脑白质病变相关性轻度认知功能障碍患者神经心理学特征分析

目的观察脑白质病变(WML)对轻度认知功能损害(mild cognitive impairment,MCI)患者神经心理学的影响。方法 WML-MCI患者和健康对照者进行常规核磁共振及神经心理学检查,观察WML对MCI患者神经心理学的影响,并对其机制进行探讨。结果 WML-MCI组与对照组相比,高血压、糖尿病和冠心病比例明显增高;词语流畅性测验、积木测验和画钟测验评分均明显降低(P<0.05);而2组间MMSE、数字广度测验和词语延迟回忆测验评分无明显差异。结论 WML影响MCI患者的认知功能,主要表现为视空间及执行功能。血管危险因素是MCI发病的危险因素。     

脑白质病变认知障碍的危险因素研究

目的研究缺血性脑白质病变患者认知功能障碍的发病率及相关危险因素。方法收集75例脑白质病变(white matter lesions,WML)患者的人口学资料和血管危险因素,并进行认知功能评定,将病例分为认知障碍组和对照组,2组对比研究,探讨WML患者认知障碍的可能危险因素。结果 75例患者中44例(58.7%)出现了不同程度的认知功能障碍。Logistic回归分析显示WML患者发生认知功能障碍与高血压(OR 4.050,95%CI 1.309～12.526)、糖尿病(OR 3.820,95%CI 1.103～13.231)和年龄(OR 1.133,95%CI 1.023～1.255)有关。结论较高比例WML患者可出现认知功能障碍,高血压、糖尿病和老龄与认知功能障碍的发生关系密切。     

Chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis causes selective recognition impairment in adult mice

Objectives: Chronic cerebral hypoperfusion (CCH) can result in vascular dementia and small vessel white matter ischemic injury. These findings have previously been demonstrated in a murine experimental model of CCH secondary to bilateral common carotid artery stenosis (BCAS). This study sought to elucidate the effects of CCH on recognition memory as assessed by the novel object recognition (NOR) test and histological analysis of the hippocampus and perirhinal cortex.

Methods: Studies were performed on ten-week-old male mice using bilateral 0.18 mm microcoils to narrow the carotid arteries in accordance with prior publications. Following surgery, BCAS (n = 6) and sham (n = 6) mice were evaluated using NOR and 8-arm radial maze testing paradigms. Tissue damage was assessed using H&E staining on a parallel cohort of mice (n = 6 BCAS, n = 7 sham).

Results: In the NOR paradigm, BCAS mice demonstrated significant deficits in short-term memory. Consistent with prior studies, BCAS mice also performed significantly worse on 8-arm radial maze testing. BCAS mice exhibited significantly more neuronal injury in the perirhinal cortex when compared to sham-operated mice. However, no significant differences in neuronal damage were observed in the CA1 region of the hippocampus.

Discussion: Experimental CCH secondary to BCAS results in recognition memory deficits on NOR testing. Damage to the perirhinal cortex, rather than to the hippocampus, may underlie this impairment.     

急性腔隙性脑梗死伴脑白质病变对认知功能的变化影响

目的探讨急性腔隙性脑梗死（LI）伴脑白质病变（WML）患者的认知功能障碍特点。方法收集137例患者和正常对照组30例,根据头颅MRIT2加权像及FLAIR像,将病例组分为LI组、WML组和u合并WML组,应用蒙特利尔认知评估量表（MoCA）进行认知评估。结果与对照组相比,WML组的延迟回忆与语言评分明显下降（P〈0．01）;LI组患者注意计算、语言、执行功能评分显著降低（P〈0．01）;LI合并WML组患者延迟记忆、视空间与执行功能评分显著降低（P〈0．01）。与LI组和WML组相比,执行功能障碍在LI合并WML组更明显（P〈0．01）。结论LI合并WML可导致患者认知功能障碍,主要表现为延迟记忆、视空间与执行等认知功能的受损;MoCA在皮层下缺血性脑血管病引起的血管性认知障碍的评定中具有很大的优势。     

