Journal of Cerebral Blood Flow & Metabolism最新文献_第4页

Temporal brain transcriptome analysis reveals key pathological events after germinal matrix hemorrhage in neonatal rats 颞叶脑转录组分析揭示了新生大鼠生发基质出血后的关键病理事件

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-05-01 DOI: 10.1177/0271678X221098811

Juan Song, Gisela Nilsson, Yiran Xu, Aura Zelco, Eridan Rocha-Ferreira, Yafeng Wang, Xiaoli Zhang, Shan Zhang, J. Ek, H. Hagberg, Changlian Zhu, Xiaoyang Wang

Germinal matrix hemorrhage (GMH) is a common complication in preterm infants and is associated with high risk of adverse neurodevelopmental outcomes. We used a rat GMH model and performed RNA sequencing to investigate the signaling pathways and biological processes following hemorrhage. GMH induced brain injury characterized by early hematoma and subsequent tissue loss. At 6 hours after GMH, gene expression indicated an increase in mitochondrial activity such as ATP metabolism and oxidative phosphorylation along with upregulation of cytoprotective pathways and heme metabolism. At 24 hours after GMH, the expression pattern suggested an increase in cell cycle progression and downregulation of neurodevelopmental-related pathways. At 72 hours after GMH, there was an increase in genes related to inflammation and an upregulation of ferroptosis. Hemoglobin components and genes related to heme metabolism and ferroptosis such as Hmox1, Alox15, and Alas2 were among the most upregulated genes. We observed dysregulation of processes involved in development, mitochondrial function, cholesterol biosynthesis, and inflammation, all of which contribute to neurodevelopmental deterioration following GMH. This study is the first temporal transcriptome profile providing a comprehensive overview of the molecular mechanisms underlying brain injury following GMH, and it provides useful guidance in the search for therapeutic interventions.

生发基质出血(GMH)是早产儿常见的并发症，并与不良神经发育结局的高风险相关。我们使用大鼠GMH模型并进行RNA测序来研究出血后的信号通路和生物学过程。GMH诱导的脑损伤以早期血肿和随后的组织损失为特征。GMH后6小时，基因表达表明线粒体活性增加，如ATP代谢和氧化磷酸化，细胞保护途径和血红素代谢上调。在GMH后24小时，表达模式表明细胞周期进程增加，神经发育相关通路下调。在GMH后72小时，与炎症相关的基因增加，铁下垂上调。血红蛋白成分及血红素代谢和铁下沉相关基因如Hmox1、Alox15、Alas2等表达上调最多。我们观察到涉及发育、线粒体功能、胆固醇生物合成和炎症的过程失调，所有这些都导致GMH后神经发育恶化。这项研究首次提供了GMH后脑损伤分子机制的全面概述，并为寻找治疗干预措施提供了有用的指导。

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引用次数: 6

The lateral entorhinal cortex is a hub for local and global dysfunction in early Alzheimer’s disease states 外侧内嗅皮层是早期阿尔茨海默病状态中局部和全局功能障碍的中心

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-04-25 DOI: 10.1177/0271678X221082016

F. Mandino, Ling Yun Yeow, Renzhe Bi, Lee Sejin, H. Bae, S. Baek, C. Lee, H. Mohammad, C. Horien, C. L. Teoh, Jasinda H. Lee, Mitchell KP Lai, Sangyong Jung, Yu Fu, M. Olivo, J. Gigg, J. Grandjean

Functional network activity alterations are one of the earliest hallmarks of Alzheimer’s disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice, thus, reveal a dichotomic hypo-connected:resting versus hyper-responsive:active phenotype. This strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related, early-AD deficits in humans.

功能网络活动的改变是阿尔茨海默病(AD)的最早标志之一，在淀粉样变和牛头病之前检测到。更好地了解这种网络改变的神经元基础可以为阿尔茨海默病的进展提供机制上的见解。在这里，我们检查了一个小鼠模型(3xTgAD小鼠)，再现了早期AD阶段。我们发现腹侧网络(包括内嗅皮层)的静息功能连通性丧失与人类报道的牛头病的空间分布一致。出乎意料的是，与休息时连通性下降相反，3xTgAD小鼠在光遗传学激活内嗅皮层后，在几个投射区域内显示出增强的fMRI信号。我们通过证明腹侧神经网络内的神经元易化和投射目标的突触高兴奋性证实了这一发现。因此，3xTgAD小鼠显示出两种低连接:静息型和高反应性:活跃型表型。受影响区域之间的这种强同伦性支持了这种病理生理模型在tau相关的人类早期ad缺陷中的可翻译性。

