慢性脑低灌注大鼠的侧支循环研究现状

侧支循环可能是缺血性卒中的潜在治疗靶点,但针对改善侧支循环的治疗目前尚未得到可靠地临床验证.因此,首先在慢性脑低灌注动物模型中开展侧支循环研究具有重要的现实意义.文章对大鼠慢性脑低灌注模型制作方法、神经行为评价、脑灌注评定、侧支循环途径以及改善侧支循环的实验研究现状进行了综述.     

大鼠慢性脑灌注不足时的运动诱发电位

目的 制备大鼠慢性脑灌注不足模型,观察运动诱发电位(MEP)变化,研究慢性脑低灌注对脑传导功能的影响.方法 采用双侧颈总动脉结扎制作慢性脑灌注不足动物模型,实验分为对照组、缺血半月组、缺血1月组和缺血2月组共4组.使用电刺激诱发,双下肢记录,刺激电极放于皮层运动区,记录电极置于对侧腓肠肌,记录皮层MEP,观察潜伏期和波幅变化.结果 慢性低灌注期MEP潜伏期显著延长(P<0.01),并随低灌注持续时间延长而出现MEP潜伏期延长更为明显.结论 慢性低灌注可以引起脑内传导功能受损,临床上MEP可用来反映慢性脑灌注不足后轴索的功能状态.     

动脉介入加压灌注治疗低灌注性脑缺血临床分析

目的慢性脑供血不足临床上常见,但常规内科治疗效果往往欠佳。病变可能反复发作甚至持续进展为脑梗死。方法本研究入组20例慢性脑灌注不足患者,经介入技术选择性动脉加压灌注治疗,观察治疗疗效。结果经介入选择性动脉加压灌注治疗后临床症状明显改善。术后随访2年病情无复发。结论对于慢性脑灌注不足患者应用小剂量尿激酶经动脉内介入加压灌注治疗能有效改善临床症状、不良反应小、安全可靠。     

慢性脑低灌注与认知功能障碍的关系

<正>慢性脑低灌注被认为是血管性痴呆及阿尔茨海默病(Alzheimer's disease,AD)等神经退行性疾病的危险因素。慢性脑低灌注状态能够导致认知功能障碍,但其基本的神经生物学机制目前知之甚少。近年来,有研究发现慢性脑低灌注可以通过神经递质紊乱、氧化应激、神经炎性反应等机制引起神经元损伤和白质病变,从而导致神经退行性改变及认     

慢性脑低灌注大鼠海马组织中IDO的变化

目的观察慢性脑低灌注大鼠海马组织中干扰素(IFN-γ)、吲哚胺2,3-双加氧酶(IDO)的表达,探讨IDO在慢性脑低灌注导致认知功能损害中的作用。方法用双侧颈总动脉永久性结扎(2VO)制作慢性脑低灌注大鼠模型,Morris水迷宫检测2VO大鼠空间学习与记忆能力变化,免疫组化检测大鼠海马CA1区IFN-γ的表达,ELISA法检测IDO的表达。结果慢性脑低灌注大鼠的空间记忆能力较假手术组显著下降,海马IFN-γ、IDO表达较假手术组增加(P<0.05)。结论 IFN-γ刺激IDO合成增加,可能参与了慢性脑低灌注导致的认知功能损害。     

糖尿病对慢性脑低灌注大鼠神经元损伤的实验研究

目的探讨糖尿病对慢性脑低灌注大鼠的学习记忆能力和神经元损伤的影响。方法以链脲佐菌素诱导产生实验性糖尿病大鼠,双侧颈总动脉结扎建立慢性脑低灌注模型,应用Y-迷宫评价错误次数和全天总反应时间,HE染色观察各组大鼠海马CAl区神经元的数目,免疫组化法检测海马区CDK5表达,结合蛋白质印迹(Westernblot)实验对海马区CDK5蛋白作半定量分析。结果与单纯糖尿病和慢性脑低灌注组大鼠比较,糖尿病合并慢性脑低灌注组大鼠从2w开始,迷宫作业错误反应次数增多,全天总反应时间延长,海马CAl区神经元数明显减少,CDK5蛋白表达减少。结论糖尿病加重慢性脑低灌注导致大鼠学习、记忆能力下降和神经元损伤,可能与CDK5表达减少有关。     

