Pub Date : 2024-10-13DOI: 10.1177/0271678X241290912
Chunmeng Tang, Greet Vanderlinden, Gwen Schroyen, Sabine Deprez, Koen Van Laere, Michel Koole
A Support Vector Machine (SVM) based approach was developed to identify a pseudo-reference region for brain PET scans with the aim of reducing interscan and intersubject variability. By training a binary linear SVM classifier with PET datasets from two different groups, potential pseudo-reference regions were identified by considering their regional average or total contribution to the classification score. This approach was evaluated in three cohorts with different brain PET tracers: (1) 11C-PiB PET scans of Alzheimer's disease (AD) patients and age-matched controls (OC); (2) baseline and blocking scans of an 11C-UCB-J PET occupancy study; and (3) 18F-DPA-714 PET scans for healthy controls (HC) and chemo-treated women with breast cancer (BC). In the first cohort, cerebellum, brainstem, and subcortical white matter were confirmed as pseudo-reference regions. The same regions were identified for the second cohort using either the VT maps or the SUV images. In the third cohort, cerebellum and brainstem were identified as pseudo-reference regions, alongside subcortical white matter and temporal cortex. In addition, the SVM-based approach demonstrated robust performance even with a reduced number of subjects, therefore confirming its applicability in identifying pseudo-reference regions without a priori assumptions and with only limited data across different PET tracers.
我们开发了一种基于支持向量机(SVM)的方法来识别脑 PET 扫描的伪参考区域,目的是减少扫描间和受试者间的变异性。通过对来自两个不同组的 PET 数据集进行二元线性 SVM 分类器训练,考虑其对分类得分的区域平均或总贡献,确定潜在的伪参考区域。该方法在使用不同脑 PET 示踪剂的三个队列中进行了评估:(1) 阿尔茨海默病(AD)患者和年龄匹配对照(OC)的 11C-PiB PET 扫描;(2) 11C-UCB-J PET 占位研究的基线和阻断扫描;(3) 健康对照(HC)和化疗妇女乳腺癌(BC)的 18F-DPA-714 PET 扫描。在第一个队列中,小脑、脑干和皮层下白质被确认为伪参考区域。第二组患者也使用 VT 图或 SUV 图像确定了相同的区域。在第三个队列中,小脑和脑干以及皮层下白质和颞叶皮质被确定为伪参考区域。此外,即使受试者人数减少,基于 SVM 的方法也能表现出稳健的性能,因此证实了该方法适用于在没有先验假设的情况下识别伪参考区域,而且只需跨不同 PET 示踪剂的有限数据。
{"title":"A support vector machine-based approach to guide the selection of a pseudo-reference region for brain PET quantification.","authors":"Chunmeng Tang, Greet Vanderlinden, Gwen Schroyen, Sabine Deprez, Koen Van Laere, Michel Koole","doi":"10.1177/0271678X241290912","DOIUrl":"https://doi.org/10.1177/0271678X241290912","url":null,"abstract":"<p><p>A Support Vector Machine (SVM) based approach was developed to identify a pseudo-reference region for brain PET scans with the aim of reducing interscan and intersubject variability. By training a binary linear SVM classifier with PET datasets from two different groups, potential pseudo-reference regions were identified by considering their regional average or total contribution to the classification score. This approach was evaluated in three cohorts with different brain PET tracers: (1) <sup>11</sup>C-PiB PET scans of Alzheimer's disease (AD) patients and age-matched controls (OC); (2) baseline and blocking scans of an <sup>11</sup>C-UCB-J PET occupancy study; and (3) <sup>18</sup>F-DPA-714 PET scans for healthy controls (HC) and chemo-treated women with breast cancer (BC). In the first cohort, cerebellum, brainstem, and subcortical white matter were confirmed as pseudo-reference regions. The same regions were identified for the second cohort using either the V<sub>T</sub> maps or the SUV images. In the third cohort, cerebellum and brainstem were identified as pseudo-reference regions, alongside subcortical white matter and temporal cortex. In addition, the SVM-based approach demonstrated robust performance even with a reduced number of subjects, therefore confirming its applicability in identifying pseudo-reference regions without a priori assumptions and with only limited data across different PET tracers.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142466521","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 : 2024-10-07DOI: 10.1177/0271678X241289772
Ilse S Altenburg, Nina G Smets, Gustav J Strijkers, Erik Ntp Bakker
Medin is a protein fragment derived from milk fat globule epidermal growth factor VIII (MFG-E8). Medin aggregates are present in the vessel wall of most subjects over 50 years of age. In this narrative review, we focus on the consequences of medin aggregation in relation to the development of dementia. Recent literature revealed medin as biomarker for dementia in CSF, specifically of a vascular subtype. Preclinical work showed that medin is associated with aging-related cerebral vascular dysfunction, vascular stiffening, hypertension, and. vascular amyloid β deposition. These findings position medin as a potential mechanistic link between aging, vascular pathology and dementia.
