Pub Date : 2024-09-01Epub Date: 2024-06-21DOI: 10.1177/0271678X241264086
Silin Wu, Xuefang Sophie Ren, Yejie Shi
The disruption of the blood-brain barrier marks a pivotal early pathological event in ischemic stroke that significantly contributes to subsequent permanent damage. Here we delve into the ramifications of a study conducted by Xu and colleagues, which underscores the essential role of the protein peroxiredoxin-4 in cerebrovascular endothelial cells. Peroxiredoxin-4 was shown to preserve blood-brain barrier integrity during the early stages after cerebral ischemia and reperfusion, ultimately leading to improved long-term outcomes.
{"title":"Early and enduring: Targeting the endothelium for blood-brain barrier protection.","authors":"Silin Wu, Xuefang Sophie Ren, Yejie Shi","doi":"10.1177/0271678X241264086","DOIUrl":"10.1177/0271678X241264086","url":null,"abstract":"<p><p>The disruption of the blood-brain barrier marks a pivotal early pathological event in ischemic stroke that significantly contributes to subsequent permanent damage. Here we delve into the ramifications of a study conducted by Xu and colleagues, which underscores the essential role of the protein peroxiredoxin-4 in cerebrovascular endothelial cells. Peroxiredoxin-4 was shown to preserve blood-brain barrier integrity during the early stages after cerebral ischemia and reperfusion, ultimately leading to improved long-term outcomes.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-03-21DOI: 10.1177/0271678X241240590
Miao Sun, Xin Huang, Xuelei Ruan, Xiuli Shang, Mengyang Zhang, Libo Liu, Ping Wang, Ping An, Yang Lin, Jin Yang, Yixue Xue
Chronic cerebral ischemia (CCI) is a clinical syndrome characterised by brain dysfunction due to decreased chronic cerebral perfusion. CCI initiates several inflammatory pathways, including pyroptosis. RNA-binding proteins (RBPs) play important roles in CCI. This study aimed to explore whether the interaction between RBP-Cpeb4 and Dclk2 affected Ehf phosphorylation to regulate neuronal pyroptosis. HT22 cells and mice were used to construct oxygen glucose deprivation (OGD)/CCI models. We found that Cpeb4 and Dclk2 were upregulated in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. Cpeb4 upregulated Dclk2 expression by increasing Dclk2 mRNA stability. Knockdown of Cpeb4 or Dclk2 inhibited neuronal pyroptosis in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. By binding to the promoter regions of Caspase1 and Caspase3, the transcription factor Ehf reduced their promoter activities and inhibited the transcription. Dclk2 phosphorylated Ehf and changed its nucleoplasmic distribution, resulting in the exit of p-Ehf from the nucleus and decreased Ehf levels. It promoted the expression of Caspase1 and Caspase3 and stimulated neuronal pyroptosis of HT22 cells induced by OGD. Cpeb4/Dclk2/Ehf pathway plays an important role in the regulation of cerebral ischemia-induced neuronal pyroptosis.
