Pub Date : 2019-11-11DOI: 10.1177/0271678X19884427
S. J. Murphy, S. T. Lim, J. Kinsella, S. Tierney, B. Egan, T. Feeley, Clare Dooley, James Kelly, S. Murphy, R. Walsh, R. Collins, T. Coughlan, D. O’Neill, J. Harbison, P. Madhavan, S. O'Neill, M. Colgan, J. Meaney, G. Hamilton, D. McCabe
The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation. We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray–Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as ‘MES+ve’ or ‘MES-ve’. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets. Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 109/L), neutrophil–platelet (3.3 vs. 2.7%), monocyte–platelet (6.3 vs. 4.55%) and lymphocyte–platelet complexes (2.91 vs. 2.53%) than ‘asymptomatic patients with GSM-echodense plaques’ (P ≤ 0.03). Recently, symptomatic carotid stenosis patients with ‘GSM-echodense plaques’ have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.
颈动脉狭窄患者斑块形态、脑微栓塞信号(MES)和血小板生物标志物之间的关系值得研究。我们结合了两项前瞻性观察性研究的数据，以评估近期有症状(≤4周的短暂性缺血发作(TIA)/缺血性卒中)与无症状颈动脉狭窄患者的颈动脉斑块形态及其与大脑MES和血小板生物标志物的关系。超声对斑块形态进行灰度中位数(GSM)和灰度weale (GW)评分。双侧经颅多普勒超声将患者分为“MES+ve”或“MES-ve”。全血细胞计数分析和流式细胞术定量CD62P和CD63表达，白细胞-血小板复合物和网状血小板。我们比较了42例近期出现症状的颈动脉狭窄患者和36例无症状患者的数据。有症状和无症状患者的中位GSM评分无差异(25 vs 30;P = 0.31)或MES+ve与MES-ve症状患者之间的差异(36 vs 25;p = 0.09)。有症状的GSM-回声致密斑块(GSM≥25)患者血小板计数(228比191 × 109/L)、中性粒细胞-血小板计数(3.3比2.7%)、单核细胞-血小板计数(6.3比4.55%)和淋巴细胞-血小板复合物计数(2.91比2.53%)均高于无症状的GSM-回声致密斑块患者(P≤0.03)。最近，有症状的颈动脉狭窄患者与无症状的患者相比，伴有“gsm -回声致密斑块”的患者血小板生成/分泌/激活增强。同时评估神经血管成像和血小板生物标志物可能有助于颈动脉狭窄的风险分层。
{"title":"Simultaneous assessment of plaque morphology, cerebral micro-embolic signal status and platelet biomarkers in patients with recently symptomatic and asymptomatic carotid stenosis","authors":"S. J. Murphy, S. T. Lim, J. Kinsella, S. Tierney, B. Egan, T. Feeley, Clare Dooley, James Kelly, S. Murphy, R. Walsh, R. Collins, T. Coughlan, D. O’Neill, J. Harbison, P. Madhavan, S. O'Neill, M. Colgan, J. Meaney, G. Hamilton, D. McCabe","doi":"10.1177/0271678X19884427","DOIUrl":"https://doi.org/10.1177/0271678X19884427","url":null,"abstract":"The relationship between plaque morphology, cerebral micro-embolic signals (MES) and platelet biomarkers in carotid stenosis patients warrants investigation. We combined data from two prospective, observational studies to assess carotid plaque morphology and relationship with cerebral MES and platelet biomarkers in patients with recently symptomatic (≤4 weeks of transient ischaemic attack (TIA)/ischaemic stroke) versus asymptomatic carotid stenosis. Plaque morphology on ultrasound was graded with Grey-Scale Median (GSM) and Gray–Weale (GW) scoring. Bilateral transcranial Doppler ultrasound classified patients as ‘MES+ve’ or ‘MES-ve’. Full blood counts were analysed and flow cytometry quantified CD62P and CD63 expression, leucocyte-platelet complexes and reticulated platelets. Data from 42 recently symptomatic carotid stenosis patients were compared with those from 36 asymptomatic patients. There were no differences in median GSM scores between symptomatic and asymptomatic patients (25 vs. 30; P = 0.31) or between MES+ve vs. MES-ve symptomatic patients (36 vs. 25; P = 0.09). Symptomatic patients with GSM-echodense plaques (GSM ≥25) had higher platelet counts (228 vs. 191 × 109/L), neutrophil–platelet (3.3 vs. 2.7%), monocyte–platelet (6.3 vs. 4.55%) and lymphocyte–platelet complexes (2.91 vs. 2.53%) than ‘asymptomatic patients with GSM-echodense plaques’ (P ≤ 0.03). Recently, symptomatic carotid stenosis patients with ‘GSM-echodense plaques’ have enhanced platelet production/secretion/activation compared with their asymptomatic counterparts. Simultaneous assessment with neurovascular imaging and platelet biomarkers may aid risk-stratification in carotid stenosis.