Cerebral amyloid angiopathy with dementia: clinicopathological studies of 17 cases

ＯｂｊｅｃｔｉｖｅｓＴｏｓｔｕｄｙｃｌｉｎｉｃｏｐａｔｈｏｌｏｇｉｃａｌｙ１７ｃａｓｅｓｏｆｃｅｒｅｂｒａｌａｍｙｌｏｉｄａｎｇｉｏｐａｔｈｙ（ＣＡＡ）ｗｉｔｈｄｅｍｅｎｔｉａａｎｄｔｏｉｎｖｅｓｔｉｇａｔｅｔｈｅｐｏｓｓｉｂｌｅｎｅｕｒｏｐａｔｈｏ...     

Nicotinamide mononucleotide adenylyltransferase 1 gene NMNAT1 regulates neuronal dendrite and axon morphogenesis in vitro

Background  Wallerian degeneration is a self-destructive process of axonal degeneration that occurs after an axonal injury or during neurodegenerative disorders such as Parkinson’s or Alzheimer’s disease. Recent studies have found that the activity of the nicotinamide adenine dinucleotide (NAD) synthase enzyme, nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) can affect the rate of Wallerian degeneration in mice and drosophila. NMNAT1 protects neurons and axons from degeneration. However, the role of NMNAT1 in neurons of central nervous system is still not well understood.

Methods  We set up the culture of primary mouse neurons in vitro and manipulated the expression level of NMNAT1 by RNA interference and gene overexpression methods. Using electroporation transfection we can up-regulate or down-regulate NMNAT1 in cultured mouse dendrites and axons and study the neuronal morphogenesis by immunocytochemistry. In all functional assays, FK-866 (CAS 658084-64-1), a highly specific non-competitive inhibitor of nicotinamide phosphoribosyltransferase was used as a pharmacological and positive control.

Results  Our results showed that knocking down NMNAT1 by RNA interference led to a marked decrease in dendrite outgrowth and branching and a significant decrease in axon growth and branching in developing cortical neurons in vitro.

Conclusions  These findings reveal a novel role for NMNAT1 in the morphogenesis of developing cortical neurons, which indicate that the loss of function of NMNAT1 may contribute to different neurodegenerative disorders in central nervous system.

     

NGF、BDNF和NT3在AD大鼠海马中的分布及表达变化

目的 观察NGF、BDNF和NT3在Alzheimer disease（AD）大鼠海马中的分布及其表达变化。方法 采用海马注射Aβ淀粉蛋白的方法建立AD模型。10d后对大鼠进行灌注,取脑,冰冻切片,用NGF、BNDF和NT3抗体行免疫组织化学染色。对海马恒定视野内NGF、BDNF和NT3的阳性细胞进行记数并进行统计学分析。结果 AD组海马中的NGF阳性细胞较正常组显著增多（P〈0．01）．且染色增强。BDNF阳性细胞较正常组明显减少（P〈0．01）．染色强度减弱。而NT3的阳性细胞数及染色强度与正常组比较差异均没有统计学意义（P〉0．05）。结论 NGF、BDNF和NT3在AD的海马中发生了不同的变化,提示NGF、BDNF和NT3在AD中发挥了不同的作用．尤其是BDNF阳性细胞的减少可能与AD的神经功能减退有关。     

11: disorders of memory and intellect.

The clinical approach to the patient with a suspected disorder of memory and intellect is to establish whether it is dementia, which parts of the brain are affected, what is the cause, what is the prognosis, and what can be done about it. The diagnosis of dementia usually requires the involvement of memory and at least one other cognitive system. Delirium and depression are important differential diagnoses. Patients with dementia should usually have some simple investigations after a careful history-taking and examination to identify "reversible" causes. The commonest cause of dementia is Alzheimer's disease, in which short-term memory disturbance is usually prominent. Other causes of dementia include cerebrovascular disease, Lewy-body disease and Pick's disease. There is now hope for patients with Alzheimer's disease (which can be treated with some success with cholinesterase inhibitors) and patients with vascular dementia, in whom aggressive control of causal risk factors may retard progression.     