{"title":"Medin, a link between vascular pathology and dementia?","authors":"Ilse S Altenburg, Nina G Smets, Gustav J Strijkers, Erik Ntp Bakker","doi":"10.1177/0271678X241289772","DOIUrl":"https://doi.org/10.1177/0271678X241289772","url":null,"abstract":"<p><p>Medin is a protein fragment derived from milk fat globule epidermal growth factor VIII (MFG-E8). Medin aggregates are present in the vessel wall of most subjects over 50 years of age. In this narrative review, we focus on the consequences of medin aggregation in relation to the development of dementia. Recent literature revealed medin as biomarker for dementia in CSF, specifically of a vascular subtype. Preclinical work showed that medin is associated with aging-related cerebral vascular dysfunction, vascular stiffening, hypertension, and. vascular amyloid β deposition. These findings position medin as a potential mechanistic link between aging, vascular pathology and dementia.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380952","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 : 2024-10-07DOI: 10.1177/0271678X241281841
Sodai Yoshimura, Maximilian Dorok, Uta Mamrak, Antonia Wehn, Eva Krestel, Igor Khalin, Nikolaus Plesnila
Current techniques for inducing intraluminal filamentous middle cerebral artery occlusion (fMCAo) in mice produce highly variable results and often cause additional infarcts in the posterior cerebral artery (PCA) territory. The aim of the current study was to develop a novel procedure to overcome these shortcomings. Male C57BL/6 mice were subjected to 60 min of fMCAo with cerebral blood flow monitored by laser Doppler flowmetry. The influence of the length of the occlusion filament coating and the combination of common carotid artery (CCA) or pterygopalatine artery (PPA) ligation on lesion volume and functional outcome 24 h after reperfusion was evaluated. The use of appropriate filament and PPA ligation while maintaining CCA perfusion prevented the development of infarcts in the PCA area, resulted in pure MCA infarcts (68.3 ± 14.5 mm3) and reduced the variability of infarct volumes by more than half (from 26-38% to 14% standard deviation/mean). Using an improved fMCAo procedure, we were able to produce PCA area-unaffected reproducible (PURE) infarcts exclusively in the MCA territory. Thus PURE-MCAo reduced outcome variability by more than 50%. Our results may thus help to reduce the number of animals in preclinical stroke research and to increase the reproducibility of the fMCAo model.
