Pub Date : 2019-05-27DOI: 10.1177/0271678X19882787
Matilda K Dahlqvist, K. Thomsen, D. Postnov, M. Lauritzen
Gamma activity arising from the interplay between pyramidal neurons and fast-spiking parvalbumin (PV) interneurons is an integral part of higher cognitive functions and is assumed to contribute significantly to brain metabolic responses. Cerebral metabolic rate of oxygen (CMRO2) responses were evoked by optogenetic stimulation of cortical PV interneurons and pyramidal neurons. We found that CMRO2 responses depended on neuronal activation, but not on the power of gamma activity induced by optogenetic stimulation. This implies that evoked gamma activity per se is not energy demanding. Optogenetic stimulation of PV interneurons during somatosensory stimulation reduced excitatory neuronal activity but did not potentiate O2 consumption as previously hypothesized. In conclusion, our data suggest that activity-driven CMRO2 responses depend on neuronal excitation rather than the cerebral rhythmic activity they induce. Excitation of both excitatory and inhibitory neurons requires energy, but inhibition of cortical excitatory neurons by interneurons does not potentiate activity-driven energy consumption.
{"title":"Modification of oxygen consumption and blood flow in mouse somatosensory cortex by cell-type-specific neuronal activity","authors":"Matilda K Dahlqvist, K. Thomsen, D. Postnov, M. Lauritzen","doi":"10.1177/0271678X19882787","DOIUrl":"https://doi.org/10.1177/0271678X19882787","url":null,"abstract":"Gamma activity arising from the interplay between pyramidal neurons and fast-spiking parvalbumin (PV) interneurons is an integral part of higher cognitive functions and is assumed to contribute significantly to brain metabolic responses. Cerebral metabolic rate of oxygen (CMRO2) responses were evoked by optogenetic stimulation of cortical PV interneurons and pyramidal neurons. We found that CMRO2 responses depended on neuronal activation, but not on the power of gamma activity induced by optogenetic stimulation. This implies that evoked gamma activity per se is not energy demanding. Optogenetic stimulation of PV interneurons during somatosensory stimulation reduced excitatory neuronal activity but did not potentiate O2 consumption as previously hypothesized. In conclusion, our data suggest that activity-driven CMRO2 responses depend on neuronal excitation rather than the cerebral rhythmic activity they induce. Excitation of both excitatory and inhibitory neurons requires energy, but inhibition of cortical excitatory neurons by interneurons does not potentiate activity-driven energy consumption.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"34 1","pages":"2010 - 2025"},"PeriodicalIF":0.0,"publicationDate":"2019-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89979459","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 : 2019-05-17DOI: 10.1177/0271678X19873658
O. Bracko, Brendah N. Njiru, Madisen A Swallow, Muhammad Ali, Mohammad Haft-Javaherian, C. Schaffer
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.
{"title":"Increasing cerebral blood flow improves cognition into late stages in Alzheimer’s disease mice","authors":"O. Bracko, Brendah N. Njiru, Madisen A Swallow, Muhammad Ali, Mohammad Haft-Javaherian, C. Schaffer","doi":"10.1177/0271678X19873658","DOIUrl":"https://doi.org/10.1177/0271678X19873658","url":null,"abstract":"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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"8 1","pages":"1441 - 1452"},"PeriodicalIF":0.0,"publicationDate":"2019-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87082346","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 : 2019-02-07DOI: 10.1177/0271678X19827251
Marco Foddis, K. Winek, K. Bentele, S. Mueller, S. Blumenau, Nadine Reichhart N, S. Crespo-Garcia, Dermot Harnett, Andranik Ivanov, A. Meisel, A. Joussen, O. Strauß, D. Beule, U. Dirnagl, C. Sassi
Brain collateral circulation is an essential compensatory mechanism in response to acute brain ischemia. To study the temporal evolution of brain macro and microcollateral recruitment and their reciprocal interactions in response to different ischemic conditions, we applied a combination of complementary techniques (T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) in two different mouse models. Hypoperfusion was either induced by permanent bilateral common carotid artery stenosis (BCCAS) or 60-min transient unilateral middle cerebral artery occlusion (MCAO). In both models, collateralization is a very dynamic phenomenon with a global effect affecting both hemispheres. Patency of ipsilateral posterior communicating artery (PcomA) represents the main variable survival mechanism and the main determinant of stroke lesion volume and recovery in MCAO, whereas the promptness of external carotid artery retrograde flow recruitment together with PcomA patency, critically influence survival, brain ischemic lesion volume and retinopathy in BCCAS mice. Finally, different ischemic gradients shape microcollateral density and size.
