosin. Since medetomidine is a potent agonist of α2 adrenoceptors, we suggested that imbalance in α1/α2 receptor-mediated signalling pathways alter the vascular reactivity leading to SBWs. The frequency of SBWs increased with intensity of mechanical lung ventilation despite the stable pH levels. In summary, we present a novel type of propagating vascular brain activity without easily detectable underlying neuronal activity, which can be utilized to study the mechanisms of vascular reactivity in functional and pharmacological MRI and has practical implications for designing fMRI experiments in anesthetized animals.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1949-1960
Shatillo A, Lipponen A, Salo RA, Tanila H, ... Giniatullin R, Gröhn OH
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1949-1960 | PMID: 29690796
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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: 10 Sep 2019:271678X19874338; epub ahead of print
Quandt F, Fischer F, Schröder J, Heinze M, ... Gerloff C, Thomalla G
J Cereb Blood Flow Metab: 10 Sep 2019:271678X19874338; epub ahead of print | PMID: 31510853
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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: 08 Sep 2019:271678X19872563; epub ahead of print
Johnson SE, McKnight CD, Lants SK, Juttukonda MR, ... Claassen DO, Donahue MJ
J Cereb Blood Flow Metab: 08 Sep 2019:271678X19872563; epub ahead of print | PMID: 31500523
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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: 25 Sep 2019:271678X19877889; epub ahead of print
He JW, Rabiller G, Nishijima Y, Akamatsu Y, ... Yazdan-Shahmorad A, Liu J
J Cereb Blood Flow Metab: 25 Sep 2019:271678X19877889; epub ahead of print | PMID: 31558106
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Abstract

Differential effects of hypothermia on neurovascular unit determine protective or toxic results: Toward optimized therapeutic hypothermia.

Lyden PD, Lamb J, Kothari S, Toossi S, Boitano P, Rajput PS

Therapeutic hypothermia (TH) benefits survivors of cardiac arrest and neonatal hypoxic-ischemic injury and may benefit stroke patients. Large TH clinical trials, however, have shown mixed results. Given the substantial pre-clinical literature supporting TH, we explored possible mechanisms for clinical trial variability. Using a standard rodent stroke model ( = 20 per group), we found smaller infarctions after 2 h pre- or post-reperfusion TH compared to 4 h. To explore the mechanism of this discrepancy, we used primary cell cultures of rodent neurons, astrocytes, or endothelial cells subjected to oxygen-glucose deprivation (OGD). Then, cells were randomly assigned to 33℃, 35℃ or 37℃ for varying durations after varying delay times. Both 33 and 35℃ TH effectively preserved all cell types, although 33℃ was superior. Longer cooling durations overcame moderate delays to cooling initiation. In contrast, TH interfered with astrocyte paracrine protection of neurons in a temperature-dependent manner. These findings suggest that longer TH is needed to overcome delays to TH onset, but shorter TH durations may be superior to longer, perhaps due to suppression of astrocytic paracrine support of neurons during injury. We propose a scheme for optimizing TH after cerebral injury to stimulate further studies of cardiac arrest and stroke.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1693-1709
Lyden PD, Lamb J, Kothari S, Toossi S, Boitano P, Rajput PS
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1693-1709 | PMID: 30461327
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Abstract

Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke.

Neal EG, Acosta SA, Kaneko Y, Ji X, Borlongan CV

Regulatory T-cells (T) may exert a neuroprotective effect on ischemic stroke by inhibiting both inflammation and effector T-cell activation. Transplantation of human bone marrow-derived stem cells (BMSCs) in ischemic stroke affords neuroprotection that results in part from the cells\' anti-inflammatory property. However, the relationship between T and BMSCs in treatment of ischemic stroke has not been fully elucidated. Here, we tested the hypothesis that T within the BMSCs represent active mediators of immunomodulation and neuroprotection in experimental stroke. Primary rat neuronal cells were subjected to an oxygen-glucose deprivation and reperfusion (OGD/R) condition. The cells were re-perfused and co-cultured with T and/or BMSCs. We detected a minority population of T within BMSCs with both immunocytochemistry (ICC) and flow cytometry identifying cells expressing phenotypic markers of CD4, CD25, and FoxP3 protein. BMSCs with the native population of T conferred maximal neuroprotection compared to the treatment conditions containing 0%, 10%, and 100% relative ratio T. Increasing the T population resulted in increased IL6 secretion and decreased FGF-β secretion by BMSCs. This study shows that a minority population of T exists within the therapeutic BMSC population, which serves as robust mediators of the immunomodulatory and neuroprotective effect provided by BMSC transplantation.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1750-1758
Neal EG, Acosta SA, Kaneko Y, Ji X, Borlongan CV
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1750-1758 | PMID: 29569981
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Abstract

Longitudinal evaluation of surrogates of regional cerebral blood flow computed from dynamic amyloid PET imaging.

