Distribution of neurofibrillary tangles in diffuse neurofibrillary tangles with calcification

Aims:  In this study, the appearance and distribution of neurofibrillary tangles (NFT) in diffuse neurofibrillary tangles with calcification (DNTC) were investigated neuropathologically in order to elucidate the detailed distribution pattern in this disease.
Methods:  The distribution of NFT in six cases neuropathologically diagnosed as DNTC (two men and four women) was studied using Gallyas–Braak silver stain. The age at death ranged from 56 to 73, with an average of 63.5 ± 7.5 years.
Results:  NFT were seen throughout the cerebral cortex, and were especially marked in the temporal and limbic cortices. The distribution pattern of NFT in the limbic lobe was similar to that in Alzheimer's disease as reported in the previous studies. In the temporal lobe, more NFT were distributed in the anterior than in the posterior area, which was confirmed in all six cases. The temporal pole showed the highest density of NFT including ghost tangles.
Conclusions:  The diffuse appearance of NFT in the cerebral cortex with the highest severity in the temporal pole was found to be a neuropathological characteristic of DNTC.     

C型Niemann-Pick病神经原纤维缠结的形成与特征

目的 探讨C型尼曼-皮克病(NPC)脑部神经原纤维缠结(NFT)形成的时相特征.方法 以17例年龄7个月至55岁的NPC患者为研究对象,采用tau蛋白和有丝分裂期相关抗体进行免疫组织化学染色和银染,分析患者脑内NFT形成的特点.结果 最早可在4岁的患者海马旁回发现典型的NFT形成,随年龄增长数量逐渐增多.在形态上与阿尔茨海默病(AD)所见高度相似,但未发现老年斑.在NPC中,有丝分裂期磷酸化表位早于tau蛋白过度磷酸化及NFT形成.结论NFT形成并非老龄化过程的结果 ,且与老年斑的存在与否并无关联.cdc2/cyclinB1可能是NFT形成的关键性早期事件,针对其活性的抑制剂对于早期干预NPC NFT的形成有重要意义.     

Reappraisal of neurofibrillary tangles

Summary We have studied the immunohistochemical reactivity and ultrastructure of both neurofibrillary tangles (NFTs) occurring with severe neurofibrillary diseases, and Pick bodies (PBs) associated with Pick's disease. The NFTs and PBs did not react immunohistochemically with the anti-nonphosphorylated neurofilament monoclonal antibody irrespective of whether they were pretreated with alkaline phosphatase. In granular neurons of the dentate fascia of Ammon's horn in cases of dementia of the Alzheimer type (DAT), NFTs either resembled PB-like inclusion bodies (Horoupian's inclusion bodies) in form, or had a perinuclear structure. Immunohistochemically and ultrastructurally, the NFTs in the dentate fascia in cases of DAT, including Horoupian's inclusion bodies, were similar to the NFTs in the pyramidal neurons of Ammon's horn, which are found most frequently in association with severe neurofibrillary diseases. Under a light microscope, Horoupian's inclusion bodies and PBs could not be differentiated and appeared to be argyrophilic round cytoplasmic inclusions in granular neurons of the dentate fascia. There were, however, ultrastructural differences. Horoupian's inclusion bodies consisted of bundles made up of straight tubules (STs), each about 15 nm in diameter. These bundles were intermixed with a few paired helical filaments which occurred at intervals of about 80 nm. On the other hand, PBs were composed of randomly distributed 15-nm-wide STs, intermixed with a very few fibrillary structures. These fibrils had a periodicity of about 160 nm, and ranged in width from about 15 nm to 30 nm. Horoupian's inclusion bodies associated with DAT and PBs associated with Pick's disease are different in this neuropathological aspect. The NFTs, including Horoupian's inclusion bodies in the dentate fascia in cases of DAT, are considered to be a manifestation of neurofibrillary degeneration.Supported partly by Grant No. 60A-4-20 from the National Center of Neurology and Psychiatry (NCNP) of the Ministry of Health and Welfare of Japan     

Increased neurofibrillary tangles in patients with Alzheimer disease with comorbid depression.