{"title":"An exploratory investigation of brain collateral circulation plasticity after cerebral ischemia in two experimental C57BL/6 mouse models","authors":"Marco Foddis, K. Winek, K. Bentele, S. Mueller, S. Blumenau, Nadine Reichhart N, S. Crespo-Garcia, Dermot Harnett, Andranik Ivanov, A. Meisel, A. Joussen, O. Strauß, D. Beule, U. Dirnagl, C. Sassi","doi":"10.1177/0271678X19827251","DOIUrl":"https://doi.org/10.1177/0271678X19827251","url":null,"abstract":"Brain collateral circulation is an essential compensatory mechanism in response to acute brain ischemia. To study the temporal evolution of brain macro and microcollateral recruitment and their reciprocal interactions in response to different ischemic conditions, we applied a combination of complementary techniques (T2-weighted magnetic resonance imaging [MRI], time of flight [TOF] angiography [MRA], cerebral blood flow [CBF] imaging and histology) in two different mouse models. Hypoperfusion was either induced by permanent bilateral common carotid artery stenosis (BCCAS) or 60-min transient unilateral middle cerebral artery occlusion (MCAO). In both models, collateralization is a very dynamic phenomenon with a global effect affecting both hemispheres. Patency of ipsilateral posterior communicating artery (PcomA) represents the main variable survival mechanism and the main determinant of stroke lesion volume and recovery in MCAO, whereas the promptness of external carotid artery retrograde flow recruitment together with PcomA patency, critically influence survival, brain ischemic lesion volume and retinopathy in BCCAS mice. Finally, different ischemic gradients shape microcollateral density and size.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"21 1","pages":"276 - 287"},"PeriodicalIF":0.0,"publicationDate":"2019-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87225567","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 : 2018-01-01DOI: 10.1177/0271678X17691986
D. Curtelin, D. Morales‐Alamo, R. Torres-Peralta, P. Rasmussen, Marcos Martin‐Rincon, Mario Perez-Valera, C. Siebenmann, I. Perez-Suarez, E. Cherouveim, A. Sheel, C. Lundby, J. Calbet
Cerebral blood flow (CBF) is regulated to secure brain O2 delivery while simultaneously avoiding hyperperfusion; however, both requisites may conflict during sprint exercise. To determine whether brain O2 delivery or CBF is prioritized, young men performed sprint exercise in normoxia and hypoxia (PIO2 = 73 mmHg). During the sprints, cardiac output increased to ∼22 L min−1, mean arterial pressure to ∼131 mmHg and peak systolic blood pressure ranged between 200 and 304 mmHg. Middle-cerebral artery velocity (MCAv) increased to peak values (∼16%) after 7.5 s and decreased to pre-exercise values towards the end of the sprint. When the sprints in normoxia were preceded by a reduced PETCO2, CBF and frontal lobe oxygenation decreased in parallel (r = 0.93, P < 0.01). In hypoxia, MCAv was increased by 25%, due to a 26% greater vascular conductance, despite 4–6 mmHg lower PaCO2 in hypoxia than normoxia. This vasodilation fully accounted for the 22 % lower CaO2 in hypoxia, leading to a similar brain O2 delivery during the sprints regardless of PIO2. In conclusion, when a conflict exists between preserving brain O2 delivery or restraining CBF to avoid potential damage by an elevated perfusion pressure, the priority is given to brain O2 delivery.