阿尔茨海默病合并白质病变患者的认知功能障碍特点分析

目的探讨阿尔茨海默病(AD)合并白质病变(WML)患者危险因素和认知功能障碍特点。方法临床收集轻度阿尔茨海默病患者77例,根据MRIT2加权像是否合并WML分为单纯AD组34例和阿尔茨海默病合并WML组43例,以78名年龄和教育程度相匹配的认知正常老年人为对照组,分别进行MMSE、数字广度测验、词语延迟回忆测验、词语流畅性测验、积木测验和画钟测验。结果 (1)与对照组和单纯AD病组相比,AD合并WML组高血压病和房颤的比例明显升高(P<0.05)。(2)与对照组相比,单纯AD组和AD合并WML组MMSE、数字广度测验、词语延迟回忆测验、词语流畅性测验、积木测验和画钟测验评分均明显降低(P<0.05)。(3)与单纯AD组相比,AD合并WML组词语流畅性测验、积木测验和画钟测验评分均显著降低(P<0.05)。结论高血压病、糖尿病和房颤可能是AD合并WML的危险因素;WML可加重AD患者视空间和执行功能障碍。     

Impact of regional white matter lesions on cognitive function in subcortical vascular cognitive impairment

Abstract

Objectives:

Exact characterization and localization of white matter lesions (WMLs) as they relate and contribute to vascular cognitive impairment is highly debated. The purpose of this study was to investigate the impact of WML on cognitive function by using a new anatomy-based classification method.

Methods:

We detected WML accurately by using a three-dimensional fluid-attenuated inversion recovery (3D FLAIR) imaging technique and subsequently segmented WMLs by using an anatomy-based method. Participants included 56 consecutive patients diagnosed with subcortical vascular cognitive impairment (SubVCI). The volume of WMLs in different anatomic regions was measured. The volume of the hippocampus, the corpus callosum (CC), any lacunar infarcts, total gray matter (GM), and total brain volumes were also calculated.

Results:

Hippocampal (P = 0·005) as well as temporal WML volumes (P = 0·039) were both independently associated with mini-mental state examination (MMSE) score. Only the parietal WML volume (P = 0·000) was independently associated with Montreal Cognitive Assessment (MoCA) score. Frontal WMLs were independently correlated with executive function. Occipital WMLs were independently associated with visuospatial and recall function. Language impairment was independently correlated with both parietal GM and parietal WML volume. Functions related to orientation were independently associated with parietal WML volume.

Discussion:

The volume of WMLs in the temporal region as well as in the hippocampus were both independently associated with MMSE score. For the MoCA score, however, only parietal WML volumes were independently correlated. White matter lesions within different anatomic regions were separately correlated with different subdomains of cognitive function.     

Chronic cerebral hypoperfusion induces white matter lesions and loss of oligodendroglia with DNA fragmentation in the rat

Cerebrovascular white matter lesions represent an age-related neurodegenerative condition that appears as a hyperintense signal on magnetic resonance images. These lesions are frequently observed in aging, hypertension and cerebrovascular disease, and are responsible for cognitive decline and gait disorders in the elderly population. In humans, cerebrovascular white matter lesions are accompanied by apoptosis of oligodendroglia, and have been thought to be caused by chronic cerebral ischemia. In the present study, we tested whether chronic cerebral hypoperfusion induces white matter lesions and apoptosis of oligodendroglia in the rat. Doppler flow meter analysis revealed an immediate reduction of cerebral blood flow ranging from 30% to 40% of that before operation; this remained at 52–64% between 7 and 30 days after operation. Transferrin-immunoreactive oligodendroglia decreased in number and the myelin became degenerated in the medial corpus callosum at 7 days and thereafter. Using the TUNEL method, the number of cells showing DNA fragmentation increased three- to eightfold between 3 and 30 days post-surgery compared to sham-operated animals. Double labeling with TUNEL and immunohistochemistry for markers of either astroglia or oligodendroglia showed that DNA fragmentation occurred in both of these glia. Messenger RNA for caspase-3 increased approximately twofold versus the sham-operated rats between 1 and 30 days post-surgery. Immunohistochemistry revealed up-regulation of caspase-3 in the oligodendroglia of the white matter, and also in the astroglia and neurons of the gray matter. Molecules involved in apoptotic signaling such as TNF- and Bax were also up-regulated in glial cells. These results indicate that chronic cerebral hypoperfusion induces white matter degeneration in association with DNA fragmentation in oligodendroglia.     

