Cerebral microbleeds predict first-ever symptomatic cerebrovascular events

Objective

Cerebral microbleeds (CMB) on gradient-echo T2*-weighted magnetic resonance image (MRI) are frequently seen in patients with cerebral diseases. In this observational study we assessed whether CMB are a predictive factor for first-ever cerebrovascular events.

Patients and methods

This study consisted of 698 subjects without a history of symptomatic cerebrovascular events, who received gradient-echo T2*-weighted MRI for 3 months between November 2003 and January 2004 in Kishiwada City Hospital, Osaka, Japan. These subjects were then observed as outpatients for over 3.5 years.

Results

The prevalence of CMB at baseline was 17.0% (119/698) in this population, and the follow-up rate was 51%. A total of 36 first-ever symptomatic cerebrovascular events were observed during the 3 and a half-year follow-up period. First-ever symptomatic cerebrovascular events occurred significantly more frequently in subjects with CMB (15 cases) than those without CMB (21 cases) (p = 0.001). Even after adjusting for age, sex and hypertension, it was revealed that the presence of CMB was an independent predictor for the first-ever symptomatic cerebrovascular event by using the Cox proportional hazards model (hazard ratio, 2.87; 95% CI, 1.27–6.48; p = 0.01).

Conclusion

The presence of CMB is an independent predictor of first-ever symptomatic cerebrovascular diseases.     

脑血管病的病变部位与脑电图波形关系的研究

目的探讨脑血管病的病变部位与脑电图波形的特点。方法对174例脑血管病患者进行脑电图监测。结果所有患者发作期都有特征性脑电图改变,脑电图改变与脑出血量的大小和缺血面积密切相关。结论脑电图对脑血管病有一定的诊断价值。     

Quantifying perivascular sympathetic innervation: Regional differences in male C57BL/6 mice at 3 and 20 months

Perivascular sympathetic innervation density (PSID) is a key determinant of vasomotor responses to sympathetic nerve activity. However, total axonal length (for en passant neurotransmission) per vessel surface area has not been well defined, particularly while preserving 3-dimensional vascular structure. We developed a novel method for quantifying PSID using 3-dimensional anatomical reconstruction and compare a variety of blood vessels in Young (3 months) and Old (20 months) male C57BL/6 mice. Individual vessels were dissected and immunolabeled for tyrosine hydroxylase. The total length of fluorescent axons in defined vessel surface areas was quantified by mapping Z-stack images (magnification = 760×). For Young mice, innervation densities (μm axon length/μm² vessel surface area) in mesenteric (0.075 ± 0.002) and femoral (0.080 ± 0.003) arteries were greater (P < 0.05) than mesenteric veins (0.052 ± 0.002) and gracilis muscle feed arteries (0.040 ± 0.002). Carotid arteries and gracilis muscle veins were not immunoreactive nor were there significant differences in PSID between Young and Old animals. We demonstrate a novel approach to quantify sympathetic innervation of the vasculature while preserving its 3-dimensional structure and document regional variation in PSID that persists with aging in mice. This analytical approach may be used for quantifying PSID in other tissues that have superficial vessels which can be studied in situ or from which embedded vessels can be excised. With appropriate visualization of neuronal projections, it may also be applied to tissues that have other sources of superficial innervation.     

急性脑血管病患者肾血流灌注研究

目的探讨急性脑血管病患者伴肾功能异常的机制及早期监测指标。方法应用99mTc-DTPA肾动态显像观察148例急性脑血管病（脑梗死80例、脑出血68例）及64名健康人的肾小球滤过率（GFR）及综合清除曲线等指标。结果急性脑血管病患者存在不同程度的肾血流灌注障碍,43．7％（35／80）的脑梗死和38．2％（26／68）的脑出血患者GFR异常,脑梗死组病灶对侧GFR降低,急性脑血管病的肾综合清除曲线异常,以抛物线型和排泄延迟居多。结论肾功能显像有助于早期发现肾功能损害;治疗脑血管病的同时应注意保护肾功能。     