Etiology and pathology of 71 dementia patients during presenile and senile periods

Etiological and pathological findings in 71 patients with dementia during presenile and senile periods were reported. According to the etiological findings these were divided into: vascular dementia (41), Alzheimer's disease (13), Pick's disease (1), Parkinsonian dementia (5), progressive supranuclear palsy (1), Huntington's disease (2), syphilitic general paralysis (2), chronic epidural hematomas (2), normal pressure hydrocephalus (1), brain tumor (1), cerebral cysticercosis cellulosae (1), hypoparathyroidism (1), and 1 case of dementia after stereotactic operations for parkinsonism. In this series, vascular dementia and Alzheimer's disease were obviously more frequent. The authors think that it might be difficult to differentiate cortical from subcortical dementia in every demented patient. They also suggest that the term arteriosclerotic dementia should cease to be used.     

Over-expression of c-fos mRNA in the hippocampal neurons in Alzheimer's disease.

OBJECTIVE: To analyze the relationship between the proto-oncogene c-fos change and neuronal degeneration in the hippocampus of the patients with Alzheimer's disease. METHODS: The post mortem human hippocampal tissues were divided into three groups, namely, the aged, the young and Alzheimer's disease (AD) groups. Each group consisted of 10 patients. The diagnosis of AD was made by clinical manifestation and argentatine (Bodían) staining. Patients of both the young and the aged groups had no neurological disorders. The proto-oncogene c-fos mRNA was investigated in the hippocampal neurons using the method of in situ hybridization. RESULTS: The optical density of stained area and the integral within proto-oncogene c-fos mRNA revealed a significant increase in the hippocampal neurons in cases of Alzheimer's disease as compared with the controls. CONCLUSIONS: The over-expression of the proto-oncogene c-fos might play a role in the pathological process of Alzheimer's disease. These changes might result from a suffering stage of the hippocampal neurons or from a compensatory mechanism in the surviving neurons which are not yet affected-by the pathological process.     

头面部感觉神经一级传入纤维终末的溃变类型及特点

目的：观察头面部感觉神经一级传入纤维终末的类型和超微结构特点,方法：用微量注射器向三叉神经节内注射微量纯酒精,损毁三叉神经一级神经元的胞体,从而导致其初级传入纤维终末溃变,电镜下对头面部感觉神经一级传入纤维终末的形成进行初步观察。结果：头面部感觉神经一级传入纤维终末产生了电子致密型和神经微丝增生型两种溃变,依据初级传入纤维终末形态大小,溃变特点分为五类：（1）普通型中央轴突终末（CCT）;（2）扇贝型中央轴突终末（SCT）;（3）细小的中央轴突终末（SCT）;（4）细小的轴突终末（ST）;（5）突触小球的中央轴突终末（GCT）;结论：三叉神经初级传入纤维终末与胶状质内的神经元建立了广泛的突触联系,是完成其复杂的痛觉调节机制的超微形态学基础。     

Pathological characteristic of Alzheimer's disease produced by lesion in nucleus basalis of Meynert in rats

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Pathogenesis of Alzheimer's disease

The 160 and 200 Kd phosphorylated and non-phosphorylated neurofilament monoclonal antibodies were used as the probe to study the cytoskeletal protein distribution inside cerebral neurons of 2 normal adults and 2 patients with Alzheimer's disease (AD). Immunocytochemical technique was applied in this study. Non-phosphorylated neurofilament was located in the perikarua, whereas, the phosphorylated neurofilament was rich in the peripheral of the neuron's cell body and axons in the normal adult brain. In AD, no significant difference was seen when non-phosphorylated neurofilament was compared with normal adult brain; but phosphorylated neurofilament was seen accumulated inside the neuron's cell bodies. We did not find any immunoreactivity of the above cytoskeletal proteins in the senile plaques. These results indicate that the accumulation of high molecular weight phosphorylated neurofilament inside the neuron's cell bodies is the early pathogenetic change of AD.     