血管生成对慢性低灌注状态下血脑屏障及脑白质损害的影响

目的 了解脑血管生成是否参与脑白质区域慢性低灌注状态下血脑屏障的破坏机制。方法 将72只雄性Wistar大鼠随机分为3组:假手术组、脑缺血组、干预组,脑缺血组及干预组大鼠结扎双侧颈总动脉构建慢性低灌注模型,干预组给予血管生成抑制剂灌胃以抑制血管生成; 对各组大鼠在相同时间点检测脑深部白质区域微血管密度、白质纤维密度以及伊文思蓝静脉注射6 h后脑白质区域组织内伊文思蓝水平。结果 脑缺血组及干预组大鼠脑白质区域血管密度和伊文思蓝浓度均显著高于假手术组,白质纤维密度显著低于假手术组,干预组微血管密度、白质纤维密度及脑组织内伊文思蓝水平显著低于脑缺血组。结论 慢性低灌注诱导的血管生成可能导致血脑屏障通透性增加,但血管生成有助于减轻白质损伤,但这种保护作用大于血脑屏障通透性改变带来的不利影响。     

Intensity of chronic cerebral hypoperfusion determines white/gray matter injury and cognitive/motor dysfunction in mice

We sought to establish a mouse model of subcortical ischemic vascular dementia (SIVD) that develops predominant white matter (WM) injury and cognitive dysfunction induced by chronic cerebral hypoperfusion. Adult C57Bl/6 male (n = 48) mice were subjected to bilateral common carotid artery stenosis with external microcoils (inner diameters: 0.16 mm, left; 0.18 mm, right). Mice were categorized according to left-side cerebral blood flow (CBF) value on day 6 into those with severe cerebral hypoperfusion (SCH; n = 16, < 30% of preoperative CBF baseline value) or moderate cerebral hypoperfusion (MCH; n = 21, 30-50% of preoperative value). Another 15 mice were sham operated. Neurological dysfunction was evaluated by Morris water maze, rotating rod, and open field tests. Histopathological examination was performed on day 35 after surgery. MCH animals showed persistent hyperlocomotion with reduced anxiety and spatial reference memory dysfunction. Rarefaction and small necrotic lesions were predominantly confined to the WM, with reactive astrocytosis, microglial infiltration, axonal loss, and myelin disruption, and these changes were dominant on the left side. SCH animals had persistent hyperlocomotion and motor dysfunction, and their ischemic lesions extended from the WM to the hippocampus and cortex. In MCH animals, myelin basic protein and neurofilament fiber densities in the WM were correlated with the time spent in the correct area in the water maze probe trials. Our MCH mouse model with the development of several types of neurological dysfunction with high reproducibility would be useful for investigating the pathomechanisms of WM injury in human SIVD.     

脑白质病变与轻度认知功能障碍的关系

目的 探讨脑白质病变(WML)与轻度认知功能障碍(MCI)的关系.方法 71例WML患者根据头颅MRI检查分为轻度组(27例)、中度组(21例)、重度组(23例),39例无WML的对照者为对照组.对入组者进行神经心理学量表检查;比较各组MCI的患病率,分析WML与MCI的相关性.结果 WML轻、中、重度组的MCI患病率明显高于对照组(均P＜0.01);WML中、重度组简易精神状态检查(MMSE)及蒙特利尔认知评估量表(MoCA)评分显著低于WML轻度组和对照组(均P＜0.01);随着WML程度的加重,除了抽象能力评分,MoCA其他各认知领域的评分均显著降低(均P＜0.05).多元线性相关分析显示,WML程度与MMSE、MoCA总分及除抽象思维能力的各认知域评分呈负相关(r=-0.252 ～-0.782,均P＜0.01).结论 WML可导致MCI,其对认知功能障碍的影响与WML的程度有关.     

