慢性前脑缺血致血管性痴呆大鼠不同脑区MAP-2的经时变化研究

目的研究微管结合蛋白-2(MAP-2)在慢性前脑缺血致血管性痴呆大鼠额、颞叶皮质和海马区的经时变化。方法采用双侧颈总动脉永久结扎方法制备慢性前脑缺血致VD大鼠动物模型;采用免疫组织化学方法检测痴呆鼠不同脑区MAP-2的经时变化情况;采用同济大学研制的HPIAS-1000高清晰彩色病理图文分析系统对不同脑区MAP-2阳性信号的面积密度进行分析。结果实验发现痴呆大鼠不同脑区MAP-2的表达随时间变化。缺血1个月、2个月、4个月后MAP-2的表达阳性面积逐渐减少,与对照组相比有统计学意义。从形态学变化角度来说,1个月时MAP-2轻度变化,提示为可逆性损伤。随着缺血时间的延长,MAP-2免疫组化染色越来越淡。至4个月时,MAP-2免疫组化染色基本消失,提示为不可逆损伤。结论慢性持续性脑血流量下降致MAP-2的改变在VD的病理生理过程中起重要作用。     

皮质下缺血性血管性认知损害扩散张量成像研究

目的通过扩散张量成像(DTI)探讨皮质下缺血性血管性认知损害患者白质微结构变化及其与认知功能之间的相关性。方法采集49例皮质下缺血性脑血管病患者[轻度血管性痴呆(VaD)10例、非痴呆型血管性认知损害(VCIND)20例、认知功能正常19例]DTI数据并观察皮质下白质微结构改变,分析VaD组患者DTI参数与认知功能间的相关性。结果与对照组相比,VaD组内侧前额叶、前扣带回、胼胝体干、双侧顶叶、右侧颞叶、双侧眶额叶,以及VCIND组右侧额下回、右侧海马、双侧楔前叶FA值减低(均P=0.000);与VCIND组比较,VaD组内侧前额叶、前扣带回、胼胝体、双侧顶叶、右侧颞叶FA值减低(P=0.000)。与对照组相比,VaD组内侧前额叶、胼胝体、双侧顶叶、双侧颞叶、前扣带回,以及VCIND组双侧楔前叶、右侧海马MD值升高(均P=0.000);与VCIND组相比,VaD组右侧内侧前额叶、前扣带回、胼胝体干、双侧顶叶、双侧颞叶MD值升高(均P=0.000)。VaD组内侧前额叶FA值与数字连线测验A时呈显著负相关(r=-0.782,P=0.007),双侧额下回MD值与数字连线试验A时程呈显著正相关(r=0.877,P=0.001)。结论 DTI对皮质下缺血性认知损害患者白质微结构改变更敏感,能够反映患者认知功能早期异常改变;内侧前额叶白质微结构的改变是影响患者执行能力的重要因素。     

脑缺血再灌注拟血管性痴呆小鼠皮层及海细胞病理形态学动态观察

目的观察脑缺血再灌注拟血管性痴呆小鼠大脑皮层及海马细胞病理形态学的较长期演变.方法复制脑缺血再灌注拟血管性痴呆小鼠模型,分别于术后7d、15d、30d脑部取材,石蜡切片,HE与Nissl染色,对皮层及海马细胞病理形态学进行较长期动态观察.结果 7d模型小鼠大脑皮质变薄,部分神经细胞核固缩,局限性神经元数目减少,出现筛网状结构,胶质细胞增生,15d、30d镜下与7d基本相同.海马CA1区细胞脱失,随时间推移逐渐加重,至术后30d,海马CA1区细胞几乎完全脱失,胶质细胞大量增生,形成结节,CA2、CA3区细胞也严重脱失,呈现海马硬化.结论海马锥体细胞的迟发性坏死是缺血性脑血管病致痴呆的病理学基础.     

脑缺血再灌注拟血管性痴呆小鼠皮层及海马细胞病理形态学动态观察

目的 观察脑缺血再灌注拟血管性痴呆小鼠大脑皮层及海马细胞病理形态学的较长期演变。方法 复制脑缺血再灌注拟血管性痴呆小鼠模型，分别于术后７ｄ、１５ｄ、３０ｄ脑部取材，石蜡切片，ＨＥ与Ｎｉｓｓｌ染色，对皮层及海马细胞病理形态学进行较长期动态观察。结果　７ｄ模型小鼠大脑皮质变薄，部分神经细胞核固缩，局限性神经元数目减少，出现筛网状结构，胶质细胞增生，１５ｄ、３０ｄ镜下与７ｄ基本相同。海马ＣＡ１区细胞脱失，随时间推移逐渐加重，至术后３０ｄ，海马ＣＡ１区细胞几乎完全脱失，胶质细胞大量增生，形成结节，ＣＡ２、ＣＡ３区细胞也严重脱失，呈现海马硬化。结论　海马锥体细胞的迟发性坏死是缺血性脑血管病致痴呆的病理学基础。     