{"title":"Cpeb4-mediated Dclk2 promotes neuronal pyroptosis induced by chronic cerebral ischemia through phosphorylation of Ehf.","authors":"Miao Sun, Xin Huang, Xuelei Ruan, Xiuli Shang, Mengyang Zhang, Libo Liu, Ping Wang, Ping An, Yang Lin, Jin Yang, Yixue Xue","doi":"10.1177/0271678X241240590","DOIUrl":"10.1177/0271678X241240590","url":null,"abstract":"<p><p>Chronic cerebral ischemia (CCI) is a clinical syndrome characterised by brain dysfunction due to decreased chronic cerebral perfusion. CCI initiates several inflammatory pathways, including pyroptosis. RNA-binding proteins (RBPs) play important roles in CCI. This study aimed to explore whether the interaction between RBP-Cpeb4 and Dclk2 affected Ehf phosphorylation to regulate neuronal pyroptosis. HT22 cells and mice were used to construct oxygen glucose deprivation (OGD)/CCI models. We found that Cpeb4 and Dclk2 were upregulated in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. Cpeb4 upregulated Dclk2 expression by increasing Dclk2 mRNA stability. Knockdown of Cpeb4 or Dclk2 inhibited neuronal pyroptosis in OGD-treated HT22 cells and CCI-induced hippocampal CA1 tissues. By binding to the promoter regions of Caspase1 and Caspase3, the transcription factor Ehf reduced their promoter activities and inhibited the transcription. Dclk2 phosphorylated Ehf and changed its nucleoplasmic distribution, resulting in the exit of p-Ehf from the nucleus and decreased Ehf levels. It promoted the expression of Caspase1 and Caspase3 and stimulated neuronal pyroptosis of HT22 cells induced by OGD. Cpeb4/Dclk2/Ehf pathway plays an important role in the regulation of cerebral ischemia-induced neuronal pyroptosis.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140184561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-03-14DOI: 10.1177/0271678X241239783
Sungtak Hong, Jyoti Singh Tomar, Jun Shen
A metabolic coupling between glutamate and N-acetylaspartate measured by in vivo magnetic resonance spectroscopy has been recently reported in the literature with inconsistent findings. In this study, confounders originating from Pearson's spurious correlation of ratios and spectral correlation due to overlapping magnetic resonance spectroscopy signals of glutamate and N-acetylaspartate were practically eliminated to facilitate the determination of any metabolic link between glutamate and N-acetylaspartate in the human brain using in vivo magnetic resonance spectroscopy. In both occipital and medial prefrontal cortices of healthy individuals, correlations between glutamate and N-acetylaspartate were found to be insignificant. Our results do not lend support to a recent hypothesis that N-acetylaspartate serves as a significant reservoir for the rapid replenishment of glutamate during signaling or stress.
{"title":"Metabolic coupling between glutamate and N-acetylaspartate in the human brain.","authors":"Sungtak Hong, Jyoti Singh Tomar, Jun Shen","doi":"10.1177/0271678X241239783","DOIUrl":"10.1177/0271678X241239783","url":null,"abstract":"<p><p>A metabolic coupling between glutamate and N-acetylaspartate measured by in vivo magnetic resonance spectroscopy has been recently reported in the literature with inconsistent findings. In this study, confounders originating from Pearson's spurious correlation of ratios and spectral correlation due to overlapping magnetic resonance spectroscopy signals of glutamate and N-acetylaspartate were practically eliminated to facilitate the determination of any metabolic link between glutamate and N-acetylaspartate in the human brain using in vivo magnetic resonance spectroscopy. In both occipital and medial prefrontal cortices of healthy individuals, correlations between glutamate and N-acetylaspartate were found to be insignificant. Our results do not lend support to a recent hypothesis that N-acetylaspartate serves as a significant reservoir for the rapid replenishment of glutamate during signaling or stress.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Preterm birth is associated with cerebrovascular development disruption and can induce white matter injuries (WMI). Transfontanellar ultrasound Doppler is the most widely used clinical imaging technique to monitor neonatal cerebral vascularisation and haemodynamics based on vascular indexes such as the resistivity index (RI); however, it has poor predictive value for brain damage. Indeed, these RI measurements are currently limited to large vessels, leading to a very limited probing of the brain's vascularisation, which may hinder prognosis. Here we show that ultrafast Doppler imaging (UfD) enables simultaneous quantification, in the whole field of view, of the local RI and vessel diameter, even in small vessels. Combining both pieces of information, we defined two new comprehensive resistivity parameters of the vascular trees. First, we showed that our technique is more sensitive in the early characterisation of the RI modifications between term and preterm neonates and for the first time we could show that the RI depends both on the vessel diameter and vascular territory. We then showed that our parameters can be used for early prediction of WMI. Our results demonstrate the potential of UfD to provide new biomarkers and pave the way for continuous monitoring of neonatal brain resistivity.