Importance of bilateral sympathetic innervation on cerebral blood flow autoregulation in the thalamus

Effects of bilateral sympathetic innervation on the regulation of cerebral blood flow to the thalamus were examined in spontaneously hypertensive rats (SHR). The superior cervical ganglion was removed on one side or bilaterally, and blood flow in the thalamus was repeatedly measured with a hydrogen clearance technique during a stepwise increase in arterial pressure. Regional blood flow in the thalamus was unchanged following acute ganglionectomy: 55 +/- 6 ml/100 g/min in the intact rats and 56 +/- 4 in the denervated rats. Sympathectomy on one side neither had effects on the pressure-flow relationship nor on the blood pressure levels of upper limits of autoregulation in the ipsilateral thalamus. In contrast, bilateral sympathetic denervation impaired the autoregulatory function in the thalamus and the upper limits were significantly lower than those in intact rats: 206 +/- 8 vs 226 +/- 10 mm Hg, respectively (P less than 0.02). It is concluded that overlapping innervation of sympathetic nerves has an important role in regulation of blood flow to the thalamus during an acute rise in arterial pressure in SHR.     

Motor, sympathetic and sensory innervation of rat skeletal muscles

This study reports on the location, number and size of motor, sympathetic and sensory neurons innervating the following muscles of rat: quadriceps femoris (QF), tibialis anterior (TA), extensor digitorum longus (EDL), peroneus longus (PL), gastrocnemius medius (GM) and soleus (SOL). Cells were labelled by application of horseradish peroxidase (HRP) to transected muscle nerves. Counts of neurons were compared with counts of myelinated (MF) and unmyelinated (UMF) fibers in normal, deafferented and chemically sympathectomized nerves. The topographical arrangement of spinal motor nuclei resembled that reported previously in other mammals and birds. Sensory somata were aggregated without precise somatotopic organization, preferentially in one of the lumbar dorsal root ganglia at a segmental level corresponding to that of the motor innervation. Because lumbar sympathetic ganglia were often poorly circumscribed, the segmental position of sympathetic ganglion cells could not be localized with certainty. Sensory and sympathetic somata demonstrated a unimodal size-frequency distribution, while QF, TA and PL motoneurons could be subdivided according to size in alpha and gamma cells. For all muscles except unsuccessfully deafferented QF, counts of motor fibers after deafferentation correlated closely with counts of labelled motoneurons. Similarly, estimates of sympathetic axons, averaging 30,7% of the UMF, in most instances exceeded only marginally the ganglion cell population. In contrast, the number of peripheral afferent fibers outnumbered markedly that of sensory cell bodies, with an average of 2.8 axons per ganglion cell.     

脑出血大鼠脑组织IGF-1的表达及其对细胞凋亡的影响

目的研究胰岛素样生长因子-1（IGF-1）在实验性大鼠脑出血（ICH）后脑组织中的表达及其对细胞凋亡的影响。方法应用立体定向技术，将自体未抗凝血注入大鼠基底节区以制备ICH模型；将动物分为正常对照组、ICH组及干预组，分别在不同时间断头取脑以制作标本，连续切片分别作IGF-1免疫组化染色及TUNEL染色。结果ICH后2h血肿周围脑组织表达IGF-1，24h达表达高峰，7d时恢复正常；TUNEL染色阳性细胞于ICH后8h开始出现，3d时达高峰，7d时仍有表达；给予外源性IGF-1后，凋亡细胞显著减少，与同时点ICH组相比差别有显著性。结论ICH后IGF-1可抑制细胞凋亡的发生，从而减轻ICH后继发性脑损伤。     