慢性脑缺血的认识现状与展望

<正>慢性脑缺血是一组由于脑灌注下降导致的慢性脑功能障碍临床症状群,作为一个一直存在争议的疾病诊断,曾有"脑动脉硬化症"、"慢性脑供血不足"、"慢性脑低灌注"、"慢性脑血管机能不全"等一系列命名。2005年国际疾病分类标准第10版和2015年中国脑血管病分类将其命名为慢性脑缺血,但未提出其诊断标准。由于临床上有大量疑似患者,而对疾病的概念、诊断标准以及是否为一独立疾病实体等存在争议,导致临床上的漏诊和滥诊普遍存在,因此需对其给予高度重视。     

慢性脑低灌注大鼠海马CA1区VEGF和磷酸化tau蛋白的表达及意义

目的 观察慢性脑低灌注大鼠海马CA1区血管内皮生长因子(VEGF)和磷酸化tau蛋白的表达及意义.方法 将SD大鼠随机分为正常对照组(对照组)、假手术组和模型组.采用永久性结扎双侧颈总动脉建立慢性脑低灌注模型(2VO);实验开始后1、2、3月,应用免疫组织化学染色法检测海马CA1区VEGF和磷酸化tau蛋白的表达.结果 与对照组和假手术组比较,模型组海马CA1区VEGF表达在1、2月时明显增高(P＜0.05),3月时各组间表达差异无显著性(P＞0.05).磷酸化tau蛋白表达在1月时各组间差异无显著性(P＞0.05);2和3月时,模型组表达较对照组和假手术组明显增高(P＜0.05).结论 慢性脑低灌注时VEGF表达增高可能是一种自身保护机制,磷酸化tau蛋白参与了慢性脑低灌注认知功能损伤过程.     

慢性脑低灌注致血管性痴呆发病机制研究进展

血管性痴呆（VaD）是一种神经退行性疾病,由整个大脑或局部大脑区域长期慢性低灌注引起,并最终发展为严重的认知功能障碍综合征。慢性脑低灌注可能是血脑屏障破坏、神经炎症、氧化应激、兴奋性毒性、神经血管解耦联、脱髓鞘和髓鞘再生失败等病理反应发生的基础,与VaD认知障碍的发生密切相关。慢性脑低灌注时血管内皮细胞功能障碍、周细胞丢失、血管周围空间增加导致血脑屏障分解和损伤,有害物质进入脑实质,造成白质病变、影响认知致VaD发生。慢性脑低灌注时促炎细胞因子过度激活,加剧神经炎症,诱发炎症—免疫级联反应,使白质损伤、神经元丢失,加速VaD发生发展。缺氧下内皮细胞中活性氧产生过量且细胞抗氧化系统无法对其适当调节,诱发氧化应激,损害内皮功能,加速神经血管功能障碍,导致白质损伤和认知损害。慢性脑低灌注时细胞能量失衡状态过度激活谷氨酸受体,使神经元功能紊乱和死亡,出现兴奋性毒性,导致细胞凋亡或坏死,最终诱发VaD。大脑能量供应紊乱、神经血管单元之间的细胞信号转导和营养耦合发生异常,使神经血管单元功能整体损害,导致一系列级联反应诱发VaD。慢性脑低灌注时少突胶质细胞祖细胞易损伤而发育停滞,致髓鞘再生失败,兴奋...     

