Pub Date : 2020-10-01DOI: 10.1177/0271678X19883040
J. Hughes, J. Beech, P. Jones, Dechao Wang, D. Menon, F. Aigbirhio, T. Fryer, J. Baron
Predicting tissue outcome early after stroke is an important goal. MRI >3 h accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Previous studies suggest that chronic-stage 11 C-flumazenil PET (FMZ-PET) is a validated marker of SNL in rats, while early-stage FMZ-PET may predict infarction. Whether early FMZ-PET also predicts SNL is unknown. Following 45-min distal MCA occlusion, adult rats underwent FMZ-PET at 1 h and 48 h post-reperfusion to map distribution volume (VT), which reflects GABA-A receptor binding. NeuN immunohistochemistry was performed at Day 14. In each rat, VT and %NeuN loss were determined in 44 ROIs spanning the hemisphere. NeuN revealed isolated SNL and cortical infarction in five and one rats, respectively. In the SNL subgroup, VT-1 h was mildly reduced and only weakly predicted SNL, while VT-48 h was significantly increased and predicted SNL both individually (p < 0.01, Kendall) and across the group (p < 0.001), i.e. the higher the VT, the stronger the SNL. Similar correlations were found in the rat with infarction. Our findings suggest GABA-A receptors are still present on injured neurons at the 48 h timepoint, and the increased 48 h VT observed here is consistent with earlier rat studies showing early GABA-A receptor upregulation. That FMZ binding at 48 h was predictive of SNL may have clinical implications.
{"title":"Early-stage 11C-Flumazenil PET predicts day-14 selective neuronal loss in a rodent model of transient focal cerebral ischemia","authors":"J. Hughes, J. Beech, P. Jones, Dechao Wang, D. Menon, F. Aigbirhio, T. Fryer, J. Baron","doi":"10.1177/0271678X19883040","DOIUrl":"https://doi.org/10.1177/0271678X19883040","url":null,"abstract":"Predicting tissue outcome early after stroke is an important goal. MRI >3 h accurately predicts infarction but is insensitive to selective neuronal loss (SNL). Previous studies suggest that chronic-stage 11 C-flumazenil PET (FMZ-PET) is a validated marker of SNL in rats, while early-stage FMZ-PET may predict infarction. Whether early FMZ-PET also predicts SNL is unknown. Following 45-min distal MCA occlusion, adult rats underwent FMZ-PET at 1 h and 48 h post-reperfusion to map distribution volume (VT), which reflects GABA-A receptor binding. NeuN immunohistochemistry was performed at Day 14. In each rat, VT and %NeuN loss were determined in 44 ROIs spanning the hemisphere. NeuN revealed isolated SNL and cortical infarction in five and one rats, respectively. In the SNL subgroup, VT-1 h was mildly reduced and only weakly predicted SNL, while VT-48 h was significantly increased and predicted SNL both individually (p < 0.01, Kendall) and across the group (p < 0.001), i.e. the higher the VT, the stronger the SNL. Similar correlations were found in the rat with infarction. Our findings suggest GABA-A receptors are still present on injured neurons at the 48 h timepoint, and the increased 48 h VT observed here is consistent with earlier rat studies showing early GABA-A receptor upregulation. That FMZ binding at 48 h was predictive of SNL may have clinical implications.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"40 1","pages":"1997 - 2009"},"PeriodicalIF":0.0,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86877839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-10-01DOI: 10.1177/0271678X19878284
H. Parfenova, Jianxiong Liu, Daniel T Hoover, A. Fedinec
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 H2S in periarachnoid cortical cerebrospinal fluid. H2S is a potent vasodilator of cerebral arterioles. SFN is not a H2S donor but it acts via stimulating H2S 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 H2S generation and cerebral vasodilation caused by SFN. The SFN-elicited vasodilation requires activation of potassium channels in cerebral arterioles. The inhibitors of KATP and BK channels glibenclamide, paxilline, and iberiotoxin blocked the vasodilator effects of topical and systemic SFN, supporting the concept that H2S 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 H2S formation in neurovascular cells followed by H2S-induced activation of KATP and BK channels in arteriolar smooth muscle.