Bilgel M, Beason-Held L, An Y, Zhou Y, Wong DF, Resnick SM

Surrogates of neuronal activity, typically measured by regional cerebral blood flow (rCBF) or glucose metabolism, can be estimated from dynamic amyloid PET imaging. Using data for 149 participants (345 visits) from the Baltimore Longitudinal Study of Aging, we assessed whether the average of early amyloid frames (EA) andcomputed from dynamic C-Pittsburgh compound B (PiB) PET can serve as surrogates of rCBF computed from O-HO-PET.had the highest longitudinal test-retest reliability. Interquartile range (IQR) of cross-sectional Pearson correlations with rCBF was 0.60-0.72 for EA and 0.63-0.72 for . Correlations between rates of change were lower (IQR 0.22-0.50 for EA, 0.25-0.55 for ). Values in the Alzheimer\'s metabolic signature meta-ROI were negatively associated with age and exhibited longitudinal declines for each PET measure. In age-adjusted analyses, meta-ROI rCBF andwere lower among amyloid+ individuals; EA andwere lower among males. Regional PiB-based measures, in particular , can be suitable surrogates of rCBF. Dynamic PiB-PET may obviate the need for a separate scan to measure neuronal activity, thereby reducing patient burden, radioactivity exposure, and cost.



J Cereb Blood Flow Metab: 30 Jan 2020; 40:288-297
Bilgel M, Beason-Held L, An Y, Zhou Y, Wong DF, Resnick SM
J Cereb Blood Flow Metab: 30 Jan 2020; 40:288-297 | PMID: 30755135
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Abstract

Early reduced behavioral activity induced by large strokes affects the efficiency of enriched environment in rats.

Wahl AS, Erlebach E, Brattoli B, Büchler U, ... Ommer B, Schwab ME

The majority of stroke patients develop post-stroke fatigue, a symptom which impairs motivation and diminishes the success of rehabilitative interventions. We show that large cortical strokes acutely reduce activity levels in rats for 1-2 weeks as a physiological response paralleled by signs of systemic inflammation. Rats were exposed early (1-2 weeks) or late (3-4 weeks after stroke) to an individually monitored enriched environment to stimulate self-controlled high-intensity sensorimotor training. A group of animals received Anti-Nogo antibodies for the first two weeks after stroke, a neuronal growth promoting immunotherapy already in clinical trials. Early exposure to the enriched environment resulted in poor outcome: Training intensity was correlated to enhanced systemic inflammation and functional impairment. In contrast, animals starting intense sensorimotor training two weeks after stroke preceded by the immunotherapy revealed better recovery with functional outcome positively correlated to the training intensity and the extent of re-innervation of the stroke denervated cervical hemi-cord. Our results suggest stroke-induced fatigue as a biological purposeful reaction of the organism during neuronal remodeling, enabling new circuit formation which will then be stabilized or pruned in the subsequent rehabilitative training phase. However, intense training too early may lead to wrong connections and is thus less effective.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2022-2034
Wahl AS, Erlebach E, Brattoli B, Büchler U, ... Ommer B, Schwab ME
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2022-2034 | PMID: 29768943
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Abstract

Therapeutic hypothermia promotes cerebral blood flow recovery and brain homeostasis after resuscitation from cardiac arrest in a rat model.