磁共振脑灌注成像在慢性颈内动脉狭窄与闭塞患者中的应用价值

目的探讨磁共振脑灌注成像对单侧慢性颈内动脉(ICA)重度狭窄、闭塞患者中的临床应用价值。方法62例单侧慢性ICA重度狭窄或闭塞患者行磁共振脑灌注加权成像(PWI)检查,计算出有关脑灌注参数图,包括相对脑血流量(rCBF)、相对脑血容量(rCBV)、相对平均通过时间(rMTT)和达峰时间(TTP)图。其中14例进行外科或介入治疗,治疗后复查MR脑灌注成像,对治疗前后结果进行比较分析。结果62例ICA慢性重度狭窄或闭塞患者,PWI均发现病变侧脑灌注异常,表现为TTP、rMTT明显延迟,而rCBF正常轻度下降,rCBV正常或轻度增高。病变侧rMTT、TTP、rCBV、与对侧比较有显著性差异(P<0.01),rCBF无显著差异(P<0.05)。40例患者TTP、rMTT延迟累及大脑中动脉分布区和分水岭区,22例仅累及分水岭区。14例患者外科或介入治疗后TTP、rMTT图灌注异常区较治疗前减小(P<0.01),病变侧TTP、rMTT值较治疗前减低(P<0.01)。结论PWI检查能够提供单侧ICA慢性重度狭窄或闭塞患者脑血流动力学受损情况,观察治疗前后脑灌注的改善情况,为评价疗效提供影像学依据。     

Cerebral hypoperfusion detected by SPECT in patients with systemic lupus erythematosus is related to clinical activity and cumulative tissue damage

Cerebral single-photon emission computed tomography (SPECT) is a sensitive technique for the detection of central nervous system (CNS) involvement in systemic lupus erythematosus (SLE). The objective was to determine whether a relationship exists between cerebral hypoperfusion as detected by cerebral SPECT, cumulative tissue damage and the clinical activity of SLE. Cerebral technetium-99m-L,L-ethyl cysteinate dimer (99mTc-ECD) SPECT was performed in two groups of patients: 10 women with SLE (Group A) who had no previous history of major neuropsychiatric (NPS) manifestations and no minor NPS symptoms in the last six months, and 57 unselected women with SLE (Group B). In the same week that SPECT was performed, the SLE disease activity index (SLEDAI), SLICC/ACR damage index, native anti-DNA antibodies (ELISA) and erythrocyte sedimentation rate (ESR) were determined. In Group A, cerebral SPECT showed moderate or severe hypoperfusion (abnormal SPECT) in five patients without NPS symptoms, unrelated to age (mean 24.8 versus 27.8 years) or disease duration (mean 6.8 versus 9 years). Patients with significant cerebral hypoperfusion had greater clinical disease activity (mean SLEDAI 13.6 versus 7.6) (SLEDAI > 7 in 5/5 versus 1/5; Fisher: 0.023; OR: 33; 95% CI: 2.3-469.8) and ESR (mean 43.6 versus 9.8; P < 0.05). In Group B, the mean age of the 57 unselected women with SLE was 37 years (SD 6.3) and the mean duration of the disease was 9.7 years (SD 6.3). Cerebral SPECT revealed normal perfusion or mild hypoperfusion (normal SPECT) in 30 patients (52.6%), and moderate or severe hypoperfusion in 27 (47.4%). Hypoperfusion was unrelated to age, duration of SLE or concentrations of anti-DNA antibodies and C3 and C4 fractions. Patients with significant cerebral hypoperfusion had more active clinical disease (mean SLEDAI 13.92; SD 8.44 versus 4.56; SD 4.15) (Mann-Whitney, P < 0.005), more cumulative tissue damage (mean SLICC 2.66; SD 2.84 versus 1.03; SD 1.51) (Mann-Whitney, P = 0.035), and higher ESR values (mean 28.7; SD 22.5 versus 17.7; SD 13.3) (Mann-Whitney, P = 0.023) than patients with normal SPECT studies. Significant cerebral hypoperfusion was related both to NPS manifestations present at the time of the study (17 of 27, 63% versus 3 of 30, 10%) (OR: 15.3) and cumulative manifestations (19 of 27, 70.4% versus 8 of 30, 26.7%) (OR: 6.5), whether mild (OR: 5.5) or severe (OR: 8.2). In conclusion, cerebral hypoperfusion detected by SPECT in patients with SLE is related to clinical activity (SLEDAI), cumulative tissue damage (SLICC) and concomitant or previous NPS manifestations.     