调节脑血流量(CBF)以确保脑氧输送，同时避免过度灌注;然而，在冲刺练习中，这两个必要条件可能会发生冲突。为了确定脑氧输送或CBF孰优先，年轻男性在常氧和缺氧条件下(PIO2 = 73 mmHg)进行短跑运动。在冲刺期间，心输出量增加到~ 22 L min - 1，平均动脉压增加到~ 131 mmHg，峰值收缩压在200至304 mmHg之间。大脑中动脉流速(MCAv)在7.5 s后增加到峰值(约16%)，并在冲刺结束时下降到运动前的值。在正常氧合条件下短跑前，PETCO2浓度降低，脑血流和额叶氧合同时降低(r = 0.93, P < 0.01)。在缺氧时，尽管PaCO2比正常缺氧低4-6 mmHg，但由于血管导度增加26%，MCAv增加25%。这种血管舒张完全解释了缺氧时CaO2降低22%的原因，无论PIO2如何，短跑期间的脑氧输送都是相似的。综上所述，当维持脑氧输送与抑制脑血流以避免灌注压升高造成的潜在损伤之间存在冲突时，应优先考虑脑氧输送。
{"title":"Cerebral blood flow, frontal lobe oxygenation and intra-arterial blood pressure during sprint exercise in normoxia and severe acute hypoxia in humans","authors":"D. Curtelin, D. Morales‐Alamo, R. Torres-Peralta, P. Rasmussen, Marcos Martin‐Rincon, Mario Perez-Valera, C. Siebenmann, I. Perez-Suarez, E. Cherouveim, A. Sheel, C. Lundby, J. Calbet","doi":"10.1177/0271678X17691986","DOIUrl":"https://doi.org/10.1177/0271678X17691986","url":null,"abstract":"Cerebral blood flow (CBF) is regulated to secure brain O2 delivery while simultaneously avoiding hyperperfusion; however, both requisites may conflict during sprint exercise. To determine whether brain O2 delivery or CBF is prioritized, young men performed sprint exercise in normoxia and hypoxia (PIO2 = 73 mmHg). During the sprints, cardiac output increased to ∼22 L min−1, mean arterial pressure to ∼131 mmHg and peak systolic blood pressure ranged between 200 and 304 mmHg. Middle-cerebral artery velocity (MCAv) increased to peak values (∼16%) after 7.5 s and decreased to pre-exercise values towards the end of the sprint. When the sprints in normoxia were preceded by a reduced PETCO2, CBF and frontal lobe oxygenation decreased in parallel (r = 0.93, P < 0.01). In hypoxia, MCAv was increased by 25%, due to a 26% greater vascular conductance, despite 4–6 mmHg lower PaCO2 in hypoxia than normoxia. This vasodilation fully accounted for the 22 % lower CaO2 in hypoxia, leading to a similar brain O2 delivery during the sprints regardless of PIO2. In conclusion, when a conflict exists between preserving brain O2 delivery or restraining CBF to avoid potential damage by an elevated perfusion pressure, the priority is given to brain O2 delivery.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"60 1","pages":"136 - 150"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76121541","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 : 2018-01-01DOI: 10.1177/0271678X16679169
A. Manaenko, Peng Yang, Derek Nowrangi, Enkhjargal Budbazar, R. Hartman, A. Obenaus, W. Pearce, John H. Zhang, Jiping Tang
Intracerebral hemorrhage (ICH) represents the deadliest subtype of all strokes. The development of brain edema, a consequence of blood–brain barrier (BBB) disruption, is the most life-threatening event after ICH. Pathophysiological conditions activate the endothelium, one of the components of BBB, inducing rearrangement of the actin cytoskeleton. Upon activation, globular actin assembles into a filamentous actin resulting in the formation of contractile actin bundles, stress fibers. The contraction of stress fibers leads to the formation of intercellular gaps between endothelial cells increasing the permeability of BBB. In the present study, we investigated the effect of ICH on stress fiber formation in CD1 mice. We hypothesized that ICH-induced formation of stress fiber is triggered by the activation of PDGFR-β and mediated by the cortactin/RhoA/LIMK pathway. We demonstrated that ICH induces formation of stress fibers. Furthermore, we demonstrated that the inhibition of PDGFR-β and its downstream reduced the number of stress fibers, preserving BBB and resulting in the amelioration of brain edema and improvement of neurological functions in mice after ICH.
