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[An autopsied case of atypical presenile dementia which shows lobar atrophy, severe neurofibrillary tangles and calcification].

We report an autopsy case of atypical presenile dementia. Shibayama, Kosaka and others had reported similar autopsy cases. These cases had the following common pathologic characteristics: circumscribed cerebral atrophy, diffuse neurofibrillary tangles (NFTs) noted in the cerebral cortex with few senile plaques (SPs), and pathological calcification. We propose the term "dementia with cerebral calcification and tangles" (DCCT) for this atypical presenile dementia. Our patient, who was female and died at the age of 65 years, also exhibited these characteristics. Her clinical diagnosis was Alzheimer's disease. She had developed apparent dementia at the age of 55. Psychological and neurological symptoms such as memory impairment, speech disturbance and abnormal behavior slowly progressed. Gradually, she had become bedridden in her own home. When she was 65 years old, she was admitted because of pneumonia, and died soon after. In the pathologic examination of our patient, the brain weight was 850 g, and severe cerebral atrophy predominant in the temporal lobe was noted. Microscopically, diffuse and numerous NFTs were also found in the cerebral cortex and brain stem. Some NFTs were observed in the dentate nucleus of the cerebellum. However, SPs were seldom noted. Calcifications were also found in the putamen, globus pallidus and cerebellar cortex. NFTs in our case had developed without the formation of SPs. The degree of the NFT formation was correlated to the extent of cerebral cortical atrophy and neuron loss. Therefore, we suspect that NFTs with neuron loss strongly contribute to clinical symptoms such as dementia. The distribution of NFTs resembles that in patients with Alzheimer's disease, they are more prominent in the temporal lobe in our case. Although there has not been any discussion about the findings of glial cells and neuropils in DCCT, our detailed examination showed argyrophilic structures in glial cells and in neuropils. Most of the glial cells appeared to be oligodendrocytes. Calcification is also a prominent characteristic of DCCT. Using analytical electron microscopy, we examined the area of calcification in the globus pallidus and cerebellum, and found an accumulation of both Fe and Ca. The role of calcification in the pathogenesis, however, remains unclear. It is very important to examine cases of atypical presenile dementia clinicopathologically, in order to study the correlation between NFTs and SPs in neurological disease, and to understand their pathogenetic significance.

Aged↗

A possible fetal antigen of Mr 70,000 in neurofibrillary tangles.

To test the hypothesis that tau-immunoreactive curly fibers represent a regenerative attempt of cortical neurons in the brain affected with Alzheimer's disease (AD), we established 2 monoclonal antibodies to isolated neurofibrillary tangles. Both antibodies extensively stained curly fibers and specifically labeled a novel protein of Mr 70,000 (p70), which was abundantly expressed in fetal brain, but undetectable in adult brain. Furthermore, the antibodies visualized curly fibers in newborn rat brain, which were very similar to those in the AD brain, and also intensely stained extending neurites of NGF-primed PC 12 cells. These observations suggest that P70 is a fetal antigen associated with growing neurites, and thus support the sprouting hypothesis.

Aging↗

Neocortical neurofibrillary tangles correlate with dementia severity in Alzheimer's disease.

OBJECTIVE: To determine the relationships between dementia severity and the extent of histopathologic lesions in a variety of brain regions. Neocortical and hippocampal ratings for neurofibrillary tangles (NFTs) and senile plaques (SPs) were compared in 70 cases of clinically and neuropathologically confirmed Alzheimer's disease. DESIGN: Neuropathologic case series. Dementia severity was assessed by postmortem chart review with use of the extended Clinical Dementia Rating Scale (CDR). Linear association between CDR scores and NFT and SP scores were assessed by partial correlation, controlling for age at death. SETTING: Studies were conducted at the Alzheimer's Disease Research Center of the Mount Sinai Medical Center, New York, NY. MAIN OUTCOME MEASURE: Association between CDR scores and neuropathologic changes assessed with the Consortium to Establish a Registry for Alzheimer's Disease semiquantitative scale. RESULTS: Among these lesion scores, only NFTs showed a significant association with CDR score, and only for neocortical regions. In particular, NFT densities in the superior temporal cortex were most strongly correlated with dementia severity, followed by those in the inferior parietal and midfrontal cortex. No such correlations were apparent for the amygdala, hippocampus, or entorhinal cortex. Medial temporal lobe structures displayed high NFT scores, even in cases of mild dementia. Senile plaques did not correlate significantly with CDR score in any region. CONCLUSIONS: These data support the notion that neocortical neuronal degeneration, as indicated by NFT formation, is a critical determinant of the clinical progression of Alzheimer's disease and suggest that medial temporal lobe structures may represent the initial site of NFT formation. While SP density correlates with age at death, there is no correlation between SP counts and dementia severity. These results further suggest that the clinical presentation of dementia may be closely related to neurodegeneration in neocortical regions within the temporal lobe.