Wang Q, Miao P, Modi HR, Garikapati S, Koehler RC, Thakor NV

Laboratory and clinical studies have demonstrated that therapeutic hypothermia (TH), when applied as soon as possible after resuscitation from cardiac arrest (CA), results in better neurological outcome. This study tested the hypothesis that TH would promote cerebral blood flow (CBF) restoration and its maintenance after return of spontaneous circulation (ROSC) from CA. Twelve Wistar rats resuscitated from 7-min asphyxial CA were randomized into two groups: hypothermia group (7 H,  = 6), treated with mild TH (33-34℃) immediately after ROSC and normothermia group (7 N,  = 6,37.0 ± 0.5℃). Multiple parameters including mean arterial pressure, CBF, electroencephalogram (EEG) were recorded. The neurological outcomes were evaluated using electrophysiological (information quantity, IQ, of EEG) methods and a comprehensive behavior examination (neurological deficit score, NDS). TH consistently promoted better CBF restoration approaching the baseline levels in the 7 H group as compared with the 7 N group. CBF during the first 5-30 min post ROSC of the two groups was 7 H:90.5% ± 3.4% versus 7 N:76.7% ± 3.5% ( < 0.01). Subjects in the 7 H group showed significantly better IQ scores after ROSC and better NDS scores at 4 and 24 h. Early application of TH facilitates restoration of CBF back to baseline levels after CA, which in turn results in the restoration of brain electrical activity and improved neurological outcome.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1961-1973
Wang Q, Miao P, Modi HR, Garikapati S, Koehler RC, Thakor NV
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1961-1973 | PMID: 29739265
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Abstract

Glucose transporter 2 mediates the hypoglycemia-induced increase in cerebral blood flow.

Lei H, Preitner F, Labouèbe G, Gruetter R, Thorens B

Glucose transporter 2 ()-positive cells are sparsely distributed in brain and play an important role in the stimulation of glucagon secretion in response to hypoglycemia. We aimed to determine if -positive cells can influence another response to hypoglycemia, i.e. increased cerebral blood flow (CBF). CBF of adult male mice devoid of , either globally () or in the nervous system only (NG2KO), and their respective controls were studied under basal glycemia and insulin-induced hypoglycemia using quantitative perfusion magnetic resonance imaging at 9.4 T. The effect on CBF of optogenetic activation of hypoglycemia responsive -positive neurons of the paraventricular thalamic area was measured in mice expressing channelrhodopsin2 under the control of thepromoter. We found that in bothmice and NG2KO mice, CBF in basal conditions was higher than in their respective controls and not further activated by hypoglycemia, as measured in the hippocampus, hypothalamus and whole brain. Conversely, optogenetic activation of -positive cells in the paraventricular thalamic nucleus induced a local increase in CBF similar to that induced by hypoglycemia. Thus,expression in the nervous system is required for the control of CBF in response to changes in blood glucose concentrations.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1725-1736
Lei H, Preitner F, Labouèbe G, Gruetter R, Thorens B
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1725-1736 | PMID: 29561214
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Abstract

Cortical microinfarcts in memory clinic patients are associated with reduced cerebral perfusion.

Ferro DA, Mutsaerts HJ, Hilal S, Kuijf HJ, ... Biessels GJ, Chen C

Cerebral cortical microinfarcts (CMIs) are small ischemic lesions associated with cognitive impairment and dementia. CMIs are frequently observed in cortical watershed areas suggesting that hypoperfusion contributes to their development. We investigated if presence of CMIs was related to a decrease in cerebral perfusion, globally or specifically in cortex surrounding CMIs. In 181 memory clinic patients (mean age 72 ± 9 years, 51% male), CMI presence was rated on 3-T magnetic resonance imaging (MRI). Cerebral perfusion was assessed from cortical gray matter of the anterior circulation using pseudo-continuous arterial spin labeling parameters(CBF) (perfusion in mL blood/100 g tissue/min) and(CoV) (reflecting arterial transit time (ATT)). Patients with CMIs had a 12% lower CBF (beta = -.20) and 22% higher spatial CoV (beta = .20) (both  < .05) without a specific regional pattern on voxel-based CBF analysis. CBF in a 2 cm region-of-interest around the CMIs did not differ from CBF in a reference zone in the contralateral hemisphere. These findings show that CMIs in memory clinic patients are primarily related to global reductions in cerebral perfusion, thus shedding new light on the etiology of vascular brain injury in dementia.



J Cereb Blood Flow Metab: 25 Sep 2019:271678X19877403; epub ahead of print
Ferro DA, Mutsaerts HJ, Hilal S, Kuijf HJ, ... Biessels GJ, Chen C
J Cereb Blood Flow Metab: 25 Sep 2019:271678X19877403; epub ahead of print | PMID: 31558107
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Abstract

Optimizing functional outcome endpoints for stroke recovery studies.