{"title":"Reliable infarction of the middle cerebral artery territory in C57BL/6 mice using pterygopalatine artery ligation and filament optimization - The PURE-MCAo model.","authors":"Sodai Yoshimura, Maximilian Dorok, Uta Mamrak, Antonia Wehn, Eva Krestel, Igor Khalin, Nikolaus Plesnila","doi":"10.1177/0271678X241281841","DOIUrl":"10.1177/0271678X241281841","url":null,"abstract":"<p><p>Current techniques for inducing intraluminal filamentous middle cerebral artery occlusion (fMCAo) in mice produce highly variable results and often cause additional infarcts in the posterior cerebral artery (PCA) territory. The aim of the current study was to develop a novel procedure to overcome these shortcomings. Male C57BL/6 mice were subjected to 60 min of fMCAo with cerebral blood flow monitored by laser Doppler flowmetry. The influence of the length of the occlusion filament coating and the combination of common carotid artery (CCA) or pterygopalatine artery (PPA) ligation on lesion volume and functional outcome 24 h after reperfusion was evaluated. The use of appropriate filament and PPA ligation while maintaining CCA perfusion prevented the development of infarcts in the PCA area, resulted in pure MCA infarcts (68.3 ± 14.5 mm<sup>3</sup>) and reduced the variability of infarct volumes by more than half (from 26-38% to 14% standard deviation/mean). Using an improved fMCAo procedure, we were able to produce <u>P</u>CA area-<u>u</u>naffected <u>re</u>producible (PURE) infarcts exclusively in the MCA territory. Thus PURE-MCAo reduced outcome variability by more than 50%. Our results may thus help to reduce the number of animals in preclinical stroke research and to increase the reproducibility of the fMCAo model.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380953","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 : 2024-10-04DOI: 10.1177/0271678X241267066
Moritz R Hernandez Petzsche, Johannes Bürkle, Gabriel Hoffmann, Claus Zimmer, Sebastian Rühling, Julian Schwarting, Silke Wunderlich, Christian Maegerlein, Tobias Boeckh-Behrens, Stefan Kaczmarz, Maria Berndt-Mück, Nico Sollmann
Arterial spin labeling (ASL) is a contrast agent-free magnetic resonance imaging (MRI) technique to measure cerebral blood flow (CBF). We sought to investigate effects of CBF within the infarct on outcome and risk of hemorrhagic transformation (HT). In 111 patients (median age: 74 years, 50 men) who had undergone mechanical thrombectomy (MT) for ischemic stroke of the anterior circulation (median interval: 4 days between MT and MRI), post-stroke %CBF difference from pseudo-continuous ASL was calculated within the diffusion-weighted imaging (DWI)-positive infarct territory following lesion segmentation in relationship to the unaffected contralateral side. Functional independence was defined as a modified Rankin Scale (mRS) of 0-2 at 90 days post-stroke. %CBF difference, pre-stroke mRS, and infarct volume were independently associated with functional independence in a multivariate regression model. %CBF difference was comparable between patients with and without HT. A subcohort of 10 patients with decreased infarct-CBF despite expanded Treatment in Cerebral Infarction (eTICI) 2c or 3 recanalization was identified (likely related to the no-reflow phenomenon). Outcome was significantly worse in this group compared to the remaining cohort. In conclusion, ASL-derived %CBF difference from the DWI-positive infarct territory independently predicted functional independence, but %CBF difference was not significantly associated with an increased risk of HT.