Decreased plasma endothelin-1 levels in asymptomatic type I diabetic patients with regional cerebral hypoperfusion assessed by Spect

The prevalence of stroke is increased in diabetic patients. The vasoconstrictor peptide endothelin-1 (ET-1) has been implicated in the development of cerebral vasospasm after stroke but its role in the physiological regulation of cerebral blood flow (CBF) is not well known. Our aim was to assess the relationship between CBF and plasma ET-1 levels in type I diabetic patients. Regional CBF was assessed semi-quantitatively by ⁹⁹Tc^m-hexamethylpropylene-amine-oxime (⁹⁹Tc^m-HMPAO) single photon emission computed tomography (SPECT) in 50 cerebral “regions of interest” (ROIs) of 19 type I diabetic patients without clinical evidence of cerebral disease, and 10 healthy control subjects. In both groups, plasma ET-1 levels were measured. Results showed that type I diabetic patients had significantly more hypoperfusion ROIs than control subjects. While up to 68.4% of the type I diabetic patients showed 3 or more hypoperfusion ROIs, only 10% of the control subjects did. Plasma ET-1 levels were lower in the type I diabetes subgroup with 3 or more hypoperfusion ROIs than in the type I diabetes subgroup with less than 3 hypoperfusion ROIs and in the control group. Moreover, an inverse correlation between the number of hypoperfusion ROIs and plasma ET-1 levels (r = 0.47, p = 0.04) was found in the type I diabetes group. It is concluded that plasma ET-1 is decreased in type I diabetic patients with subclinical abnormalities of regional CBF assessed by cerebral SPECT. This fact may reflect a compensatory response to the reduction of the brain perfusion in order to prevent ischemic events in these patients.     

Predicting Hemodynamic Changes of Cerebral Blood Flow during Temporal Carotid Occlusion: A Review of Current Knowledge with Implication for Carotid Artery Stenting

Carotid artery disease (CAD) plays an important role in the stroke development and its prevalence increases with aging of the population. Its wide variability of clinical manifestation ranges from incidental asymptomatic finding to devastating or fatal stroke, although cerebral collateral circulation is considered one of the major modifying factors. Over time, carotid artery stenting (CAS) has evolved into a reputable method for the treatment of patients with severe CAD. With expanding use of proximal protection systems resembling surgical clamp, there is an increasing demand to understand collateral cerebral circulation to protect patients from periprocedural hypoperfusion, which increases the risk of cerebral events. Transcranial Doppler ultrasound (TCD) is a useful tool allowing monitoring in real time during procedure patien$\acute{t}$s cerebral hemodynamic status providing the operator with valuable information. Its role in predicting periprocedural hypoperfusion is, however, less well established. In this article, we discuss the role of cerebral collateral circulation, summarize the current knowledge regarding its evaluation with TCD and suggest future implications for CAS.     

Single-photon-emission computed tomography of the brain in the evaluation of cerebral lupus

We sought to determine whether single-photon-emission computed tomography (SPECT) of the brain is useful for detecting abnormalities of regional cerebral blood flow in patients with cerebral lupus. Twenty lupus patients with clinical evidence of cerebral involvement underwent SPECT and CT scanning of the brain, as well as clinical, expert neurologic, and serologic evaluation. Fifteen patients (75%) had a clear regional cerebral hypoperfusion. Seven of 8 patients (88%) who were ultimately thought to have active cerebral lupus had abnormal SPECT scan findings, while 8 of 12 patients (67%) who were ultimately thought not to have active cerebral lupus had abnormal SPECT scan findings. There was no correlation of SPECT findings with CT scan results, overall disease activity, or serologic findings. Regional cerebral blood flow measured by SPECT is often abnormal in patients with active cerebral lupus, but is also frequently abnormal in lupus patients with neuropsychiatric symptoms not attributable to cerebral lupus activity.     

脑梗死前期MR脑灌注成像的临床意义

目的 探讨脑梗死前期MR脑灌注成像的表现和分期临床应用价值。方法 采用脑MR灌注成像对18例脑血管病患者的170层脑灌注图像和对照组20例非脑血管病患者的197层脑灌注成像进行分析，计算每层图像的患／健侧比值，并与对照组的正常比值及其范围比较。以非参数统计方法、多元方差分析和两两比较分析病例组和对照组脑灌注血流动力学参数及其分期。结果 病例组和对照组的4个血流动力学参数均有显著性差异（P〈O.01）。TTP（time to peak）和MTT可（mean traasit time）与发病的相关系数较高，分别为O.422和0.371，rCBV（regional cerebral blood volume）和rCBF（regional cerebral blood flow）较低，且为负值。脑梗死前期分期特征为：I1期TTP稍有延长，I2期MTT显著延长，Ⅱ1期rCBF明显下降，Ⅱ2期rCBV下降。结论 脑灌注成像可提供脑梗死前期的血流动力学参数变化的信息，并可以对其参数变化进行分期。     

