Journal: J Cereb Blood Flow Metab

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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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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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

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

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

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

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

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

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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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

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

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

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



J Cereb Blood Flow Metab: 08 Sep 2019:271678X19874643; epub ahead of print
Puig O, Henriksen OM, Vestergaard MB, Hansen AE, ... Lindberg U, Law I
J Cereb Blood Flow Metab: 08 Sep 2019:271678X19874643; epub ahead of print | PMID: 31500521
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Abstract

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

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

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



J Cereb Blood Flow Metab: 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

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

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

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

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



J Cereb Blood Flow Metab: 08 Sep 2019:271678X19872564; epub ahead of print
Milej D, He L, Abdalmalak A, Baker WB, ... Yodh AG, St Lawrence K
J Cereb Blood Flow Metab: 08 Sep 2019:271678X19872564; epub ahead of print | PMID: 31500522
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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

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

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

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

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

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

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

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

Neurovascular coupling and cerebral autoregulation in atrial fibrillation.

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

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



J Cereb Blood Flow Metab: 18 Aug 2019:271678X19870770; epub ahead of print
Junejo RT, Braz ID, Lucas SJ, van Lieshout JJ, ... Lip GY, Fisher JP
J Cereb Blood Flow Metab: 18 Aug 2019:271678X19870770; epub ahead of print | PMID: 31426699
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Abstract

Physiologic predictors of collateral circulation and infarct growth during anesthesia - Detailed analyses of the GOLIATH trial.

Raychev R, Liebeskind DS, Yoo AJ, Rasmussen M, ... Saver J, Simonsen CZ

Collateral circulation plays a pivotal role in acute ischemic stroke due to large vessel occlusion (LVO) and may be affected by multiple variables during sedation for endovascular therapy (EVT). We conducted detailed analyses of the GOLIATH trial to identify predictors of collateral circulation grade and infarct growth. We also modified the ASITN collateral grading scale and sought to determine its impact on clinical outcome and infarct growth. Multivariable analysis was used to identify predictors of collaterals and infarct growth. Ordinal analysis demonstrated nominal, but non-significant association between modified ASITN scale and infarct growth. Among all analyzed baseline clinical and procedural variables, the most significant predictors of infarct growth at 24 h were phenylephrine dose (estimate 6.78;  = 0.014) and baseline infarct volume (estimate 0.93;  = 0.03). The most significant predictors of worse collateral grade were mean arterial pressure (MAP) <70 mmHg (OR 0.35;  = 0.048) and baseline infarct volume (OR 0.96;  = 0.003). Hypotension during sedation for EVT for LVO negatively impacts collateral circulation, while higher pressor dose is a strong predictor of infarct growth. Avoidance of anesthesia-induced hypotension and consequent need for pressor therapy may prevent collateral failure and minimize infarct growth.



J Cereb Blood Flow Metab: 31 Jul 2019:271678X19865219; epub ahead of print
Raychev R, Liebeskind DS, Yoo AJ, Rasmussen M, ... Saver J, Simonsen CZ
J Cereb Blood Flow Metab: 31 Jul 2019:271678X19865219; epub ahead of print | PMID: 31366300
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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

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

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

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

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

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

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

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

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

Inhibition of histone deacetylase 3 by MiR-494 alleviates neuronal loss and improves neurological recovery in experimental stroke.

Zhao H, Li G, Zhang S, Li F, ... Ji X, Luo Y

HDAC3 is an essential negative regulator of neuronal plasticity and memory formation. Although a chemical inhibitor has been invented, little is known about its endogenous modulators. We explored whether miR-494 affects HDAC3-mediated neuronal injury following acute ischemic stroke. A substantial increase in plasma miR-494 was detected in AIS patients and was positively associated with the mRS at one year after symptom onset. The miR-494 levels were transiently increased in the infarcted brain tissue of mice. In contrast, miR-494 levels were reduced in neurons but increased in the medium after OGD. Intracerebroventricular injection of miR-494 agomir reduced neuronal apoptosis and infarct volume at the acute stage of MCAO, promoted axonal plasticity and long-term outcomes at the recovery stage, suppressed neuronal ataxin-3 and HDAC3 expression and increased acetyl-H3K9 levels in the ipsilateral hemisphere. In vitro studies confirmed that miR-494 posttranslationally inhibited HDAC3 in neurons and prevented OGD-induced neuronal axonal injury. The HDAC3 inhibitor increased acetyl-H3K9 levels and reversed miR-494 antagomir-aggravated acute cerebral ischemic injury, as well as brain atrophy and long-term functional recovery. These results suggest that miR-494 may serve as a predictive biomarker of functional outcomes in AIS patients and a potential therapeutic target for the treatment of ischemic stroke.



J Cereb Blood Flow Metab: 10 Sep 2019:271678X19875201; epub ahead of print
Zhao H, Li G, Zhang S, Li F, ... Ji X, Luo Y
J Cereb Blood Flow Metab: 10 Sep 2019:271678X19875201; epub ahead of print | PMID: 31510852
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Abstract

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

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

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



J Cereb Blood Flow Metab: 06 Sep 2019:271678X19874790; epub ahead of print
Eide PK, Valnes LM, Pripp AH, Mardal KA, Ringstad G
J Cereb Blood Flow Metab: 06 Sep 2019:271678X19874790; epub ahead of print | PMID: 31495299
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Abstract

Increasing cerebral blood flow improves cognition into late stages in Alzheimer\'s disease mice.

