Journal of Cerebral Blood Flow & Metabolism最新文献_第7页

Clinical relevance of asymptomatic intracerebral hemorrhage post thrombectomy depends on angiographic collateral score 血栓切除术后无症状脑出血的临床相关性取决于血管造影侧支评分

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-08-01 DOI: 10.1177/0271678X19871253

J. Nawabi, H. Kniep, G. Broocks, T. Faizy, G. Schön, G. Thomalla, J. Fiehler, U. Hanning

Asymptomatic intracerebral hemorrhage (aICH) is a common phenomenon in patients with acute ischemic stroke (AIS) treated with endovascular thrombectomy (ET). However, the impact of aICH on the functional outcome remains widely unclear. In this study, we aimed at identifying predictors for aICH and analyzing its impact on functional outcome. Patients with AIS due to large artery occlusion in the anterior circulation treated with successful ET were enrolled in a tertiary stroke center. Patients with aICH or without intracerebral hemorrhage were included according to post-treatment CT performed within 72 h; 100 consecutive patients fulfilled the inclusion criteria and 30% classified with aICH. In logistic regression analysis, lower collateral score (OR 0.24; 95% CI 0.12–0.46, p < 0.0001) was significantly associated with aICH. Less patients with aICH achieved an independent outcome (mRS 0–2, 16.7% vs. 44.3%, p = 0.007). Poor outcome (mRS 4–6) was significantly higher in patients with aICH (41.4% vs. 70%, p = 0.021). Patients with aICH had a lower ratio of independent outcome (OR 0.23, 95% CI 0.05–0.1.05, p = 0.041) than without ICH. There were no differences concerning poor outcome (p = 0.5). Lower collateral status was a strong independent predictor for aICH. aICH after successful ET may decrease the likelihood of an independent functional outcome without influencing poor outcome.

无症状脑出血(aICH)是急性缺血性卒中(AIS)行血管内取栓术(ET)的常见现象。然而，aICH对功能结果的影响仍不清楚。在这项研究中，我们旨在确定aICH的预测因素并分析其对功能结局的影响。经ET治疗成功的前循环大动脉闭塞导致AIS的患者被纳入三级卒中中心。根据治疗后72h内CT检查纳入有aICH或无脑出血的患者;连续100例患者符合纳入标准，其中30%为aICH。logistic回归分析中，侧支评分较低(OR 0.24;95% CI 0.12-0.46, p < 0.0001)与aICH显著相关。获得独立结局的aICH患者较少(mRS 0-2, 16.7%比44.3%，p = 0.007)。不良预后(mRS 4-6)在aICH患者中明显较高(41.4%比70%，p = 0.021)。缺血性脑出血患者的独立结局比(OR 0.23, 95% CI 0.05-0.1.05, p = 0.041)低于非缺血性脑出血患者。在不良预后方面没有差异(p = 0.5)。较低的侧支状态是aICH强有力的独立预测因子。ET成功后的急性脑出血可能会降低独立功能预后的可能性，但不会影响不良预后。

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引用次数: 16

Vasomotor influences on glymphatic-lymphatic coupling and solute trafficking in the central nervous system 血管舒缩对中枢神经系统淋巴-淋巴偶联和溶质运输的影响

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-08-01 DOI: 10.1177/0271678X19874134