Intracranial aneurysms and subarachnoid hemorrhage in children and adolescents

Thirty-eight cases of symptomatic cerebral aneurysms or spontaneous subarachnoid hemorrhage in children and adolescents were observed from 1965 to 1984; 33 cases were treated from 1970 to date. This group represents 2.6% of the total number of patients with subarachnoid hemorrhage treated at our institute in the same period. The cause of subarachnoid hemorrhage was unknown in 7 cases; an intracranial aneurysm had ruptured in 29 cases, and was unruptured but symptomatic in 2 remaining cases. Three aneurysms were mycotic. The most frequent aneurysmal locations were the internal carotid bifurcation and the anterior communicating artery; peripheral branches of the middle cerebral artery were also a relatively common location. Four patients were 3 years of age or younger: each presented peculiar clinical features, and 3 of the 4 had middle cerebral artery aneurysms. The remaining 34 patients were all above 9 years of age. Two groups were identified: (a) in 14 patients between 10 and 15 years of age, the aneurysm was most commonly at the internal carotid bifurcation (37%), and an intracerebral hematoma was observed in 50% of these cases; (b) in 20 patients between 16 and 20 years of age, the most common aneurysmal location was the anterior communicating artery (35%), and intracerebral hematomas were rare (10% of cases). Among patients with aneurysms, 19 underwent surgical exclusion by clip, with 10% morbidity and 5% mortality; 5 patients in moribund conditions were not operated on; 5 patients were conservatively treated; in 2 patients the aneurysm had disappeared at a second angiography. Ischemic deterioration from vasospasm was observed only in 3 patients, all above 17 years of age, and with a consistent or thick subarachnoid blood deposition on early CT scan. Hydrocephalus was also rarely observed (13% of cases), requiring a shunt in only 3 patients. Overall management results were significantly better than in adult patients, with 73% good results and 21% deaths. The better prognosis in the group under 20 years of age is probably accounted for (a) by the frequently observed reversibility of neural injury in young patients and (b) the very low incidence of ischemic disturbances in this age group.     

Sympathetic innervation of lymph nodes in mice

Noradrenergic innervation of popliteal and mesenteric lymph nodes in mice was examined with fluorescence histochemistry. Dense varicose plexuses entered the nodes with the vasculature in the hilar region and continued with the vasculature into the medullary region. Fine, delicate varicosities and small vascular plexuses continued into the cortical and paracortical regions surrounding the germinal centers; some varicosities ended among lymphocytes. A subcapsular plexus contributed fibers into the cortical and paracortical regions. Chemical measurements revealed the presence of norepinephrine in lymph nodes that was depletable with 6-hydroxydopamine. Depletion of norepinephrine from lymph nodes with this agent resulted in a diminished primary immune response in draining lymph nodes following subcutaneous injection of an antigen in two mouse strains, but had no effect in two other strains. These findings suggest that noradrenergic fibers innervate both the vasculature and parenchymal regions of lymph nodes, and may participate in the modulation of immune responses in these organs.     

Comparison of cerebral blood flow and injury following intracerebral and subdural hematoma in the rat

Subdural hematomas (SDH) can induce ischemia and neuronal damage in the underlying cortex. However, the extent to which intracerebral hematomas (ICH) produce reductions in cerebral blood flow (CBF) sufficient to cause ischemic damage is uncertain. Intracranial hemorrhage was induced by the injection of 100 or 200 microl of blood into the subdural space (SDH) or into the caudate nucleus (ICH) of the rat. CBF was measured using [14C]-iodoantipyrine autoradiography at 4 h. Brain damage was measured using 2,3, 5-triphenyl tetrazolium chloride (TTC) staining at 24 h and brain edema was measured using the wet/dry weight method. Brain ion contents were measured at 24 h using a flame photometer and chloridometer. In the CBF studies, the volume of tissue perfused below the ischemic threshold (<20 ml/100 g/min) for SDH was 122+/-35 mm3 (sham: 3.3+/-1.7 mm3). Following ICH, there was a small volume of tissue perfused below the ischemic threshold 50+/-11 mm3 (sham: 3. 3+/-2.5 mm3) but this volume corresponded closely to the volume of clot (71+/-5 mm3). The extent of brain damage, measured by TTC staining, in the cerebral cortex correlated with the increasing volume of the subdural blood clot (sham: 9+/-3 mm3; 200 microl: 81+/-19 mm3; P<0.01). Conversely, minimal brain damage was detected following ICH. The injection of blood into the subdural space or into the brain parenchyma induced blood volume-dependent increases in brain water content at 24 h. Increases in brain water content after SDH, were confined to the cerebral cortex (sham: 0.1+/-0.1 g/g dry weight; 200 microl: 0.8+/-0.3 g/g dry weight; P<0.001). In contrast, increases in brain water content after ICH were predominantly in the subcortical region (sham: 0.1+/-0.1 g/g dry weight; 200 microl: 0.4+/-0.2 g/g dry weight; P<0.01). The present investigations demonstrate differences in CBF, brain injury and edema formation following SDH and ICH indicating that these conditions may require different therapeutic interventions.     