早产与脑血管发育障碍有关,并可诱发脑白质损伤(WMI)。根据血管指数(如电阻率指数(RI))监测新生儿脑血管化和血流动力学,经颅骨超声多普勒是最广泛应用的临床成像技术;然而,它对脑损伤的预测价值很低。事实上,这些 RI 测量目前仅限于大血管,导致对脑血管的探测非常有限,这可能会妨碍预后。在这里,我们展示了超快多普勒成像(UfD)能在整个视野中同时量化局部 RI 和血管直径,即使在小血管中也是如此。结合这两项信息,我们定义了血管树的两个新的综合电阻率参数。首先,我们证明了我们的技术在早期鉴定足月和早产新生儿的 RI 变化特征方面更加灵敏,并且首次证明了 RI 同时取决于血管直径和血管区域。随后,我们证明了我们的参数可用于早期预测 WMI。我们的研究结果证明了 UfD 在提供新生物标记物方面的潜力,并为持续监测新生儿脑电阻率铺平了道路。
{"title":"Quantification of brain-wide vascular resistivity via ultrafast Doppler in human neonates helps early detection of white matter injury.","authors":"Flora Faure, Jérôme Baranger, Marianne Alison, Béatrice Boutillier, Alice Frérot, Chung Lim, Grégory Planchette, Mickael Prigent, Mickaël Tanter, Olivier Baud, Valérie Biran, Charlie Demené","doi":"10.1177/0271678X241232197","DOIUrl":"10.1177/0271678X241232197","url":null,"abstract":"<p><p>Preterm birth is associated with cerebrovascular development disruption and can induce white matter injuries (WMI). Transfontanellar ultrasound Doppler is the most widely used clinical imaging technique to monitor neonatal cerebral vascularisation and haemodynamics based on vascular indexes such as the resistivity index (RI); however, it has poor predictive value for brain damage. Indeed, these RI measurements are currently limited to large vessels, leading to a very limited probing of the brain's vascularisation, which may hinder prognosis. Here we show that ultrafast Doppler imaging (UfD) enables simultaneous quantification, in the whole field of view, of the local RI and vessel diameter, even in small vessels. Combining both pieces of information, we defined two new comprehensive resistivity parameters of the vascular trees. First, we showed that our technique is more sensitive in the early characterisation of the RI modifications between term and preterm neonates and for the first time we could show that the RI depends both on the vessel diameter and vascular territory. We then showed that our parameters can be used for early prediction of WMI. Our results demonstrate the potential of UfD to provide new biomarkers and pave the way for continuous monitoring of neonatal brain resistivity.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139716099","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-03-15DOI: 10.1177/0271678X241240582
Sandeepa Sur, Zixuan Lin, Yang Li, Sevil Yasar, Paul B Rosenberg, Abhay Moghekar, Xirui Hou, Dengrong Jiang, Rita R Kalyani, Kaisha Hazel, George Pottanat, Cuimei Xu, Jay J Pillai, Peiying Liu, Marilyn Albert, Hanzhang Lu
Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aβ42/40, total tau, and Aβ42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.
{"title":"CO<sub>2</sub> cerebrovascular reactivity measured with CBF-MRI in older individuals: Association with cognition, physical function, amyloid and tau proteins.","authors":"Sandeepa Sur, Zixuan Lin, Yang Li, Sevil Yasar, Paul B Rosenberg, Abhay Moghekar, Xirui Hou, Dengrong Jiang, Rita R Kalyani, Kaisha Hazel, George Pottanat, Cuimei Xu, Jay J Pillai, Peiying Liu, Marilyn Albert, Hanzhang Lu","doi":"10.1177/0271678X241240582","DOIUrl":"10.1177/0271678X241240582","url":null,"abstract":"<p><p>Vascular pathology is the second leading cause of cognitive impairment and represents a major contributing factor in mixed dementia. However, biomarkers for vascular cognitive impairment and dementia (VCID) are under-developed. Here we aimed to investigate the potential role of CO2 Cerebrovascular Reactivity (CVR) measured with phase-contrast quantitative flow MRI in cognitive impairment and dementia. Forty-five (69 ± 7 years) impaired (37 mild-cognitive-impairment and 8 mild-dementia by syndromic diagnosis) and 22 cognitively-healthy-control (HC) participants were recruited and scanned on a 3 T MRI. Biomarkers of AD pathology were measured in cerebrospinal fluid. We found that CBF-CVR was lower (p = 0.027) in the impaired (mean±SE, 3.70 ± 0.15%/mmHg) relative to HC (4.28 ± 0.21%/mmHg). After adjusting for AD pathological markers (Aβ42/40, total tau, and Aβ42/p-tau181), higher CBF-CVR was associated with better cognitive performance, including Montreal Cognitive Assessment, MoCA (p = 0.001), composite cognitive score (p = 0.047), and language (p = 0.004). Higher CBF-CVR was also associated with better physical function, including gait-speed (p = 0.006) and time for five chair-stands (p = 0.049). CBF-CVR was additionally related to the Clinical-Dementia-Rating, CDR, including global CDR (p = 0.026) and CDR Sum-of-Boxes (p = 0.015). CBF-CVR was inversely associated with hemoglobin A1C level (p = 0.017). In summary, CBF-CVR measured with phase-contrast MRI shows associations with cognitive performance, physical function, and disease-severity, independent of AD pathological markers.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140136815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-01Epub Date: 2024-07-25DOI: 10.1177/0271678X241264083