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"60 1","pages":"2201 - 2214"},"PeriodicalIF":0.0,"publicationDate":"2019-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89141164","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 : 2019-11-11DOI: 10.1177/0271678X19887783
R. Dijkhuizen
A symposium dedicated to the readership of the Journal of Cerebral Blood Flow and Metabolism was organized by the Journal’s editorial team at the BRAIN 2019 meeting in Yokohama, Japan. The JCBFM Symposium offered excellent presentations by two top-cited authors and two Associate Editors, with topics ranging from basic science to clinical studies, followed by stimulating discussion with the audience. Hence, the JCBFM Symposium was a great example of committed participation of authors, editors and readers of the Journal, who all contribute to the advancement of translational neurovascular research.
{"title":"The JCBFM Symposium at BRAIN 2019","authors":"R. Dijkhuizen","doi":"10.1177/0271678X19887783","DOIUrl":"https://doi.org/10.1177/0271678X19887783","url":null,"abstract":"A symposium dedicated to the readership of the Journal of Cerebral Blood Flow and Metabolism was organized by the Journal’s editorial team at the BRAIN 2019 meeting in Yokohama, Japan. The JCBFM Symposium offered excellent presentations by two top-cited authors and two Associate Editors, with topics ranging from basic science to clinical studies, followed by stimulating discussion with the audience. Hence, the JCBFM Symposium was a great example of committed participation of authors, editors and readers of the Journal, who all contribute to the advancement of translational neurovascular research.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"22 1","pages":"225 - 227"},"PeriodicalIF":0.0,"publicationDate":"2019-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82418596","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 : 2019-11-07DOI: 10.1177/0271678X19884742
L. Formisano, G. Laudati, N. Guida, L. Mascolo, Angelo Serani, O. Cuomo, Maria Cantile, F. Boscia, P. Molinaro, S. Anzilotti, Vincenzo Pizzorusso, G. di Renzo, G. Pignataro, L. Annunziato
The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na+/Ca+ exchanger isoform 3 (ncx3) after stroke are still unknown. Overexpression or knocking-down of HDAC4/HDAC5 down-regulates or increases, respectively, NCX3 mRNA and protein. Likewise, MC1568 (class IIa HDACs inhibitor), but not MS-275 (class I HDACs inhibitor) increased NCX3 promoter activity, gene and protein expression. Furthermore, HDAC4 and HDAC5 physically interacted with the transcription factor downstream regulatory element antagonist modulator (DREAM). As MC1568, DREAM knocking-down prevented HDAC4 and HDAC5 recruitment to the ncx3 promoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation of ncx3 promoter. Conversely, the tMCAO-induced NCX3 reduction was prevented by intracerebroventricular injection of siDREAM, siHDAC4, and siHDAC5. Notably, MC1568 prevented oxygen glucose deprivation plus reoxygenation and tMCAO-induced neuronal damage, whereas its neuroprotective effect was abolished by ncx3 knockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulates ncx3 gene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.