Aged↗

Rapid induction of intraneuronal neurofibrillary tangles in apolipoprotein E-deficient mice.

Cultured hippocampal slices prepared from apolipoprotein E-deficient mice were exposed to an inhibitor of cathepsins B and L and then processed for immunocytochemistry using antibodies against human paired helical filaments. Dense, AT8-immunopositive deposits were found in the subiculum, stratum oriens of hippocampal field CA1, and the hilus of the dentate gyrus. This distribution agrees with that described for tangles in Alzheimer's disease. The appearance of the labeled structures fell into categories that correspond to previously proposed stages in the progression of intraneuronal neurofibrillary tangles in human hippocampus. Electron microscopic analyses confirmed that microtubule disruption and twisted bundles of filaments were present in neurons in the affected areas. These results support the hypothesis that partial lysosomal dysfunction is a contributor to Alzheimer's disease and suggest a simple model for studying an important component of the disease.

Alzheimer Disease↗

Apolipoprotein E polymorphism influences not only cerebral senile plaque load but also Alzheimer-type neurofibrillary tangle formation.

Only recently, evidence was provided that apolipoprotein E allele epsilon 4 located on Chromosome 19 is associated with late onset (i.e. senile) sporadic Alzheimer's disease. Histologically, Alzheimer's disease is associated with intraneuronal neurofibrillary changes and extraneuronal A4/beta-amyloid deposition. We set out with a histological staging system which considers the gradual development of Alzheimer's disease-related histological changes over time and correlates highly with the cognitive decline ante mortem. Our analysis revealed that both the mean stage for A4/beta-amyloid deposits and the mean stage for neurofibrillary tangles get significantly shifted upwards in epsilon 4-carriers. This represents an earlier onset of the histopathological process of about one decade. The fact that both types of Alzheimer's disease-related changes correlate positively with the prevalence of the epsilon 4-allele suggests for a causal relationship between the apolipoprotein E polymorphism and the development of Alzheimer's disease.

Age Factors↗

Alzheimer's disease: the relationship between the density of senile plaques, neurofibrillary tangles and A4 protein in human patients.

The numerical density of senile plaques (SP) and neurofibrillary tangles (NFT) as revealed by the Glees silver method was compared with SP and NFT revealed by the Gallyas method and with amyloid (A4) deposits in immunostained sections in 6 elderly cases of Alzheimer's disease. The density of NFT was generally greater and A4 lower in tissue from hippocampus compared with the neocortex suggesting that A4 deposition was less important than the degree of paired helical filament (PHF) related damage in the hippocampus. The density of Glees SP was positively correlated Gallyas SP weakly correlated with A4 deposit number. A stepwise multiple regression analysis which included A4 deposit and Gallyas SP density and accounted for 54% of the variation in Glees SP density. Hence, different populations of SP were revealed by the different staining methods. The results suggested that the Glees method may stain a population of SP in a region of cortex where both amyloid deposition and neurofibrillary changes have occurred.

Alzheimer Disease↗

Methenamine-silver staining: a simple and sensitive staining method for senile plaques and neurofibrillary tangles.

An improved methenamine-silver impregnation method is presented which exhibits sensitivity for amyloid substances comparable to that of anti-beta protein immunostaining. In optimally treated sections, this technique stained both beta-amyloid deposits and neurofibrillary tangles, which are known to have a beta-pleated structure. This simple procedure allows a large number of sections to be stained for routine examination.

Alzheimer Disease↗

Neurofibrillary tangle parkinsonian disorders--tau pathology and tau genetics.

A number of related conditions, including progressive supranuclear palsy (PSP), corticobasal degeneration, Pick's disease, and the parkinsonism dementia complex of Guam, are characterized by the deposition of tau neurofibrillary tangles in the absence of amyloid pathology. These diseases share some overlap in their topography and clinical features but can be subdivided into three main groups according to the isoforms of the alternatively spliced tau gene that are deposited. The recent description of mutation in tau in frontotemporal dementia, and a common variant of tau that predisposes to PSP, and the relationship of these changes to the tau protein subgroups offers new insights into the pathogenesis of these disorders.