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引用次数: 3

Genetic ablation of smooth muscle KIR2.1 is inconsequential to the function of mouse cerebral arteries 平滑肌KIR2.1基因消融对小鼠脑动脉功能影响不大

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-04-11 DOI: 10.1177/0271678X221093432

Paulina M Kowalewska, J. Fletcher, W. Jackson, S. Brett, Michelle S Kim, G. Mironova, Nadia Haghbin, David M. Richter, N. Tykocki, M. Nelson, D. Welsh

Cerebral blood flow is a finely tuned process dependent on coordinated changes in arterial tone. These changes are strongly tied to smooth muscle membrane potential and inwardly rectifying K+ (KIR) channels are thought to be a key determinant. To elucidate the role of KIR2.1 in cerebral arterial tone development, this study examined the electrical and functional properties of cells, vessels and living tissue from tamoxifen-induced smooth muscle cell (SMC)-specific KIR2.1 knockout mice. Patch-clamp electrophysiology revealed a robust Ba2+-sensitive inwardly rectifying K+ current in cerebral arterial myocytes irrespective of KIR2.1 knockout. Immunolabeling clarified that KIR2.1 expression was low in SMCs while KIR2.2 labeling was remarkably abundant at the membrane. In alignment with these observations, pressure myography revealed that the myogenic response and K+-induced dilation were intact in cerebral arteries post knockout. At the whole organ level, this translated to a maintenance of brain perfusion in SMC KIR2.1−/− mice, as assessed with arterial spin-labeling MRI. We confirmed these findings in superior epigastric arteries and implicated KIR2.2 as more functionally relevant in SMCs. Together, these results suggest that subunits other than KIR2.1 play a significant role in setting native current in SMCs and driving arterial tone.

脑血流是一个精细调节的过程，依赖于动脉张力的协调变化。这些变化与平滑肌膜电位密切相关，而向内整流的K+ (KIR)通道被认为是一个关键的决定因素。为了阐明KIR2.1在脑动脉张力发育中的作用，本研究检测了他莫昔芬诱导的平滑肌细胞(SMC)特异性KIR2.1敲除小鼠的细胞、血管和活组织的电学和功能特性。膜片钳电生理显示，无论KIR2.1基因敲除与否，脑动脉肌细胞中都存在强大的Ba2+敏感内向整流K+电流。免疫标记表明，KIR2.1在SMCs中的表达较低，而KIR2.2在膜上的表达显著丰富。与这些观察结果一致，压力肌图显示，敲除后脑动脉的肌原性反应和K+诱导的扩张是完整的。在整个器官水平上，通过动脉自旋标记MRI评估，这转化为SMC KIR2.1 - / -小鼠脑灌注的维持。我们在腹壁上动脉中证实了这些发现，并暗示KIR2.2在SMCs中具有更大的功能相关性。综上所述，这些结果表明，KIR2.1以外的亚基在SMCs中设定原生电流和驱动动脉张力方面发挥了重要作用。

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引用次数: 4

Thanks to Reviewers 感谢审稿人

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-04-11 DOI: 10.1177/0271678X221076492

引用次数: 0

Free-water diffusion MRI detects structural alterations surrounding white matter hyperintensities in the early stage of cerebral small vessel disease 自由水扩散MRI检测早期脑血管疾病白质高信号周围的结构改变

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-04-11 DOI: 10.1177/0271678X221093579

C. Mayer, Felix L. Nägele, M. Petersen, B. Frey, U. Hanning, O. Pasternak, E. Petersen, C. Gerloff, G. Thomalla, B. Cheng

In cerebral small vessel disease (CSVD), both white matter hyperintensities (WMH) of presumed vascular origin and the normal-appearing white matter (NAWM) contain microstructural brain alterations on diffusion-weighted MRI (DWI). Contamination of DWI-derived metrics by extracellular free-water can be corrected with free-water (FW) imaging. We investigated the alterations in FW and FW-corrected fractional anisotropy (FA-t) in WMH and surrounding tissue and their association with cerebrovascular risk factors. We analysed 1,000 MRI datasets from the Hamburg City Health Study. DWI was used to generate FW and FA-t maps. WMH masks were segmented on FLAIR and T1-weighted MRI and dilated repeatedly to create 8 NAWM masks representing increasing distance from WMH. Linear models were applied to compare FW and FA-t across WMH and NAWM masks and in association with cerebrovascular risk. Median age was 64 ± 14 years. FW and FA-t were altered 8 mm and 12 mm beyond WMH, respectively. Smoking was significantly associated with FW in NAWM (p = 0.008) and FA-t in WMH (p = 0.008) and in NAWM (p = 0.003) while diabetes and hypertension were not. Further research is necessary to examine whether FW and FA-t alterations in NAWM are predictors for developing WMH.