James R Goodman, Jeffrey J. Iliff

Despite the recent description of meningeal lymphatic vessels draining solutes from the brain interstitium and cerebrospinal fluid (CSF), the physiological factors governing cranial lymphatic efflux remain largely unexplored. In agreement with recent findings, cervical lymphatic drainage of 70 kD and 2000 kD fluorescent tracers injected into the adult mouse cortex was significantly impaired in the anesthetized compared to waking animals (tracer distribution across 2.1 ± 4.5% and 23.7 ± 15.8% of deep cervical lymph nodes, respectively); however, free-breathing anesthetized mice were markedly hypercapnic and acidemic (paCO2 = 64 ± 8 mmHg; pH = 7.22 ± 0.05). Mechanical ventilation normalized arterial blood gases in anesthetized animals, and rescued lymphatic efflux of interstitial solutes in anesthetized mice. Experimental hypercapnia blocked cervical lymphatic efflux of intraparenchymal tracers. When tracers were injected into the subarachnoid CSF compartment, glymphatic influx into brain tissue was virtually abolished by hypercapnia, while lymphatic drainage was not appreciably altered. These findings demonstrate that cervical lymphatic drainage of interstitial solutes is, in part, regulated by upstream changes in glymphatic CSF-interstitial fluid exchange. Further, they suggest that maintaining physiological blood gas values in studies of glymphatic exchange and meningeal lymphatic drainage may be critical to defining the physiological regulation of these processes.

尽管最近描述了脑膜淋巴管从脑间质和脑脊液(CSF)中排出溶质，但控制颅淋巴流出的生理因素仍未得到充分研究。与最近的研究结果一致，与醒着的动物相比，注射70 kD和2000 kD荧光示踪剂的成年小鼠皮质在麻醉后颈部淋巴引流明显受损(示踪剂分布在2.1±4.5%和23.7±15.8%的颈深淋巴结);然而，自由呼吸麻醉小鼠明显高碳酸血症和酸性(paCO2 = 64±8 mmHg;pH = 7.22±0.05)。机械通气使麻醉动物的动脉血气正常化，并恢复麻醉小鼠间质溶质的淋巴外排。实验性高碳酸血症阻断了淋巴实质内示踪剂的颈部淋巴外排。当将示踪剂注射到蛛网膜下腔CSF室时，高碳酸血症几乎消除了进入脑组织的淋巴内流，而淋巴引流没有明显改变。这些发现表明，间质溶质的颈部淋巴引流在一定程度上受淋巴csf -间质液交换上游变化的调节。此外，他们认为在研究淋巴交换和脑膜淋巴引流时维持生理血气值可能对确定这些过程的生理调节至关重要。

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引用次数: 24

Cerebrovascular effects of endothelin-1 investigated using high-resolution magnetic resonance imaging in healthy volunteers 利用高分辨率磁共振成像技术研究内皮素-1对健康志愿者脑血管的影响

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-08-01 DOI: 10.1177/0271678X19874295

A. Hougaard, Samaira Younis, Afrim Iljazi, K. Haanes, U. Lindberg, Mark B. Vestergaard, F. Amin, K. Sugimoto, L. Kruse, C. Ayata, M. Ashina

Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO2) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO2. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.

内皮素-1 (ET-1)是一种从血管内皮中释放的高效血管收缩肽。ET-1在脑血管疾病中发挥重要作用，并可能通过血管收缩和脑血流量(CBF)减少而恶化急性缺血性卒中和动脉瘤性蛛网膜下腔出血的结局。高血压、糖尿病和急性心肌梗死等增加中风风险的疾病与血浆ET-1水平升高有关。全身ET-1输注对人体内脑血管的影响尚未被研究过。在双向交叉、随机、双盲设计中，我们使用先进的3特斯拉MRI方法研究了高剂量静脉注射ET-1对14名健康志愿者颅内内外动脉周长、整体和局部CBF以及脑氧代谢率(cro2)的影响。ET-1输注后，我们观察到平均动脉血压升高14%，大脑中动脉(MCA)周长降低5%，但对脑外动脉没有影响，对CBF或cmor2没有影响。总的来说，这些发现表明MCA收缩继发于血压升高，而不是由于ET-1的直接血管收缩作用。我们认为，与ET-1在蛛网膜下腔的作用相反，血管内ET-1对人类的脑血管没有直接作用。

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引用次数: 12

Distinct roles of ezrin, radixin and moesin in maintaining the plasma membrane localizations and functions of human blood–brain barrier transporters ezrin, radixin和moesin在维持人血脑屏障转运蛋白的质膜定位和功能中的独特作用