Association between acute sympathetic response,early onset vasospasm,and delayed vasospasm following spontaneous subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) is accompanied by a marked acute sympathetic response, and evidence exists for sympathetic participation in the development of cerebral vasospasm (VS). The purpose of this observational investigation was to assess the association between acute central catecholaminergic activity, early VS and delayed VS following SAH. SAH grade 3–5 patients who received ventriculostomy, and in whom bilateral temporal transcranial insonation was performed, were enrolled. Cerebrospinal fluid (CSF) was sampled (<48 hours) and assayed for catecholamines, which were correlated to measures of early and delayed sonographic anterior circulation VS. Clinical independent predictors of early VS included age (odds ratio .946 [95% confidence interval .902–.991]), CT scan score (4.27 [1.30–14.0]) and neurogenic cardiomyopathy (6.5 [1.24–34.1]). Age (.925 [.859–.996]) and CT scan score (8.30 [1.33–5.17]) also independently predicted delayed VS. Any early VS independently predicted conventionally defined delayed VS (10.9 [2.64–45.0]), and severe delayed VS was independently predicted by any early VS (9.87 [2.45–39.7]) and by conventionally defined early VS (12.3 [2.80–54.1]). The norepinephrine:3,4-dihydroxyphenylglycol ratio (NE/DHPG) independently predicted severe delayed VS (3.38 [1.01–11.35]), for which DHPG was a negative predictor (.356 [.151–.839]). Epinephrine was a negative predictor of any early VS (.574 [.357–.921]), any delayed VS (.372 [.158–.875]), and delayed conventional VS (.402 [.200–.807]). Early and delayed VS appear to be related processes that are generally unrelated to the acute central sympathetic response following SAH. The one exception may be severe delayed VS which may be associated with noradrenergic activation.     

Animal models of spontaneous intracerebral hemorrhage

Objectives: Intracerebral hemorrhage (ICH) is a type of stroke that results in significant mortality and morbidity. Currently there is no definitive treatment for this disease. The paucity of animal models that reflect the heterogeneity of this spontaneous human disease could be the reason. Methods: In this review, we searched the literature for animal models of spontaneous ICH and found eight relevant papers.

Results: Two were related to hypertension and six were related to cerebral amyloid angiopathy (CAA). One model used double transgenic mice overexpressing human renin and angiotensinogen which caused the mice to be hypertensive. Induction of ICH, however required addition of a high salt diet and nitric oxide synthase inhibition. Another mouse model of hypertension employed subcutaneous angiotensin II infusion and nitric oxide synthase inhibition plus acute injections of angiotensin to further elevate blood pressure. Five CAA models were in transgenic mice overexpressing amyloid precursor protein. One relied on the natural development of CAA in squirrel monkeys.

Conclusions: While all of the spontaneous ICH models have some advantages, the disadvantages include the sporadic time of onset of ICH and variability in size and location of ICH. Since there are no known efficacious treatments for ICH, it is not known if findings in the animal models will find treatments that are effective in humans.     

