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PubMed2001

Lead content of brain tissue in diffuse neurofibrillary tangles with calcification (DNTC): the possibility of lead neurotoxicity.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of presenile dementia, characterized pathologically by fronto-temporal atrophy with neurofibrillary tangles (NFTs), neuropil threads and Fahr-type calcification, in which no senile plaques are observed. As already noted, chronic exposure to lead (Pb) might be one of the etiological factors of Fahr-type calcification. Until now, there have been no reports in which Pb concentration has been quantified in DNTC brains. We examined the concentration of Pb in fresh-frozen brain tissue and in 10% formalin-fixed brain tissue from six cases of DNTC, four cases of Alzheimer's disease, and in nine non-demented elderly controls by flameless atomic absorption spectrometry, and demonstrated a high concentration of Pb in DNTC brains. Although it remains unclear how these findings are related to the formation of NFTs, they suggest that Pb neurotoxicity may be involved in the pathogenesis of DNTC.

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PubMed1994

Diffuse neurofibrillary tangles with calcification: a new presenile dementia.

The term "diffuse neurofibrillary tangles with calcification" (DNTC) is proposed for a new form of presenile dementia. It is characterised by slowly progressive cortical dementia in the presenium, localised temporal or temporofrontal lobar atrophy, numerous neurofibrillary tangles widespread in the cerebral cortex, and pronounced calcareous deposits; 16 cases of DNTC, have been reported.

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PubMed2000

Increased neocortical neurofibrillary tangle density in subjects with Alzheimer disease and psychosis.

BACKGROUND: Psychosis is common in patients with Alzheimer disease. While the relationship between psychosis and clinical variables has been examined frequently, few studies have examined the relationship between psychosis and the 2 major neuropathological hallmarks of Alzheimer disease: neurofibrillary tangles and senile plaques. We characterized the occurrence of psychosis in relation to dementia severity and determined if subjects with Alzheimer disease and psychosis had a greater neurofibrillary tangle or senile plaque burden than subjects with Alzheimer disease and no psychosis. METHODS: One hundred nine subjects with Alzheimer disease were followed longitudinally with semistructured assessments in order to assign a Clinical Dementia Rating and determine whether psychosis was present. After the subjects died, their brains were obtained for histological examination. Analysis of variance was used to compare the densities of neurofibrillary tangles, total senile plaques, and cored senile plaques in subjects with psychosis vs subjects without psychosis, in several neocortical regions, the hippocampus, and the entorhinal cortex. RESULTS: Psychosis occurred commonly in Alzheimer disease, affecting 63% of subjects. The frequency of psychosis increased with increasing dementia severity. More importantly, we found that subjects with psychosis had a 2.3-fold (95% confidence interval, 1.2-3.9) greater density of neocortical neurofibrillary tangles than did subjects without psychosis. The increase was independent of dementia severity. No similar relationship with psychosis was seen for total senile plaques or cored senile plaques. CONCLUSIONS: The increase in psychosis frequency that occurs with the progression of dementia severity and the independent association between psychosis and neurofibrillary tangle density suggest the possibility that some common underlying process or processes specific to Alzheimer disease may regulate both phenomena. Arch Gen Psychiatry. 2000;57:1165-1173.

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PubMed1983

Comparative immunocytochemical characterization of neurofibrillary tangles in experimental maytansine and aluminum encephalopathies.

The neurofibrillary tangles induced by maytansine and aluminum are stained by the peroxidase-anti-peroxidase method, using antibodies raised against the 68, 150 and 200 kdaltons polypeptide subunits of normal neurofilaments. The immunoreaction with each of the 3 antisera occurs regardless of the location of the neurofilament accumulation, whether in perikarya, dendrites or axons. It is very likely that the filaments of the neurofibrillary tangles induced by both aluminum and maytansine contain all the 3 neurofilament subunits.

Aluminum↗

PubMed1987

The association of aluminum Alzheimer's disease, and neurofibrillary tangles.

Alzheimer's disease is a progressive neurodegenerative disease characterized by the development of large numbers of neurofibrillary tangles in certain neuronal populations. Aluminum salts inoculated into experimental animals produce neurofilamentous lesions which are similar, but not identical, to the neurofibrillary tangle of Alzheimer's disease. Although a few reports suggest evidence of increased amounts of aluminum in the brains of Alzheimer's disease victims, such bulk analysis studies have been difficult to replicate. Using scanning electron microscopy with x-ray spectrometry, we have identified accumulations of aluminum in neurofibrillary tangle-bearing neurons of Alzheimer's disease. Similar accumulations have been identified in the neurofibrillary tangle-bearing neurons found in the brains of indigenous natives of Guam who suffer from parkinsonism with dementia and from amyotrophic lateral sclerosis. This ongoing research still cannot ascribe a causal role of aluminum in the pathogenesis of the neurofibrillary tangle; however, it does suggest that environmental factors may play an important part in the formation of this abnormality.

Aluminum↗

PubMed1977

Motor neurone disease with neurofibrillary tangles in a Brazilian woman.

The occurrence of neurofibrillary tangles in both the cerebral cortex and brain stem is typically seen in the Guam type of amyotrophic lateral sclerosis, but is exceedingly rare in the classical form of the disease. Only 3 cases of sporadic amyotrophic lateral sclerosis with such histopathologic features have so far been reported, all in the United States. A 49-year-old Brazilian woman had an 18-month history of amyotrophic lateral sclerosis involving predominantly the left-sided extremities with prominent bulbar signs. Autopysi disclosed moderate to severe loss of motor neurones in the hypoglossal nuclei and anterior spinal horns, absence of pyramidal tract demyelination, depigmentation of the substantia nigra and numerous neurofibrillary tangles in the hypothalamic region, parahippocampal gyrus, reticular substance of the mesencephalon and pons and in some brain stem nuclei. The topographical distribution of these changes was closely similar to that of Guamanian amyotrophic lateral sclerosis.