神经元型一氧化氮合酶在血管性痴呆大鼠海马中的表达

目的 探讨神经元型一氧化氮合酶(nNOS)在血管性痴呆(VD)大鼠海马中的表达。方法 将60只大鼠随机分为：对照组、VD12h组、VD1d组、VD3d组、VD7d组。采用反复夹闭双侧颈总动脉方法建立VD大鼠模型，用HE染色观察各组大鼠海马CA1区神经元的数目；应用免疫组化染色和Western印迹方法检测nNOS在大鼠海马中的表达。结果 VD12h组、VD1d组、VD3d组、VD7d组大鼠海马CA1区神经元数均明显下降。nNOS在对照组大鼠海马CA1区中弱表达．在VD12h组表达增强．VD1d组进一步增强，VD3d和7d组表达逐渐减弱。结论 nNOS可能参与缺血早期海马神经元的损害，是VD的发病机制之一。     

慢性前脑缺血致血管性痴呆大鼠不同脑区NF200的经时变化研究

目的研究神经丝蛋白200(NF200)在慢性前脑缺血致血管性痴呆大鼠额、颞叶皮质和皮质下白质的经时变化。方法采用双侧颈总动脉永久结扎方法制备慢性前脑缺血动物模型;采用免疫组织化学方法检测痴呆鼠不同脑区NF200的经时变化情况;采用同济大学研制的HPIAS-1000高清晰彩色病理图文分析系统对不同脑区NF200阳性信号的面积密度进行分析。结果实验发现双侧颈总动脉永久结扎后不同脑区NF200的表达随时间变化。缺血1 m,2 m,4 m后NF200的表达阳性面积逐渐减少,与对照组相比有统计学意义。在形态学变化方面,1 m时NF200轻度变化,提示为可逆性损伤。随着缺血时间的延长,NF200免疫组化染色越来越淡。至4 m时,NF200免疫组化染色基本消失,提示为不可逆损伤。结论慢性持续性脑血流量下降致NF200的改变在血管性痴呆的病理生理过程中起一定作用。     

血管性痴呆大鼠海马区核因子-κB、环氧合酶-2的表达变化

目的通过检测血管性痴呆(vascular dementia,VD)大鼠海马CA1区核因子-κBp65(nuclear factor-κB p65,NF-κBp65)与环氧合酶-2(cyclooxygenase-2,COX-2)的表达,探讨NF-κB、COX-2对VD大鼠的损伤作用。方法28只大鼠随机分为两组,假手术(SOG)组(n=13)和模型(VD)组(n=15),采用HE染色,光镜下观察海马CA1区锥体细胞的改变,免疫组化方法检测海马CA1区NF-κBp65、COX-2蛋白的表达。结果与假手术组相比,模型组组海马CA1区锥体细胞损伤、丧失明显,NF-κBp65、COX-2蛋白表达高于假手术组,与假手术组相比有统计学意义(P(0.01)。结论血管性痴呆大鼠海马CA1区NF-κBp65、COX-2蛋白的表达增加,NF-κBp65、COX-2蛋白的高表达可能是学习记忆障碍的原因之一。     

慢性低灌注大鼠血清及脑组织中MCP-1及IL-8的表达

目的 观察慢性低灌注大鼠的血清及脑组织中单核细胞趋化蛋白-1( MCP-1)及白细胞介素-8(IL-8)的表达,探讨炎性细胞因子在慢性低灌注致血管性痴呆发病中的可能机制.方法 Wistar大鼠180只,随机分为正常对照组、假手术对照组和模型组,通过永久性结扎大鼠的双侧颈总动脉导致前脑缺血建立慢性低灌注动物模型,在术后1d、3d、7d、14d、1个月、2个月、3个月、4个月的时间点,采用免疫组化和ELISA的方法,观察大鼠的血清及脑组织中MCP-1及IL-8的表达水平和演变过程.结果 模型组大鼠学习记忆能力随缺血时间的延长减退越明显.缺血1个月后,白质髓鞘脱失、间质疏松呈空泡样改变逐渐明显,以胼胝体及脑室周围白质明显.免疫组化染色证实MCP-1高表达,缺血早期以皮质及海马等部位多见,后期以白质的表达最为显著,见于脑室周围白质、胼胝体等区域.ELISA显示MCP-1在大鼠脑组织及血清中均出现两次高表达,而IL-8仅出现一次高表达,且脑组织中的表达滞后于血清中的表达,但组织中蛋白的表达量远高于血清中的表达.结论 (1)慢性持续性脑缺血可致大鼠出现进行性认知功能障碍；(2)趋化因子MCP-1及IL-8的慢性持续性高表达可能在慢性缺血致血管性痴呆病理损伤过程中起了一定的作用.     