{"title":"HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage","authors":"L. Formisano, G. Laudati, N. Guida, L. Mascolo, Angelo Serani, O. Cuomo, Maria Cantile, F. Boscia, P. Molinaro, S. Anzilotti, Vincenzo Pizzorusso, G. di Renzo, G. Pignataro, L. Annunziato","doi":"10.1177/0271678X19884742","DOIUrl":"https://doi.org/10.1177/0271678X19884742","url":null,"abstract":"The histone deacetylases (HDACs)-dependent mechanisms regulating gene transcription of the Na+/Ca+ exchanger isoform 3 (ncx3) after stroke are still unknown. Overexpression or knocking-down of HDAC4/HDAC5 down-regulates or increases, respectively, NCX3 mRNA and protein. Likewise, MC1568 (class IIa HDACs inhibitor), but not MS-275 (class I HDACs inhibitor) increased NCX3 promoter activity, gene and protein expression. Furthermore, HDAC4 and HDAC5 physically interacted with the transcription factor downstream regulatory element antagonist modulator (DREAM). As MC1568, DREAM knocking-down prevented HDAC4 and HDAC5 recruitment to the ncx3 promoter. Importantly, DREAM, HDAC4, and HDAC5 recruitment to the ncx3 gene was increased in the temporoparietal cortex of rats subjected to transient middle cerebral artery occlusion (tMCAO), with a consequent histone-deacetylation of ncx3 promoter. Conversely, the tMCAO-induced NCX3 reduction was prevented by intracerebroventricular injection of siDREAM, siHDAC4, and siHDAC5. Notably, MC1568 prevented oxygen glucose deprivation plus reoxygenation and tMCAO-induced neuronal damage, whereas its neuroprotective effect was abolished by ncx3 knockdown. Collectively, we found that: (1) DREAM/HDAC4/HDAC5 complex epigenetically down-regulates ncx3 gene transcription after stroke, and (2) pharmacological inhibition of class IIa HDACs reduces stroke-induced neurodetrimental effects.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"255 1","pages":"2081 - 2097"},"PeriodicalIF":0.0,"publicationDate":"2019-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75851023","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 : 2019-10-14DOI: 10.1177/0271678X19882782
K. van Leyen, Xiaoying Wang, M. Selim, E. Lo
Abstract The recently completed EXTEND trial tested the idea that tissue plasminogen activator thrombolysis can be safely extended up to 9 h after stroke onset if automated perfusion imaging indicates the presence of a salvageable penumbra. This important trial contributes to an ongoing paradigm shift for stroke therapy. Combined with the introduction of endovascular therapy, image-guided patient selection is expanding the toolbox of the stroke practitioner. At the same time, pushing the limits of reperfusion has raised important questions about mechanisms to pursue for combination therapy as well as potential approaches to mitigate side effects and optimize treatments for patients with various co-morbidities.
{"title":"Opening the time window","authors":"K. van Leyen, Xiaoying Wang, M. Selim, E. Lo","doi":"10.1177/0271678X19882782","DOIUrl":"https://doi.org/10.1177/0271678X19882782","url":null,"abstract":"Abstract The recently completed EXTEND trial tested the idea that tissue plasminogen activator thrombolysis can be safely extended up to 9 h after stroke onset if automated perfusion imaging indicates the presence of a salvageable penumbra. This important trial contributes to an ongoing paradigm shift for stroke therapy. Combined with the introduction of endovascular therapy, image-guided patient selection is expanding the toolbox of the stroke practitioner. At the same time, pushing the limits of reperfusion has raised important questions about mechanisms to pursue for combination therapy as well as potential approaches to mitigate side effects and optimize treatments for patients with various co-morbidities.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"35 1","pages":"2539 - 2540"},"PeriodicalIF":0.0,"publicationDate":"2019-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81344286","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 : 2019-10-08DOI: 10.1177/0271678X19881449
Jinwei Pang, John H. Zhang, Yong Jiang
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?
{"title":"Delayed recanalization in acute ischemic stroke patients: Late is better than never?","authors":"Jinwei Pang, John H. Zhang, Yong Jiang","doi":"10.1177/0271678X19881449","DOIUrl":"https://doi.org/10.1177/0271678X19881449","url":null,"abstract":"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?","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"112 1","pages":"2536 - 2538"},"PeriodicalIF":0.0,"publicationDate":"2019-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79222873","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 : 2019-10-04DOI: 10.1177/0271678X19876876
J. Moxon, A. Trollope, Brittany Dewdney, Catherine de Hollander, Domenico R. Nastasi, J. Maguire, J. Golledge
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; p < 0.001; n = 171 animals) and improved blood–brain barrier integrity (standardized mean difference: –2.02; 95% confidence intervals: –3.27, –0.77; p = 0.002; n = 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.