Bracko O, Njiru BN, Swallow M, Ali M, Haft-Javaherian M, Schaffer CB

Alzheimer\'s disease is associated with a 20-30% reduction in cerebral blood flow. In the APP/PS1 mouse model of Alzheimer\'s disease, inhibiting neutrophil adhesion using an antibody against the neutrophil specific protein Ly6G was recently shown to drive rapid improvements in cerebral blood flow that was accompanied by an improvement in performance on short-term memory tasks. Here, in a longitudinal aging study, we assessed how far into disease development a single injection of anti-Ly6G treatment can acutely improve short-term memory function. We found that APP/PS1 mice as old as 15-16 months had improved performance on the object replacement and Y-maze tests of spatial and working short-term memory, measured at one day after anti-Ly6G treatment. APP/PS1 mice at 17-18 months of age or older did not show acute improvements in cognitive performance, although we did find that capillary stalls were still reduced and cerebral blood flow was still increased by 17% in 21-22-months-old APP/PS1 mice given anti-Ly6G antibody. These data add to the growing body of evidence suggesting that cerebral blood flow reductions are an important contributing factor to the cognitive dysfunction associated with neurodegenerative disease. Thus, interfering with neutrophil adhesion could be a new therapeutic approach for Alzheimer\'s disease.



J Cereb Blood Flow Metab: 06 Sep 2019:271678X19873658; epub ahead of print
Bracko O, Njiru BN, Swallow M, Ali M, Haft-Javaherian M, Schaffer CB
J Cereb Blood Flow Metab: 06 Sep 2019:271678X19873658; epub ahead of print | PMID: 31495298
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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

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

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

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

A peptide derived from melanotransferrin delivers a protein-based interleukin 1 receptor antagonist across the BBB and ameliorates neuropathic pain in a preclinical model.

Thom G, Tian MM, Hatcher JP, Rodrigo N, ... Webster CI, Gabathuler R

Delivery of biologic drugs across the blood-brain barrier is becoming a reality. However, the solutions often involve the assembly of complex multi-specific antibody molecules. Here we utilize a simple 12 amino-acid peptide originating from the melanotransferrin (MTf) protein that has shown improved brain delivery properties. 3D confocal fluorescence microscopic analysis demonstrated brain parenchymal localisation of a fluorescently labelled antibody (NIP228) when chemically conjugated to either the MTf peptide or full-length MTf protein. Measurement of plasma kinetics demonstrated the MTf peptide fusions had very similar kinetics to an unmodified NIP228 control antibody, whereas the fusion to MTf protein had significantly reduced plasma exposure most likely due to a higher tissue distribution in the periphery. Brain exposure for the MTf peptide fusions was significantly increased for the duration of the study, exceeding that of the fusions to full length MTf protein. Using a neuropathic pain model, we have demonstrated that fusions to interleukin-1 receptor antagonist (IL-1RA) are able to induce significant and durable analgesia following peripheral administration. These data demonstrate that recombinant and chemically conjugated MTf-based brain delivery vectors can deliver therapeutic levels of drug to the central nervous system.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2074-2088
Thom G, Tian MM, Hatcher JP, Rodrigo N, ... Webster CI, Gabathuler R
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2074-2088 | PMID: 29845881
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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

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

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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Impact:
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

VLA-4 mediated adhesion of melanoma cells on the blood-brain barrier is the critical cue for melanoma cell intercalation and barrier disruption.

García-Martín AB, Zwicky P, Gruber T, Matti C, ... Hewer E, Lyck R

Melanoma is the most aggressive skin cancer in humans. One severe complication is the formation of brain metastasis, which requires extravasation of melanoma cells across the tight blood-brain barrier (BBB). Previously, VLA-4 has been assigned a role for the adhesive interaction of melanoma cells with non-BBB endothelial cells. However, the role of melanoma VLA-4 for breaching the BBB remained unknown. In this study, we used a mouse in vitro BBB model and imaged the shear resistant arrest of melanoma cells on the BBB. Similar to effector T cells, inflammatory conditions of the BBB increased the arrest of melanoma cells followed by a unique post-arrest behavior lacking immediate crawling. However, over time, melanoma cells intercalated into the BBB and compromised its barrier properties. Most importantly, antibody ablation of VLA-4 abrogated melanoma shear resistant arrest on and intercalation into the BBB and protected the BBB from barrier breakdown. A tissue microarray established from human brain metastasis revealed that indeed a majority of 92% of all human melanoma brain metastases stained VLA-4 positive. We propose VLA-4 as a target for the inhibition of brain metastasis formation in the context of personalized medicine identifying metastasizing VLA-4 positive melanoma.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1995-2010
García-Martín AB, Zwicky P, Gruber T, Matti C, ... Hewer E, Lyck R
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1995-2010 | PMID: 29762071
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Abstract

Dl-3-N-butylphthalide attenuates ischemic reperfusion injury by improving the function of cerebral artery and circulation.

Qin C, Zhou P, Wang L, Mamtilahun M, ... Yang GY, Wang Y

Dl-3-N-butylphthalide (NBP) is approved in China for the treatment of ischemic stroke. Previous studies have shown that NBP promotes recovery after stroke via multiple mechanisms. However, the effect of NBP on vascular function and thrombosis remains unclear. Here, we aim to study the effect of NBP on vascular function using a rat model of transient middle cerebral artery occlusion (MCAO) and a state-of-the-art high-resolution synchrotron radiation angiography. Eighty SD rats underwent MCAO surgery. NBP (90 mg/kg) was administrated daily by gavage. Synchrotron radiation angiography was used to evaluate the cerebral vascular perfusion, vasoconstriction, and vasodilation in real-time. Neurological scores, brain infarction and atrophy were evaluated. Real-time PCR was used to assess the expression levels of thrombosis and vasoconstriction-related genes. Results revealed that NBP attenuated thrombosis after MCAO and reduced brain infarct and atrophy volume. NBP administrated at 1 and 4 h after MCAO prevented the vasoconstriction of the artery and maintained its diameter at normal level. Administrated at one week after surgery, NBP functioned as a vasodilator in rats after MCAO while displayed no vasodilating effect in sham group. Our results suggested that NBP attenuates brain injury via increasing the regional blood flow by reducing thrombosis and vasoconstriction.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2011-2021
Qin C, Zhou P, Wang L, Mamtilahun M, ... Yang GY, Wang Y
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2011-2021 | PMID: 29762050
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Abstract

Quantitative hemodynamic analysis of cerebral blood flow and neurovascular coupling using optical coherence tomography angiography.