半自动MRI定量方法测定脑白质高信号体积与病变定性评分的相关性

背景：在磁共振T2加权像和液体衰减反转恢复像中脑白质病变表现为白质高信号,目前对脑白质高信号体积、部位与认知功能损害的关系仍存在争议。 目的：以头颅磁共振对皮质下缺血性脑血管病患者白质高信号进行定量和定性测定,分析高信号体积和部位与认知损害的关系。 设计、时间及地点：于2007-12/2008-09在河北省人民医院神经内科完成。 对象：依据影像学诊断标准确定皮质下缺血性脑血管病53例,记录症状和体征,并进行神经心理学评估。 方法：采用美国GE公司生产的半自动1.5T MRI机对患者行头MRI扫描,定量测定脑白质高信号体积,并结合脑白质病变定性评分。 主要观察指标：分析皮质下缺血性脑血管病患者脑白质高信号体积与评分的相关性,以及白质病变与认知损害的关系。 结果：脑白质高信号体积和评分高度相关（rs=0.989, P < 0.001）,两者呈曲线关系。分层多元线性回归分析显示,白质高信号体积、白质高信号总评分的变化可以分别解释简明精神状态检查评分改变的10.5%和6.8%,前者较后者能更敏感地预测简明精神状态检查评分变化。不同区域脑白质病变中,仅基底核区白质高信号评分与简明精神状态检查评分有关（t=-2.126, P=0.039）,其他各区域白质高信号评分均非简明精神状态检查评分独立预测指标。 结论：脑白质高信号体积与评分均可应用于脑白质病变的测定,前者测定较脑白质高信号评分更敏感;皮质下缺血性脑血管病患者认知功能损害随着脑白质病变的增多,尤其是基底核区白质病变的增多而加重。     

FK506 ameliorates the discrimination learning impairment due to preventing the rarefaction of white matter induced by chronic cerebral hypoperfusion in rats

We examined the effects of the immunosuppressant tacrolimus (FK506) on the discrimination learning impairment induced by chronic cerebral hypoperfusion in rats. Chronic cerebral hypoperfusion was prepared by permanent ligation of bilateral common carotid arteries for male Wistar rats aged 9 weeks. FK506 (0.05 mg/kg, s.c.) recovered the learning impairment and also prevented the rarefaction of white matter and striatal neuronal cell damage. Our findings suggest that FK506 ameliorates the learning impairment mainly due to preventing neuropathological alterations.     

Cumulative white matter changes in the gerbil brain under chronic cerebral hypoperfusion

Summary An animal model of chronic brain hypoperfusion has been developed by applying coiled clips to the bilateral carotid artery of Mongorian gerbils. The brain tissue damage was neuropathologically studied after 1, 4, 8, and 12 weeks of hypoperfusion. The hippocampus, basal ganglia, and cerebral cortex of the chronically hypoperfused gerbil showed lesions with various severity which are probably due to ischemic episodes. In the cerebral white matter, however, two types of lesions were observed; one similar to those in the gray matter, and the other observed only in the white matter after more than an 8-week duration of brain hypoperfusion. The lesion specific to the white matter showed rarefaction and gliosis without locally associated ischemic changes. This type of the white matter lesion was never found in the gerbil brain before 8 weeks and, significantly, increased in number and size by 12 weeks post operation. The accumulation of the white matter lesions is characteristic in the gerbil with chronic hypoperfusion. The observed white matter-specific lesion resembles the histological changes in aged brain with cerebrovascular diseases.     