{"title":"Inhibition of stress fiber formation preserves blood–brain barrier after intracerebral hemorrhage in mice","authors":"A. Manaenko, Peng Yang, Derek Nowrangi, Enkhjargal Budbazar, R. Hartman, A. Obenaus, W. Pearce, John H. Zhang, Jiping Tang","doi":"10.1177/0271678X16679169","DOIUrl":"https://doi.org/10.1177/0271678X16679169","url":null,"abstract":"Intracerebral hemorrhage (ICH) represents the deadliest subtype of all strokes. The development of brain edema, a consequence of blood–brain barrier (BBB) disruption, is the most life-threatening event after ICH. Pathophysiological conditions activate the endothelium, one of the components of BBB, inducing rearrangement of the actin cytoskeleton. Upon activation, globular actin assembles into a filamentous actin resulting in the formation of contractile actin bundles, stress fibers. The contraction of stress fibers leads to the formation of intercellular gaps between endothelial cells increasing the permeability of BBB. In the present study, we investigated the effect of ICH on stress fiber formation in CD1 mice. We hypothesized that ICH-induced formation of stress fiber is triggered by the activation of PDGFR-β and mediated by the cortactin/RhoA/LIMK pathway. We demonstrated that ICH induces formation of stress fibers. Furthermore, we demonstrated that the inhibition of PDGFR-β and its downstream reduced the number of stress fibers, preserving BBB and resulting in the amelioration of brain edema and improvement of neurological functions in mice after ICH.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"18 1","pages":"102 - 87"},"PeriodicalIF":0.0,"publicationDate":"2018-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78124811","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 : 2017-12-01DOI: 10.1177/0271678X16671964
S. Hoffmann, H. Harms, L. Ulm, D. Nabavi, B. Mackert, I. Schmehl, G. Jungehulsing, J. Montaner, A. Bustamante, M. Hermans, F. Hamilton, Jos Göhler, U. Malzahn, C. Malsch, P. Heuschmann, C. Meisel, A. Meisel
Stroke-associated pneumonia is a frequent complication after stroke associated with poor outcome. Dysphagia is a known risk factor for stroke-associated pneumonia but accumulating evidence suggests that stroke induces an immunodepressive state increasing susceptibility for stroke-associated pneumonia. We aimed to confirm that stroke-induced immunodepression syndrome is associated with stroke-associated pneumonia independently from dysphagia by investigating the predictive properties of monocytic HLA-DR expression as a marker of immunodepression as well as biomarkers for inflammation (interleukin-6) and infection (lipopolysaccharide-binding protein). This was a prospective, multicenter study with 11 study sites in Germany and Spain, including 486 patients with acute ischemic stroke. Daily screening for stroke-associated pneumonia, dysphagia and biomarkers was performed. Frequency of stroke-associated pneumonia was 5.2%. Dysphagia and decreased monocytic HLA-DR were independent predictors for stroke-associated pneumonia in multivariable regression analysis. Proportion of pneumonia ranged between 0.9% in the higher monocytic HLA-DR quartile (≥21,876 mAb/cell) and 8.5% in the lower quartile (≤12,369 mAb/cell). In the presence of dysphagia, proportion of pneumonia increased to 5.9% and 18.8%, respectively. Patients without dysphagia and normal monocytic HLA-DR expression had no stroke-associated pneumonia risk. We demonstrate that dysphagia and stroke-induced immunodepression syndrome are independent risk factors for stroke-associated pneumonia. Screening for immunodepression and dysphagia might be useful for identifying patients at high risk for stroke-associated pneumonia.