Gene transfer of hepatocyte growth factor to subarachnoid space in cerebral hypoperfusion model

Although cerebral hypoperfusion caused by cerebral occlusive disease leads to cerebral ischemic events, an effective treatment has not yet been established. Recently, a novel therapeutic strategy for ischemic disease using angiogenic growth factors to expedite and/or augment collateral artery development has been proposed. Therapeutic angiogenesis might be useful for the treatment of cerebral occlusive disease. Hepatocyte growth factor (HGF) is a potent angiogenic factor, in addition to vascular endothelial growth factor (VEGF), whereas in the nervous system HGF also acts as neurotrophic factor. Therefore, we hypothesized that gene transfer of these angiogenic growth factors could induce angiogenesis, thus providing an effective therapy for cerebral hypoperfusion or stroke. In this study, we employed a highly efficient gene transfer method, the viral envelop (Hemagglutinating Virus of Japan [HVJ]-liposome) method, because we previously documented that beta-galactosidase gene could be transfected into the brain by the HVJ-liposome method. Indeed, we confirmed wide distribution of transgene expression using beta-galactosidase via injection into the subarachnoid space. Of importance, transfection of HGF or VEGF gene into the subarachnoid space 7 days before occlusion induced angiogenesis on the brain surface as assessed by alkaline phosphatase staining (P<0.01). In addition, significant improvement of cerebral blood flow (CBF) was observed by laser Doppler imaging (LDI) 7 days after occlusion (P<0.01). Unexpectedly, transfection of HGF or VEGF gene into the subarachnoid space immediately after occlusion of the bilateral carotid arteries also induced angiogenesis on the brain surface and had a significant protective effect on the impairment of CBF by carotid occlusion (P<0.01). Interestingly, coinjection of recombinant HGF with HGF gene transfer revealed a further increase in CBF (P<0.01). Here, we demonstrated successful therapeutic angiogenesis using HGF or VEGF gene transfer into the subarachnoid space to improve cerebral hypoperfusion, thus providing a new therapeutic strategy for cerebral ischemic disease.     

Dopaminergic degeneration is enhanced by chronic brain hypoperfusion and inhibited by angiotensin receptor blockage

The possible interaction between brain hypoperfusion related to aging and/or vascular disease, vascular parkinsonism and Parkinson’s disease, as well as the possible contribution of aging-related chronic brain hypoperfusion in the development or severity of Parkinson’s disease are largely unknown. We used a rat model of chronic cerebral hypoperfusion to study the long-term effects of hypoperfusion on dopaminergic neurons and the possible synergistic effects between chronic hypoperfusion and factors that are deleterious to dopaminergic neurons, such as the dopaminergic neurotoxin 6-hydroxydopamine. Chronic hypoperfusion induced significant loss of dopaminergic neurons and striatal dopaminergic terminals and a reduction in striatal dopamine levels. Furthermore, intrastriatal administration of 6-hydroxydopamine in rats subjected to chronic hypoperfusion induced a significantly greater loss of dopaminergic neurons than in sham-operated control rats. The dopaminergic neuron loss was significantly reduced by oral treatment with angiotensin type 1 receptor antagonist candesartan (3 mg/kg/day). The levels of angiotensin type 2 receptors were lower and the levels of angiotensin type 1 receptors, interleukin-1 β and nicotinamide adenine dinucleotide phosphate oxidase activity were higher in the substantia nigra of rats subjected to chronic hypoperfusion than in control rats; this was significantly reduced by treatment with candesartan. The results suggest that early treatment of vascular disease should be considered in the treatment of aged Parkinson’s disease patients and Parkinson’s disease patients with cerebrovascular risk factors. The findings also suggest that inhibition of brain renin–angiotensin activity may be useful as a neuroprotective strategy.     