Shin P, Choi W, Joo J, Oh WY

Functional hyperemia in the rat cortex was investigated using high-speed optical coherence tomography (OCT) angiography and Doppler OCT. OCT angiography (OCTA) was performed to image the hemodynamic stimulus-response over a wide field of view. Temporal changes in vessel diameters in different vessel compartments, which were determined as the diameters of erythrocyte flows in OCT angiograms, were measured in order to monitor localized hemodynamic changes. Our results showed that the dilation of arterioles at the site of activation was accompanied by the dilation of upstream arteries. Relatively negligible dilation was observed in veins. An increase in the OCTA signal was observed during stimulus in multiple capillaries, which may imply that capillary blood flow increases as a result of the expanded arterial blood volume. These results agree with previous observations using two-photon laser scanning microscopy (TPLSM). Doppler OCT was performed to quantitatively measure stimulus-induced blood flow response in pial arteries. The measurement showed small but clear hemodynamic response in upstream arteries with diameters exceeding 100 m. Our results demonstrate the potential of OCTA and Doppler OCT for the investigation of neurovascular coupling in small animal models.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:1983-1994
Shin P, Choi W, Joo J, Oh WY
J Cereb Blood Flow Metab: 29 Sep 2019; 39:1983-1994 | PMID: 29757059
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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

Exacerbated brain edema in a rat streptozotocin model of hyperglycemic ischemic stroke: Evidence for involvement of blood-brain barrier Na-K-Cl cotransport and Na/H exchange.

Yuen NY, Chechneva OV, Chen YJ, Tsai YC, ... Anderson SE, O\'Donnell ME

Cerebral edema is exacerbated in diabetic ischemic stroke through poorly understood mechanisms. We showed previously that blood-brain barrier (BBB) Na-K-Cl cotransport (NKCC) and Na/H exchange (NHE) are major contributors to edema formation in normoglycemic ischemic stroke. Here, we investigated whether hyperglycemia-exacerbated edema involves changes in BBB NKCC and NHE expression and/or activity and whether inhibition of NKCC or NHE effectively reduces edema and injury in a type I diabetic model of hyperglycemic stroke. Cerebral microvascular endothelial cell (CMEC) NKCC and NHE abundances and activities were determined by Western blot, radioisotopic flux and microspectrofluorometric methods. Cerebral edema and Na in rats subjected to middle cerebral artery occlusion (MCAO) were assessed by nuclear magnetic resonance methods. Hyperglycemia exposures of 1-7d significantly increased CMEC NKCC and NHE abundance and activity. Subsequent exposure to ischemic factors caused more robust increases in NKCC and NHE activities than in normoglycemic CMEC. MCAO-induced edema and brain Na uptake were greater in hyperglycemic rats. Intravenous bumetanide and HOE-642 significantly attenuated edema, brain Na uptake and ischemic injury. Our findings provide evidence that BBB NKCC and NHE contribute to increased edema in hyperglycemic stroke, suggesting that these Na transporters are promising therapeutic targets for reducing damage in diabetic stroke.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1678-1692
Yuen NY, Chechneva OV, Chen YJ, Tsai YC, ... Anderson SE, O'Donnell ME
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1678-1692 | PMID: 29739261
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Abstract

Longitudinal MRI dynamics of recent small subcortical infarcts and possible predictors.

Pinter D, Gattringer T, Enzinger C, Seifert-Held T, ... Khalil M, Fazekas F

We aimed to explore the morphological evolution of recent small subcortical infarcts (RSSIs) over 15 months. Moreover, we hypothesized that quantitative lesion apparent diffusion coefficient (ADC) values and serum neurofilament light (NfL) levels predict subsequent lacunar cavitation. We prospectively studied 78 RSSI patients, who underwent pre-defined follow-up investigations three and 15 months poststroke using 3 T MRI including high-resolution T1 sequences. To identify potential predictors of cavitation, we determined RSSI size and quantitative ADC values, and serum NfL using the SIMOA technique. The majority of RSSIs showed cavitation at three months ( = 61, 78%) with only minimal changes regarding cavitation status thereafter. The maximum axial lacunar diameter decreased from 8 mm at three to 7 mm at 15 months ( < 0.05). RSSIs which cavitated had lower lesional ADC values and were associated with higher baseline NfL levels compared to those without cavitation, but did not differ regarding lesion size. In logistic regression analysis, only baseline NfL levels predicted cavitation ( = 0.017). In this prospective study using predefined high-resolution MRI protocols, the majority of RSSIs evolved into lacunes during the first three months poststroke with not much change thereafter. Serum NfL seems to be a promising biomarker for more advanced subsequent tissue destruction in RSSIs.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1669-1677
Pinter D, Gattringer T, Enzinger C, Seifert-Held T, ... Khalil M, Fazekas F
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1669-1677 | PMID: 29737904
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Abstract

Blood pressure reduction in hypertensive acute ischemic stroke patients does not affect cerebral blood flow.