出血性卒中的脑血流自动调节研究进展

脑血流自动调节 （cerebral autoregulation, CA） 是人体在一定血压或脑灌注压波动范围内维持脑血流量 （cerebral blood flow） 相对稳定的能力, 可避免脑组织发生高灌注或低灌注。 CA在出血性卒中中存在不同程度受损, 且与临床因素及预后密切相关。 对出血性卒中患者行CA监测不仅可评估临床预后, 还可为动脉血压及脑灌注压的管理提供参考信息。 本文主要就脑出血 （intracerebral hemorrhage, ICH） 和蛛网膜下腔出血 （subarachnoid hemorrhage, SAH） 的CA相关进展做一综述, 旨在探讨CA在上述疾病中的改变及其临床应用价值。     

Correlation between serum IL-1beta levels and cerebral edema extent in a hypertensive intracerebral hemorrhage rat model

Abstract

Background: Interleukin-1beta (IL-1beta) is a pro-inflammatory cytokine that is increased following hypertensive intracerebral hemorrhage (ICH), potentially related to neural damage by cerebral edema.

Objective: To investigate the correlation between post-ICH serum IL-1beta and cerebral edema in a hypertensive rat model.

Methods: We used 30 successful ICH male spontaneously hypertensive rats (SHR) subjected to autologous blood infusion and displaying behavioral abnormalities (ICH group), and 30 sham-operated rats. Cerebral edema was assessed at 8, 16, 24, 48, 72, and 120 hours using dry and wet right hemisphere weighing, and serum IL-1beta levels were determined by enzyme-linked immunosorbent assay (ELISA). Nonlinear regression was performed between serum IL-1beta levels and cerebral edema extent at different time intervals after ICH.

Results: No significant difference was observed in preoperative blood pressure between the two groups. In ICH rats, behavioral abnormalities were observed at all time points except at 120 hours Intracerebral hemorrhage rats exhibited significantly increased serum IL-1beta levels between 16 and 72 hours, and increased cerebral edema between 24 and 72 hours (all P < 0·05 vs sham-operated rats), but no significant differences were found in the sham-operated group. Serum IL-1beta and cerebral edema in the ICH group returned to baseline by 120 hours Serum IL-1beta levels were positively correlated with cerebral edema (r = 0·906, P = 0·001).

Conclusion: Serum IL-1beta was related to cerebral edema extent in hypertensive ICH rats, which may eventually be useful as an indicator for progression of cerebral edema after ICH, and contributing to the choice of a treatment strategy.     

急性脑血管病患者血清和脑脊液中胰岛素样生长因子-1的测定及其临床意义

目的　探讨急性脑血管病患者血清及脑脊液中胰岛素样生长因子 - 1(IGF - 1)浓度的变化及其临床意义。方法　观察 40例脑血管病患者和 2 0例正常人血清及脑脊液IGF - 1浓度。病例组 :脑梗死组2 0例 ,脑出血组 2 0例 ,所有患者均在发病后第 3天抽取静脉血 2ml,其中脑梗死组在抽血当天作腰穿抽取脑脊液 2ml。IGF - 1采用酶联免疫分析方法测定。应用SPSS统计软件包进行统计分析 ,组间比较采用t检验。结果　病例组与对照组血清中IGF - 1浓度有明显统计学差异 (P <0 .0 1) ,脑梗死组与脑出血组血清中IGF - 1浓度无统计学差异 (P >0 .0 5 )。脑梗死组与对照组脑脊液中IGF - 1浓度有明显统计学差异 (P <0 .0 1)。结论　脑梗死和脑出血患者急性期血清IGF - 1浓度明显降低 ,脑梗死组患者急性期脑脊液IGF - 1浓度明显增高。     