Evidence of cerebral hypoperfusion in scleroderma patients

OBJECTIVES: To investigate regional cerebral blood flow by (99m)Tc-hexamethylpropylenamineoxime (HMPAO) single photon emission computed tomography (SPECT) in a series of 40 patients (mean age 58.5+/-11.5 yr) affected by systemic sclerosis (SSc) in comparison with age-matched healthy controls. METHODS: Subjects affected by concomitant severe pathologies that might interfere with the interpretation of the SPECT results were excluded. SPECT findings were correlated with the severity of peripheral microvascular involvement, as assessed by nailfold videocapillaroscopy (NVC). Whenever possible, patients underwent magnetic resonance imaging (MRI) of the brain. RESULTS: Twenty-one SSc patients (52%) showed hypoperfusion in two or more regions of interest (ROIs) at the SPECT analysis. MRI was available in 14 of these patients, and was shown to be altered in eight of them (57%). One patient with both abnormal SPECT and abnormal MRI was affected by mild cognitive impairment. Transcranial Doppler sonography was normal in all but one of these patients with hypoperfusion. Nineteen patients exhibited a normal brain SPECT scan, but the MRI was shown to be altered in 3/12 of them (25%). No significant differences were found between the group of SSc patients showing hypoperfusion and those showing a normal SPECT scan regarding age, the duration of disease, the presence of vascular risk factors or damage of other organs typically involved in the disease, and the severity of peripheral microvascular involvement (NVC). CONCLUSIONS: Focal or diffuse cerebral hypoperfusion was found in more than half of the neurologically asymptomatic SSc patients studied, paralleling the incidence of altered brain MRI. The hypoperfusion was not linked to ageing and possibly reflects the cerebral location of the microangiopathic process characterizing the disease.     

少突胶质前体细胞在青老年大鼠慢性脑灌注不足中的活化改变

目的观察少突胶质前体细胞(oligodendrocyte progenitor cells,OPC)在大鼠慢性脑缺血损害中反应性变化及老化对此过程的影响。方法分别在青年(3个月龄)与老年(24个月龄)大鼠慢性灌注不足模型中,运用免疫组化方法检测NG2抗体标记的阳性OPC在灌注不足2周、1个月和3个月后形态数量及分布等改变。结果慢性灌注不足大鼠脑内存在NG2标记的免疫组化染色的阳性OPC明显反应性增生,与非缺血青老年对照组比较,差异有统计学意义(P<0.01),在皮质、皮质下、海马、胼胝体及室下区等处均有分布,以皮质下接近白质区域以及海马齿状回最为显著,2周、1个月最为明显,但于灌注不足后青年大鼠脑内NG2标记的免疫组化染色的阳性OPC染色强度和数量仍高于老年组(P<0.05)。结论慢性灌注不足过程中脑内OPC具有明显增殖活化,其反应性受月龄因素影响,并可能为慢性脑缺血损伤后的一种代偿适应或修复机制。     

Dopaminergic Therapy Modulates Cortical Perfusion in Parkinson Disease With and Without Dementia According to Arterial Spin Labeled Perfusion Magnetic Resonance Imaging

Arterial spin labeling (ASL) magnetic resonance imaging analyses allow for the quantification of altered cerebral blood flow, and provide a novel means of examining the impact of dopaminergic treatments. The authors examined the cerebral perfusion differences among 17 Parkinson disease (PD) patients, 17 PD with dementia (PDD) patients, and 17 healthy controls and used ASL-MRI to assess the effects of dopaminergic therapies on perfusion in the patients. The authors demonstrated progressive widespread cortical hypoperfusion in PD and PDD and robust effects for the dopaminergic therapies. Specifically, dopaminergic medications further decreased frontal lobe and cerebellum perfusion in the PD and PDD groups, respectively. These patterns of hypoperfusion could be related to cognitive dysfunctions and disease severity. Furthermore, desensitization to dopaminergic therapies in terms of cortical perfusion was found as the disease progressed, supporting the concept that long-term therapies are associated with the therapeutic window narrowing. The highly sensitive pharmaceutical response of ASL allows clinicians and researchers to easily and effectively quantify the absolute perfusion status, which might prove helpful for therapeutic planning.