Kate M, Asdaghi N, Gioia LC, Buck B, ... Beaulieu C, Butcher K

The effect of blood pressure (BP) reduction on cerebral blood flow (CBF) in acute ischemic stroke is unknown. We measured regional CBF with perfusion-weighted MRI before and after BP treatment in a three-armed non-randomized prospective controlled trial. Treatment arm assignment was based on acute mean arterial pressure (MAP). Patients with (MAP) >120 mmHg ( = 14) were treated with intravenous labetalol and sublingual (SL) nitroglycerin (labetalol group). Those with MAP 100-120 mmHg ( = 17) were treated with SL nitroglycerin (0.3 mg) (\'NTG Group\') and those with baseline MAP<100 mmHg ( = 18) were not treated with antihypertensive drugs (untreated group). Forty-nine patients (18 female, mean age 65.3 ± 12.9 years) were serially imaged. Labetalol reduced MAP by 12.5 (5.7-17.7) mmHg,  = 0.0002. MAP remained stable in the NTG (6.0 (0.4-16,  = 0.3) mmHg and untreated groups (-0.3 (-2.3-7.0,  = 0.2) mmHg. The volume of total hypoperfused tissue (CBF<18 ml/100 g/min) did not increase after labetalol (-1.1 ((-6.5)-(-0.2)) ml,  = 0.1), NTG (0 ((-1.5)-4.5) ml,  = 0.72), or no treatment 0.25 ((-10.1)-4.5) ml,  = 0.87). Antihypertensive therapy, based on presenting BP, in acute stroke patients was not associated with an increased volume of total hypoperfused tissue.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1878-1887
Kate M, Asdaghi N, Gioia LC, Buck B, ... Beaulieu C, Butcher K
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1878-1887 | PMID: 29737226
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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

Substitution of venous for arterial blood sampling in the determination of regional rates of cerebral protein synthesis with L-[1-C]leucine PET: A validation study.

Tomasi G, Veronese M, Bertoldo A, Smith CB, Schmidt KC

We developed and validated a method to estimate input functions for determination of regional rates of cerebral protein synthesis (rCPS) with L-[1-C]leucine PET without arterial sampling. The method is based on a population-derived input function (PDIF) approach, with venous samples for calibration. Population input functions were constructed from arterial blood data measured in 25 healthy 18-24-year-old males who underwent L-[1-C]leucine PET scans while awake. To validate the approach, three additional groups of 18-27-year-old males underwent L-[1-C]leucine PET scans with both arterial and venous blood sampling: 13 awake healthy volunteers, 10 sedated healthy volunteers, and 5 sedated subjects with fragile X syndrome. Rate constants of the L-[1-C]leucine kinetic model were estimated voxel-wise with measured arterial input functions and with venous-calibrated PDIFs. Venous plasma leucine measurements were used with venous-calibrated PDIFs for rCPS computation. rCPS determined with PDIFs calibrated with 30-60 min venous samples had small errors (RMSE: 4-9%), and no statistically significant differences were found in any group when compared to rCPS determined with arterial input functions. We conclude that in young adult males, PDIFs calibrated with 30-60 min venous samples can be used in place of arterial input functions for determination of rCPS with L-[1-C]leucine PET.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1849-1863
Tomasi G, Veronese M, Bertoldo A, Smith CB, Schmidt KC
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1849-1863 | PMID: 29664322
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Abstract

The AAA + ATPase Thorase is neuroprotective against ischemic injury.

Zhang J, Yang J, Wang H, Sherbini O, ... Dawson TM, Dawson VL

Neuronal preconditioning in vitro or in vivo with a stressful but non-lethal stimulus leads to new protein expression that mediates a profound neuroprotection against glutamate excitotoxicity and experimental stroke. The proteins that mediate neuroprotection are relatively unknown and under discovery. Here we find that the expression of the AAA + ATPase Thorase is induced by preconditioning stimulation both in vitro and in vivo. Thorase provides neuroprotection in an ATP-dependent manner against oxygen-glucose deprivation (OGD) neurotoxicity or glutamate N-Methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity in vitro. Knock-down of Thorase prevents the establishment of preconditioning induced neuroprotection against OGD or NMDA neurotoxicity. Transgenic overexpression of Thorase provides neuroprotection in vivo against middle cerebral artery occlusion (MCAO)-induced stroke in mice, while genetic deletion of Thorase results in increased injury in vivo following stroke. These results define Thorase as a neuroprotective protein and understanding Thorase signaling could offer a new therapeutic strategy for the treatment of neurologic disorders.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1836-1848
Zhang J, Yang J, Wang H, Sherbini O, ... Dawson TM, Dawson VL
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1836-1848 | PMID: 29658368
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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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Impact:
Abstract

Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain.

Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, ... Arnold S, Galkin A

Mortality from perinatal hypoxic-ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on HO release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochromeoxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1790-1802
Stepanova A, Konrad C, Guerrero-Castillo S, Manfredi G, ... Arnold S, Galkin A
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1790-1802 | PMID: 29629602
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Abstract

EphrinB2 activation enhances angiogenesis, reduces amyloid-β deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats.

Xing S, Pan N, Xu W, Zhang J, ... Pei Z, Zeng J

Cerebral infarction causes secondary neurodegeneration and angiogenesis in thalamus, which impacts functional recovery after stroke. Here, we hypothesize that activation of ephrinB2 could stimulate angiogenesis and restore the secondary neurodegeneration in thalamus after cerebral infarction. Focal cerebral infarction was induced by middle cerebral artery occlusion (MCAO). Secondary damage, angiogenesis, amyloid-β (Aβ) deposits, levels of ephrinB2 and receptor for advanced glycation end product (RAGE) in the ipsilateral thalamus were determined by immunofluorescence and immunoblot. The contribution of ephrinB2 to angiogenesis was determined by siRNA-mediated knockdown of ephrinB2 and pharmacological activation of ephrinB2. The results showed that formation of new vessels and ephrinB2 expression was markedly increased in the ipsilateral thalamus at seven days after MCAO. EphrinB2 knockdown markedly suppressed angiogenesis coinciding with increased Aβ accumulation, neuronal loss and gliosis in the ipsilateral thalamus. In contrast, clustered EphB2-Fc significantly enhanced angiogenesis, alleviated Aβ accumulation and the secondary thalamic damage, which was accompanied by accelerated function recovery. Additionally, activation of ephrinB2 significantly reduced RAGE levels in the ipsilateral thalamus. Our findings suggest that activation of ephrinB2 promotes angiogenesis, ameliorates Aβ accumulation and the secondary thalamic damage after cerebral infarction. Additionally, RAGE might be involved in Aβ clearance by activating ephrinB2 in the thalamus.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1776-1789
Xing S, Pan N, Xu W, Zhang J, ... Pei Z, Zeng J
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1776-1789 | PMID: 29624118
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Impact:
Abstract