一种神经丝研究方法的建立及应用

本文世界首次报道用抗磷酸化神经丝单克隆抗体及抗非磷酸化神经丝单克隆抗体和免疫胶体金为探针.对3例神经外科手术取材的颞叶大脑皮质神经元进行了电镜免疫细胞化学研究。结果发现,在神经元核周质的内侧部、树突存在有磷酸化神经丝;在神经元核周质的外侧部也存在有非磷酸化神经丝。值得提出的是在整个细胞核内,尤其在核仁内,存在着大量的磷酸化神经丝和非磷酸化神经丝。本文提出了统一的细胞核浆骨架的新概念。     

The molecular bases of Alzheimer's disease and other neurodegenerative disorders

Alzheimer's disease, the cause of one of the most common types of dementia, is a brain disorder affecting the elderly and is characterized by the formation of two main protein aggregates: senile plaques and neurofibrillary tangles, which are involved in the process leading to progressive neuronal degeneration and death. Neurodegeneration in Alzheimer's disease is a pathologic condition of cells rather than an accelerated way of aging. The senile plaques are generated by a deposition in the human brain of fibrils of the beta-amyloid peptide (Abeta), a fragment derived from the proteolytic processing of the amyloid precursor protein (APP). Tau protein is the major component of paired helical filaments (PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs). Experiments with hippocampal cells in culture have indicated a relationship between fibrillary amyloid and the cascade of molecular signals that trigger tau hyperphosphorylations. Two main protein kinases have been shown to be involved in anomalous tau phosphorylations: the cyclin-dependent kinase Cdk5 and glycogen synthase kinase GSK3beta. Cdk5 plays a critical role in brain development and is associated with neurogenesis as revealed by studies in brain cells in culture and neuroblastoma cells. Deregulation of this protein kinase as induced by extracellular amyloid loading results in tau hyperphosphorylations, thus triggering a sequence of molecular events that lead to neuronal degeneration. Inhibitors of Cdk5 and GSK3beta and antisense oligonucleotides exert protection against neuronal death. On the other hand, there is cumulative evidence from studies in cultured brain cells and on brains that oxidative stress constitutes a main factor in the modification of normal signaling pathways in neuronal cells, leading to biochemical and structural abnormalities and neurodegeneration as related to the pathogenesis of Alzheimer's disease. This review is focused on the main protein aggregates responsible for neuronal death in both sporadic and familial forms of Alzheimer's disease, as well as on the alterations in the normal signaling pathways of functional neurons directly involved in neurodegeneration. The analysis is extended to the action of neuroprotective factors including selective inhibitors of tau phosphorylating protein kinases, estrogens, and antioxidants among other molecules that apparently prevent neuronal degeneration.     

微管相关蛋白30和ubiquitin在老年性痴呆病神经元纤维缠结中的表达

采用尸检脑组织标本，经免疫组织化学染色观察微管相关蛋白３０（ＭＡＰ３０）和ｕｂｉｑｕｉｔｉｎ免疫反应产物在老年性痴呆病（ＡＤ）患者海马神经元的分布及变化，探讨微管相关蛋白与ＡＤ发病机制之间的关系。     

Management of neurodegenerative disorders: Parkinson's disease and Alzheimer's disease

Neurodegenerative disorders result from premature progressive degeneration of specific neurons, and manifest as diseases or syndromes with varied combinations of cognitive, motor, sensory and autonomic dysfunctions. The management involves pharmacotherapy as well as non-pharmacological measures and also to lessen the burden of the care-givers. The medications available for medical treatment are: Levodopa, dopamine agonists, amantadine, anticholinergics, enzyme inhibitors, etc. Advanced Parkinson's disease is concerned with management of motor complications and non-motor complications. Recently surgical treatment is a great option for managing motor complication. Orthostatic hypotension, gait distiurbances, emotional and psychiatric problems, sleep disturbances can be managed and had been discussed in brief. Currently there is no medication available for the cure of Alzheimer's disease. The specific medications claimed to improve patient's well being and cognition include cholinesterase inhibitors, N-methyl-D-aspartate receptor antagonist, anti-oxidants, and anti-amyloid therapy. While medical and surgical treatments for Parkinson's disease have revolutionised the management, still drug therapy for Alzheimer's disease is dismal.     