Balkaya M, Cho S

Novel therapeutic intervention that aims to enhance the endogenous recovery potential of the brain during the subacute phase of stroke has produced promising results. The paradigm shift in treatment approaches presents new challenges to preclinical and clinical researchers alike, especially in the functional endpoints domain. Shortcomings of the \"neuroprotection\" era of stroke research are yet to be fully addressed. Proportional recovery observed in clinics, and potentially in animal models, requires a thorough reevaluation of the methods used to assess recovery. To this end, this review aims to give a detailed evaluation of functional outcome measures used in clinics and preclinical studies. Impairments observed in clinics and animal models will be discussed from a functional testing perspective. Approaches needed to bridge the gap between clinical and preclinical research, along with potential means to measure the moving target recovery, will be discussed. Concepts such as true recovery of function and compensation and methods that are suitable for distinguishing the two are examined. Often-neglected outcomes of stroke, such as emotional disturbances, are discussed to draw attention to the need for further research in this area.



J Cereb Blood Flow Metab: 13 Sep 2019:271678X19875212; epub ahead of print
Balkaya M, Cho S
J Cereb Blood Flow Metab: 13 Sep 2019:271678X19875212; epub ahead of print | PMID: 31522590
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Abstract

Classifying intracranial stenosis disease severity from functional MRI data using machine learning.

Waddle SL, Juttukonda MR, Lants SK, Davis LT, ... Jordan LC, Donahue MJ

Translation of many non-invasive hemodynamic MRI methods to cerebrovascular disease patients has been hampered by well-known artifacts associated with delayed blood arrival times and reduced microvascular compliance. Using machine learning and support vector machine (SVM) algorithms, we investigated whether arrival time-related artifacts in these methods could be exploited as novel contrast sources to discriminate angiographically confirmed stenotic flow territories. Intracranial steno-occlusive moyamoya patients ( = 53; age = 45 ± 14.2 years; sex = 43 F) underwent (i) catheter angiography, (ii) anatomical MRI, (iii) cerebral blood flow (CBF)-weighted arterial spin labeling, and (iv) cerebrovascular reactivity (CVR)-weighted hypercapnic blood-oxygenation-level-dependent MRI. Mean, standard deviation (std), and 99th percentile of CBF, CVR, CVR, and CVR were calculated in major anterior and posterior flow territories perfused by vessels with vs. without stenosis (≥70%) confirmed by catheter angiography. These and demographic variables were input into SVMs to evaluate discriminatory capacity for stenotic flow territories using k-fold cross-validation and receiver-operating-characteristic-area-under-the-curve to quantify variable combination relevance. Anterior circulation CBF-std, attributable to heterogeneous endovascular signal and prolonged arterial transit times, was the best performing single variable and CVR-mean and CBF-std, both reflective of delayed vascular compliance, were a high-performing two-variable combination (specificity = 0.67; sensitivity = 0.75). Findings highlight the relevance of hemodynamic imaging and machine learning for identifying cerebrovascular impairment.



J Cereb Blood Flow Metab: 30 Mar 2020; 40:705-719
Waddle SL, Juttukonda MR, Lants SK, Davis LT, ... Jordan LC, Donahue MJ
J Cereb Blood Flow Metab: 30 Mar 2020; 40:705-719 | PMID: 31068081
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Abstract

Effect of lactate administration on brain lactate levels during hypoglycemia in patients with type 1 diabetes.

Wiegers EC, Rooijackers HM, Tack CJ, Philips BW, ... van der Graaf M, de Galan BE

Administration of lactate during hypoglycemia suppresses symptoms and counterregulatory responses, as seen in patients with type 1 diabetes and impaired awareness of hypoglycemia (IAH), presumably because lactate can substitute for glucose as a brain fuel. Here, we examined whether lactate administration, in a dose sufficient to impair awareness of hypoglycemia, affects brain lactate levels in patients with normal awareness of hypoglycemia (NAH). Patients with NAH ( = 6) underwent two euglycemic-hypoglycemic clamps (2.8 mmol/L), once with sodium lactate infusion (NAH w|lac) and once with saline infusion (NAH w|placebo). Results were compared to those obtained during lactate administration in patients with IAH ( = 7) (IAH w|lac). Brain lactate levels were determined continuously with J-difference editing H-MRS. During lactate infusion, symptom and adrenaline responses to hypoglycemia were considerably suppressed in NAH. Infusion of lactate increased brain lactate levels modestly, but comparably, in both groups (mean increase in NAH w|lac: 0.12 ± 0.05 µmol/g and in IAH w|lac: 0.06 ± 0.04 µmol/g). The modest increase in brain lactate may suggest that the excess of lactate is immediately metabolized by the brain, which in turn may explain the suppressive effects of lactate on awareness of hypoglycemia observed in patients with NAH.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1974-1982
Wiegers EC, Rooijackers HM, Tack CJ, Philips BW, ... van der Graaf M, de Galan BE
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1974-1982 | PMID: 29749805
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Abstract

Altered folate binding protein expression and folate delivery are associated with congenital hydrocephalus in the hydrocephalic Texas rat.