Brain↗

Immunocytochemistry of neurofibrillary tangles with antibodies to subregions of tau protein: identification of hidden and cleaved tau epitopes and a new phosphorylation site.

Antibodies to multiple epitopes spanning the length of the tau molecule were used to study Alzheimer neurofibrillary tangles (NFT) using immunocytochemical methods and several different methods of fixation and tissue processing, including staining of vibratome sections, hydrated autoclaving of paraffin sections and immunofluorescence of NFT isolated from fresh brain tissue. Smears and sections were pretreated with trypsin and/or phosphatase to further characterize antibody binding. In tissue fixed briefly in periodate-lysine-paraformaldehyde, tau immunoreactivity was detected in astrocytes, but only a few tau epitopes were detected in NFT with this fixation method. In contrast, all tau epitopes were detected in NFT in tissue fixed in formaldehyde for prolonged periods of time. In the hippocampus, the number of NFT detected in the dentate fascia was in proportion to the duration of dementia, as we previously noted. Dentate fascia NFT were intracellular (i-NFT) and were reactive with antibodies recognizing epitopes in both the carboxy- and amino-terminal regions of tau, but not the microtubule-binding domain of tau, suggesting that microtubule-binding domain epitopes are hidden in i-NFT. In contrast, NFT in the subiculum and layer II of the parahippocampal cortex were mostly extracellular (e-NFT), especially in severe cases of long duration. e-NFT were immunoreactive with antibodies to the microtubule-binding domain, but only weakly reactive with antibodies to carboxy- or amino-terminal epitopes, suggesting that e-NFT may contain fragments of tau. In both isolated NFT and NFT in sections, amino-terminal epitopes, including the Alz-50 epitope, were sensitive to trypsin proteolysis, which suggests that the lack of staining of e-NFT by antibodies to the amino-terminal regions of tau is due to proteolysis. Antibodies reactive with amino-terminal epitopes also stained fewer NFT following hydrated autoclaving, while those reacting with the carboxy half of tau stained more NFT after hydrated autoclaving. Thus, although carboxy-terminal regions are not detected in e-NFT, they are probably masked, rather than proteolytically cleaved, since they can be revealed by hydrated autoclaving. Finally, phosphatase treatment of isolated NFT revealed enhanced immunostaining not only with Tau-1, as in previous studies demonstrating abnormal phosphorylation of tau proteins in NFT, but also with an antibody to exon 2, which reveals yet another phosphorylation site in tau of NFT.

Aged↗

Neurofibrillary tangles in ALS and Parkinsonism-dementia complex focus in Kii, Japan.

Brains of 41 residents without neurodegenerative diseases in the high-incidence area of ALS/parkinsonism-dementia complex (ALS/PDC) of the Kii Peninsula of Japan were neuropathologically examined. Neurofibrillary tangles (NFTs) in the hippocampal area were present in 11 of the 41 cases, but the frequency of NFT-positive cases in each age group was similar to that of the normal Japanese population and far less than that of Guamanians without ALS/PDC.

Adolescent↗

Paired helical filaments are not the major binding sites for wheat germ and Dolichos biflorus agglutinins in the neurofibrillary tangles of Alzheimer's disease.

The isolated paired helical filaments (PHF) that occur in the neurofibrillary tangles of Alzheimer's disease were assayed to determine if they contained N-acetyl-glucosamine and N-acetyl-galactosamine residues. The enzyme-linked lectin assay was used to detect their total content in the PHF preparation. The assay employed biotinylated Dolichos biflorus and wheat germ agglutinins and was developed with avidin-horseradish peroxidase. The total PHF preparation was shown to contain very little of these glycosyl groups compared to equal amounts of highly glycosylated control proteins. Colloidal gold-labeled lectins were used to study the PHF by electron microscopy to assess whether the minor amount of lectin binding in the total preparation was directly associated with the PHF. These studies showed no significant association of the colloidal gold-labeled lectins with the isolated filaments. We conclude that the PHF themselves contain few or no N-acetyl-glucosamine or N-acetyl-galactosamine residues.

Acetylglucosamine↗

Alzheimer's neurofibrillary tangles are penetrated by astroglial processes and appear eosinophilic in their final stages.