痴呆模型大鼠中脑腹侧被盖区多巴胺能神经元的形态学改变

目的观察铝中毒痴呆模型大鼠中脑腹侧被盖区(VTA)多巴胺(DA)神经元的形态学变化,探讨中枢多巴胺递质在学习、记忆中的作用.方法以慢性铝中毒方式建立痴呆模型,以酪氨酸羟化酶(TH)为DA神经元的阳性标记物,采取免疫细胞化学ABC法观察中脑VTA TH免疫反应阳性神经元的形态学改变,利用图像分析系统测算VTA TH免疫反应阳性神经元的数目,分析试验结果.结果痴呆模型组中脑VTA TH免疫反应阳性神经元数量明显下降(P＜0.01),部分神经元出现突起消失、胞体肿胀或碎裂等表现.结论中脑VTA DA神经元与认知功能关系密切,其病变可能同老年性痴呆有关.     

Pathological and biochemical alterations of astrocytes in ovariectomized rats injected with D-galactose:A potential contribution to Alzheimer's disease processes

Astrocytes are implicated in the pathological changes of Alzheimer's disease. Our previous studies have demonstratedthat estrogen deprivation and oxidative stress act synergistically to accelerate0 the progress of Alzheimer's disease. Long-term D-galac-tose injection combined with ovariectomy may serve as a rodent model for Alzheimer's disease. To address the potential contributionof astroglia to the Alzheimer's disease pathogenesis, we investigated pathological and biochemical alterations of astrocytes under thisanimal model. Ovadectomized rats injected with D-galactose for 2 weeks showed extensive localization of glial fibrillary acidic proteinimmunoreactive astrocytes and slightly elevated glutathione levels in the hippocampus without significant impairments in the watermaze test and deficits of the cholinergic analyses, compared to the saline-injected rats. Ovariectomized rats injected with D-galactosefor 6 weeks, however, exhibited degeneration of astrocytes and decreased glutathione levels in the hippocampus, accompanied withsevere dysfunction of behavioral test and deficiency of cholinergic terminals. Electron microscopy further confirmed the pathologicalchanges of astrocytes, especially in the aggregated area of synapse and brain microvessels. Consistent with degeneration of perivascu-lar astrocytic endfeet, analysis of the horseradish peroxidase demonstrated an impairment of the blood-brain barrier permeability.These findings indicate that biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronaldeficits in the course of Alzheimer's disease. Restoring neuroprotective potential of astrocytes may be a useful therapeutic target forAlzheimer's disease and other neurodegenerative diseases.     

Pathological and biochemical alterations of astrocytes in ovariectomized rats injected with D-galactose:A potential contribution to Alzheimer's disease processes

Astrocytes are implicated in the pathological changes of Alzheimer's disease. Our previous studies have demonstrated that estrogen deprivation and oxidative stress act synergistically to accelerate the progress of Alzheimer's disease. Long-term D-galactose injection combined with ovariectomy may serve as a rodent model for Alzheimer's disease. To address the potential contribution of astroglia to the Alzheimer's disease pathogenesis, we investigated pathological and biochemical alterations of astrocytes under this animal model. Ovadectomized rats injected with D-galactose for 2 weeks showed extensive localization of glial fibrillary acidic protein immunoreactive astrocytes and slightly elevated glutathione levels in the hippocampus without significant impairments in the water maze test and deficits of the cholinergic analyses, compared to the saline-injected rats. Ovariectomized rats injected with D-galactose for 6 weeks, however, exhibited degeneration of astrocytes and decreased glutathione levels in the hippocampus, accompanied with severe dysfunction of behavioral test and deficiency of cholinergic terminals. Electron microscopy further confirmed the pathological changes of astrocytes, especially in the aggregated area of synapse and brain microvessels. Consistent with degeneration of perivascular astrocytic endfeet, analysis of the horseradish peroxidase demonstrated an impairment of the blood-brain barrier permeability. These findings indicate that biochemical and pathological alterations of astrocytes may partially contribute to exacerbating neuronal deficits in the course of Alzheimer's disease. Restoring neuroprotective potential of astrocytes may be a useful therapeutic target for Alzheimer's disease and other neurodegenerative diseases.     