{"title":"Cerebral blood flow from arterial spin labeling as an imaging biomarker of outcome after endovascular therapy for ischemic stroke.","authors":"Moritz R Hernandez Petzsche, Johannes Bürkle, Gabriel Hoffmann, Claus Zimmer, Sebastian Rühling, Julian Schwarting, Silke Wunderlich, Christian Maegerlein, Tobias Boeckh-Behrens, Stefan Kaczmarz, Maria Berndt-Mück, Nico Sollmann","doi":"10.1177/0271678X241267066","DOIUrl":"10.1177/0271678X241267066","url":null,"abstract":"<p><p>Arterial spin labeling (ASL) is a contrast agent-free magnetic resonance imaging (MRI) technique to measure cerebral blood flow (CBF). We sought to investigate effects of CBF within the infarct on outcome and risk of hemorrhagic transformation (HT). In 111 patients (median age: 74 years, 50 men) who had undergone mechanical thrombectomy (MT) for ischemic stroke of the anterior circulation (median interval: 4 days between MT and MRI), post-stroke %CBF difference from pseudo-continuous ASL was calculated within the diffusion-weighted imaging (DWI)-positive infarct territory following lesion segmentation in relationship to the unaffected contralateral side. Functional independence was defined as a modified Rankin Scale (mRS) of 0-2 at 90 days post-stroke. %CBF difference, pre-stroke mRS, and infarct volume were independently associated with functional independence in a multivariate regression model. %CBF difference was comparable between patients with and without HT. A subcohort of 10 patients with decreased infarct-CBF despite expanded Treatment in Cerebral Infarction (eTICI) 2c or 3 recanalization was identified (likely related to the no-reflow phenomenon). Outcome was significantly worse in this group compared to the remaining cohort. In conclusion, ASL-derived %CBF difference from the DWI-positive infarct territory independently predicted functional independence, but %CBF difference was not significantly associated with an increased risk of HT.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371955","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 : 2024-10-03DOI: 10.1177/0271678X241274685
Olivia A Jones, Saffwan Mohamed, Rainer Hinz, Alastair Paterson, Oluwaseun A Sobowale, Ben R Dickie, Laura M Parkes, Adrian R Parry-Jones
Neuroinflammation is a promising therapeutic target in intracerebral hemorrhage (ICH), characterized in the brain by microglial activation and blood-brain barrier (BBB) breakdown. In this study, 36 acute, spontaneous, supratentorial ICH patients underwent dynamic contrast-enhanced MRI to measure BBB permeability (Ktrans) 1-3 days post-onset and 16 returned for [11C](R)-PK11195 PET to quantify microglial activation (BPND), 2-7 days post-onset. We first tested if these markers were increased and co-localized in the perihematomal brain and found that perihematomal Ktrans and BPND were increased vs. the contralateral brain, but regions of high Ktrans and BPND only overlapped by a mean of 4.9%. We then tested for associations of perihematomal Ktrans and BPND with clinical characteristics (age, ICH volume & location, blood pressure), other markers of inflammation (edema, IL-6, and CRP), and long-term functional outcome (90-day mRS). Lower perihematomal BPND was associated with increasing age. Lobar hemorrhage was associated with greater Ktrans than deep, but Ktrans and BPND were not associated with ICH volume, or other inflammatory markers. While perihematomal Ktrans and BPNDwere not associated with outcome, contralateral Ktrans was significantly associated with greater 90-day mRS. Exploratory analyses demonstrated that blood pressure variability over 72 h was also associated with contralateral Ktrans.
{"title":"Neuroinflammation and blood-brain barrier breakdown in acute, clinical intracerebral hemorrhage.","authors":"Olivia A Jones, Saffwan Mohamed, Rainer Hinz, Alastair Paterson, Oluwaseun A Sobowale, Ben R Dickie, Laura M Parkes, Adrian R Parry-Jones","doi":"10.1177/0271678X241274685","DOIUrl":"10.1177/0271678X241274685","url":null,"abstract":"<p><p>Neuroinflammation is a promising therapeutic target in intracerebral hemorrhage (ICH), characterized in the brain by microglial activation and blood-brain barrier (BBB) breakdown. In this study, 36 acute, spontaneous, supratentorial ICH patients underwent dynamic contrast-enhanced MRI to measure BBB permeability (<i>K</i><sup>trans</sup>) 1-3 days post-onset and 16 returned for [<sup>11</sup>C](<i>R</i>)-PK11195 PET to quantify microglial activation (<i>BP<sub>ND</sub></i>), 2-7 days post-onset. We first tested if these markers were increased and co-localized in the perihematomal brain and found that perihematomal <i>K</i><sup>trans</sup> and <i>BP<sub>ND</sub></i> were increased vs. the contralateral brain, but regions of high <i>K</i><sup>trans</sup> and <i>BP<sub>ND</sub></i> only overlapped by a mean of 4.9%. We then tested for associations of perihematomal <i>K</i><sup>trans</sup> and <i>BP<sub>ND</sub></i> with clinical characteristics (age, ICH volume & location, blood pressure), other markers of inflammation (edema, IL-6, and CRP), and long-term functional outcome (90-day mRS). Lower perihematomal <i>BP<sub>ND</sub></i> was associated with increasing age. Lobar hemorrhage was associated with greater <i>K</i><sup>trans</sup> than deep, but <i>K</i><sup>trans</sup> and <i>BP<sub>ND</sub></i> were not associated with ICH volume, or other inflammatory markers. While perihematomal <i>K</i><sup>trans</sup> and <i>BP<sub>ND</sub></i>were not associated with outcome, contralateral <i>K</i><sup>trans</sup> was significantly associated with greater 90-day mRS. Exploratory analyses demonstrated that blood pressure variability over 72 h was also associated with contralateral <i>K</i><sup>trans</sup>.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142365389","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 : 2024-10-01Epub Date: 2024-05-26DOI: 10.1177/0271678X241258563
Jiannan Huang, Megan Oh, Caroline Robert, Xiangyuan Huang, Marco Egle, Daniel J Tozer, Christopher Chen, Saima Hilal
Cortical cerebral microinfarcts (CMIs) are associated with loss of white matter (WM) integrity and cognitive impairment in cross-sectional studies, while further investigation using longitudinal datasets is required. This study aims to establish the association between cortical CMIs and WM integrity assessed by diffusion-tensor imaging (DTI) measures and to investigate whether DTI measures mediate the relationship between cortical CMIs and cognitive decline. Cortical CMIs were graded on 3T MRI. DTI measures were derived from histogram analysis of mean diffusivity (MD) and fractional anisotropy (FA). Cognitive function was assessed using a neuropsychological test battery. Linear mixed-effect models were employed to examine associations of cortical CMIs with longitudinal changes in DTI measures and cognitive function. Final analysis included 231 patients (71.14 ± 7.60 years). Presence of cortical CMIs at baseline was associated with longitudinal changes in MD median and peak height and FA median and peak height, as well as global cognition (β = -0.50, 95%CI: -0.91, -0.09) and executive function (β = -0.77, 95%CI: -1.25, -0.28). MD median mediated the cross-sectional association between cortical CMIs and global cognition. Further studies are required to investigate whether cortical CMIs and loss of WM integrity are causally related or if they are parallel mechanisms that contribute to cognitive decline.
{"title":"Loss of white matter integrity mediates the association between cortical cerebral microinfarcts and cognitive dysfunction: A longitudinal study.","authors":"Jiannan Huang, Megan Oh, Caroline Robert, Xiangyuan Huang, Marco Egle, Daniel J Tozer, Christopher Chen, Saima Hilal","doi":"10.1177/0271678X241258563","DOIUrl":"10.1177/0271678X241258563","url":null,"abstract":"<p><p>Cortical cerebral microinfarcts (CMIs) are associated with loss of white matter (WM) integrity and cognitive impairment in cross-sectional studies, while further investigation using longitudinal datasets is required. This study aims to establish the association between cortical CMIs and WM integrity assessed by diffusion-tensor imaging (DTI) measures and to investigate whether DTI measures mediate the relationship between cortical CMIs and cognitive decline. Cortical CMIs were graded on 3T MRI. DTI measures were derived from histogram analysis of mean diffusivity (MD) and fractional anisotropy (FA). Cognitive function was assessed using a neuropsychological test battery. Linear mixed-effect models were employed to examine associations of cortical CMIs with longitudinal changes in DTI measures and cognitive function. Final analysis included 231 patients (71.14 ± 7.60 years). Presence of cortical CMIs at baseline was associated with longitudinal changes in MD median and peak height and FA median and peak height, as well as global cognition (β = -0.50, 95%CI: -0.91, -0.09) and executive function (β = -0.77, 95%CI: -1.25, -0.28). MD median mediated the cross-sectional association between cortical CMIs and global cognition. Further studies are required to investigate whether cortical CMIs and loss of WM integrity are causally related or if they are parallel mechanisms that contribute to cognitive decline.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141155236","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 : 2024-10-01Epub Date: 2024-03-28DOI: 10.1177/0271678X241241907
Annabel J Sorby-Adams, Oana C Marian, Isabella M Bilecki, Levi E Elms, Nawaf Yassi, Rebecca J Hood, Janet K Coller, Shannon M Stuckey, W Taylor Kimberly, Tracy D Farr, Anna V Leonard, Emma Thornton, Robert Vink, Renée J Turner
Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (n = 24) were subject to 2-hours tMCAo and randomized (n = 6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.