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-07-01 DOI: 10.1177/0271678X19868880

Yutaro Hoshi, Yasuo Uchida, T. Kuroda, M. Tachikawa, P. Couraud, Takashi Suzuki, T. Terasaki

The purpose of this study was to clarify the roles of ERM proteins (ezrin/radixin/moesin) in the regulation of membrane localization and transport activity of transporters at the human blood–brain barrier (BBB). Ezrin or moesin knockdown in a human in vitro BBB model cell line (hCMEC/D3) reduced both BCRP and GLUT1 protein expression levels on the plasma membrane. Radixin knockdown reduced not only BCRP and GLUT1, but also P-gp membrane expression. These results indicate that P-gp, BCRP and GLUT1 proteins are maintained on the plasma membrane via different ERM proteins. Furthermore, moesin knockdown caused the largest decrease of P-gp and BCRP efflux activity among the ERM proteins, whereas GLUT1 influx activity was similarly reduced by knockdown of each ERM protein. To investigate how moesin knockdown reduced P-gp efflux activity without loss of P-gp from the plasma membrane, we examined the role of PKCβI. PKCβI increased P-gp phosphorylation and reduced P-gp efflux activity. Radixin and moesin proteins were detected in isolated human brain capillaries, and their protein abundances were within a 3-fold range, compared with those in hCMEC/D3 cell line. These findings may mean that ezrin, radixin and moesin maintain the functions of different transporters in different ways at the human BBB.

本研究的目的是阐明ERM蛋白(ezrin/radixin/moesin)在调节人血脑屏障(BBB)转运蛋白的膜定位和转运活性中的作用。在体外血脑屏障模型细胞系(hCMEC/D3)中，Ezrin或moesin敲低可降低质膜上BCRP和GLUT1蛋白的表达水平。radxin的下调不仅降低了BCRP和GLUT1的表达，还降低了P-gp膜的表达。这些结果表明，P-gp、BCRP和GLUT1蛋白通过不同的ERM蛋白维持在质膜上。此外，moesin敲低引起ERM蛋白中P-gp和BCRP外排活性的最大下降，而GLUT1内流活性也同样因敲低ERM蛋白而降低。为了研究moesin敲除如何在不损失P-gp的情况下降低P-gp外排活性，我们研究了PKCβI的作用。pkc β 1增加P-gp磷酸化，降低P-gp外排活性。在离体人脑毛细血管中检测到Radixin和moesin蛋白，与hCMEC/D3细胞系相比，其蛋白丰度在3倍范围内。这些发现可能意味着ezrin, radixin和moesin在人类血脑屏障中以不同的方式维持不同转运蛋白的功能。

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引用次数: 16

Higher cardiovascular fitness level is associated with lower cerebrovascular reactivity and perfusion in healthy older adults. 在健康的老年人中，较高的心血管健康水平与较低的脑血管反应性和灌注量有关。

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-07-01 Epub Date: 2019-07-25 DOI: 10.1177/0271678X19862873

Brittany Intzandt, Dalia Sabra, Catherine Foster, Laurence Desjardins-Crépeau, Richard D Hoge, Christopher J Steele, Louis Bherer, Claudine J Gauthier

Aging is accompanied by vascular and structural changes in the brain, which include decreased grey matter volume (GMV), cerebral blood flow (CBF), and cerebrovascular reactivity (CVR). Enhanced fitness in aging has been related to preservation of GMV and CBF, and in some cases CVR, although there are contradictory relationships reported between CVR and fitness. To gain a better understanding of the complex interplay between fitness and GMV, CBF and CVR, the present study assessed these factors concurrently. Data from 50 participants, aged 55 to 72, were used to derive GMV, CBF, CVR and VO₂peak. Results revealed that lower CVR was associated with higher VO₂peak throughout large areas of the cerebral cortex. Within these regions lower fitness was associated with higher CBF and a faster hemodynamic response to hypercapnia. Overall, our results indicate that the relationships between age, fitness, cerebral health and cerebral hemodynamics are complex, likely involving changes in chemosensitivity and autoregulation in addition to changes in arterial stiffness. Future studies should collect other physiological outcomes in parallel with quantitative imaging, such as measures of chemosensitivity and autoregulation, to further understand the intricate effects of fitness on the aging brain, and how this may bias quantitative measures of cerebral health.