血管性痴呆大鼠海马区核因子-κB、环氧合酶-2的表达变化

目的 通过检测血管性痴呆(vascular dementia,VD)大鼠海马CA1区核因子-κBp65(nuclear factor-κB p65, NF-κBp65)与环氧合酶-2(cyclooxygenase-2,COX、2)的表达,探讨NF -κB和COX-2的损伤作用.方法 28只大鼠随机分为假手术组(SOG)13只和模型组(VD)15只,取海马CA1区为观察部位,HE染色观察锥体细胞的改变,免疫组化检测NF-κBp65、COX-2的表达.结果 与SOG相比,VD大鼠海马CA1区锥体细胞损伤、丧失明显,NF-κBp65、COX-2蛋白增加,差异有统计学意义(P﹤0.01).结论 VD大鼠海马CA1区NF-κBp65、COX-2蛋白的高表达可能是学习记忆障碍的原因之一.     

脑脉泰对慢性前脑缺血致血管性痴呆大鼠脑血流量及海马神经元凋亡的影响

目的 研究慢性前脑缺血致血管性痴呆大鼠海马区局部脑血流量（rCBF）改变及细胞凋亡情况,探讨脑脉泰治疗血管性痴呆的疗效及可能机制。方法 采用双侧劲总动脉永久结扎法(2VO)制备慢性前脑缺血致血管性痴呆的动物模型,随机分为假手术对照组,模型对照组,给药组（脑脉泰）。手术后4周,HE染色观察神经元形态学改变,免疫组化染色检测海马区Caspase-3,bax蛋白表达变化。应用激光多普勒血流仪检测各组大鼠海马局部脑血流量。 结果 模型组大鼠海马Caspase-3、Bax阳性细胞灰度平均值低于假手术组、给药组,差异均具有显著性（P<0.05）;模型组海马rCBF低于假手术组、给药组,差异均具有显著性（P<0.05）。 结论 VD模型大鼠海马rCBF下降,海马神经细胞凋亡增加;脑脉泰可能通过增加海马局部脑血流量,直接或间接抑制海马神经细胞凋亡从而减轻VD认知功能障碍。     

Voxel-based analyses of gray/white matter volume and diffusion tensor data in major depression

The purpose of this study is to use voxel-based analysis to simultaneously elucidate regional changes in gray/white matter volume, mean diffusivity (MD), and fractional anisotropy (FA) in patients with unipolar major depressive disorder. We studied 21 right-handed patients and 42 age- and gender-matched right-handed normal subjects. Local areas showing significant gray matter volume reduction in depressive patients compared with controls were observed in the right parahippocampal gyrus, hippocampus, bilateral middle frontal gyri, bilateral anterior cingulate cortices, left parietal and occipital lobes, and right superior temporal gyrus. Local areas showing an increase of MD in depressive patients were observed in the bilateral parahippocampal gyri, hippocampus, pons, cerebellum, left frontal and temporal lobes, and right frontal lobe. There was no significant difference between the two groups for FA and white matter volume in the entire brain. Although there was no local area where brain volume and MD were significantly correlated with disease severity, FA tended to correlate negatively with total days depressed in the right anterior cingulate and the left frontal white matter. These results suggest that the frontolimbic neural circuit might play an important role in the neuropathology of patients with major depressive disorder.     