{"title":"NK1 tachykinin receptor antagonist treatment reduces cerebral edema and intracranial pressure in an ovine model of ischemic stroke.","authors":"Annabel J Sorby-Adams, Oana C Marian, Isabella M Bilecki, Levi E Elms, Nawaf Yassi, Rebecca J Hood, Janet K Coller, Shannon M Stuckey, W Taylor Kimberly, Tracy D Farr, Anna V Leonard, Emma Thornton, Robert Vink, Renée J Turner","doi":"10.1177/0271678X241241907","DOIUrl":"10.1177/0271678X241241907","url":null,"abstract":"<p><p>Following ischemic stroke, substance P (SP)-mediated neurogenic inflammation is associated with profound blood-brain barrier (BBB) dysfunction, cerebral edema, and elevated intracranial pressure (ICP). SP elicits its effects by binding the neurokinin 1 tachykinin receptor (NK1-R), with administration of an NK1-R antagonist shown to ameliorate BBB dysfunction and cerebral edema in rodent and permanent ovine stroke models. Given the importance of reperfusion in clinical stroke, this study examined the efficacy of NK1-R antagonist treatment in reducing cerebral edema and ICP in an ovine model of transient middle cerebral artery occlusion (tMCAo). Anesthetized sheep (<i>n = </i>24) were subject to 2-hours tMCAo and randomized (<i>n = </i>6/group) to receive early NK1-R treatment (days 1-3 post-stroke), delayed NK1-R treatment (day 5 post-stroke), or saline vehicle. At 6-days post-stroke animals were re-anaesthetized and ICP measured, followed by MRI to evaluate infarction, edema and BBB dysfunction. Following both early and delayed NK1-R antagonist administration, ICP was significantly reduced on day 6 compared to vehicle animals (p < 0.05), accompanied by a reduction in cerebral edema, midline shift and BBB dysfunction (p < 0.05). This study demonstrates that NK1-R antagonist treatment is an effective novel therapy for cerebral edema and elevated ICP following stroke in an ovine model, warranting future clinical evaluation.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305755","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 : 2024-10-01Epub Date: 2024-05-10DOI: 10.1177/0271678X241254772
Harshal Sawant, Bowen Sun, Erin Mcgrady, Ji Chen Bihl
MicroRNAs (miRNA) are endogenously produced small, non-coded, single-stranded RNAs. Due to their involvement in various cellular processes and cross-communication with extracellular components, miRNAs are often coined the "grand managers" of the cell. miRNAs are frequently involved in upregulation as well as downregulation of specific gene expression and thus, are often found to play a vital role in the pathogenesis of multiple diseases. Central nervous system (CNS) diseases prove fatal due to the intricate nature of both their development and the methods used for treatment. A considerable amount of ongoing research aims to delineate the complex relationships between miRNAs and different diseases, including each of the neurological disorders discussed in the present review. Ongoing research suggests that specific miRNAs can play either a pathologic or restorative and/or protective role in various CNS diseases. Understanding how these miRNAs are involved in various regulatory processes of CNS such as neuroinflammation, neurovasculature, immune response, blood-brain barrier (BBB) integrity and angiogenesis is of empirical importance for developing effective therapies. Here in this review, we summarized the current state of knowledge of miRNAs and their roles in CNS diseases along with a focus on their association with neuroinflammation, innate immunity, neurovascular function and BBB.