Prospective memory impairment in patients with white matter lesions

Objective: A vast majority of the episodic memory literature in white matter lesions (WML) had focused on “retrospective memory (RM)”, little was known about prospective memory (PM) in WML patients. The aim of our study was to investigate the effect of WML patients on event-based prospective memory (EBPM) and time-based prospective memory (TBPM). In addition, our study attempted to understand the possible mechanisms of PM damage in WML patients.

Methods: A total of 42 WML patients and 40 age and education level matched healthy controls were included. EBPM (an action whenever particular words were presented) and TBPM (an action at certain times) were performed to test the involvement of PM in WML. The extent of WML within cholinergic pathways were assessed using the cholinergic pathways hyperintensities scale (CHIPS).

Results: A significant difference was found in the performance of Montreal Cognitive Assessment (MOCA) (21.8?±?3.9 vs. 26.6?±?1.7, p?<?0.05) and TBPM (2.88?±?1.21 vs. 4.27?±?0.78, p?<?0.05), but not Mini-Mental State Examination (MMSE) (26.9?±?2.8 vs. 27.3?±?1.2, p?>?0.05) and EBPM (3.62?±?1.25 vs.4.47?±?1.11, p?>?0.05) in WML patients compared with the healthy controls. Moreover, TBPM and MOCA scores were negatively correlated with CHIPS scores.

Conclusions: WML patients were impaired in TBPM but not in EBPM, supporting that EBPM and TBPM have different neural mechanisms. Our results demonstrated that WML are involved in the TBPM probably by affecting the central cholinergic pathway.     

Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study

Activation of glial cells and white matter changes (rarefaction of the white matter) induced in the rat brain by permanent bilateral occlusion of the commom carotid arteries were immunohistochemically investigated up to 90 days. One day after ligation of the arteries, expression of the major histocompatibility complex (MHC) class I antigen in microglia increased in the white matter including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. After 3 days of occlusion, MHC class I antigen was still elevated and in addition MHC class II antigen and leukocyte common antigen were up-regulated in the microglia in these same regions. Astroglia, labeled with glial fibrillary acidic protein, increased in number in these regions after 7 days of occlusion. A few lymphocytes, labeled with CD4 or CD8 antibodies, were scattered in the neural parenchyma 1 h after occlusion. Activation of glial cells and infiltration of lymphocytes persisted after 90 days of occlusion in the white matter and the retinofugal pathway. However, cellular activation and infiltration in microinfarcts of the gray matter was less extensive and was substantially diminished 30 days after occlusion. The white matter changes were most intense in the optic nerve and optic tract, moderate in the medial part of the corpus callosum, internal capsule and anterior commissure, and slight in the fiber bundles of the caudoputamen. These results indicated that chronic cerebral hypoperfusion induced glial activation preferentially in the white matter. This activation seemed to be an early indicator of the subsequent changes in the white matter.     

VEGF overexpression improves mice cognitive abilities after unilateral common carotid artery occlusion

Angiogenesis and neurogenesis are adaptive responses protecting cerebral tissue from hypoxic–ischemic injury. Both processes seem to be governed by hypoxia-induced growth factors, of which vascular endothelial growth factor (VEGF) is a prominent example. The aim of this study was to investigate the influence of VEGF overexpression (V1 mice) on mice cognitive function and cerebral structure under moderate cerebral oligemia.In 33 V1 and wild-type (wt) mice, the left common carotid artery was permanently occluded (CCAO) under acute (48 h) and subchronic (12 days) conditions. Sham operation was performed in 35 mice (controls). Psychometric testing was done using holeboard test and Morris Water Maze system, immunohistochemistry was performed for detection of cerebral apoptosis, nestin and CD31 expression.The results show that under control conditions V1 mice showed better spatial cognitive abilities as compared to their wt littermates. During CCAO, time and distance to reach a hidden platform in Water Maze were shorter in V1 mice as compared to wt animals, indicative of faster learning and better spatial memory processes. While no signs of necrosis or apoptosis were detected, immunohistochemistry showed that VEGF transgenity was related to higher number of nestin-positive precursor cells. Finally, acute CCAO was paralleled by a reduction of CD31 staining in wt but not V1 mice.We conclude that VEGF overexpression led to a protective effect on cognitive function, because V1 mice showed evidence for faster spatial learning and better memory, as well as an increased number of neuronal precursor cells and a prevention of endothelial cell loss after CCAO.     