衰老伴随着大脑血管和结构的变化，包括灰质体积（GMV）、脑血流量（CBF）和脑血管反应性（CVR）的下降。衰老过程中体能的增强与 GMV 和 CBF 的保持有关，在某些情况下还与 CVR 有关，但 CVR 与体能之间的关系报道相互矛盾。为了更好地了解体能与 GMV、CBF 和 CVR 之间复杂的相互作用，本研究同时对这些因素进行了评估。本研究使用了 50 名年龄在 55 岁至 72 岁之间的参与者的数据来推导 GMV、CBF、CVR 和 VO2 峰值。结果显示，在大脑皮层的大部分区域，较低的 CVR 与较高的 VO2 峰值相关。在这些区域内，较低的体能与较高的 CBF 和对高碳酸血症更快的血液动力学反应有关。总之，我们的研究结果表明，年龄、体能、大脑健康和大脑血流动力学之间的关系是复杂的，除了动脉僵化的变化外，可能还涉及化学敏感性和自动调节的变化。未来的研究应在定量成像的同时收集其他生理结果，如化学敏感性和自动调节的测量结果，以进一步了解体能对衰老大脑的复杂影响，以及这可能对大脑健康的定量测量产生的偏差。

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引用次数: 0

Calibrated fMRI for dynamic mapping of CMRO2 responses using MR-based measurements of whole-brain venous oxygen saturation 校准的fMRI动态映射cmoro2反应使用基于核磁共振测量全脑静脉氧饱和度

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-07-01 DOI: 10.1177/0271678X19867276

Erin K. Englund, M. Fernández-Seara, Ana E. Rodriguez-Soto, Hyunyeol Lee, Zachary B. Rodgers, M. Vidorreta, J. Detre, F. Wehrli

Functional MRI (fMRI) can identify active foci in response to stimuli through BOLD signal fluctuations, which represent a complex interplay between blood flow and cerebral metabolic rate of oxygen (CMRO2) changes. Calibrated fMRI can disentangle the underlying contributions, allowing quantification of the CMRO2 response. Here, whole-brain venous oxygen saturation (Y v ) was computed alongside ASL-measured CBF and BOLD-weighted data to derive the calibration constant, M, using the proposed Y v -based calibration. Data were collected from 10 subjects at 3T with a three-part interleaved sequence comprising background-suppressed 3D-pCASL, 2D BOLD-weighted, and single-slice dual-echo GRE (to measure Y v via susceptometry-based oximetry) acquisitions while subjects breathed normocapnic/normoxic, hyperoxic, and hypercapnic gases, and during a motor task. M was computed via Y v -based calibration from both hypercapnia and hyperoxia stimulus data, and results were compared to conventional hypercapnia or hyperoxia calibration methods. Mean M in gray matter did not significantly differ between calibration methods, ranging from 8.5 ± 2.8% (conventional hyperoxia calibration) to 11.7 ± 4.5% (Yv-based calibration in response to hyperoxia), with hypercapnia-based M values between (p = 0.56). Relative CMRO2 changes from finger tapping were computed from each M map. CMRO2 increased by ∼20% in the motor cortex, and good agreement was observed between the conventional and proposed calibration methods.