Jingsong Ruan, Minkyung Kang, Abhijit Nirwane, Yao Yao
Although most laminin isoforms are neuroprotective in stroke, mural cell-derived laminin-α5 plays a detrimental role in an ischemia-reperfusion model. To determine whether this deleterious effect is an intrinsic feature of mural cell-derived laminin-α5 or unique to ischemic stroke, we performed loss-of-function studies using middle-aged mice with laminin-α5 deficiency in mural cells (α5-PKO) in an intracerebral hemorrhage (ICH) model. Control and α5-PKO mice exhibited comparable changes in all parameters examined, including hematoma size, neuronal death, neurological function, blood-brain barrier integrity, and reactive gliosis. These findings highlight a minimal role of mural cell-derived laminin-α5 in ICH. Together with the detrimental role of mural cell-derived laminin-α5 in ischemic stroke, these negative results in ICH model suggest that mural cell-derived laminin-α5 may exert distinct functions in different diseases.
虽然大多数层粘连蛋白异构体在中风中具有神经保护作用,但壁细胞衍生的层粘连蛋白-α5在缺血再灌注模型中却起着有害作用。为了确定这种有害作用是壁细胞衍生的层粘连蛋白-α5的固有特性还是缺血性脑卒中特有的特性,我们在脑内出血(ICH)模型中使用缺乏壁细胞层粘连蛋白-α5(α5-PKO)的中年小鼠进行了功能缺失研究。对照组小鼠和α5-PKO小鼠在血肿大小、神经元死亡、神经功能、血脑屏障完整性和反应性胶质细胞增多等所有检测指标上都表现出了相似的变化。这些发现突显了壁细胞衍生的层粘连蛋白-α5在 ICH 中的作用微乎其微。加上壁细胞衍生的层粘连蛋白-α5在缺血性中风中的有害作用,这些在ICH模型中的负面结果表明,壁细胞衍生的层粘连蛋白-α5可能在不同的疾病中发挥不同的功能。
{"title":"A dispensable role of mural cell-derived laminin-<b>α</b>5 in intracerebral hemorrhage.","authors":"Jingsong Ruan, Minkyung Kang, Abhijit Nirwane, Yao Yao","doi":"10.1177/0271678X241264083","DOIUrl":"10.1177/0271678X241264083","url":null,"abstract":"<p><p>Although most laminin isoforms are neuroprotective in stroke, mural cell-derived laminin-α5 plays a detrimental role in an ischemia-reperfusion model. To determine whether this deleterious effect is an intrinsic feature of mural cell-derived laminin-α5 or unique to ischemic stroke, we performed loss-of-function studies using middle-aged mice with laminin-α5 deficiency in mural cells (α5-PKO) in an intracerebral hemorrhage (ICH) model. Control and α5-PKO mice exhibited comparable changes in all parameters examined, including hematoma size, neuronal death, neurological function, blood-brain barrier integrity, and reactive gliosis. These findings highlight a minimal role of mural cell-derived laminin-α5 in ICH. Together with the detrimental role of mural cell-derived laminin-α5 in ischemic stroke, these negative results in ICH model suggest that mural cell-derived laminin-α5 may exert distinct functions in different diseases.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11418671/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141758935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1177/0271678X241276951
Isabell Nessel, Luke Whiley, Simon C Dyall, Adina T Michael-Titus
Traumatic brain injury (TBI) leads to major membrane lipid breakdown. We investigated plasma lipids over 3 days post-TBI, to identify a signature of acute human TBI and assess its correlation with neuronal injury and inflammation. Plasma from patients with TBI (Abbreviated Injury Scale (AIS)3 - serious injury, n = 5; AIS4 - severe injury, n = 8), and controls (n = 13) was analysed for lipidomic profile, neurofilament light (NFL) and cytokines, and the omega-3 index was measured in red blood cells. A lipid signature separated TBI from controls, at 24 and 72 h. Major species driving the separation were: lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and hexosylceramide (HexCer). Docosahexaenoic acid (DHA, 22:6) and LPC (0:0/22:6) decreased post-injury. NFL levels were increased at 24 and 72 h post-injury in AIS4 TBI vs. controls. Interleukin (IL-)6, IL-2 and IL-13 were elevated at 24 h in AIS4 patients vs. controls. NFL and IL-6 were negatively correlated with several lipids. The omega-3 index at admission was low in all patients (controls: 4.3 ± 1.1% and TBI: 4.0 ± 1.1%) and did not change significantly over 3 days post-injury. We have identified specific lipid changes, correlated with markers of injury and inflammation in acute TBI. These observations could inform future lipid-based therapeutic approaches.