{"title":"Stroke-induced immunodepression and dysphagia independently predict stroke-associated pneumonia – The PREDICT study","authors":"S. Hoffmann, H. Harms, L. Ulm, D. Nabavi, B. Mackert, I. Schmehl, G. Jungehulsing, J. Montaner, A. Bustamante, M. Hermans, F. Hamilton, Jos Göhler, U. Malzahn, C. Malsch, P. Heuschmann, C. Meisel, A. Meisel","doi":"10.1177/0271678X16671964","DOIUrl":"https://doi.org/10.1177/0271678X16671964","url":null,"abstract":"Stroke-associated pneumonia is a frequent complication after stroke associated with poor outcome. Dysphagia is a known risk factor for stroke-associated pneumonia but accumulating evidence suggests that stroke induces an immunodepressive state increasing susceptibility for stroke-associated pneumonia. We aimed to confirm that stroke-induced immunodepression syndrome is associated with stroke-associated pneumonia independently from dysphagia by investigating the predictive properties of monocytic HLA-DR expression as a marker of immunodepression as well as biomarkers for inflammation (interleukin-6) and infection (lipopolysaccharide-binding protein). This was a prospective, multicenter study with 11 study sites in Germany and Spain, including 486 patients with acute ischemic stroke. Daily screening for stroke-associated pneumonia, dysphagia and biomarkers was performed. Frequency of stroke-associated pneumonia was 5.2%. Dysphagia and decreased monocytic HLA-DR were independent predictors for stroke-associated pneumonia in multivariable regression analysis. Proportion of pneumonia ranged between 0.9% in the higher monocytic HLA-DR quartile (≥21,876 mAb/cell) and 8.5% in the lower quartile (≤12,369 mAb/cell). In the presence of dysphagia, proportion of pneumonia increased to 5.9% and 18.8%, respectively. Patients without dysphagia and normal monocytic HLA-DR expression had no stroke-associated pneumonia risk. We demonstrate that dysphagia and stroke-induced immunodepression syndrome are independent risk factors for stroke-associated pneumonia. Screening for immunodepression and dysphagia might be useful for identifying patients at high risk for stroke-associated pneumonia.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"15 1","pages":"3671 - 3682"},"PeriodicalIF":0.0,"publicationDate":"2017-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84698731","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 : 2017-11-01DOI: 10.1177/0271678X16665623
Nefize Turan, B. Miller, R. A. Heider, M. Nadeem, I. Sayeed, D. Stein, G. Pradilla
The most important aspect of a preclinical study seeking to develop a novel therapy for neurological diseases is whether the therapy produces any clinically relevant functional recovery. For this purpose, neurobehavioral tests are commonly used to evaluate the neuroprotective efficacy of treatments in a wide array of cerebrovascular diseases and neurotrauma. Their use, however, has been limited in experimental subarachnoid hemorrhage studies. After several randomized, double-blinded, controlled clinical trials repeatedly failed to produce a benefit in functional outcome despite some improvement in angiographic vasospasm, more rigorous methods of neurobehavioral testing became critical to provide a more comprehensive evaluation of the functional efficacy of proposed treatments. While several subarachnoid hemorrhage studies have incorporated an array of neurobehavioral assays, a standardized methodology has not been agreed upon. Here, we review neurobehavioral tests for rodents and their potential application to subarachnoid hemorrhage studies. Developing a standardized neurobehavioral testing regimen in rodent studies of subarachnoid hemorrhage would allow for better comparison of results between laboratories and a better prediction of what interventions would produce functional benefits in humans.