在脑小血管疾病(CSVD)中，弥散加权MRI (DWI)显示，推测血管起源的白质高信号(WMH)和正常的白质(NAWM)均包含脑微结构改变。细胞外自由水对dwi衍生指标的污染可以用自由水(FW)成像进行校正。我们研究了WMH和周围组织中FW和FW校正分数各向异性(FA-t)的变化及其与脑血管危险因素的关系。我们分析了来自汉堡城市健康研究的1000个核磁共振数据集。DWI生成FW和FA-t图。在FLAIR和t1加权MRI上对WMH掩膜进行分割，并反复扩张，形成8个NAWM掩膜，代表与WMH的距离越来越远。采用线性模型比较WMH和NAWM口罩的FW和FA-t及其与脑血管风险的关系。中位年龄64±14岁。FW和FA-t分别比WMH高8 mm和12 mm。吸烟与NAWM患者FW (p = 0.008)、WMH患者FA-t (p = 0.008)和NAWM患者FA-t (p = 0.003)有显著相关性，而糖尿病和高血压患者则无显著相关性。需要进一步研究NAWM中FW和FA-t的改变是否为WMH发生的预测因子。

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引用次数: 9

Altered glymphatic enhancement of cerebrospinal fluid tracer in individuals with chronic poor sleep quality 慢性睡眠质量差患者脑脊液示踪剂的淋巴增强改变

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-03-29 DOI: 10.1177/0271678X221090747

P. Eide, A. Pripp, Benedikte Berge, H. Hrubos-Strøm, G. Ringstad, L. Valnes

Chronic sleep disturbance is a risk factor for dementia disease, possibly due to impaired sleep-dependent clearance of toxic metabolic by-products. We compared enrichment of a cerebrospinal fluid (CSF) tracer within brain of patients reporting good or poor sleep quality, assessed by the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Tracer enrichment in a selection of brain regions was assessed using multiphase magnetic resonance imaging up to 48 hours after intrathecal administration of the contrast agent gadobutrol (0.5 ml of 1 mmol/ml) serving as tracer. Tracer enrichment differed between patients with good (PSQI ≤5) and poor (PSQI >5) sleep quality in a cohort of non-dementia individuals (n = 44; age 42.3 ± 14.5 years), and in patients with the dementia subtype idiopathic normal pressure hydrocephalus (n = 24; age 71.0 ± 4.9 years). Sleep impairment was associated with increased CSF tracer enrichment in several brain regions. Cortical brain volume as well as entorhinal cortex thickness was reduced in the oldest cohort and was correlated with the severity of sleep disturbance and the degree of cortical tracer enrichment. We suggest chronic sleep disturbance is accompanied by altered glymphatic function along enlarged perivascular spaces.

慢性睡眠障碍是痴呆症的一个危险因素，可能是由于睡眠依赖性对有毒代谢副产物的清除受损。通过匹兹堡睡眠质量指数(PSQI)问卷评估，我们比较了报告睡眠质量良好或较差的患者脑内脑脊液(CSF)示踪剂的丰富程度。在鞘内给予造影剂gadobutrol (0.5 ml / 1mmol /ml)作为示踪剂后48小时，使用多相磁共振成像评估示踪剂在选定脑区域的富集情况。在一组非痴呆个体中，睡眠质量好的(PSQI≤5)和睡眠质量差的(PSQI >5)患者的示踪剂富集程度存在差异(n = 44;年龄(42.3±14.5岁)，痴呆亚型特发性常压脑积水患者(n = 24;年龄(71.0±4.9岁)。睡眠障碍与脑脊液示踪剂在几个脑区富集增加有关。在年龄最大的队列中，皮质脑容量和内嗅皮质厚度减少，并与睡眠障碍的严重程度和皮质示踪剂富集程度相关。我们认为慢性睡眠障碍伴随着淋巴功能的改变以及血管周围空间的扩大。