{"title":"Role of miRNAs in neurovascular injury and repair.","authors":"Harshal Sawant, Bowen Sun, Erin Mcgrady, Ji Chen Bihl","doi":"10.1177/0271678X241254772","DOIUrl":"10.1177/0271678X241254772","url":null,"abstract":"<p><p>MicroRNAs (miRNA) are endogenously produced small, non-coded, single-stranded RNAs. Due to their involvement in various cellular processes and cross-communication with extracellular components, miRNAs are often coined the \"grand managers\" of the cell. miRNAs are frequently involved in upregulation as well as downregulation of specific gene expression and thus, are often found to play a vital role in the pathogenesis of multiple diseases. Central nervous system (CNS) diseases prove fatal due to the intricate nature of both their development and the methods used for treatment. A considerable amount of ongoing research aims to delineate the complex relationships between miRNAs and different diseases, including each of the neurological disorders discussed in the present review. Ongoing research suggests that specific miRNAs can play either a pathologic or restorative and/or protective role in various CNS diseases. Understanding how these miRNAs are involved in various regulatory processes of CNS such as neuroinflammation, neurovasculature, immune response, blood-brain barrier (BBB) integrity and angiogenesis is of empirical importance for developing effective therapies. Here in this review, we summarized the current state of knowledge of miRNAs and their roles in CNS diseases along with a focus on their association with neuroinflammation, innate immunity, neurovascular function and BBB.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494855/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140898356","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 : 2024-10-01Epub Date: 2024-06-16DOI: 10.1177/0271678X241261942
Basavaraju G Sanganahalli, Jelena M Mihailovic, Hemendra J Vekaria, Daniel Coman, Andrew T Yackzan, Abeoseh Flemister, Chetan Aware, Kathryn Wenger, W Brad Hubbard, Patrick G Sullivan, Fahmeed Hyder, Ai-Ling Lin
Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer's disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using in vivo1H-[13C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.
{"title":"mTOR inhibition enhances synaptic and mitochondrial function in Alzheimer's disease in an APOE genotype-dependent manner.","authors":"Basavaraju G Sanganahalli, Jelena M Mihailovic, Hemendra J Vekaria, Daniel Coman, Andrew T Yackzan, Abeoseh Flemister, Chetan Aware, Kathryn Wenger, W Brad Hubbard, Patrick G Sullivan, Fahmeed Hyder, Ai-Ling Lin","doi":"10.1177/0271678X241261942","DOIUrl":"10.1177/0271678X241261942","url":null,"abstract":"<p><p>Apolipoprotein ε4 (APOE4) carriers develop brain metabolic dysfunctions decades before the onset of Alzheimer's disease (AD). A goal of the study is to identify if rapamycin, an inhibitor for the mammalian target of rapamycin (mTOR) inhibitor, would enhance synaptic and mitochondrial function in asymptomatic mice with human APOE4 gene (E4FAD) before they showed metabolic deficits. A second goal is to determine whether there may be genetic-dependent responses to rapamycin when compared to mice with human APOE3 alleles (E3FAD), a neutral AD genetic risk factor. We fed asymptomatic E4FAD and E3FAD mice with control or rapamycin diets for 16 weeks from starting from 3 months of age. Neuronal mitochondrial oxidative metabolism and excitatory neurotransmission rates were measured using <i>in vivo</i> <sup>1</sup>H-[<sup>13</sup>C] proton-observed carbon-edited magnetic resonance spectroscopy, and isolated mitochondrial bioenergetic measurements using Seahorse. We found that rapamycin enhanced neuronal mitochondrial function, glutamate-glutamine cycling, and TCA cycle rates in the asymptomatic E4FAD mice. In contrast, rapamycin enhances glycolysis, non-neuronal activities, and inhibitory neurotransmission of the E3FAD mice. These findings indicate that rapamycin might be able to mitigate the risk for AD by enhancing brain metabolic functions for cognitively intact APOE4 carriers, and the responses to rapamycin are varied by APOE genotypes. Consideration of precision medicine may be needed for future rapamycin therapeutics.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494852/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141327544","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 : 2024-10-01Epub Date: 2024-06-04DOI: 10.1177/0271678X241251976