{"title":"Neurobehavioral testing in subarachnoid hemorrhage: A review of methods and current findings in rodents","authors":"Nefize Turan, B. Miller, R. A. Heider, M. Nadeem, I. Sayeed, D. Stein, G. Pradilla","doi":"10.1177/0271678X16665623","DOIUrl":"https://doi.org/10.1177/0271678X16665623","url":null,"abstract":"The most important aspect of a preclinical study seeking to develop a novel therapy for neurological diseases is whether the therapy produces any clinically relevant functional recovery. For this purpose, neurobehavioral tests are commonly used to evaluate the neuroprotective efficacy of treatments in a wide array of cerebrovascular diseases and neurotrauma. Their use, however, has been limited in experimental subarachnoid hemorrhage studies. After several randomized, double-blinded, controlled clinical trials repeatedly failed to produce a benefit in functional outcome despite some improvement in angiographic vasospasm, more rigorous methods of neurobehavioral testing became critical to provide a more comprehensive evaluation of the functional efficacy of proposed treatments. While several subarachnoid hemorrhage studies have incorporated an array of neurobehavioral assays, a standardized methodology has not been agreed upon. Here, we review neurobehavioral tests for rodents and their potential application to subarachnoid hemorrhage studies. Developing a standardized neurobehavioral testing regimen in rodent studies of subarachnoid hemorrhage would allow for better comparison of results between laboratories and a better prediction of what interventions would produce functional benefits in humans.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"78 1","pages":"3461 - 3474"},"PeriodicalIF":0.0,"publicationDate":"2017-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90572113","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 : 2017-11-01DOI: 10.1177/0271678X16678874
A. Boers, Ivo G. H. Jansen, O. Berkhemer, A. Yoo, Hester F. Lingsma, C. Slump, Y. Roos, R. V. van Oostenbrugge, D. Dippel, A. van der Lugt, W. V. van Zwam, H. Marquering, C. Majoie
Intra-arterial therapy (IAT) for ischemic stroke aims to save brain tissue. Collaterals are thought to contribute to prolonged penumbra sustenance. In this study, we investigate the effect of collateral status on brain tissue salvage with IAT. In 500 patients randomized between IAT and standard care, collateral status was graded from 0 (absent) to 3 (good). Final infarct volumes (FIV) were calculated on post-treatment CT. FIVs were compared between treatment groups per collateral grade. Multivariable linear regression with interaction terms was performed to study whether collaterals modified IAT effect on FIV. Four-hundred-forty-nine patients were included in the analysis. Median FIV for the IAT group was significantly lower with 54.5 mL (95% IQR: 21.8–145.0) than for the controls with 81.8 mL (95% IQR: 40.0–154.0) (p = 0.020). Treatment effect differed across collateral grades, although there was no significant interaction (unadjusted p = 0.054; adjusted p = 0.105). For grade 3, IAT resulted in a FIV reduction of 30.1 mL (p = 0.024). For grade 2 and 1, this difference was, respectively, 28.4 mL (p = 0.028) and 28.4 mL (p = 0.29). For grade 0, this was 88.6 mL (p = 0.28) in favour of controls. IAT saves substantially more brain tissue as compared to standard care. We observed a trend of increasing effect of IAT with higher collateral grades.