Alzheimer's neurofibrillary tangles (ANT) in the hippocampal area were studied immunohistochemically using antisera against glial fibrillary acidic protein (GFAP) and S-100 protein in 48 patients with or without dementia between 52 and 92 years old. In 27 of the 38 brains that developed ANT in the hippocampal area, some ANT were immunostained with these antisera. Flame-shaped or globose-shaped immunostains were occasionally continuous with astroglial cell bodies and processes. They appeared particularly in the entorhinal cortex, subiculum and CA1. The ANT, immunostained with GFAP and S-100 antisera, apparently correspond to slightly eosinophilic tangles in H&E sections and to less argentophilic tangles in silver-impregnated sections in all of the 27 brains. ANT of another 11 brains were consistently negative with these antisera. The GFAP-positive eosinophilic tangles were encountered in the brains of older patients (P less than 0.01) and with more abundant formation of ANT (P less than 0.001). This alteration was present in all of the 20 brains with more than 100 ANT per section and none of the eight brains with less than 10 ANT. These findings suggest that in the last stages, ANT are penetrated by eosinophilic processes of astrocytes, and appear eosinophilic, and that the presence of GFAP-positive eosinophilic tangles indicates the abundant formation of ANT.

Age Factors↗

Antibodies to neurofibrillary tangles of Alzheimer's disease raised from human and animal neurofilament fractions.

Antibodies reacting with neurofibrillary tangles (NFT) of Alzheimer's disease were consistently obtained using neurofilament (NF) fractions as antigen. NF fractions were obtained from normal human spinal roots or guinea pig peripheral nerves and used to immunize BALB/c mice. Mice receiving a total dose of 300 to 600 micrograms of protein developed antibodies that were indistinguishable with immunostaining of tissues and of polypeptides separated on sodium dodecyl sulfate-polyacrylamide electrophoresis gels. These antibodies reacted with NFT from cases of Alzheimer's disease and with NFT induced with aluminum, as well as with structures rich in NF such as central and peripheral axons and cerebellar basket fibers. When used to immunostain polypeptides separated by sodium dodecyl sulfate-polyacrylamide electrophoresis, all antisera recognized the three NF subunits. Absorption of the antisera with 5 micrograms/ml of purified human NF proteins blocked immunostaining of Alzheimer's NFT. It is concluded that human and animal NF fractions are excellent antigens to produce antibodies that consistently react with NFT of Alzheimer's disease. The present findings further support existing evidence that the paired helical filaments of Alzheimer's disease share antigenic determinants with normal NF.

Alzheimer Disease↗

Apolipoprotein E polymorphism is associated with both senile plaque load and Alzheimer-type neurofibrillary tangle formation.

Recent work provided evidence that the apolipoprotein (apo) E polymorphism is associated with late-onset sporadic Alzheimer's disease. The major histological hallmarks of Alzheimer's disease are the extraneuronal deposition of A4/beta-amyloid and the intraneuronal formation of neurofibrillary tangles, the latter correlating strongly with the psychometric status. We examined the relationship between the apo E polymorphism and Alzheimer's disease-related histological changes using a staging system which accounts for the progression of the disease over time and correlates well with the cognitive decline ante mortem. We observed a significant positive correlation between both neurofibrillary changes and A4/beta-amyloid deposits and the epsilon 4 gene dose. We estimated that the presence of one apo E4 allele leads to an earlier onset of the histopathological process of about one decade. The association of both types of Alzheimer's disease-related changes with the prevalence of the epsilon 4-allele suggests that the apo E polymorphism causally contributes to the development of Alzheimer's disease.

Aging↗

Silver staining profiles distinguish Pick bodies from neurofibrillary tangles of Alzheimer type: comparison between Gallyas and Campbell-Switzer methods.

Silver staining profiles of Pick bodies (PBs) and their relation to tau-like immunoreactivity were examined on hippocampal sections and compared with those of neurofibrillary tangles of Alzheimer type (NFTs). Pairs of mirror sections were double-fluorolabeled with an anti-paired helical filament tau (AT8) antibody and thiazin red (TR), a fluorochrome that identifies fibrillary structures such as NFTs. One of the paired sections was subsequently stained using the Gallyas method (GAL), and the other using the Campbell-Switzer method (CS). By comparison of the same microscopic field on fluorolabeled sections and on both silver-stained paired sections, four different profiles of each structure could be distinguished: AT8 immunoreactivity, affinity to TR, argyrophilia with GAL or CS staining. PBs, containing mainly three-repeat (3R) tau, were positive for CS but not for GAL and its affinity to TR was, at most, weak. This selective affinity of PBs to CS is in sharp contrast with tau-positive structures of corticobasal degeneration/progressive supranuclear palsy, which are positive for GAL but not for CS, as we reported previously. This contrast is explainable if the argyrophilia with CS is related to deposits containing 3R tau, while that with GAL is linked to those containing four-repeat (4R) tau. Indeed, NFTs, containing both 3R and 4R tau, are positive for both CS and GAL, as expected. Taken together, differences in molecular composition of tau protein in these deposits are linked to their argyrophilic properties that are dependent on the staining method. Although explanations for these empirical differences are not yet available, awareness of this clear distinction is potentially of diagnostic and pathological relevance.