Hyaluronan impairs the barrier integrity of brain microvascular endothelial cells through a CD44-dependent pathway.

Al-Ahmad AJ, Patel R, Palecek SP, Shusta EV

Hyaluronan (HA) constitutes the most abundant extracellular matrix component during brain development, only to become a minor component rapidly after birth and in adulthood to remain in specified regions. HA signaling has been associated with several neurological disorders, yet the impact of HA signaling at the blood-brain barrier (BBB) function remains undocumented. In this study, we investigated the impact of HA on BBB properties using human-induced pluripotent stem cell (iPSC) -derived and primary human and rat BMECs. The impact of HA signaling on developmental and mature BMECs was assessed by measuring changes in TEER, permeability, BMECs markers (GLUT1, tight junction proteins, P-gp) expression and localization, CD44 expression and hyaluronan levels. In general, HA treatment decreased barrier function and reduced P-gp activity with effects being more prominent upon treatment with oligomeric forms of HA (oHA). Such effects were exacerbated when applied during BMEC differentiation phase (considered as developmental BBB). We noted a hyaluronidase activity as well as an increase in CD44 expression during prolonged oxygen-glucose deprivation stress. Inhibition of HA signaling by antibody blockade of CD44 abrogated the detrimental effects of HA treatment. These results suggest the importance of HA signaling through CD44 on BBB properties.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1759-1775
Al-Ahmad AJ, Patel R, Palecek SP, Shusta EV
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1759-1775 | PMID: 29589805
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Abstract

Quantitative positron emission tomography reveals regional differences in aerobic glycolysis within the human brain.

Blazey T, Snyder AZ, Su Y, Goyal MS, ... Arbeláez AM, Raichle ME

Glucose and oxygen metabolism are tightly coupled in the human brain, with the preponderance of the brain\'s glucose supply used to generate ATP via oxidative phosphorylation. A fraction of glucose is consumed outside of oxidative phosphorylation despite the presence of sufficient oxygen to do so. We refer to this process as aerobic glycolysis. A recent positron emission tomography study reported that aerobic glycolysis is uniform within gray matter. Here, we analyze the same data and demonstrate robust regional differences in aerobic glycolysis within gray matter, a finding consistent with previously published data.



J Cereb Blood Flow Metab: 29 Sep 2019; 39:2096-2102
Blazey T, Snyder AZ, Su Y, Goyal MS, ... Arbeláez AM, Raichle ME
J Cereb Blood Flow Metab: 29 Sep 2019; 39:2096-2102 | PMID: 29569986
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Abstract

Cerebrovascular blood oxygenation level dependent pulsatility at baseline and following acute exercise among healthy adolescents.

Theyers AE, Goldstein BI, Metcalfe AW, Robertson AD, MacIntosh BJ

Arterial stiffness is linked to cerebral small vessel damage and neurodegeneration, but barriers to accessing deep cerebrovascular anatomy limit our ability to assess the brain. This study describes an adaptation of a cardiac-related scrubbing method as a means of generating blood oxygenation level-dependent pulsatility maps based on the cardiac cycle. We examine BOLD pulsatility at rest, based on the non-parametric deviation from null metric, as well as changes following acute physiological stress from 20 min of moderate-intensity cycling in 45 healthy adolescents. We evaluate the influence of repetition time (TR) and echo time (TE) using simulated and multi-echo empirical data, respectively. There were tissue-specific and voxel-wise BOLD pulsatility decreases 20 min following exercise cessation. BOLD pulsatility detection was comparable over a range of TR and TE values when scan volumes were kept constant; however, short TRs (≤500 ms) and TEs (∼14 ms) acquisitions would yield the most efficient detection. Results suggest cardiac-related BOLD pulsatility may represent a robust and easily adopted method of mapping cerebrovascular pulsatility with voxel-wise resolution.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1737-1749
Theyers AE, Goldstein BI, Metcalfe AW, Robertson AD, MacIntosh BJ
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1737-1749 | PMID: 29561225
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Abstract

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

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

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



J Cereb Blood Flow Metab: 20 Aug 2019:271678X19871253; epub ahead of print
Nawabi J, Kniep H, Broocks G, Faizy TD, ... Fiehler J, Hanning U
J Cereb Blood Flow Metab: 20 Aug 2019:271678X19871253; epub ahead of print | PMID: 31433715
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Abstract

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

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

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



J Cereb Blood Flow Metab: 19 Aug 2019:271678X19869034; epub ahead of print
Kim JH, Taylor AJ, Wang DJ, Zou X, Ress D
J Cereb Blood Flow Metab: 19 Aug 2019:271678X19869034; epub ahead of print | PMID: 31429358
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Abstract

cGMP-dependent protein kinase I in vascular smooth muscle cells improves ischemic stroke outcome in mice.