Ipsilateral and contralateral MRI volumetric abnormalities in chronic unilateral temporal lobe epilepsy and their clinical correlates

PURPOSE: To assess the presence, extent, and clinical correlates of quantitative MR volumetric abnormalities in ipsilateral and contralateral hippocampus, and temporal and extratemporal lobe regions in unilateral temporal lobe epilepsy (TLE). METHODS: In total, 34 subjects with unilateral left (n = 15) or right (n = 19) TLE were compared with 65 healthy controls. Regions of interest included the ipsilateral and contralateral hippocampus as well as temporal, frontal, parietal, and occipital lobe gray and white matter. Clinical markers of neurodevelopmental insult (initial precipitating insult, early age of recurrent seizures) and chronicity of epilepsy (epilepsy duration, estimated number of lifetime generalized seizures) were related to magnetic resonance (MR) volume abnormalities. RESULTS: Quantitative MR abnormalities extend beyond the ipsilateral hippocampus and temporal lobe with extratemporal (frontal and parietal lobe) reductions in cerebral white matter, especially ipsilateral but also contralateral to the side of seizure onset. Volumetric abnormalities in ipsilateral hippocampus and bilateral cerebral white matter are associated with factors related to both the onset and the chronicity of the patients' epilepsy. CONCLUSIONS: These cross-sectional findings support the view that volumetric abnormalities in chronic TLE are associated with a combination of neurodevelopmental and progressive effects, characterized by a prominent disruption in ipsilateral hippocampus and neural connectivity (i.e., white matter volume loss) that extends beyond the temporal lobe, affecting both ipsilateral and contralateral hemispheres.     

Pathological and biochemical studies on a case of Pick disease with severe white matter atrophy

We report on a male patient with Pick disease who had shown severe white matter atrophy and dilatation of the lateral ventricle in the frontal lobe from an early stage. Upon admission to our hospital 2 years after disease onset, the patient showed apathy, and MRI revealed severe atrophy of the cortex and white matter of the frontal lobe. He died at age 74, 11 years after disease onset. Autopsy revealed severe atrophy of the frontal and temporal lobes, severe loss of white matter in the frontal lobe, dilatation of the lateral ventricles, and cortical thinning. Histopathological examination showed severe loss of myelinated fibers in the frontal white matter and severe neuronal loss with gliosis in the frontal and temporal cortices. Many Pick bodies were seen. Our patient had a rare case of Pick disease predominantly affecting the frontal lobe with severe involvement of the white matter from an early stage. This case suggests that myelinated fibers in the white matter as well as cerebral neurons are primarily affected in Pick disease.     

Long-term time course of regional changes in cholinergic indices following transient ischemia in the spontaneously hypertensive rat brain

Using an animal model of forebrain ischemia in spontaneously hypertensive rats (SHR) by 3-h bilateral carotid occlusion, and various indices of the cerebral cholinergic system were assessed for periods up to 24 weeks. The lesions observed histologically in the hippocampus of SHR 2 weeks after ischemia were less severe than those in the frontal cortex. Marked elevation of acetylcholine concentration was transiently observed in the frontal cortex, hippocampus and thalamus + midbrain at 2 weeks, and in the striatum at 1–4 weeks after ischemia. Choline acetyltransferase activity remained unchanged in all regions throughout the experimental period except for a minimal decrease in the frontal cortex at 4 weeks. Choline esterase (ChE) activity was slightly decreased in the frontal cortex at 2–4 weeks after ischemia but recovered by 8 weeks. A decrease in the hippocampus was seen at 8 weeks. The B_max for the M1-receptor was significantly reduced by 2 weeks in the frontal cortex and by 4 weeks in the hippocampus. Low B_max values in both regions persisted through week 24. These delayed hippocampul changes in the ChE activity and M1-receptor in SHR were similar to those of the very much delayed changes in M1-receptor previously reported in the gerbil model for transient ischemia. In contrast, Wistar-Kyoto rats (WKY), used as normotensive controls, exhibited no histological or biochemical changes for up to 24 weeks. The difference between SHR and WKY may depend on the more severe cerebral blood flow depletion during carotid ligation in the former. The chronic state of SHR after the transient ischemia may be a useful pathophysiological model for human cerebral infarctions with hypertension.     

Memory and executive function in older adults: relationships with temporal and prefrontal gray matter volumes and white matter hyperintensities

Forty-eight healthy adults aged 65-85 were recruited for structural magnetic resonance scans after an extensive neuropsychological battery that ensured a high degree of variability across the sample in performance on long-term memory tests, and on tests traditionally thought to rely on prefrontal cortex. Gray matter volumes were measured for three gyri in the frontal lobe (superior, middle, inferior), six gyri in the temporal lobe (superior, middle, inferior, fusiform, parahippocampal, and hippocampus), and the occipital lobe. Gray matter volumes declined across the age range evaluated, but with substantial regional variation--greatest in the inferior frontal, superior temporal, and middle temporal gyri but negligible in the occipital lobe. Both memory performance and executive function declined as the number of hyperintense regions in the subcortical white matter increased. Memory performance was also significantly correlated with gray matter volumes of the middle frontal gyrus (MFG), and several regions of temporal neocortex. However, the correlations were all in the negative direction; better memory performance was associated with smaller volumes. Several previous reports of significant negative correlations between gray matter volumes and memory performance are described, so that the possible reasons for this surprising finding are discussed.     