缺血性脑卒中的动脉内治疗(IAT)旨在挽救脑组织。侧枝被认为有助于延长半影期的维持。在这项研究中，我们探讨了侧支状态对IAT脑组织抢救的影响。在500名随机分为IAT和标准治疗的患者中，侧枝状态从0(无)到3(良好)分级。治疗后CT计算最终梗死体积(FIV)。按侧枝分级比较不同治疗组间的fiv。采用带交互项的多变量线性回归研究了抵押品是否改变了IAT对FIV的影响。449名患者被纳入分析。IAT组的中位FIV为54.5 mL (95% IQR: 21.8-145.0)，显著低于对照组的81.8 mL (95% IQR: 40.0-154.0) (p = 0.020)。治疗效果在侧枝分级之间存在差异，但没有显著的相互作用(未经调整p = 0.054;调整后p = 0.105)。对于3级患者，IAT导致FIV减少30.1 mL (p = 0.024)。对于2级和1级，差异分别为28.4 mL (p = 0.028)和28.4 mL (p = 0.29)。对于0级，这是88.6 mL (p = 0.28)有利于对照组。与标准治疗相比，IAT节省了更多的脑组织。我们观察到，随着抵押品等级的提高，IAT的效果有增加的趋势。
{"title":"Collateral status and tissue outcome after intra-arterial therapy for patients with acute ischemic stroke","authors":"A. Boers, Ivo G. H. Jansen, O. Berkhemer, A. Yoo, Hester F. Lingsma, C. Slump, Y. Roos, R. V. van Oostenbrugge, D. Dippel, A. van der Lugt, W. V. van Zwam, H. Marquering, C. Majoie","doi":"10.1177/0271678X16678874","DOIUrl":"https://doi.org/10.1177/0271678X16678874","url":null,"abstract":"Intra-arterial therapy (IAT) for ischemic stroke aims to save brain tissue. Collaterals are thought to contribute to prolonged penumbra sustenance. In this study, we investigate the effect of collateral status on brain tissue salvage with IAT. In 500 patients randomized between IAT and standard care, collateral status was graded from 0 (absent) to 3 (good). Final infarct volumes (FIV) were calculated on post-treatment CT. FIVs were compared between treatment groups per collateral grade. Multivariable linear regression with interaction terms was performed to study whether collaterals modified IAT effect on FIV. Four-hundred-forty-nine patients were included in the analysis. Median FIV for the IAT group was significantly lower with 54.5 mL (95% IQR: 21.8–145.0) than for the controls with 81.8 mL (95% IQR: 40.0–154.0) (p = 0.020). Treatment effect differed across collateral grades, although there was no significant interaction (unadjusted p = 0.054; adjusted p = 0.105). For grade 3, IAT resulted in a FIV reduction of 30.1 mL (p = 0.024). For grade 2 and 1, this difference was, respectively, 28.4 mL (p = 0.028) and 28.4 mL (p = 0.29). For grade 0, this was 88.6 mL (p = 0.28) in favour of controls. IAT saves substantially more brain tissue as compared to standard care. We observed a trend of increasing effect of IAT with higher collateral grades.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"1 1","pages":"3589 - 3598"},"PeriodicalIF":0.0,"publicationDate":"2017-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89686151","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 : 2017-11-01DOI: 10.1177/0271678X16668890
J. Tong, R. Mizrahi, S. Houle, S. Kish, I. Boileau, J. Nobrega, P. Rusjan, Alan A. Wilson
In a recent clinical trial, the drug BIA 10-2474, a putative fatty acid amide hydrolase(FAAH) inhibitor, was responsible for severe adverse events (SAEs), including one death. To date, there has been little reliable information divulged about the potency of BIA 10-2474 at FAAH in the central nervous system. We synthesised BIA 10-2474 and determined its ability to inhibit FAAH ex vivo in rat brain using a FAAH selective radiotracer. BIA 10-2474 proved to be a potent FAAH inhibitor with IC50s of 50–70 µg/kg (i.p.) in various brain regions. This information may be useful for determining the cause of the SAEs.
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Pub Date : 2017-11-01DOI: 10.1177/0271678X16686594
W. Kunz, W. Sommer, C. Höhne, M. Fabritius, Felix Schuler, F. Dorn, A. Othman, F. Meinel, Louisa von Baumgarten, M. Reiser, B. Ertl-Wagner, K. Thierfelder
Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the related supratentorial region. Our aim was to analyze its influence on morphologic and functional outcome in acute ischemic stroke. Subjects with stroke caused by a large vessel occlusion of the anterior circulation were selected from an initial cohort of 1644 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Two experienced readers evaluated the posterior fossa in terms of CCD absence (CCD−) or presence (CCD+). A total of 156 patients formed the study cohort with 102 patients (65.4%) categorized as CCD− and 54 (34.6%) as CCD+. In linear and logistic regression analyses, no significant association between CCD and final infarction volume (β = −0.440, p = 0.972), discharge mRS ≤ 2 (OR = 1.897, p = 0.320), or 90-day mRS ≤ 2 (OR = 0.531, p = 0.492) was detected. CCD+ patients had larger supratentorial cerebral blood flow deficits (median: 164 ml vs. 115 ml; p = 0.001) compared to CCD−patients. Regarding complications, CCD was associated with a higher rate of parenchymal hematomas (OR = 4.793, p = 0.035). In conclusion, CCD is frequently encountered in acute ischemic stroke caused by large vessel occlusion of the anterior circulation. CCD was associated with the occurrence of parenchymal hematoma in the ipsilateral cerebral infarction but did not prove to significantly influence patient outcome.