Swayback (enzootic ataxia) in Alberta lambs

Swayback (enzootic ataxia), a disease not previously described in Canada, occurred in newborn lambs in Alberta in 1972. Of 100 lambs born in one flock, over 60 succumbed in the enzootic. The diagnosis was based on the presence of a) gross cavitations and gelatinous lesions of the cerebral white matter in 16 of 24 (66.67%) lambs examined, b) central chromatolysis and hyalinization of neurons of the red and vestibular nuclei and reticular formation and of the lateral and ventral horns of the spinal cord, c) myelin deficiencies of the dorsolateral and sulcomarginal funiculi of the spinal cord and d) low hepatic and serum copper levels in affected lambs and low serum copper levels in the ewes. The feeding of sugar beet-(beta saccharifera) top silage to the ewes during pregnancy, lambing and lactation, and its relationship to the enzootic is discussed.     

Medullomyoblastoma: a case report

Medullomyoblastoma is a rare childhood tumor of the central nervous system and there have been only seventeen cases reported in the English literature. A case of medullomyoblastoma arising from the cerebellar vermis was reported. Postmortem examination revealed diffuse leptomeningeal dissemination and supratentorial metastasis. In addition to classical histologic examination, the immunohistochemical and ultrastructural features were studied. Besides skeletal muscle differentiation, neither neuronal nor astrocytic differentiation were identified. The myoblastic element was confirmed by the demonstration of thick and thin myofilaments and Z bands on electron microscopy and by positive immunostaining for myoglobin.     

帕金森病体外实验细胞模型的建立

目的： 探讨1-甲基-4-苯基-四氢吡啶离子（MPP⁺ ）对小鼠胚胎中脑原代培养多巴胺能神经元的毒性作用及其机制。在体外建立帕金森病（PD）实验研究的细胞模型。方法：采用小鼠胚胎（孕14 d）中脑进行原代细胞培养，实验分为对照组和不同浓度(0.1、１、10和15 μmol•L^-1)MPP⁺药物实验组，应用酪氨酸羟化酶（TH）免疫化学细胞染色方法 和Hoechst33342荧光染色对多巴胺能神经元的损伤及凋亡进行测定。结果：对照组中多巴胺能神经元的数量为(875±23)个/孔。在0.1、１、10和15 μmol•L^-1 MPP⁺实验组，多巴胺能神经元的数量分别为(612±25)、(586±32)、(459±16)和(435±19)个/孔，与对照组比较，MPP⁺实验组多巴胺能神经元数量均明显降低（P<0.05）,多巴胺能神经元突起的数目和长度明显减少。Hoechst33342 染色发现，对照组中凋亡细胞数占总细胞数的(5.45±0.29)%,10 μmol•L^-1 MPP⁺药物治疗组细胞凋亡率为(26.97±1.36)%，显著高于对照组水平（P<0.05）。结论：0.1、１、10 和15 μmol•L^-1 MPP⁺均引起多巴胺能神经元的数量显著减少，随着药物浓度的增加，多巴胺能神经元减少的程度越显著。MPP⁺引起的多巴胺能神经元的变性死亡可能通过凋亡途径所诱导。     

胶质母细胞瘤的常规MRI诊断

目的:通过分析胶质母细胞瘤的MR表现,探讨其影像学特征。方法:回顾性分析21例经手术病理证实的胶质母细胞瘤的临床资料及MRI特征,对肿瘤的发病部位、形态、信号、瘤周水肿、占位效应以及强化特征进行分析。结果:20例病灶位于大脑半球,1例位于小脑半球,其中4例跨中线生长。MR表现为长T1、长T2为主的混杂信号团块20例,结节状1例,21例中16例有"流空效应",阳性率为76.2%;增强扫描呈厚薄不一的不规则花环状、花瓣状强化18例,整个病灶或环壁呈"栅栏"状,19例增强病例中18例可见假"栅栏"征,阳性率达94.7%,1例呈结节状轻度强化。20例病灶有明显瘤周水肿和占位效应,仅1例不明显。结论:胶质母细胞瘤具有一定特征性MR表现,肿瘤体积较大,累及多个脑叶,形态不规则,信号不均匀,囊变坏死多见,瘤内可见出血,可跨中线生长,水肿和占位征象明显。尤其是假"栅栏"征及"流空效应"对诊断胶质母细胞瘤更具特征性。