高血压大鼠脑内小血管改变及其继发损伤的研究

目的通过对比研究自发高血压大鼠(SHR)与非高血压W istar大鼠(NHR)脑内血管及其继发神经元、髓鞘病理改变,阐述高血压病对脑血管及中枢神经系统的影响。方法将10只SHR和10只W istar大鼠分为单纯高血压组及非高血压对照组。M orris水迷宫观察大鼠空间记忆能力,HE染色观察大鼠脑内小血管的形态、数量,额叶、颞叶、海马、丘脑神经元细胞的改变,LFB染色观察脑室周围髓鞘改变,并结合图像分析、统计学方法综合分析行为学、脑内小血管及神经元细胞、脑室周围深部白质髓鞘改变的关系。结果单纯高血压组记忆功能较非高血压对照组明显下降(P<0.05);单纯高血压组与非高血压对照组比较,无论皮层还是皮层下小动脉直径明显变小(P<0.05)。单纯高血压组神经元及髓鞘较非高血压对照组明显脱失(P<0.05)。结论长期高血压可造成脑内小动脉狭窄;狭窄的小动脉可导致神经元、髓鞘脱失,神经功能受损;实验条件下,神经元、髓鞘脱失可致血管性痴呆。     

慢性应激抑郁模型大鼠左右大脑化学发光强度不对称性改变

目的检测抑郁大鼠模型左右海马、额叶、颞叶化学发光强度的改变,探讨抑郁症大鼠大脑不对称性损伤的可能机制。方法建立大鼠慢性应激抑郁模型,采用过氧化氢诱导化学发光法观察大鼠海马、额叶、颞叶组织的化学发光强度。结果抑郁模型大鼠左侧海马、颞叶、额叶化学发光强度值均高于正常对照组,差异有统计学意义[海马：（84．17±4．22）VS（65．67±10．44）;额叶：（157．33±9．3]）VS（123．00±8．34）;颞叶：（153．67±11．96）VS（120．17±9．35）;t分别为～6．893,-10．600,r-6．144;P〈0．051]l,而右侧海马、额叶、颞叶组织化学发光强度的比较差异无统计学意义（P〉0．05）。结论抑郁症对大鼠大脑组织的损伤存在自由基生成和脂质过氧化反应不对称性改变。     

Disconnection of hippocampal networks contributes to memory dysfunction in individuals with temporal lobe epilepsy

A deficit in declarative memory function is common among individuals with temporal lobe epilepsy. The purpose of this study is to evaluate the relationship between the volume of the hippocampus, entorhinal cortex along with the surrounding parahippocampal white matter and memory performance in those with temporal lobe epilepsy. T1 weighted MRI scans were acquired using a 3‐D pulse sequence in 50 individuals with temporal lobe epilepsy. Hippocampal and entorhinal cortex volumes were derived by manually tracing consecutive coronal slices aligned perpendicular to the long axis of the hippocampus. In addition, parahippocampal white matter volumes were determined using voxel based morphometry. Finally, declarative memory was assessed using immediate and delayed verbal and visual memory tests from the Wechsler Memory Scale third edition. Significant correlations were seen between right and left hippocampal volumes and delayed verbal memory test scores. In addition, left parahippocampal white matter showed positive correlations with immediate and delayed verbal and visual recall. Furthermore, regression models found that the right hippocampus and left parahippocampal white matter were the best predictors of immediate and delayed verbal and visual memory performance. These results show that a decrease in white matter fibers projecting to the hippocampus may cause a disruption of incoming multi‐modal sensory information, contributing to the memory decline seen in individuals with temporal lobe epilepsy.     

White matter: beyond focal disconnection

The complex phenomenology of white matter dementia and many neuropsychiatric disorders implies that they originate from involvement of distributed neural networks, and white matter neuropathology is increasingly implicated in the pathogenesis of these network disconnection syndromes. White matter disorders produce functional asynchrony of interdependent cerebral regions subserving normal cognitive and emotional functions. Accumulating evidence suggests that white matter dementia primarily reflects disturbed frontal systems connectivity, whereas disruption of frontal and temporal lobe systems is implicated in the pathogenesis of neuropsychiatric disorders. Continued study of normal and abnormal white matter promises to help resolve challenging problems in behavioral neurology and neuropsychiatry.