我们研究了萝卜硫素(SFN)，一种来自十字花科蔬菜的异硫氰酸盐，在新生猪颅窗脑血流调节中的作用。局部给药(10 μ M-1 mM)或全身给药(0.4 mg/kg / ip)可引起动脉小动脉立即和持续扩张，同时蛛网膜周围皮质脑脊液中H2S升高。H2S是脑小动脉的有效血管扩张剂。SFN不是H2S供体，但它通过刺激脑内由半胱硫氨酸γ-裂解酶(CSE)和半胱硫氨酸β-合成酶(CBS)催化的H2S生成而起作用。CSE/CBS抑制剂丙基甘氨酸、β-氰- l -丙氨酸和氨基乙酸阻断SFN引起的脑H2S生成和脑血管舒张。sfn引起的血管舒张需要激活脑小动脉中的钾通道。KATP和BK通道抑制剂格列本酰胺、paxilline和iberiotoxin阻断了局部和全身SFN的血管扩张作用，支持H2S是SFN在脑循环中血管扩张特性的介质的概念。总的来说，我们提供了第一个证据，证明SFN是一种脑渗透性化合物，通过非基因组机制增加脑血流量，该机制通过激活神经血管细胞中CSE/ cbs催化的H2S形成，随后H2S诱导小动脉平滑肌中KATP和BK通道的激活来介导。
{"title":"Vasodilator effects of sulforaphane in cerebral circulation: A critical role of endogenously produced hydrogen sulfide and arteriolar smooth muscle KATP and BK channels in the brain","authors":"H. Parfenova, Jianxiong Liu, Daniel T Hoover, A. Fedinec","doi":"10.1177/0271678X19878284","DOIUrl":"https://doi.org/10.1177/0271678X19878284","url":null,"abstract":"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 H2S in periarachnoid cortical cerebrospinal fluid. H2S is a potent vasodilator of cerebral arterioles. SFN is not a H2S donor but it acts via stimulating H2S 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 H2S generation and cerebral vasodilation caused by SFN. The SFN-elicited vasodilation requires activation of potassium channels in cerebral arterioles. The inhibitors of KATP and BK channels glibenclamide, paxilline, and iberiotoxin blocked the vasodilator effects of topical and systemic SFN, supporting the concept that H2S 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 H2S formation in neurovascular cells followed by H2S-induced activation of KATP and BK channels in arteriolar smooth muscle.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"54 1","pages":"1987 - 1996"},"PeriodicalIF":0.0,"publicationDate":"2020-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81488329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-01DOI: 10.1177/0271678X19879230
Samantha Rossano, T. Toyonaga, S. Finnema, M. Naganawa, Yihuan Lu, N. Nabulsi, J. Ropchan, S. De Bruyn, C. Otoul, A. Stockis, J. Nicolas, Paul Martin, J. Mercier, Yiyun Huang, R. P. Maguire, R. Carson
11C-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 11C-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 11C-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 (VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼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.
{"title":"Assessment of a white matter reference region for 11C-UCB-J PET quantification","authors":"Samantha Rossano, T. Toyonaga, S. Finnema, M. Naganawa, Yihuan Lu, N. Nabulsi, J. Ropchan, S. De Bruyn, C. Otoul, A. Stockis, J. Nicolas, Paul Martin, J. Mercier, Yiyun Huang, R. P. Maguire, R. Carson","doi":"10.1177/0271678X19879230","DOIUrl":"https://doi.org/10.1177/0271678X19879230","url":null,"abstract":"11C-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 11C-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 11C-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 (VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"26 1","pages":"1890 - 1901"},"PeriodicalIF":0.0,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87135018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-01DOI: 10.1177/0271678X19874770
Nina Karalija, Lars Jonassson, J. Johansson, G. Papenberg, Alireza Salami, M. Andersson, K. Riklund, L. Nyberg, C. Boraxbekk
In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-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 11C-raclopride binding potential (BPND) 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 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64–78 years). Mean 11C-raclopride BPND 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 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND 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 11C-raclopride measurements represent a true D2 signal.
{"title":"High long-term test–retest reliability for extrastriatal 11C-raclopride binding in healthy older adults","authors":"Nina Karalija, Lars Jonassson, J. Johansson, G. Papenberg, Alireza Salami, M. Andersson, K. Riklund, L. Nyberg, C. Boraxbekk","doi":"10.1177/0271678X19874770","DOIUrl":"https://doi.org/10.1177/0271678X19874770","url":null,"abstract":"In vivo dopamine D2-receptor availability is frequently assessed with 11C-raclopride and positron emission tomography. Due to low signal-to-noise ratios for 11C-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 11C-raclopride binding potential (BPND) 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 11C-raclopride BPND values in healthy, older adults (n = 27, age: 64–78 years). Mean 11C-raclopride BPND 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 11C-raclopride BPND values correlated with previously determined 18F-fallypride BPND 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 11C-raclopride measurements represent a true D2 signal.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"27 1","pages":"1859 - 1868"},"PeriodicalIF":0.0,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78833673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-09-01DOI: 10.1177/0271678X19874338
F. Quandt, F. Fischer, Julian Schröder, Marlene Heinze, S. Kessner, C. Malherbe, R. Schulz, B. Cheng, J. Fiehler, C. Gerloff, G. Thomalla
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.