Childhood cerebrovascular diseases not associated with vascular malformations

Of 76 patients in the pediatric age group suffering from cerebrovascular diseases treated in the years 1970–1983, 26 patients (34%) did not harbor intracranial vascular malformations (aneurysms or arterovenous malformations). Two groups of patients were identified: (a) those suffering from a spontaneous intracranial hemorrhage (16 cases); (b) those suffering from an ischemic stroke (10 cases). Of those with spontaneous intracranial hemorrhage, 10 patients underwent surgery and evacuation of the hematoma. In 2 cases the hematoma was located in the posterior fossa, in 1 case in the upper brain stem, and in 3 cases in the basal ganglia; in the remainder the hematoma was supratentorial. Two patients died soon after the hemorrhage. Eight of the surviving patients completely recovered. In those with ischemic stroke, none suffered from congenital heart disease, a well-known predisposing factor. In this second group 1 patient died and 9 survived. Only one patient showed complete recovery. The data indicate that a hemorrhagic stroke is more common than an ischemic stroke in a child presenting with acute onset of hemiparesis and/or loss of conciousness: thus the value of CT scan as the first diagnostic procedure is clear, owing to the possibility of emergency surgical treatment. In children with ischemic strokes, a complete laboratory/clinical evaluation should be undertaken in order to exclude preexisting heart disease, coagulation disorders or lipoprotein abnormalities, and less common systemic diseases.     

大鼠实验性脑出血后脑组织中c-fos基因的表达与局部脑血流的改变

目的 探讨大鼠实验性脑出血后脑组织中即刻早期基因c-fos的表达和局部脑血流的变化。方法 采用Nath改良法建立大鼠脑出血模型；免疫组化法及RT－PCR法测定其脑组织中fos蛋白和c-fos mRNA的表达；氢清除法测定其局部脑血流。结果 大鼠血肿周围区（基底节）在脑出血后1小时即出现fos蛋白的表达，至3小时达高峰；c-fos mRNA于出血后1小时达表达高峰,至3小时后仍有较高水平的表达；出血后1小时全脑的的血流量均下降，4小时恢复至对照组水平，并维持至出血后24小时，随着的24小时内再次出现脑血流下降。结论 大鼠脑出血后，血肿周围区和双侧皮质区的脑组织中存在着c-fos基因的快速而长久的诱导表达。局部脑血流的下降相对短暂，且脑血流的下降在时程上与c-fos基因的表达不相一致。     

脑出血后IGF-1在脑组织中的表达及其对细胞凋亡的影响

目的研究胰岛素样生长因子-1（IGF-1）在实验性大鼠脑出血后脑组织中的表达厦其对细胞凋亡的影响。方法应用立体定向技术,将自体未抗凝血注入大鼠基底节区以制备脑出血模型;将动物分为正常对照组、实验组厦干预组,分别在不同时间断头取脑以制作标本,连续切片分别作IGF-1阳性细胞免疫组化染色及TUNEL染色。结果脑出血后2h血肿周围脑组织表达IGF-1,24h达表达高峰,7d时恢复正常;TUNEL染色阳性细胞于脑出血后8h开始出现,3d时达高峰,7d时仍有表达;给予外源性IGF-1后,凋亡细胞显著减少,与同时点实验组相比,差别有显著性。结论脑出血后IGF-1可抑制细胞凋亡的发生,从而减轻脑出血后继发性脑损伤。     

同型半胱氨酸与脑血管病的关系

目的探讨同型半胱氨酸(Hcy)与脑血管病(CVD)的关系。方法采用高效液相色谱分析法,检测34例脑出血(CH)及59例脑梗死(CI)患者的Hcy,并与29名同龄健康对照组比较。结果CVD组有40例伴Hcy升高,占43.0%,平均血浆Hcy水平(18.28±12.60)μmol L,明显高于对照组(10.17±3.68)μmol L(P<0.01),但CH组与CI组之间无显著差异(P>0.05)。结论高Hcy血症不但与CI有关,而且与CH也密切相关,是CVD的独立危险因素之一。