OBJECTIVE: Recent evidence suggests that a history of major depression may lead to increases in hippocampal neuropathology in Alzheimer disease (AD). The authors tested the hypothesis that neuritic plaques and neurofibrillary tangles are more pronounced in the brains of patients with AD with comorbid depression as compared with patients with AD without depression. METHODS: Brain samples from patients were selected from the U.S. National Alzheimer's Coordinating Center database. The primary analysis included 7164 individuals: 6468 had AD as the primary neuropathologic diagnosis and 696 were considered neuropathologically normal. Depression at study inclusion was rated as present or absent in consensus conferences. Neuropathologic ratings from the Consortium to Establish a Registry in Alzheimer's Disease rating of neuritic plaques and Braak staging of neurofibrillary tangles were used for between-group analyses. RESULTS: Brains of patients with AD with comorbid depression showed higher levels of cortical tangle formation than brains of patients with AD without comorbid depression. Results remained stable when controlling for age, gender, level of education, and cognitive status. Within patients with AD, comorbid depression increased the odds for advanced neuropathologic disease stage (odds ratio: 1.47; 95% confidence interval: 1.03-2.08). CONCLUSION: In AD, the presence of depression comorbidity corresponds to increases in AD-related neuropathologic changes beyond age, gender, level of education, and cognitive status, suggesting an interaction between depression and the neuropathologic processes in AD.     

Glial fibrillary tangles in diffuse neurofibrillary tangles with calcification

In the present study the occurrence and distribution of glial fibrillary tangles (GFT) and their related structures in diffuse neurofibrillary tangles with calcification (DNTC) were investigated using Gallyas-Braak (GB) stain. Six cases neuropathologically diagnosed as DNTC were studied (two males and four females). The age at death ranged from 56 to 73 years, with an average of 63.5+/-7.5 years. GFT were classified morphologically, and their immunoreactivites for tau and ubiquitin were examined. Glial cells with GFT were identified with astrocytes and oligodendrocytes by immunostain for glial fibrillary acidic protein and transferrin, respectively. A small number of coiled bodies detected within the oligodendrocytes in the white matter of the cerebrum were positive for tau and ubiquitin. Cell clusters of thorn-shaped astrocytes were detected in the subcortical and subpial regions where gliosis occurred. Thorn-shaped astrocytes were positive for tau, but negative for ubiquitin. A small number of tuft-shaped astrocytes detected prominently in the temporal cortex and amygdala with numerous neurofibrillary tangles were positive for tau and ubiquitin. All three types of GFT were detected, especially in the temporal and limbic lobes, which were the most severely affected sites in DNTC. Moreover, various-shaped neurofibrillary tangles, aggregated rods and some argyrophilic threads were differentiated from GFT. They were positive for GB, but not detected within the glial cells.     

Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease.

The authors used 2-(1-(6-[(2-[18F]fluoroethyl)(methyl)amino]-2-naphthyl)ethylidene)malononitrile ([18F]FDDNP), a hydrophobic radiofluorinated derivative of 2-(1-[6-(dimethylamino)-2-naphthyl]ethylidene)malononitrile (DDNP), in conjunction with positron emission tomography to determine the localization and load of neurofibrillary tangles (NFTs) and beta-amyloid senile plaques (APs) in the brains of living Alzheimer disease (AD) patients. Previous work illustrated the in vitro binding characteristics of [18F]FDDNP to synthetic beta-amyloid(1-40) fibrils and to NFTs and APs in human AD brain specimens. In the present study, greater accumulation and slower clearance was observed in AP- and NFT-dense brain areas and correlated with lower memory performance scores. The relative residence time of the probe in brain regions affected by AD was significantly greater in patients with AD (n=9) than in control subjects (n=7; p=0.0007). This noninvasive technique for monitoring AP and NFT development is expected to facilitate diagnostic assessment of patients with AD and assist in response-monitoring during experimental treatments.     

阿尔茨海默病患者脑中双螺旋丝的体外去磷酸化作用

目的探讨阿尔茨海默病（ＡＤ）脑损伤逆转的可能性及其途径。方法用去磷酸化和免疫印迹法研究ＡＤ脑损伤可逆性。结果蛋白磷酸酯酶（ＰＰ）２Ａ和ＰＰ２Ｂ可使ＡＤ神经原纤维缠结中的Ｉ型双螺旋丝（ＰＨＦＩｔａｕ）在Ｓｅｒ１９９／Ｓｅｒ２０２去磷酸化，Ｓｅｒ３９６／Ｓｅｒ４０４部分去磷酸化；此外，ＰＰ２Ａ和ＰＰ２Ｂ可分别使ＰＨＦＩＩｔａｕ的Ｓｅｒ４６和Ｓｅｒ２３５去磷酸化；去磷酸化后ＰＨＦＩＩｔａｕ的相对电泳迁移率加快。Ｍｎ２＋和Ｍｇ２＋可增加上述酶对ＰＨＦＩＩｔａｕ的去磷酸化作用。酶的去磷酸化作用具有浓度依赖性，随着酶浓度的增加，去磷酸化作用增强。结论因为ｔａｕ蛋白异常过度磷酸化并形成ＰＨＦ被认为是ＡＤ神经原纤维退化的基础，ＰＨＦ可在体外被蛋白磷酸酯酶去磷酸化的结果提示，ＡＤ脑损伤可能是可逆的。     