Shvedova M, Litvak MM, Roberts JD, Fukumura D, ... Feil R, Atochin DN

Recent works highlight the therapeutic potential of targeting cyclic guanosine monophosphate (cGMP)-dependent pathways in the context of brain ischemia/reperfusion injury (IRI). Although cGMP-dependent protein kinase I (cGKI) has emerged as a key mediator of the protective effects of nitric oxide (NO) and cGMP, the mechanisms by which cGKI attenuates IRI remain poorly understood. We used a novel, conditional cGKI knockout mouse model to study its role in cerebral IRI. We assessed neurological deficit, infarct volume, and cerebral perfusion in tamoxifen-inducible vascular smooth muscle cell-specific cGKI knockout mice and control animals. Stroke experiments revealed greater cerebral infarct volume in smooth muscle cell specific cGKI knockout mice (males: 96 ± 16 mm; females: 93 ± 12 mm, mean±SD) than in all control groups: wild type (males: 66 ± 19; females: 64 ± 14), cGKI control (males: 65 ± 18; females: 62 ± 14), cGKI control with tamoxifen (males: 70 ± 8; females: 68 ± 10). Our results identify, for the first time, a protective role of cGKI in vascular smooth muscle cells during ischemic stroke injury. Moreover, this protective effect of cGKI was found to be independent of gender and was mediated via improved reperfusion. These results suggest that cGKI in vascular smooth muscle cells should be targeted by therapies designed to protect brain tissue against ischemic stroke.



J Cereb Blood Flow Metab: 17 Aug 2019:271678X19870583; epub ahead of print
Shvedova M, Litvak MM, Roberts JD, Fukumura D, ... Feil R, Atochin DN
J Cereb Blood Flow Metab: 17 Aug 2019:271678X19870583; epub ahead of print | PMID: 31423931
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Abstract

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

Secomb TW, Bullock KV, Boas DA, Sakadžić S

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



J Cereb Blood Flow Metab: 17 Aug 2019:271678X19870068; epub ahead of print
Secomb TW, Bullock KV, Boas DA, Sakadžić S
J Cereb Blood Flow Metab: 17 Aug 2019:271678X19870068; epub ahead of print | PMID: 31423930
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Abstract

Optogenetic assessment of VIP, PV, SOM and NOS inhibitory neuron activity and cerebral blood flow regulation in mouse somato-sensory cortex.

Krawchuk MB, Ruff CF, Yang X, Ross SE, Vazquez AL

The impact of different neuronal populations on local cerebral blood flow (CBF) regulation is not well known and insight into these relationships could enhance the interpretation of brain function and dysfunction from brain imaging data. We investigated the role of sub-types of inhibitory neuron activity on the regulation of CBF using optogenetics, laser Doppler flowmetry and different transgenic mouse models (parvalbumin (PV), vasoactive intestinal peptide (VIP), somatostatin (SOM) and nitric oxide synthase (NOS)). Whisker stimulation was used to verify that typical CBF responses were obtained in all mice. Photo-stimulation of SOM-cre and NOS-cre mice produced significant increases in CBF that were similar to whisker responses. In NOS-cre mice, CBF responses scaled with the photo-stimulus pulse duration and frequency. In SOM-cre mice, CBF increases were followed by decreases. In VIP-cre mice, photo-stimulation did not consistently produce significant changes in CBF, while slower increases in CBF that peaked 14-18 s after stimulation onset were observed in PV-cre mice. Control experiments performed in non-expressing regions showed no changes in CBF. These findings suggest that dysfunction in NOS or SOM neurons can have a significant impact on vascular responses that are detected by brain imaging methods like functional magnetic resonance imaging (fMRI).



J Cereb Blood Flow Metab: 15 Aug 2019:271678X19870105; epub ahead of print
Krawchuk MB, Ruff CF, Yang X, Ross SE, Vazquez AL
J Cereb Blood Flow Metab: 15 Aug 2019:271678X19870105; epub ahead of print | PMID: 31418628
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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

Distinct roles of ezrin, radixin and moesin in maintaining the plasma membrane localizations and functions of human blood-brain barrier transporters.

Hoshi Y, Uchida Y, Kuroda T, Tachikawa M, ... Suzuki T, Terasaki T

The purpose of this study was to clarify the roles of ERM proteins (ezrin/radixin/moesin) in the regulation of membrane localization and transport activity of transporters at the human blood-brain barrier (BBB). Ezrin or moesin knockdown in a human in vitro BBB model cell line (hCMEC/D3) reduced both BCRP and GLUT1 protein expression levels on the plasma membrane. Radixin knockdown reduced not only BCRP and GLUT1, but also P-gp membrane expression. These results indicate that P-gp, BCRP and GLUT1 proteins are maintained on the plasma membrane via different ERM proteins. Furthermore, moesin knockdown caused the largest decrease of P-gp and BCRP efflux activity among the ERM proteins, whereas GLUT1 influx activity was similarly reduced by knockdown of each ERM protein. To investigate how moesin knockdown reduced P-gp efflux activity without loss of P-gp from the plasma membrane, we examined the role of PKCβI. PKCβI increased P-gp phosphorylation and reduced P-gp efflux activity. Radixin and moesin proteins were detected in isolated human brain capillaries, and their protein abundances were within a 3-fold range, compared with those in hCMEC/D3 cell line. These findings may mean that ezrin, radixin and moesin maintain the functions of different transporters in different ways at the human BBB.



J Cereb Blood Flow Metab: 13 Aug 2019:271678X19868880; epub ahead of print
Hoshi Y, Uchida Y, Kuroda T, Tachikawa M, ... Suzuki T, Terasaki T
J Cereb Blood Flow Metab: 13 Aug 2019:271678X19868880; epub ahead of print | PMID: 31409174
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Abstract

Calibrated fMRI for dynamic mapping of CMRO responses using MR-based measurements of whole-brain venous oxygen saturation.