功能磁共振成像(fMRI)可以通过BOLD信号波动识别对刺激反应的活动病灶，BOLD信号波动代表了血流量和脑氧代谢率(cro2)变化之间的复杂相互作用。校准的功能磁共振成像可以解开潜在的贡献，允许量化cmor2反应。在这里，计算全脑静脉氧饱和度(Y v)与asl测量的CBF和bold加权数据一起，使用提出的基于Y v的校准，得出校准常数M。数据来自10名受试者，在3T时，当受试者呼吸正氧/正氧、高氧和高氧气体时，通过三部分交错序列收集数据，包括背景抑制的3D-pCASL、2D bold加权和单层双回波GRE(通过基于电纳的氧饱和度测量Y v)采集。根据高碳酸血症和高氧刺激数据，通过基于Y v的校准计算M，并将结果与传统的高碳酸血症或高氧校准方法进行比较。两种校准方法之间灰质的平均M值无显著差异，从8.5±2.8%(常规高氧校准)到11.7±4.5%(高氧条件下基于yv的校准)，基于高氧的M值介于两者之间(p = 0.56)。从每个M图中计算手指轻敲引起的相对cro2变化。运动皮层中的cmoro2增加了~ 20%，在常规校准方法和提出的校准方法之间观察到良好的一致性。

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引用次数: 6

Within-lesion heterogeneity of subcortical DWI lesion evolution, and stroke outcome: A voxel-based analysis 皮质下DWI病变演变和脑卒中结局的病变内异质性:基于体素的分析

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-07-01 DOI: 10.1177/0271678X19865916

M. Duering, Ruth Adam, F. Wollenweber, Anna Bayer-Karpinska, E. Baykara, Leidy Y Cubillos-Pinilla, B. Gesierich, M. Á. Araque Caballero, Sophia Stoecklein, M. Ewers, O. Pasternak, M. Dichgans

The fate of subcortical diffusion-weighted imaging (DWI) lesions in stroke patients is highly variable, ranging from complete tissue loss to no visible lesion on follow-up. Little is known about within-lesion heterogeneity and its relevance for stroke outcome. Patients with subcortical stroke and recruited through the prospective DEDEMAS study (NCT01334749) were examined at baseline (n = 45), six months (n = 45), and three years (n = 28) post-stroke. We performed high-resolution structural MRI including DWI. Tissue fate was determined voxel-wise using fully automated tissue segmentation. Within-lesion heterogeneity at baseline was assessed by free water diffusion imaging measures. The majority of DWI lesions (66%) showed cavitation on six months follow-up but the proportion of tissue turning into a cavity was small (9 ± 13.5% of the DWI lesion). On average, 69 ± 25% of the initial lesion resolved without any visually apparent signal abnormality. The extent of cavitation at six months post-stroke was independently associated with clinical outcome, i.e. modified Rankin scale score at six months (OR = 4.71, p = 0.005). DWI lesion size and the free water-corrected tissue mean diffusivity at baseline independently predicted cavitation. In conclusion, the proportion of cavitating tissue is typically small, but relevant for clinical outcome. Within-lesion heterogeneity at baseline on advanced diffusion imaging is predictive of tissue fate.

脑卒中患者皮质下弥散加权成像(DWI)病变的命运是高度可变的，从完全的组织丢失到随访时没有可见的病变。我们对病变内异质性及其与脑卒中预后的相关性知之甚少。通过前瞻性DEDEMAS研究(NCT01334749)招募的皮质下脑卒中患者在脑卒中后基线(n = 45)、6个月(n = 45)和3年(n = 28)进行了检查。我们进行了高分辨率结构MRI包括DWI。使用全自动组织分割确定组织命运体素。通过自由水扩散成像措施评估基线时病变内异质性。多数DWI病变(66%)在随访6个月时出现空化，但组织变为空化的比例很小(占DWI病变的9±13.5%)。平均69±25%的初始病变消失，无任何明显的视觉信号异常。脑卒中后6个月的空化程度与临床结果独立相关，即6个月时的改良Rankin量表评分(OR = 4.71, p = 0.005)。DWI病变大小和自由水校正组织的基线平均扩散率独立预测空化。总之，空化组织的比例通常很小，但与临床结果有关。病灶内弥散成像基线异质性可预测组织预后。