Increased Mr 60,000 protein phosphorylation is correlated with neocortical neurofibrillary tangles in Alzheimer's disease

Increased Mr 60,000 protein phosphorylation has been found in the cytosol fraction of brain tissue from Alzheimer's disease patients. A correlation between this biochemical change and the morphologic abnormalities found in Alzheimer's disease was sought. Three neuropathologic features were studied: neurofibrillary tangles and neuritic plaques, findings characteristic of Alzheimer's disease, and gliosis, a non-specific change. The number of tangles correlated well with the extent of Mr 60,000 protein phosphorylation (p less than 0.001); but the number of plaques did not. To investigate the possibility that gliosis causes the increased Mr 60,000 protein phosphorylation, cases of Pick's disease and multi-infarct dementia were also studied. The levels of Mr 60,000 protein phosphorylation in these cases were comparable to those seen in normal controls. These findings suggest that the increased Mr 60,000 protein phosphorylation is closely related to diseased, tangle-bearing neurons and is not directly related to neuritic plaque formation or secondary gliosis.     

Hypersialylation is a common feature of neurofibrillary tangles and granulovacuolar degenerations in Alzheimer's disease and tauopathy brains

Glycosylation is one of the major post‐translational modifications of proteins. The status of sialylation of the neuropathological hallmarks of various neurodegenerative disorders was investigated in this study. Here, we report the novel findings that two phosphorylated tau (p‐tau)‐containing structures associated with Alzheimer's disease (AD), that is, neurofibrillary tangles (NFTs) and granulovacuolar degenerations (GVDs), were hypersialylated. The NFTs, GVDs and dystrophic neurites of senile plaques (SPs) in AD hippocampi were clearly visualized by immunohistochemistry using an anti‐sialic acid (SA) antibody. In contrast, the amyloid core of SPs was not sialylated at all. Interestingly, other p‐tau‐containing structures, that is, globose‐type NFTs in progressive supranuclear palsy and Pick bodies and ballooned neurons in frontotemporal lobar degeneration with Pick bodies, were also hypersialylated. Unlike the p‐tau‐containing structures observed in tauopathies, the hallmarks of other neurodegenerative disorders, such as Lewy bodies in Parkinson's disease, glial cytoplasmic inclusions in multiple system atrophy, Bunina bodies, skein‐like inclusions and round inclusions in amyotrophic lateral sclerosis, intranuclear inclusions in neuronal intranuclear inclusion disease and physiological bodies or granules (lipofuscin granules, corpora amylacea and melanin granules), were not immunolabeled by the anti‐SA antibody. Because this antibody specifically identified NFTs and GVDs, immunostaining for sialylation represents a useful tool to screen these structures in a diagnostic setting. These results clearly indicate that the pathological hallmarks of various tauopathies are commonly hypersialylated, and that sialylation plays an important role in the process of p‐tau accumulation in AD and other tauopathies.     

Racemized D-aspartate in Alzheimer neurofibrillary tangles.

Normal protein-bound L-aspartyl/L-asparaginyl residues may undergo posttranslational modification by racemization to D-aspartate. Based on preliminary results reported here, proteins associated with Alzheimer neurofibrillary tangle preparations contain a greater number of these racemized D-aspartyl residues than the unaffected proteins from the surrounding gray matter or in comparable preparations from normal brains.     

Relationship in the formation process between neurofibrillary tangles and Lewy bodies in the hippocampus of dementia with Lewy bodies brains

Using tau immunohistochemistry and alpha-synuclein immunohistochemistry, we quantitatively investigated the most frequent sites and the formation process of neurofibrillary tangles (NFT) and Lewy bodies (LB) in the hippocampus from 20 patients with dementia with Lewy bodies (DLB). NFT were most frequently found in the CA2 and the subiculum-pre-CA1, while LB were most frequently found in the CA3-4 and the subiculum-pre-CA1. In the intrahippocampal routes of the perforant pathway, tau immunoelectron microscopy demonstrated distal axons containing aggregated tau-positive microtubules, while alpha-synuclein immunoelectron microscopy revealed terminal axons containing aggregated alpha-synuclein-positive tubular or filamentous components. These findings suggest that NFT and LB are first formed in the CA2 and the CA3-4 related to degeneration of the nonperforating route of the perforant pathway, respectively, and subsequently in the subiculum-pre-CA1 chiefly related to degeneration of the perforating route. Coexistence of NFT and LB in the same neurons was found most frequently in the subiculum-pre-CA1. In addition, coexistence of tau and alpha-synuclein was found in terminal axons of the perforant pathway, and tau accumulated not in paired helical filaments but in the periphery of alpha-synuclein-positive components immunoelectron-microscopically, suggesting that alpha-synuclein stimulates the accumulation of phosphorylated tau in terminal axons.     

Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy

Summary The fine structure of neurofibrillary tangles in the hippocampal gyrus, substantia nigra, pontine nuclei and locus coeruleus of the brain was postmortem studied in a case of progressive supranuclear palsy. Straight tubules and twisted tubules were observed in both the cortical and subcortical neurofibrillary tangles. Most tubules appeared separately in each neuron but a few straight tubules were mixed with the twisted tubules in the cortical tangles. The implication and possible significance of this findings are discussed.     

Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy

Summary Ultrastructure of neurofibrillary tangles was investigated on the subcortical neurons of an autopsy case of progressive supranuclear palsy. The patient was a 64-year-old female and suffered from her illness for 9 years. Two kinds of ultrastructure were observed in the subcortical neurofibrillary tangles, i.e. the 150 A straight tubules and the 220 A twisted tubules. They appeared separately in each neuron and a transition between these two structures could not be remarked. Besides, a few particles with a paracrystalline hexagonal structure were observed in some subcortical neurons.     

Reappraisal of the fine structure of Alzheimer's neurofibrillary tangles

Summary Alzheimer's neurofibrillary tangles were studied by electron microscopy. The study includes four cases of Alzheimer's disease, two cases of atypical senile dementia, and one case of progressive supranuclear palsy. In Alzheimer's disease the tangles were composed of either straight filaments or paired helical filaments. In progressive supranuclear palsy the tangles were composed of 15 nm straight filaments or helical filaments. A few straight filaments were mixed with paired helical filaments. In atypical senile dementia, both straight and paired helical filaments comprised the tangles and one type of filaments appeared to intermingle with the other in the same neurons.     

C-reactive protein-like immunoreactivity in the neurofibrillary tangles of Alzheimer's disease

C-reactive protein (CRP) is a plasma acute-phase protein, normally not found in the brain. Previous studies have demonstrated the presence of CRP in the senile plaques of Alzheimer's disease (AD). In this study, the presence of CRP-like immunoreactivity in AD neurofibrillary tangles (NFT) was demonstrated following pre-treatment of tissue sections with formic acid. CRP-like immunoreactivity was observed in both extracellular and intracellular NFT and was co-localized with the NFT marker PHF-1 and the amyloid P component (AP). The CRP-like immunoreactive NFT were less numerous and more limited in their distribution than PHF-1 or AP-immunoreactive NFT. The present results further support an involvement of inflammatory processes in the etiology of AD.     

Association of cholinesterases with amyloid in extracellular neurofibrillary tangles

Double-labeling techniques conclusively demonstrated that extracellular neurofibrillary tangles immunoreactive for β protein were also positive for cholinesterases. Ultrastructurally, cholinesterases decorated bundles of amyloid-like filaments, which appeared intermingled with straight filaments and cellular processes. A lighter labeling of esterases was also seen over most straight filaments. These observations extend the consistent association of cholinesterases with fibrillary β-amyloid protein to a new location in neurofibrillary tangles.     

Electron microscopic study of neurofibrillary tangles in Steele-Richardson-Olszewski syndrome

Summary The neurofibrillary tangles found in the neurons of a case of Steele-Richardson-Olszewski syndrome were studied by electron microscopy. Both the flame-shaped and globose type of tangles were present. The neurofibrillary tangles were composed of bundles of straight tubules measuring approximately 150 Å in diameter. This ultrastructural appearance of the tangles in Steele-Richardson-Olszewski syndrome is different from the appearance of tangles found in other neurological disorders and is probably indicative of intraneuronal accumulation of a new type of fibrous protein.This investigation received financial support from the World Health Organization.     

A case of diffuse neurofibrillary tangles with calcification

We report a 79-year-old female with atypical senile dementia with Fahr-type calcification. The patient started to show memory disturbance at the age of 75 years, followed by visual hallucination, stereotypy, personality changes such as irritability, aggression and disinhibition. Brain computed tomography (CT) demonstrated bilateral and symmetric calcification of the basal ganglia and thalamus. Magnetic resonance imaging (MRI) revealed diffuse cortical atrophy pronounced in the fronto-temporal areas. On MRI T1-weighted images the calcified areas showed a mixture of low- and high-intensity signals. Based on the overlapping clinical symptoms of Alzheimer's disease and Pick's disease, together with the brain CT and MRI findings, we clinically diagnosed the patient as having 'diffuse neurofibrillary tangles with calcification' (DNTC). The characteristics of psychiatric symptoms and neuroradiological findings in DNTC are discussed.