{"title":"A plasma lipid signature in acute human traumatic brain injury: Link with neuronal injury and inflammation markers.","authors":"Isabell Nessel, Luke Whiley, Simon C Dyall, Adina T Michael-Titus","doi":"10.1177/0271678X241276951","DOIUrl":"https://doi.org/10.1177/0271678X241276951","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) leads to major membrane lipid breakdown. We investigated plasma lipids over 3 days post-TBI, to identify a signature of acute human TBI and assess its correlation with neuronal injury and inflammation. Plasma from patients with TBI (Abbreviated Injury Scale (AIS)3 - serious injury, n = 5; AIS4 - severe injury, n = 8), and controls (n = 13) was analysed for lipidomic profile, neurofilament light (NFL) and cytokines, and the omega-3 index was measured in red blood cells. A lipid signature separated TBI from controls, at 24 and 72 h. Major species driving the separation were: lysophosphatidylcholine (LPC), phosphatidylcholine (PC) and hexosylceramide (HexCer). Docosahexaenoic acid (DHA, 22:6) and LPC (0:0/22:6) decreased post-injury. NFL levels were increased at 24 and 72 h post-injury in AIS4 TBI vs. controls. Interleukin (IL-)6, IL-2 and IL-13 were elevated at 24 h in AIS4 patients vs. controls. NFL and IL-6 were negatively correlated with several lipids. The omega-3 index at admission was low in all patients (controls: 4.3 ± 1.1% and TBI: 4.0 ± 1.1%) and did not change significantly over 3 days post-injury. We have identified specific lipid changes, correlated with markers of injury and inflammation in acute TBI. These observations could inform future lipid-based therapeutic approaches.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072918","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-23DOI: 10.1177/0271678X241277621
Yao Wang, Ziwei Yang, Xiumei Zheng, Xiao Liang, Lin Wu, Chengsi Wu, Jiankun Dai, Yuan Cao, Meng Li, Fuqing Zhou
Neuroimaging studies have indicated that altered cerebral blood flow (CBF) was associated with the long-term symptoms of postacute sequelae of SARS-CoV-2 infection (PASC), also known as "long COVID". COVID-19 and long COVID were found to be strongly associated with host gene expression. Nevertheless, the relationships between altered CBF, clinical symptoms, and gene expression in the central nervous system (CNS) remain unclear in individuals with long COVID. This study aimed to explore the genetic mechanisms of CBF abnormalities in individuals with long COVID by transcriptomic-neuroimaging spatial association. Lower CBF in the left frontal-temporal gyrus was associated with higher fatigue and worse cognition in individuals with long COVID. This CBF pattern was spatially associated with the expression of 2,178 genes, which were enriched in the molecular functions and biological pathways of COVID-19. Our study suggested that lower CBF is associated with persistent clinical symptoms in long COVID individuals, possibly as a consequence of the complex interactions among multiple COVID-19-related genes, which contributes to our understanding of the impact of adverse CNS outcomes and the trajectory of development to long COVID.