{"title":"Normalization of reduced functional connectivity after revascularization of asymptomatic carotid stenosis","authors":"F. Quandt, F. Fischer, Julian Schröder, Marlene Heinze, S. Kessner, C. Malherbe, R. Schulz, B. Cheng, J. Fiehler, C. Gerloff, G. Thomalla","doi":"10.1177/0271678X19874338","DOIUrl":"https://doi.org/10.1177/0271678X19874338","url":null,"abstract":"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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"3 1","pages":"1838 - 1848"},"PeriodicalIF":0.0,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80860139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Our purpose is to assess the role of deep medullary veins in pathogenesis of lacunes in patients with cerebral small vessel disease (cSVD). We included patients with baseline and 2.5-year follow-up MRI in CIRCLE study. Susceptibility Weighted Imaging-Phase images were used to evaluate deep medullary veins based on a brain region-based visual score, and T2-Fluid-Attenuated-Inversion-Recovery images were used to evaluate lacunes. Cerebral blood flow and microstructural parameters in white matter hyperintensities and normal appearing white matter were also analyzed. A total of 203 cSVD patients were analyzed and 101 (49.8%) patients had baseline lacunes. Among them, 64 patients had follow-up MRI, including 16 (25.0%) with new lacunes. The patients’ deep medullary veins median score was 9 (7–12). At baseline, high deep medullary veins score was independently associated with the presence of lacunes after adjusting for age, diabetes mellitus, white matter hyperintensities volume and cerebral blood flow or white matter microstructural parameters (all p < 0.001). Longitudinally, high deep medullary veins score was independently associated with new lacunes after adjusting for gender (p < 0.001). The association was also independent of white matter hyperintensities volumes, cerebral blood flow or white matter microstructural parameters (all p < 0.05). Our results suggest that deep medullary veins disruption might be involved in pathogenesis of lacunes.
{"title":"Role of deep medullary veins in pathogenesis of lacunes: Longitudinal observations from the CIRCLE study","authors":"Ying Zhou, Qingqing Li, Ruiting Zhang, Wenhua Zhang, Shenqiang Yan, Jinjin Xu, Shuyue Wang, Minming Zhang, M. Lou","doi":"10.1177/0271678X19882918","DOIUrl":"https://doi.org/10.1177/0271678X19882918","url":null,"abstract":"Our purpose is to assess the role of deep medullary veins in pathogenesis of lacunes in patients with cerebral small vessel disease (cSVD). We included patients with baseline and 2.5-year follow-up MRI in CIRCLE study. Susceptibility Weighted Imaging-Phase images were used to evaluate deep medullary veins based on a brain region-based visual score, and T2-Fluid-Attenuated-Inversion-Recovery images were used to evaluate lacunes. Cerebral blood flow and microstructural parameters in white matter hyperintensities and normal appearing white matter were also analyzed. A total of 203 cSVD patients were analyzed and 101 (49.8%) patients had baseline lacunes. Among them, 64 patients had follow-up MRI, including 16 (25.0%) with new lacunes. The patients’ deep medullary veins median score was 9 (7–12). At baseline, high deep medullary veins score was independently associated with the presence of lacunes after adjusting for age, diabetes mellitus, white matter hyperintensities volume and cerebral blood flow or white matter microstructural parameters (all p < 0.001). Longitudinally, high deep medullary veins score was independently associated with new lacunes after adjusting for gender (p < 0.001). The association was also independent of white matter hyperintensities volumes, cerebral blood flow or white matter microstructural parameters (all p < 0.05). Our results suggest that deep medullary veins disruption might be involved in pathogenesis of lacunes.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"52 1","pages":"1797 - 1805"},"PeriodicalIF":0.0,"publicationDate":"2020-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81861286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-08-01DOI: 10.1177/0271678X19880161
Danielle N. Edwards, K. Salmeron, D. Lukins, A. Trout, J. Fraser, G. Bix
Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell β1 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.
{"title":"Integrin α5β1 inhibition by ATN-161 reduces neuroinflammation and is neuroprotective in ischemic stroke","authors":"Danielle N. Edwards, K. Salmeron, D. Lukins, A. Trout, J. Fraser, G. Bix","doi":"10.1177/0271678X19880161","DOIUrl":"https://doi.org/10.1177/0271678X19880161","url":null,"abstract":"Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell β1 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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"144 1","pages":"1695 - 1708"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77514856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-08-01DOI: 10.1177/0271678X19872563
Skylar E Johnson, C. McKnight, Sarah K. Lants, Meher R. Juttukonda, M. Fusco, R. Chitale, Paula C Donahue, D. Claassen, M. Donahue
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 T1-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 (n = 23; age = 41.8 ± 13.4 years), or in a cohort of participants at two time points without interval surgeries (n = 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.