{"title":"The effect of angiopoietin-1 upregulation on the outcome of acute ischaemic stroke in rodent models: A meta-analysis","authors":"J. Moxon, A. Trollope, Brittany Dewdney, Catherine de Hollander, Domenico R. Nastasi, J. Maguire, J. Golledge","doi":"10.1177/0271678X19876876","DOIUrl":"https://doi.org/10.1177/0271678X19876876","url":null,"abstract":"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; p < 0.001; n = 171 animals) and improved blood–brain barrier integrity (standardized mean difference: –2.02; 95% confidence intervals: –3.27, –0.77; p = 0.002; n = 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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"17 1","pages":"2343 - 2354"},"PeriodicalIF":0.0,"publicationDate":"2019-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89424289","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 : 2019-10-01DOI: 10.1177/0271678X19880450
M. Nørgaard, M. Ganz, C. Svarer, V. Frokjaer, D. Greve, S. Strother, G. Knudsen
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 [11C]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 [11C]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 (p < 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.
{"title":"Different preprocessing strategies lead to different conclusions: A [11C]DASB-PET reproducibility study","authors":"M. Nørgaard, M. Ganz, C. Svarer, V. Frokjaer, D. Greve, S. Strother, G. Knudsen","doi":"10.1177/0271678X19880450","DOIUrl":"https://doi.org/10.1177/0271678X19880450","url":null,"abstract":"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 [11C]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 [11C]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 (p < 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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"7 1","pages":"1902 - 1911"},"PeriodicalIF":0.0,"publicationDate":"2019-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82450528","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 : 2019-09-29DOI: 10.1177/0271678X19878889
Travis C. Jackson, Keri L Janesko-Feldman, S. Carlson, S. E. Kotermanski, P. Kochanek
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.
{"title":"Robust RBM3 and β-klotho expression in developing neurons in the human brain","authors":"Travis C. Jackson, Keri L Janesko-Feldman, S. Carlson, S. E. Kotermanski, P. Kochanek","doi":"10.1177/0271678X19878889","DOIUrl":"https://doi.org/10.1177/0271678X19878889","url":null,"abstract":"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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"110 1","pages":"2355 - 2367"},"PeriodicalIF":0.0,"publicationDate":"2019-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83761587","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 : 2019-09-26DOI: 10.1177/0271678X19877403
D. Ferro, H. Mutsaerts, S. Hilal, H. Kuijf, E. Petersen, J. Petr, Susanne J. van Veluw, N. Venketasubramanian, Tan Boon Yeow, G. Biessels, Christopher L H Chen
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 cerebral blood flow (CBF) (perfusion in mL blood/100 g tissue/min) and spatial coefficient of variation (CoV) (reflecting arterial transit time (ATT)). Patients with CMIs had a 12% lower CBF (beta = −.20) and 22% higher spatial CoV (beta = .20) (both p < .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.
{"title":"Cortical microinfarcts in memory clinic patients are associated with reduced cerebral perfusion","authors":"D. Ferro, H. Mutsaerts, S. Hilal, H. Kuijf, E. Petersen, J. Petr, Susanne J. van Veluw, N. Venketasubramanian, Tan Boon Yeow, G. Biessels, Christopher L H Chen","doi":"10.1177/0271678X19877403","DOIUrl":"https://doi.org/10.1177/0271678X19877403","url":null,"abstract":"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 cerebral blood flow (CBF) (perfusion in mL blood/100 g tissue/min) and spatial coefficient of variation (CoV) (reflecting arterial transit time (ATT)). Patients with CMIs had a 12% lower CBF (beta = −.20) and 22% higher spatial CoV (beta = .20) (both p < .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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"54 1","pages":"1869 - 1878"},"PeriodicalIF":0.0,"publicationDate":"2019-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85216334","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 : 2019-09-14DOI: 10.1177/0271678X19875212
M. Balkaya, Sunghee Cho
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.
{"title":"Optimizing functional outcome endpoints for stroke recovery studies","authors":"M. Balkaya, Sunghee Cho","doi":"10.1177/0271678X19875212","DOIUrl":"https://doi.org/10.1177/0271678X19875212","url":null,"abstract":"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.","PeriodicalId":15356,"journal":{"name":"Journal of Cerebral Blood Flow & Metabolism","volume":"35 1","pages":"2323 - 2342"},"PeriodicalIF":0.0,"publicationDate":"2019-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85544864","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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