{"title":"Cerebral blood flow alterations and host genetic association in individuals with long COVID: A transcriptomic-neuroimaging study.","authors":"Yao Wang, Ziwei Yang, Xiumei Zheng, Xiao Liang, Lin Wu, Chengsi Wu, Jiankun Dai, Yuan Cao, Meng Li, Fuqing Zhou","doi":"10.1177/0271678X241277621","DOIUrl":"https://doi.org/10.1177/0271678X241277621","url":null,"abstract":"<p><p>Neuroimaging studies have indicated that altered cerebral blood flow (CBF) was associated with the long-term symptoms of postacute sequelae of SARS-CoV-2 infection (PASC), also known as \"long COVID\". COVID-19 and long COVID were found to be strongly associated with host gene expression. Nevertheless, the relationships between altered CBF, clinical symptoms, and gene expression in the central nervous system (CNS) remain unclear in individuals with long COVID. This study aimed to explore the genetic mechanisms of CBF abnormalities in individuals with long COVID by transcriptomic-neuroimaging spatial association. Lower CBF in the left frontal-temporal gyrus was associated with higher fatigue and worse cognition in individuals with long COVID. This CBF pattern was spatially associated with the expression of 2,178 genes, which were enriched in the molecular functions and biological pathways of COVID-19. Our study suggested that lower CBF is associated with persistent clinical symptoms in long COVID individuals, possibly as a consequence of the complex interactions among multiple COVID-19-related genes, which contributes to our understanding of the impact of adverse CNS outcomes and the trajectory of development to long COVID.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-21DOI: 10.1177/0271678X241276312
Khanum Ridler, Gaia Rizzo, Ethan S Burstein, Anton Forsberg Morén, Vladimir Stepanov, Christer Halldin, Eugenii A Rabiner
Two complimentary techniques were used to estimate occupancy of pimavanserin (a selective 5-HT2A/2C inverse agonist) to 5-HT2A and 5-HT2C receptors in non-human primate brains. One employed the 5-HT2A/2C selective radioligand [11C]CIMBI-36 combined with quantification of binding potentials in brain regions known to be enriched in 5-HT2A (cortex) or 5-HT2C (choroid plexus) receptors to estimate occupancy. Pimavanserin was 6-10 fold more potent displacing [11C]CIMBI-36 from cortex (ED50 = 0.007 mg/kg; EC50 = 0.6 ng/ml) than from choroid plexus (ED50 =0.046 mg/kg; EC50 = 6.0 ng/ml). The assignment of [11C]CIMBI-36 binding to 5-HT2A and 5-HT2C receptors by anatomical brain structure was confirmed using the 5-HT2A selective inverse agonist MDL 100,907 and the 5-HT2C selective antagonist SB 242584 to displace [11C]CIMBI-36. The second technique employed a novel, 5-HT2C selective tracer called [11C]AC1332. [11C]AC1332 bound robustly to choroid plexus, moderately to hippocampus, and minimally to cortex. Pimavanserin displaced [11C]AC1332 with similar potency (ED50 = 0.062 mg/kg; EC50 = 2.5 ng/ml) as its potency displacing [11C]CIMBI-36 binding from choroid plexus. These results demonstrate the feasibility of simultaneously estimating drug occupancy of 5-HT2A and 5-HT2C receptors in vivo, and the utility of a novel 5-HT2C receptor selective tracer ligand.