最近的研究表明，脑皮质缺血可能影响脉络膜丛的功能，这种交流可能通过传统的脑脊液循环途径和/或可能的淋巴途径介导。在这里，我们研究了新血管生成后动脉健康的改善改变(i)颅内脑脊液容量和(ii)脉络膜丛灌注的假设。非动脉粥样硬化性颅内狭窄患者(如Moyamoya)的脑脊液和组织体积测量通过t1加权MRI获得，皮层和脉络膜丛灌注通过灌注加权动脉自旋标记MRI获得。间接手术血运重建术后重复测量，引起血运重建术部位附近的皮质新生血管生成(n = 23;年龄= 41.8±13.4岁)，或在两个时间点没有间隔手术的队列参与者(n = 10;年龄= 41.7±10.7岁)。回归分析用于评估灌注和体积对状态的依赖性(时间1 vs. 2)。术后，脑脊液和组织体积均未发生显著变化。手术患者术后皮层灌注增加，脉络膜丛灌注减少;在没有手术的参与者中，皮层灌注减少，脉络膜丛灌注增加。研究结果在稳态机制的背景下进行了讨论，即动脉健康、血管旁血流和/或缺血可以影响脉络膜丛灌注。
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Pub Date : 2020-08-01DOI: 10.1177/0271678X19871253
J. Nawabi, H. Kniep, G. Broocks, T. Faizy, G. Schön, G. Thomalla, J. Fiehler, U. Hanning
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, p < 0.0001) was significantly associated with aICH. Less patients with aICH achieved an independent outcome (mRS 0–2, 16.7% vs. 44.3%, p = 0.007). Poor outcome (mRS 4–6) was significantly higher in patients with aICH (41.4% vs. 70%, p = 0.021). Patients with aICH had a lower ratio of independent outcome (OR 0.23, 95% CI 0.05–0.1.05, p = 0.041) than without ICH. There were no differences concerning poor outcome (p = 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.
无症状脑出血(aICH)是急性缺血性卒中(AIS)行血管内取栓术(ET)的常见现象。然而，aICH对功能结果的影响仍不清楚。在这项研究中，我们旨在确定aICH的预测因素并分析其对功能结局的影响。经ET治疗成功的前循环大动脉闭塞导致AIS的患者被纳入三级卒中中心。根据治疗后72h内CT检查纳入有aICH或无脑出血的患者;连续100例患者符合纳入标准，其中30%为aICH。logistic回归分析中，侧支评分较低(OR 0.24;95% CI 0.12-0.46, p < 0.0001)与aICH显著相关。获得独立结局的aICH患者较少(mRS 0-2, 16.7%比44.3%，p = 0.007)。不良预后(mRS 4-6)在aICH患者中明显较高(41.4%比70%，p = 0.021)。缺血性脑出血患者的独立结局比(OR 0.23, 95% CI 0.05-0.1.05, p = 0.041)低于非缺血性脑出血患者。在不良预后方面没有差异(p = 0.5)。较低的侧支状态是aICH强有力的独立预测因子。ET成功后的急性脑出血可能会降低独立功能预后的可能性，但不会影响不良预后。
{"title":"Clinical relevance of asymptomatic intracerebral hemorrhage post thrombectomy depends on angiographic collateral score","authors":"J. Nawabi, H. Kniep, G. Broocks, T. Faizy, G. Schön, G. Thomalla, J. Fiehler, U. Hanning","doi":"10.1177/0271678X19871253","DOIUrl":"https://doi.org/10.1177/0271678X19871253","url":null,"abstract":"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, p < 0.0001) was significantly associated with aICH. Less patients with aICH achieved an independent outcome (mRS 0–2, 16.7% vs. 44.3%, p = 0.007). Poor outcome (mRS 4–6) was significantly higher in patients with aICH (41.4% vs. 70%, p = 0.021). Patients with aICH had a lower ratio of independent outcome (OR 0.23, 95% CI 0.05–0.1.05, p = 0.041) than without ICH. There were no differences concerning poor outcome (p = 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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"36 1","pages":"1599 - 1607"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84777037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-08-01DOI: 10.1177/0271678X19874134
James R Goodman, Jeffrey J. Iliff
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 (paCO2 = 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.
{"title":"Vasomotor influences on glymphatic-lymphatic coupling and solute trafficking in the central nervous system","authors":"James R Goodman, Jeffrey J. Iliff","doi":"10.1177/0271678X19874134","DOIUrl":"https://doi.org/10.1177/0271678X19874134","url":null,"abstract":"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 (paCO2 = 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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"16 1","pages":"1724 - 1734"},"PeriodicalIF":0.0,"publicationDate":"2020-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86399396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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