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引用次数: 17

Cerebrovascular responses to somatomotor stimulation in Parkinson’s disease: A multivariate analysis 帕金森病患者对躯体运动刺激的脑血管反应:一项多变量分析

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-03-15 DOI: 10.1177/0271678X211065204

Sam C Barnes, R. Panerai, L. Beishon, M. Hanby, T. Robinson, V. Haunton

Parkinson’s disease (PD) is a common neurodegenerative disorder, yet little is known about cerebral haemodynamics in this patient population. Previous studies assessing dynamic cerebral autoregulation (dCA), neurovascular coupling (NVC) and vasomotor reactivity (VMR) have yielded conflicting findings. By using multi-variate modelling, we aimed to determine whether cerebral blood flow (CBF) regulation is impaired in PD patients. 55 healthy controls (HC) and 49 PD patients were recruited. PD subjects underwent a second recording following a period of abstinence from their anti-Parkinsonian medication. Continuous bilateral transcranial Doppler in the middle cerebral arteries, beat-to-beat mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram), and end-tidal CO2 (EtCO2; capnography) were measured. After a 5-min baseline period, a passive motor paradigm comprising 60 s of elbow flexion was performed. Multi-variate modelling quantified the contributions of MAP, ETCO2 and neural stimulation to changes in CBF velocity (CBFV). dCA, VMR and NVC were quantified to assess the integrity of CBF regulation. Neural stimulation was the dominant input. dCA, NVC and VMR were all found to be impaired in the PD population relative to HC (p < 0.01, p = 0.04, p < 0.01, respectively). Our data suggest PD may be associated with depressed CBF regulation. This warrants further assessment using different neural stimuli.

帕金森病(PD)是一种常见的神经退行性疾病，但对该患者群体的脑血流动力学知之甚少。先前评估动态大脑自动调节(dCA)、神经血管耦合(NVC)和血管运动反应(VMR)的研究得出了相互矛盾的结果。通过使用多变量模型，我们旨在确定PD患者的脑血流量(CBF)调节是否受损。健康对照(HC) 55例，PD患者49例。PD受试者在一段时间停止服用抗帕金森药物后进行了第二次记录。连续双侧经颅多普勒测量大脑中动脉，每搏平均动脉血压(MAP;Finapres)，心率(HR;潮末CO2 (EtCO2;摄摄)。5分钟基线期后，进行被动运动模式，包括60秒的肘关节屈曲。多元模型量化了MAP、ETCO2和神经刺激对脑血流速度(CBFV)变化的贡献。量化dCA、VMR和NVC以评估CBF调节的完整性。神经刺激是主要的输入。PD组dCA、NVC、VMR均较HC组受损(p < 0.01, p = 0.04, p < 0.01)。我们的数据表明PD可能与CBF调节下降有关。这需要使用不同的神经刺激进一步评估。

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引用次数: 3

Activation of lactate receptor HCAR1 down-modulates neuronal activity in rodent and human brain tissue 乳酸受体HCAR1的激活下调了啮齿动物和人类脑组织中的神经元活性

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2022-03-03 DOI: 10.1177/0271678X221080324

M. Briquet, A. Rocher, Maxime Alessandri, Nadia Rosenberg, Haíssa de Castro Abrantes, Joel Wellbourne-Wood, Céline Schmuziger, V. Ginet, J. Puyal, E. Pralong, R. Daniel, S. Offermanns, J. Chatton

Lactate can be used by neurons as an energy substrate to support their activity. Evidence suggests that lactate also acts on a metabotropic receptor called HCAR1, first described in the adipose tissue. Whether HCAR1 also modulates neuronal circuits remains unclear. In this study, using qRT-PCR, we show that HCAR1 is present in the human brain of epileptic patients who underwent resective surgery. In brain slices from these patients, pharmacological HCAR1 activation using a non-metabolized agonist decreased the frequency of both spontaneous neuronal Ca2+ spiking and excitatory post-synaptic currents (sEPSCs). In mouse brains, we found HCAR1 expression in different regions using a fluorescent reporter mouse line and in situ hybridization. In the dentate gyrus, HCAR1 is mainly present in mossy cells, key players in the hippocampal excitatory circuitry and known to be involved in temporal lobe epilepsy. By using whole-cell patch clamp recordings in mouse and rat slices, we found that HCAR1 activation causes a decrease in excitability, sEPSCs, and miniature EPSCs frequency of granule cells, the main output of mossy cells. Overall, we propose that lactate can be considered a neuromodulator decreasing synaptic activity in human and rodent brains, which makes HCAR1 an attractive target for the treatment of epilepsy.