Jimenez AR, Naz N, Miyan JA

Hydrocephalus (HC) is an imbalance in cerebrospinal fluid (CSF) secretion/absorption resulting in fluid accumulation within the brain with consequential pathophysiology. Our research has identified a unique cerebral folate system in which depletion of CSF 10-formyl-tetrahydrofolate-dehydrogenase (FDH) is associated with cortical progenitor cell-cycle arrest in hydrocephalic Texas (H-Tx) rats. We used tissue culture, immunohistochemistry, in-situ PCR and RT-PCR and found that the in-vitro proliferation of arachnoid cells is highly folate-dependent with exacerbated proliferation occurring in hydrocephalic CSF that has low FDH but high folate-receptor-alpha (FRα) and folate. Adding FDH to this CSF prevented aberrant proliferation indicating a regulatory function of FDH on CSF folate concentration. Arachnoid cells have no detectable mRNA for FRα or FDH, but FDH mRNA is found in the choroid plexus (CP) and CSF microvesicles. Co-localization of FDH, FRα and folate suggests important functions of FDH in cerebral folate transport, buffering and function. In conclusion, abnormal CSF levels of FDH, FRα and folate inhibit cortical cell proliferation but allow uncontrolled arachnoid cell division that should increase fluid absorption by increasing the arachnoid although this fails in the hydrocephalic brain. FDH appears to buffer available folate to control arachnoid proliferation and function.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2061-2073
Jimenez AR, Naz N, Miyan JA
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2061-2073 | PMID: 29798726
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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: 06 Sep 2019:271678X19874509; epub ahead of print
Neglia L, Fumagalli S, Orsini F, Zanetti A, Perego C, De Simoni MG
J Cereb Blood Flow Metab: 06 Sep 2019:271678X19874509; epub ahead of print | PMID: 31495300
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Abstract

Oxygen dependency of mitochondrial metabolism indicates outcome of newborn brain injury.

Bale G, Mitra S, de Roever I, Sokolska M, ... Robertson NJ, Tachtsidis I

There is a need for a method of real-time assessment of brain metabolism during neonatal hypoxic-ischaemic encephalopathy (HIE). We have used broadband near-infrared spectroscopy (NIRS) to monitor cerebral oxygenation and metabolic changes in 50 neonates with HIE undergoing therapeutic hypothermia treatment. In 24 neonates, 54 episodes of spontaneous decreases in peripheral oxygen saturation (desaturations) were recorded between 6 and 81 h after birth. We observed differences in the cerebral metabolic responses to these episodes that were related to the predicted outcome of the injury, as determined by subsequent magnetic resonance spectroscopy derived lactate/N-acetyl-aspartate. We demonstrated that a strong relationship between cerebral metabolism (broadband NIRS-measured cytochrome-c-oxidase (CCO)) and cerebral oxygenation was associated with unfavourable outcome; this is likely to be due to a lower cerebral metabolic rate and mitochondrial dysfunction in severe encephalopathy. Specifically, a decrease in the brain tissue oxidation state of CCO greater than 0.06 µM per 1 µM brain haemoglobin oxygenation drop was able to predict the outcome with 64% sensitivity and 79% specificity (receiver operating characteristic area under the curve = 0.73). With further work on the implementation of this methodology, broadband NIRS has the potential to provide an early, cotside, non-invasive, clinically relevant metabolic marker of perinatal hypoxic-ischaemic injury.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2035-2047
Bale G, Mitra S, de Roever I, Sokolska M, ... Robertson NJ, Tachtsidis I
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2035-2047 | PMID: 29775114
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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: 08 Sep 2019:271678X19874295; epub ahead of print
Hougaard A, Younis S, Iljazi A, Haanes KA, ... Ayata C, Ashina M
J Cereb Blood Flow Metab: 08 Sep 2019:271678X19874295; epub ahead of print | PMID: 31500524
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This program is still in alpha version.