Englund EK, Fernández-Seara MA, Rodríguez-Soto AE, Lee H, ... Detre JA, Wehrli FW

Functional MRI (fMRI) can identify active foci in response to stimuli through BOLD signal fluctuations, which represent a complex interplay between blood flow and cerebral metabolic rate of oxygen (CMRO) changes. Calibrated fMRI can disentangle the underlying contributions, allowing quantification of the CMRO response. Here, whole-brain venous oxygen saturation () was computed alongside ASL-measured CBF and BOLD-weighted data to derive the calibration constant, , using the proposed -based calibration. Data were collected from 10 subjects at 3T with a three-part interleaved sequence comprising background-suppressed 3D-pCASL, 2D BOLD-weighted, and single-slice dual-echo GRE (to measurevia susceptometry-based oximetry) acquisitions while subjects breathed normocapnic/normoxic, hyperoxic, and hypercapnic gases, and during a motor task.was computed via -based calibration from both hypercapnia and hyperoxia stimulus data, and results were compared to conventional hypercapnia or hyperoxia calibration methods. Meanin gray matter did not significantly differ between calibration methods, ranging from 8.5 ± 2.8% (conventional hyperoxia calibration) to 11.7 ± 4.5% (Y-based calibration in response to hyperoxia), with hypercapnia-basedvalues between ( = 0.56). Relative CMRO changes from finger tapping were computed from eachmap. CMRO increased by ∼20% in the motor cortex, and good agreement was observed between the conventional and proposed calibration methods.



J Cereb Blood Flow Metab: 07 Aug 2019:271678X19867276; epub ahead of print
Englund EK, Fernández-Seara MA, Rodríguez-Soto AE, Lee H, ... Detre JA, Wehrli FW
J Cereb Blood Flow Metab: 07 Aug 2019:271678X19867276; epub ahead of print | PMID: 31394960
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Abstract

Modeling hyperosmotic blood-brain barrier opening within human tissue-engineered in vitro brain microvessels.

Linville RM, DeStefano JG, Sklar MB, Chu C, Walczak P, Searson PC

As the majority of therapeutic agents do not cross the blood-brain barrier (BBB), transient BBB opening (BBBO) is one strategy to enable delivery into the brain for effective treatment of CNS disease. Intra-arterial infusion of the hyperosmotic agent mannitol reversibly opens the BBB; however, widespread clinical use has been limited due to the variability in outcomes. The current model for mannitol-induced BBBO assumes a transient but homogeneous increase in permeability; however, the details are poorly understood. To elucidate the mechanism of hyperosmotic opening at the cellular level, we developed a tissue-engineered microvessel model using stem cell-derived human brain microvascular endothelial cells (BMECs) perturbed with clinically relevant mannitol doses. This model recapitulates physiological shear stress, barrier function, microvessel geometry, and cell-matrix interactions. Using live-cell imaging, we show that mannitol results in dose-dependent and spatially heterogeneous increases in paracellular permeability through the formation of transient focal leaks. Additionally, we find that the degree of BBB opening and subsequent recovery is modulated by treatment with basic fibroblast growth factor. These results show that tissue-engineered BBB models can provide insight into the mechanisms of BBBO and hence improve the reproducibility of hyperosmotic therapies for treatment of CNS disease.



J Cereb Blood Flow Metab: 07 Aug 2019:271678X19867980; epub ahead of print
Linville RM, DeStefano JG, Sklar MB, Chu C, Walczak P, Searson PC
J Cereb Blood Flow Metab: 07 Aug 2019:271678X19867980; epub ahead of print | PMID: 31394959
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Abstract

Normal variations in brain oxygen extraction fraction are partly attributed to differences in end-tidal CO.

Jiang D, Lin Z, Liu P, Sur S, ... Albert M, Lu H

Cerebral oxygen extraction fraction is an important physiological index of the brain\'s oxygen consumption and supply and has been suggested to be a potential biomarker for a number of diseases such as stroke, Alzheimer\'s disease, multiple sclerosis, sickle cell disease, and metabolic disorders. However, in order for oxygen extraction fraction to be a sensitive biomarker for personalized disease diagnosis, inter-subject variations in normal subjects must be minimized or accounted for, which will otherwise obscure its interpretation. Therefore, it is essential to investigate the physiological underpinnings of normal differences in oxygen extraction fraction. This work used two studies, one discovery study and one verification study, to examine the extent to which an individual\'s end-tidal CO can explain variations in oxygen extraction fraction. It was found that, across normal subjects, oxygen extraction fraction is inversely correlated with end-tidal CO. Approximately 50% of the inter-subject variations in oxygen extraction fraction can be attributed to end-tidal CO differences. In addition, oxygen extraction fraction was found to be positively associated with age and systolic blood pressure. By accounting for end-tidal CO, age, and systolic blood pressure of the subjects, normal variations in oxygen extraction fraction can be reduced by 73%, which is expected to substantially enhance the utility of oxygen extraction fraction as a disease biomarker.



J Cereb Blood Flow Metab: 04 Aug 2019:271678X19867154; epub ahead of print
Jiang D, Lin Z, Liu P, Sur S, ... Albert M, Lu H
J Cereb Blood Flow Metab: 04 Aug 2019:271678X19867154; epub ahead of print | PMID: 31382788
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Abstract

Empathy in stroke rats is modulated by social settings.