乳酸可以被神经元用作能量基质来支持它们的活动。有证据表明，乳酸也作用于一种叫做HCAR1的代谢受体，这种受体最初是在脂肪组织中发现的。HCAR1是否也调节神经回路仍不清楚。在这项研究中，我们使用qRT-PCR，发现HCAR1存在于接受切除手术的癫痫患者的人脑中。在这些患者的脑切片中，使用非代谢激动剂的药理激活HCAR1降低了自发神经元Ca2+尖峰和兴奋性突触后电流(sEPSCs)的频率。在小鼠大脑中，我们使用荧光报告小鼠系和原位杂交发现HCAR1在不同区域表达。在齿状回中，HCAR1主要存在于苔藓细胞中，苔藓细胞是海马兴奋性回路的关键参与者，已知与颞叶癫痫有关。通过对小鼠和大鼠切片的全细胞膜片钳记录，我们发现HCAR1激活导致颗粒细胞(苔藓细胞的主要输出物)的兴奋性、sEPSCs和微型EPSCs频率降低。总之，我们提出乳酸可以被认为是一种神经调节剂，可以降低人类和啮齿动物大脑中的突触活性，这使得HCAR1成为治疗癫痫的一个有吸引力的靶点。

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引用次数: 10

Thanks to Reviewers 感谢审稿人

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2021-02-25 DOI: 10.1159/000485431

引用次数: 0

Test-retest repeatability of [¹⁸F]Flortaucipir PET in Alzheimer's disease and cognitively normal individuals. 阿尔茨海默氏症患者和认知能力正常者的[18F]Flortaucipir PET测试-重复性。

Journal of Cerebral Blood Flow & Metabolism

Pub Date : 2020-12-01 Epub Date: 2019-10-01 DOI: 10.1177/0271678X19879226

Tessa Timmers, Rik Ossenkoppele, Denise Visser, Hayel Tuncel, Emma E Wolters, Sander Cj Verfaillie, Wiesje M van der Flier, Ronald Boellaard, Sandeep Sv Golla, Bart Nm van Berckel

The aim of this study was to investigate the test-retest (TRT) repeatability of various parametric quantification methods for [¹⁸F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer's disease and six cognitively normal subjects. All underwent two 130-min dynamic [¹⁸F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40-60, 80-100 and 110-130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest-test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68-2.15) to 6.84% (2.99-11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78-3.58) vs. SUVr_80-100: 3.05% (1.28-5.52), p < 0.001. Furthermore, for SUVr_80-100 and SUVr_110-130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.

本研究旨在探讨[18F]氟替瑞匹正电子发射断层扫描（PET）各种参数量化方法的重复性。我们纳入了八名阿尔茨海默病引起的痴呆或轻度认知障碍患者和六名认知能力正常的受试者。所有受试者都在 3 ± 1 周内接受了两次 130 分钟的动态 [18F]Flortaucipir PET 扫描。我们使用参考区域模型受体参数映射（RPM）、简化参考组织方法2（SRTM2）和参考洛根（RLogan）以及以小脑灰质为参考区域的标准化摄取值比（SUVr，时间间隔为注射后40-60、80-100和110-130分钟）对数据进行了分析。我们首先获得了所有脑区的分布容积比或 SUVr，然后获得了三个 tau 特定感兴趣区（ROI）的分布容积比或 SUVr。TRT重复性（%）定义为|重测-测试|/（平均（测试+重测））×100。× 100.对于所有方法和所有 ROI，TRT 重复性介于（中位数 (IQR)0.84% (0.68-2.15) 到 6.84% (2.99-11.50)。尽管半定量模型（即 SUVr）的表现略差于定量模型，但所有使用的参考方法的 TRT 重复性都很好，例如 RPM 的 TRT 重复性为 1.98% (0.78%) ：1.98% (0.78-3.58) vs. SUVr80-100: 3.05% (1.28-5.52)，P 80-100 和 SUVr110-130，平均 SUVr 越高，观察到的差异越大。总之，虽然所有使用的模型的 TRT 重复性都很好，但定量方法的表现略好于半定量方法。

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引用次数: 0