交叉小脑分离(CCD)是由相关的幕上区功能障碍引起的对侧小脑半球灌注不足和代谢不足的现象。我们的目的是分析其对急性缺血性脑卒中形态学和功能结局的影响。由前循环大血管闭塞引起的卒中患者从1644例连续患者中选择，这些患者接受了包括全脑CT灌注在内的多参数CT检查。两位经验丰富的读者根据CCD缺失(CCD−)或存在(CCD+)来评估后窝。研究共纳入156例患者，其中102例(65.4%)为CCD -， 54例(34.6%)为CCD+。在线性和逻辑回归分析中，CCD与最终梗死体积(β = - 0.440, p = 0.972)、放电mRS≤2 (OR = 1.897, p = 0.320)、90天mRS≤2 (OR = 0.531, p = 0.492)无显著相关性。CCD+患者幕上脑血流缺陷较大(中位数:164 ml vs 115 ml;p = 0.001)。在并发症方面，CCD与较高的实质血肿发生率相关(OR = 4.793, p = 0.035)。综上所述，CCD在前循环大血管闭塞引起的急性缺血性中风中是常见的。CCD与同侧脑梗死实质血肿的发生有关，但未被证明对患者预后有显著影响。
{"title":"Crossed cerebellar diaschisis in acute ischemic stroke: Impact on morphologic and functional outcome","authors":"W. Kunz, W. Sommer, C. Höhne, M. Fabritius, Felix Schuler, F. Dorn, A. Othman, F. Meinel, Louisa von Baumgarten, M. Reiser, B. Ertl-Wagner, K. Thierfelder","doi":"10.1177/0271678X16686594","DOIUrl":"https://doi.org/10.1177/0271678X16686594","url":null,"abstract":"Crossed cerebellar diaschisis (CCD) is the phenomenon of hypoperfusion and hypometabolism of the contralateral cerebellar hemisphere caused by dysfunction of the related supratentorial region. Our aim was to analyze its influence on morphologic and functional outcome in acute ischemic stroke. Subjects with stroke caused by a large vessel occlusion of the anterior circulation were selected from an initial cohort of 1644 consecutive patients who underwent multiparametric CT including whole-brain CT perfusion. Two experienced readers evaluated the posterior fossa in terms of CCD absence (CCD−) or presence (CCD+). A total of 156 patients formed the study cohort with 102 patients (65.4%) categorized as CCD− and 54 (34.6%) as CCD+. In linear and logistic regression analyses, no significant association between CCD and final infarction volume (β = −0.440, p = 0.972), discharge mRS ≤ 2 (OR = 1.897, p = 0.320), or 90-day mRS ≤ 2 (OR = 0.531, p = 0.492) was detected. CCD+ patients had larger supratentorial cerebral blood flow deficits (median: 164 ml vs. 115 ml; p = 0.001) compared to CCD−patients. Regarding complications, CCD was associated with a higher rate of parenchymal hematomas (OR = 4.793, p = 0.035). In conclusion, CCD is frequently encountered in acute ischemic stroke caused by large vessel occlusion of the anterior circulation. CCD was associated with the occurrence of parenchymal hematoma in the ipsilateral cerebral infarction but did not prove to significantly influence patient outcome.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"104 1","pages":"3615 - 3624"},"PeriodicalIF":0.0,"publicationDate":"2017-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76042141","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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