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引用次数: 10

Changes in volumetric and metabolic parameters relate to differences in exposure to sub-concussive head impacts. 体积和代谢参数的变化与头部受到亚撞击的程度不同有关。

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-07-01 Epub Date: 2019-07-15 DOI: 10.1177/0271678X19862861

Allen A Champagne, Nicole S Coverdale, Mike Germuska, Alex A Bhogal, Douglas J Cook

Structural and calibrated magnetic resonance imaging data were acquired on 44 collegiate football players prior to the season (PRE), following the first four weeks in-season (PTC) and one month after the last game (POST). Exposure data collected from g-Force accelerometers mounted to the helmet of each player were used to split participants into HIGH (N = 22) and LOW (N = 22) exposure groups, based on the frequency of impacts sustained by each athlete. Significant decreases in grey-matter volume specific to the HIGH group were documented at POST (P = 0.009), compared to baseline. Changes in resting cerebral blood flow (CBF₀), corrected for partial volume effects, were observed within the HIGH group, throughout the season (P < 0.0001), suggesting that alterations in perfusion may follow exposure to sub-concussive collisions. Co-localized significant increases in cerebral metabolic rate of oxygen consumption (CMRO₂|₀) mid-season were also documented in the HIGH group, with respect to both PRE- and POST values. No physiological changes were observed in the LOW group. Therefore, cerebral metabolic demand may be elevated in players with greater exposure to head impacts. These results provide novel insight into the effects of sub-concussive collisions on brain structure and cerebrovascular physiology and emphasize the importance of multi-modal imaging for a complete characterization of cerebral health.

在赛季前（PRE）、赛季前四周（PTC）和最后一场比赛后一个月（POST），对 44 名大学橄榄球运动员进行了结构和校准磁共振成像数据采集。通过安装在每位运动员头盔上的加速度计收集到的暴露数据，根据每位运动员受到冲击的频率，将参与者分为高暴露组（22 人）和低暴露组（22 人）。与基线相比，高暴露组的灰质体积在暴露后明显减少（P = 0.009）。在整个赛季中（P 2|0），在高分组中观察到了静息脑血流量（CBF0）的变化，并对部分体积效应进行了校正。低组未观察到生理变化。因此，受到头部撞击较多的球员的脑代谢需求可能会升高。这些结果为了解亚撞击对大脑结构和脑血管生理学的影响提供了新的视角，并强调了多模态成像对全面描述大脑健康状况的重要性。

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引用次数: 0

Physiologic predictors of collateral circulation and infarct growth during anesthesia – Detailed analyses of the GOLIATH trial 麻醉期间侧支循环和梗死生长的生理预测因素- GOLIATH试验的详细分析

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-06-01 DOI: 10.1177/0271678X19865219

R. Raychev, D. Liebeskind, A. Yoo, M. Rasmussen, D. Arnaudov, Scott C. Brown, J. Saver, C. Simonsen

Collateral circulation plays a pivotal role in acute ischemic stroke due to large vessel occlusion (LVO) and may be affected by multiple variables during sedation for endovascular therapy (EVT). We conducted detailed analyses of the GOLIATH trial to identify predictors of collateral circulation grade and infarct growth. We also modified the ASITN collateral grading scale and sought to determine its impact on clinical outcome and infarct growth. Multivariable analysis was used to identify predictors of collaterals and infarct growth. Ordinal analysis demonstrated nominal, but non-significant association between modified ASITN scale and infarct growth. Among all analyzed baseline clinical and procedural variables, the most significant predictors of infarct growth at 24 h were phenylephrine dose (estimate 6.78; p = 0.014) and baseline infarct volume (estimate 0.93; p = 0.03). The most significant predictors of worse collateral grade were mean arterial pressure (MAP) <70 mmHg (OR 0.35; p = 0.048) and baseline infarct volume (OR 0.96; p = 0.003). Hypotension during sedation for EVT for LVO negatively impacts collateral circulation, while higher pressor dose is a strong predictor of infarct growth. Avoidance of anesthesia-induced hypotension and consequent need for pressor therapy may prevent collateral failure and minimize infarct growth.