{"title":"Imaging the 5-HT<sub>2C</sub> receptor with PET: Evaluation of 5-HT<sub>2C</sub> and 5-HT<sub>2A</sub> affinity of pimavanserin in the primate brain.","authors":"Khanum Ridler, Gaia Rizzo, Ethan S Burstein, Anton Forsberg Morén, Vladimir Stepanov, Christer Halldin, Eugenii A Rabiner","doi":"10.1177/0271678X241276312","DOIUrl":"https://doi.org/10.1177/0271678X241276312","url":null,"abstract":"<p><p>Two complimentary techniques were used to estimate occupancy of pimavanserin (a selective 5-HT<sub>2A/2C</sub> inverse agonist) to 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors in non-human primate brains. One employed the 5-HT<sub>2A/2C</sub> selective radioligand [<sup>11</sup>C]CIMBI-36 combined with quantification of binding potentials in brain regions known to be enriched in 5-HT<sub>2A</sub> (cortex) or 5-HT<sub>2C</sub> (choroid plexus) receptors to estimate occupancy. Pimavanserin was 6-10 fold more potent displacing [<sup>11</sup>C]CIMBI-36 from cortex (ED<sub>50</sub> = 0.007 mg/kg; EC<sub>50</sub> = 0.6 ng/ml) than from choroid plexus (ED<sub>50</sub> =0.046 mg/kg; EC<sub>50</sub> = 6.0 ng/ml). The assignment of [<sup>11</sup>C]CIMBI-36 binding to 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors by anatomical brain structure was confirmed using the 5-HT<sub>2A</sub> selective inverse agonist MDL 100,907 and the 5-HT<sub>2C</sub> selective antagonist SB 242584 to displace [<sup>11</sup>C]CIMBI-36. The second technique employed a novel, 5-HT<sub>2C</sub> selective tracer called [<sup>11</sup>C]AC1332. [<sup>11</sup>C]AC1332 bound robustly to choroid plexus, moderately to hippocampus, and minimally to cortex. Pimavanserin displaced [<sup>11</sup>C]AC1332 with similar potency (ED<sub>50</sub> = 0.062 mg/kg; EC<sub>50</sub> = 2.5 ng/ml) as its potency displacing [<sup>11</sup>C]CIMBI-36 binding from choroid plexus. These results demonstrate the feasibility of simultaneously estimating drug occupancy of 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors in vivo, and the utility of a novel 5-HT<sub>2C</sub> receptor selective tracer ligand.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-20DOI: 10.1177/0271678X241276386
Yu Xiao, Zhenghua Liu, Xinghua Wan
Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) can be measured using arterial spin labeling (ASL) and quantitative susceptibility mapping (QSM) sequences, respectively. ASL and QSM sequences were performed on 13 healthy participants and 46 patients with unilateral or bilateral Middle cerebral artery (MCA) occlusion. M1-M3 and M4-M6 correspond to anterior, lateral, and posterior MCA territories within the insular ribbon and centrum semiovale, respectively. In patients with unilateral MCA occlusion, significant decreases in CBF were observed in the lesions in M1, M3, M5 and M6 regions, as well as in the contralateral M3 and M5 regions. The OEF of the lesion in the M1-M4 and M6 regions, and the contralateral M1-M3 regions were significantly higher. Additionally, the cerebral metabolic rate of oxygen (CMRO2) in the lesions of the M3 and M6 regions, and the contralateral M3 region, were significantly lower compared to the corresponding regions of healthy participants. For patients with bilateral MCA occlusion, the CMRO2 in the left M5 region and the right M3 and M6 regions were significantly lower than that in the corresponding regions of healthy participants. In conclusion, abnormal hemodynamics occur in the contralateral hemisphere of patients with unilateral MCA occlusion.
{"title":"Oxygen extraction fraction change in M1-M6 brain regions of patients with unilateral or bilateral middle cerebral artery occlusion.","authors":"Yu Xiao, Zhenghua Liu, Xinghua Wan","doi":"10.1177/0271678X241276386","DOIUrl":"https://doi.org/10.1177/0271678X241276386","url":null,"abstract":"<p><p>Cerebral blood flow (CBF) and oxygen extraction fraction (OEF) can be measured using arterial spin labeling (ASL) and quantitative susceptibility mapping (QSM) sequences, respectively. ASL and QSM sequences were performed on 13 healthy participants and 46 patients with unilateral or bilateral Middle cerebral artery (MCA) occlusion. M1-M3 and M4-M6 correspond to anterior, lateral, and posterior MCA territories within the insular ribbon and centrum semiovale, respectively. In patients with unilateral MCA occlusion, significant decreases in CBF were observed in the lesions in M1, M3, M5 and M6 regions, as well as in the contralateral M3 and M5 regions. The OEF of the lesion in the M1-M4 and M6 regions, and the contralateral M1-M3 regions were significantly higher. Additionally, the cerebral metabolic rate of oxygen (CMRO<sub>2</sub>) in the lesions of the M3 and M6 regions, and the contralateral M3 region, were significantly lower compared to the corresponding regions of healthy participants. For patients with bilateral MCA occlusion, the CMRO<sub>2</sub> in the left M5 region and the right M3 and M6 regions were significantly lower than that in the corresponding regions of healthy participants. In conclusion, abnormal hemodynamics occur in the contralateral hemisphere of patients with unilateral MCA occlusion.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142004368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}