Shinozuka K, Tajiri N, Ishikawa H, Tuazon JP, ... Kaneko Y, Borlongan CV

Rodents display \"empathy\" defined as perceived physical pain or psychological stress by cagemates when co-experiencing socially distinct traumatic events. The present study tested the hypothesis that empathy occurs in adult rats subjected to an experimental neurological disorder, by allowing co-experience of stroke with cagemates. Psychological stress was measured by general locomotor activity, Rat Grimace Scale (RGS), and plasma corticosterone. Physiological correlates were measured by Western blot analysis of advanced glycation endproducts (AGE)-related proteins in the thymus. General locomotor activity was impaired in stroke animals and in non-stroke rats housed with stroke rats suggesting transfer of behavioral manifestation of psychological stress from an injured animal to a non-injured animal leading to social inhibition. RGS was higher in stroke rats regardless of social settings. Plasma corticosterone levels at day 3 after stroke were significantly higher in stroke animals housed with stroke rats, but not with non-stroke rats, indicating that empathy upregulated physiological stress level. The expression of five proteins related to AGE in the thymus reflected the observed pattern of general locomotor activity, RGS, and plasma corticosterone levels. These results indicate that stroke-induced psychological stress manifested on both the behavioral and physiological levels and appeared to be affected by empathy-associated social settings.



J Cereb Blood Flow Metab: 31 Jul 2019:271678X19867908; epub ahead of print
Shinozuka K, Tajiri N, Ishikawa H, Tuazon JP, ... Kaneko Y, Borlongan CV
J Cereb Blood Flow Metab: 31 Jul 2019:271678X19867908; epub ahead of print | PMID: 31366299
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Abstract

Controversial roles for dexamethasone in glioblastoma - Opportunities for novel vascular targeting therapies.

Dubinski D, Hattingen E, Senft C, Seifert V, ... Devraj K, Plate KH

Glioblastoma is a highly aggressive and treatment resistant primary brain tumor. Features of glioblastoma include peritumoral cerebral edema, the major contributor to neurological impairment. Although the current clinical approach to edema management is administration of the synthetic corticoid dexamethasone, increasing evidence indicates numerous adverse effects of dexamethasone on glioblastoma burden at the molecular, cellular and clinical level. The contradictions of dexamethasone for glioblastoma and brain metastasis therapy are discussed in this article. Finally, alternative strategies for cerebrovascular edema therapy with vascular stabilizing, anti-permeability agents that are either approved or in clinical trials for diabetic retinopathy and macula edema, are addressed.



J Cereb Blood Flow Metab: 30 Jul 2019; 39:1460-1468
Dubinski D, Hattingen E, Senft C, Seifert V, ... Devraj K, Plate KH
J Cereb Blood Flow Metab: 30 Jul 2019; 39:1460-1468 | PMID: 31238763
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Abstract

Insights from thrombi retrieved in stroke due to large vessel occlusion.

Bacigaluppi M, Semerano A, Gullotta GS, Strambo D

The recent advances of endovascular procedures to treat stroke due to large cerebral vessel occlusion have made it possible to analyze the retrieved thrombus material. Analysis of cerebral thrombi is emerging as a relevant opportunity to complement the diagnostic workup of etiology, to develop new lytic approaches and to optimize the acute treatment of stroke due to large vessel occlusion. Nonetheless, retrieved thrombi are frequently discarded since their informative potential is often neglected and standards are missing. This review provides an overview of the current knowledge and expanding research relating to thrombus composition analysis in large vessel occlusions. We first discuss the heterogeneity of thrombogenic factors that underlie the thrombotic formation in stroke and its implications to identify stroke etiology and thrombus age. Further, we show that understanding structural characteristics of thrombus is pivotal for the development of new-targeted lytic therapies as well as to improve, through thrombus modeling, the development of thrombectomy devices. Finally, we discuss the on-going attempts to identify a signature of thrombus composition indirectly through imaging and peripheral blood biomarkers, which might in future assist treatment decision-making as well as secondary prevention. Thrombus analysis might contribute to the advancement and optimization of personalized stroke treatments.



J Cereb Blood Flow Metab: 30 Jul 2019; 39:1433-1451
Bacigaluppi M, Semerano A, Gullotta GS, Strambo D
J Cereb Blood Flow Metab: 30 Jul 2019; 39:1433-1451 | PMID: 31213164
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Abstract

Neuronal glucose metabolism is impaired while astrocytic TCA cycling is unaffected at symptomatic stages in the hSOD1 mouse model of amyotrophic lateral sclerosis.

Tefera TW, Borges K

Although alterations in energy metabolism are known in ALS, the specific mechanisms leading to energy deficit are not understood. We measured metabolite levels derived from injected [1-C]glucose and [1,2-C]acetate (i.p.) in cerebral cortex and spinal cord extracts of wild type and hSOD1 mice at onset and mid disease stages using high-pressure liquid chromatography, H and C nuclear magnetic resonance spectroscopy. Levels of spinal and cortical CNS total lactate, [3-C]lactate, total alanine and [3-C]alanine, but not cortical glucose and [1-C]glucose, were reduced mostly at mid stage indicating impaired glycolysis. The [1-C]glucose-derived [4-C]glutamate, [4-C]glutamine and [2-C]GABA amounts were diminished at mid stage in cortex and both time points in spinal cord, suggesting decreased [3-C]pyruvate entry into the TCA cycle. Lack of changes in [1,2-C]acetate-derived [4,5-C]glutamate, [4,5-C]glutamine and [1,2-C]GABA levels indicate unchanged astrocytic C-acetate metabolism. Reduced levels of leucine, isoleucine and valine in CNS suggest compensatory breakdown to refill TCA cycle intermediate levels. Unlabelled, [2-C] and [4-C]GABA concentrations were decreased in spinal cord indicating that impaired glucose metabolism contributes to hyperexcitability and supporting the use of treatments which increase GABA amounts. In conclusion, CNS glucose metabolism is compromised, while astrocytic TCA cycling appears to be normal in the hSOD1 mouse model at symptomatic disease stages.



J Cereb Blood Flow Metab: 30 Aug 2019; 39:1710-1724
Tefera TW, Borges K
J Cereb Blood Flow Metab: 30 Aug 2019; 39:1710-1724 | PMID: 29553298
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This program is still in alpha version.