Elevated leukocyte count in asymptomatic subjects is associated with a higher risk for cerebral white matter lesions

Objective

Cerebral white matter lesions (WMLs) are radiologic markers of small vessel disease in brain, and inflammatory processes were related to WMLs. We propose to determine if elevated leukocyte count was associated with a higher risk of WMLs.

Methods

1586 asymptomatic subjects who visited our hospital for a routine health check-up were enrolled. Leukocyte counts were measured and the presence of moderate to severe WMLs was determined by brain MRI.

Results

Thirty (1.9%) had moderate to severe WMLs, and a significant greater proportion (4.1%) of subjects in the highest leukocyte count quartile had moderate to severe WMLs. After adjusting by C-reactive protein, aspirin use and cardiovascular risk factors, the highest quartile of leukocyte count (≥6.7 × 10⁹/L) was significantly associated with moderate to severe WMLs compared with the lowest quartile [adjusted odds ratio, 4.03; 95% confidence interval, 1.05-15.5].

Conclusion

The authors report for the first time that an elevated leukocyte count is independently associated with moderate to severe WMLs.     

慢性颈内动脉闭塞导致认知功能障碍的研究进展

慢性颈内动脉闭塞(CICAO)是认知功能障碍的独立危险因素,可通过多种机制影响脑部结构及血流动力学情况(包括淀粉样蛋白沉积、炎症介质形成、脑灌注不足等),导致非心脑血管事件风险增加。颈动脉系统重度狭窄或闭塞部位不同所致认知功能减退的表现形式可能存在差异,控制高血压等高危因素可降低其发生风险。临床上对于CICAO患者脑血流动力学情况常用的评估手段为CT灌注成像检查(CTP),其可能通过间接评估侧支循环及其他血流动力学指标来预测患者出现认知功能减退的风险,但准确性仍有争议。目前临床上常用药物可在一定程度上改善患者的认知功能,尚无根治药物,血管内介入治疗可能通过降低脑梗死再发及改善脑灌注而改善认知功能,但对于纳入患者的标准仍需严格评估,其安全性及有效性仍需进一步探索。该文基于该类疾病的研究现状,对其发病机制、影响因素、评估手段及治疗方案进行综述,以期为临床诊疗及后续研究提供参考。     

慢性脑低灌注大鼠海马Arc低表达与其认知功能障碍的相关性研究

目的 探讨慢性脑低灌注大鼠海马活性调节的细胞骨架相关蛋白(activity-regulated cytoskeletal-associated protein,Arc)的低表达与其认知功能障碍的相关性。方法 大鼠慢性脑低灌注模型使用持久性双颈总动脉结扎术(2-vessel occlusion,2-VO); 大鼠随机分成假手术组和2-VO组,每组各6只。术后第8周行Morris水迷宫评价其认知功能; 实时定量聚合酶链式反应(Real time quantitative polymerase chain reaction,RT-qPCR)及蛋白免疫印迹法检测大鼠海马Arc mRNA及蛋白表达水平。结果(1)2-VO组大鼠第2～5 d的逃逸潜伏期比假手术组明显延长(P<0.01)及其在原平台区域游泳时间明显比假手术组短(P<0.01);(2)2-VO组大鼠海马Arc mRNA水平及免疫反应条带相对灰度值分别比假手术组明显降低(P均<0.01);(3)空间探索实验中2-VO大鼠在原平台区域游泳时间与海马Arc免疫反应条带相对灰度值呈正相关(r=0.7085,P<0.05)。结论 慢性脑低灌注大鼠的认知功能障碍可能与海马Arc的低表达相关。