Aged↗

Apolipoprotein E interaction with the neurofibrillary tangles and senile plaques in Alzheimer disease: implications for disease pathogenesis.

Apolipoprotein E (ApoE) genotype is a significant risk factor for the development of Alzheimer disease (AD) and the ApoE protein is associated with senile plaques (SP) and neurofibrillary tangles (NFT), the pathological lesions of AD. Despite this data, the relevance of ApoE to the disease pathogenesis is unknown. In this study we sought to understand the role that ApoE protein could play in the pathogenesis of AD. Using an in situ binding technique, we showed that ApoE bound avidly to SP and NFT in diseased brain. Molecular characterization of ApoE binding suggested that binding to NFT was mediated by tau, the main protein component of NFT, and that ApoE binding to SP was mediated by amyloid-beta, the main protein component of SP. There was no significant difference in binding or binding characteristics between the different ApoE isoforms, ApoE3 and ApoE4. These findings suggest that the interaction of ApoE with tau and amyloid-beta proteins in AD could play a important role in the formation of NFT and SP, respectively, contributing to the pathogenesis of AD.

Alzheimer Disease↗

On the relationship between measles virus and Alzheimer neurofibrillary tangles in subacute sclerosing panencephalitis.

We have studied the relationship between measles virus and the accumulation of abnormally phosphorylated tau (PHF-tau) in nine cases of subacute sclerosing panencephalitis (SSPE). By assessing the presence of viral intranuclear inclusions and neurofibrillary tangles (NFT) in each case, we found no correlation between presence and amount of measles virus and the numbers of neurons containing PHF-tau. Immunohistochemical double labeling in a case with long duration of disease and severe histopathologic change revealed no strict colocalization of measles virus antigen and PHF-tau throughout different brain regions. In areas containing both antigens, most neurons carrying measles virus did not have a tangle and vice versa, eventhough some colocalization beyond that expected by chance was observed in specific cortical areas. These results indicate that, although secondary to viral infection, NFT formation in SSPE is not restricted to cells carrying viral antigen. Conversely, measles virus infected cells do not necessarily accumulate PHF-tau. This lack of colocalization at the cellular level, throughout different brain areas and among different cases suggests that the formation of NFT in SSPE is not directly induced by the infectious agent. The formation of NFT in this disease appears to be elicited through a specific type of tissue damage and, thus, to be an epiphenomenon. This pathogenetic detail may be of interest for our understanding of the role of neurofibrillary degeneration in the pathogenesis of other more frequent neurodegenerative diseases with cytoskeletal pathology.

Adolescent↗

Amyloid-induced neurofibrillary tangle formation in Alzheimer's disease: insight from transgenic mouse and tissue-culture models.

Of all forms of dementia, Alzheimer's disease is the most prevalent. It is histopathologically characterized by beta-amyloid-containing plaques, tau-containing neurofibrillary tangles, reduced synaptic density and neuronal loss in selected brain areas. For the rare familial forms of Alzheimer's disease, pathogenic mutations have been identified in both the gene encoding the precursor of the Abeta peptide, APP, itself and in the presenilin genes which encode part of the APP-protease complex. For the more frequent sporadic forms of Alzheimer's disease, the pathogenic trigger has not been unambiguously identified. Whether Abeta is again the main cause remains to be heavily discussed. In a related disorder termed frontotemporal dementia, which is characterized by tangles in the absence of beta-amyloid deposition, mutations have been identified in tau which also lead to neurodegeneration and dementia. For Alzheimer's disease the existence of familial forms lead to the proposition of the amyloid cascade hypothesis, which claims that beta-amyloid causes or enhances the tangle pathology. In this review, we describe tau transgenic mouse models in which aspects of the tau-associated pathology, including tangle formation, has been achieved. Moreover, tau transgenic mouse and tissue-culture models were used to test the amyloid cascade hypothesis. In addition, we discuss alternative hypotheses to explain the sporadic forms. The animal and tissue-culture models will provide insight into the underlying biochemical mechanisms of tau aggregation and nerve cell degeneration. These mechanisms may be partially shared between sporadic Alzheimer's disease, the familial forms and frontotemporal dementia. Eventually, Alzheimer's disease may be redefined based on biochemical events rather than phenotype.

Alzheimer Disease↗