侧支循环在大血管闭塞(LVO)引起的急性缺血性卒中中起着关键作用，在血管内镇静治疗(EVT)过程中可能受到多种因素的影响。我们对GOLIATH试验进行了详细的分析，以确定侧枝循环分级和梗死生长的预测因子。我们还修改了ASITN侧支分级量表，并试图确定其对临床结果和梗死生长的影响。多变量分析用于确定侧枝和梗死生长的预测因子。顺序分析显示，修改后的ASITN量表与梗死生长之间存在名义上但不显著的关联。在所有分析的基线临床和程序变量中，24小时梗死生长最显著的预测因子是苯肾上腺素剂量(估计6.78;P = 0.014)和基线梗死面积(估计0.93;p = 0.03)。侧支血管等级较差的最显著预测因子是平均动脉压(MAP) <70 mmHg (OR 0.35;p = 0.048)和基线梗死体积(OR 0.96;p = 0.003)。LVO EVT镇静期间的低血压会对侧支循环产生负面影响，而较高的加压剂量是梗死生长的有力预测因子。避免麻醉引起的低血压和随后的降压治疗可以防止侧支衰竭和减少梗死的增长。

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引用次数: 26

Brain endothelial specific gene therapy improves experimental Sandhoff disease 脑内皮特异性基因治疗改善实验性山德霍夫病

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-06-01 DOI: 10.1177/0271678X19865917

Godwin K. Dogbevia, H. Grasshoff, A. Othman, Anke Penno, M. Schwaninger

In Tay-Sachs and Sandhoff disease, a deficiency of the lysosomal enzyme β-hexosaminidase causes GM2 and other gangliosides to accumulate in neurons and triggers neurodegeneration. Although the pathology centers on neurons, β-hexosaminidase is mainly expressed outside of neurons, suggesting that gene therapy of these diseases should target non-neuronal cells to reconstitute physiological conditions. Here, we tested in Hexb−/− mice, a model of Sandhoff disease, to determine whether endothelial expression of the genes for human β-hexosaminidase subunit A and B (HEXA, HEXB) is able to reduce disease symptoms and prolong survival of the affected mice. The brain endothelial selective vectors AAV-BR1-CAG-HEXA and AAV-BR1-CAG-HEXB transduced brain endothelial cells, which subsequently released β-hexosaminidase enzyme. In vivo intravenous administration of the gene vectors to adult and neonatal mice prolonged survival. They improved neurological function and reduced accumulation of the ganglioside GM2 and the glycolipid GA2 as well as astrocytic activation. Overall, the data demonstrate that endothelial cells are a suitable target for intravenous gene therapy of GM2 gangliosidoses and possibly other lysosomal storage disorders.

在Tay-Sachs病和Sandhoff病中，溶酶体酶β-己糖氨酸酶缺乏导致GM2和其他神经节苷类物质在神经元中积聚并引发神经变性。虽然病理以神经元为中心，但β-己糖氨酸酶主要在神经元外表达，提示这些疾病的基因治疗应针对非神经元细胞来重建生理状况。在这里，我们在Sandhoff病模型Hexb - / -小鼠中进行了测试，以确定内皮表达人β-己糖氨酸酶亚基a和B (HEXA, Hexb)基因是否能够减轻疾病症状并延长受影响小鼠的生存期。脑内皮选择载体AAV-BR1-CAG-HEXA和AAV-BR1-CAG-HEXB转导脑内皮细胞，随后释放β-己糖氨酸酶。成年和新生小鼠体内静脉注射基因载体延长了存活时间。它们改善了神经功能，减少了神经节苷脂GM2和糖脂GA2的积累以及星形胶质细胞的激活。总的来说，这些数据表明内皮细胞是静脉注射GM2神经节脂质剂量和其他溶酶体储存疾病基因治疗的合适靶点。

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引用次数: 14