Xiaolong Ya, Long Ma, Hao Li, Peicong Ge, Zhiyao Zheng, Siqi Mou, Chenglong Liu, Yan Zhang, Rong Wang, Qian Zhang, Xun Ye, Dong Zhang, Jizong Zhao
Carotid atherosclerosis is a major cause of stroke. Hemodynamic forces, such as shear stress and oscillatory shear, play an important role in the initiation and progression of atherosclerosis. The alteration of the immune microenvironment is the fundamental pathological mechanism by which diverse external environmental factors impact the formation and progression of plaques. However, Current research on the relationship between hemodynamics and immunity in atherosclerosis still lack of comprehensive understanding. In this study, we combined computational fluid dynamics (CFD) and Mass cytometry (CyTOF) technologies to explore the changes in the immune microenvironment within plaques under different hemodynamic conditions. Our results indicated that neutrophils were enriched in adverse flow environments. M2-like CD163+CD86+ macrophages were predominantly enriched in high WSS and low OSI environments, while CD163-CD14+ macrophages were enriched in low WSS and high OSI environments. Functional analysis further revealed T cell pro-inflammatory activation and dysregulation in modulation, along with an imbalance in M1-like/M2-like macrophages, suggesting their potential involvement in the progression of atherosclerotic lesions mediated by adverse flow patterns. Our study elucidated the potential mechanisms by which hemodynamics regulated the immune microenvironment within plaques, providing intervention targets for future precision therapies.
{"title":"Exploring the relationship between hemodynamics and the immune microenvironment in carotid atherosclerosis: Insights from CFD and CyTOF technologies.","authors":"Xiaolong Ya, Long Ma, Hao Li, Peicong Ge, Zhiyao Zheng, Siqi Mou, Chenglong Liu, Yan Zhang, Rong Wang, Qian Zhang, Xun Ye, Dong Zhang, Jizong Zhao","doi":"10.1177/0271678X241251976","DOIUrl":"10.1177/0271678X241251976","url":null,"abstract":"<p><p>Carotid atherosclerosis is a major cause of stroke. Hemodynamic forces, such as shear stress and oscillatory shear, play an important role in the initiation and progression of atherosclerosis. The alteration of the immune microenvironment is the fundamental pathological mechanism by which diverse external environmental factors impact the formation and progression of plaques. However, Current research on the relationship between hemodynamics and immunity in atherosclerosis still lack of comprehensive understanding. In this study, we combined computational fluid dynamics (CFD) and Mass cytometry (CyTOF) technologies to explore the changes in the immune microenvironment within plaques under different hemodynamic conditions. Our results indicated that neutrophils were enriched in adverse flow environments. M2-like CD163+CD86+ macrophages were predominantly enriched in high WSS and low OSI environments, while CD163-CD14+ macrophages were enriched in low WSS and high OSI environments. Functional analysis further revealed T cell pro-inflammatory activation and dysregulation in modulation, along with an imbalance in M1-like/M2-like macrophages, suggesting their potential involvement in the progression of atherosclerotic lesions mediated by adverse flow patterns. Our study elucidated the potential mechanisms by which hemodynamics regulated the immune microenvironment within plaques, providing intervention targets for future precision therapies.</p>","PeriodicalId":15325,"journal":{"name":"Journal of Cerebral Blood Flow and Metabolism","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141247836","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}