Alzheimer Disease↗

PubMed2006

Alzheimer's neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes.

In the realm of dementia, it is astonishing to note that neurofibrillary tangles (NFT) are microscopically identical in a childhood illness (SSPE) and in a dementia of late adult life (Alzheimer's disease). The words "Alzheimer-type" NFT in peer reviewed scientific articles written by acknowledged experts underscore the striking similarities in "tangles" in two different diseases. Subacute Sclerosing Panencephalitis (SSPE) is caused by infection with atypical measles virus. Alzheimer's disease has no known cause. There is little controversy in suggesting that all of the Tangles in SSPE infected neurons are produced by slow viral type variant of Measles infection. But the mere suggestion that infection might be a cause of Alzheimer's disease confounds the establishment. If a good case is to be made for infection in Alzheimer's disease, an excellent nerve cell infection model is needed. Monkeys have provided a very reasonable model. Recently, a primate neuroborreliosis brain infection model demonstrated that Borrelia injected into the skin of monkeys resulted in the appearance of Borrelia transcriptomes in brain neurons. If Borrelia can travel from skin to brain in the monkey, then why not look at human Alzheimer's tissues to see if the DNA of Borrelia is present in the human brain? The molecular detection tools perfected in animal neuroborreliosis studies have been applied to human Alzheimer's disease brain tissues. Seven of ten cases of Alzheimer's disease from McLean Hospital Brain Bank of Harvard University yielded positive signals for infectious DNA in a small pilot study. Alzheimer's diseased neurons analyzed with DNA probes, produced little "dots" of positive staining. Granulovacuolar bodies in Alzheimer's diseased neurons (little dots in a bubble), are one of the expected microscopic profiles of Alzheimer's disease. "Little dots" inside nerve cells are also signatures of viral infectious agents inside of nerve cells. So with the assistance of the microscope and the tools of molecular biology, a new model of infection emerges as a cause of "Alzheimer's-type" neurofibrillary tangles. Here I hypothesize that it is chronic infection of human neurons in Alzheimer's disease that produces neurofibrillary tangles by a pathway similar to the chronic SSPE infection tangle pathway. In addition, transmission of infection from nerve to nerve is proposed to explain the evolution of Alzheimer's disease. Herein is offered a new view for the origins and for the progression of diseased nerves with tangle formations in Alzheimer's disease based on infection.

Alzheimer Disease↗

PubMed1979

Alzheimer neurofibrillary tangles: antiserum and immunohistological staining.

A 50,000-dalton polypeptide has been purified from fractions enriched with neurofibrillary tangles of paired helical filaments from human autopsy specimens of Alzheimer disease and senile dementia of the Alzheimer type. An antiserum to this polypeptide was raised in a rabbit. This antiserum formed an immunoprecipitation line with the purified antigen and with human neurotubules in ouchterlony double-diffusion plates. The reactivity of the anti-paired helical filament protein serum with neurofibrillary tangles was studied by immunofluorescence on cryostat sections of hippocampus from Alzheimer autopsy tissue and by the peroxidase-antiperoxidase technique on paraffin sections of an Alzheimer brain biopsy. The tangles were stained with the antiserum in both systems. Preimmune rabbit serum and unrelated hyperimmune sera, used as controls, did not stain the tangles. These results show that the 50,000-dalton polypeptide purified from the neurofibrillary tangle-enriched fractions is a constituent of Alzheimer neurofibrillary tangles and, perhaps, of the paired helical filaments of which the tangles are composed.

Alzheimer Disease↗

PubMed1986

Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease.

Neurofibrillary tangles (NFT) are a hallmark of Alzheimer's disease (AD), and their presence correlates with the presence of dementia. A major constituent of NFT is the insoluble paired helical filament which shares some antigenic relationships with normal cytoskeletal elements, particularly neurofilaments. If neurofilament proteins (200, 145-160, and 68 kilodaltons [kd]) participate in the formation of NFT, the distribution of these constituents might be expected to be abnormal. To examine this issue, we used immunocytochemical methods to localize phosphorylated and nonphosphorylated epitopes of neurofilament proteins in hippocampal neurons of controls and patients with AD. Normally, the 200-kd neurofilament protein is not phosphorylated in the perikarya of neurons. However, in AD, many pyramidal neurons contained immunoreactive phosphorylated neurofilaments. Patterns of immunoreactivity (linear, flame-shaped, or skein-like within perikarya) greatly resembled the appearance of silver-stained NFT. This pattern of immunoreactivity was not present in hippocampal pyramidal neurons in controls, except in one aged patient in whom adjacent silver-stained sections revealed a few NFT. Patterns of immunoreactivity with antibodies for nonphosphorylated neurofilament proteins were similar in control and AD neurons. Our results indicate that some NFT are associated with abnormal distributions of high molecular weight phosphorylated neurofilament proteins. One domain of the 200-kd protein is believed to be a component of the side arms which link neurofilaments and interact with microtubules. Abnormal interactions of perikaryal neurofilaments could play a role in the genesis of NFT, and this abnormality of the cytoskeleton could contribute to the dysfunction of neurons at risk in AD.

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PubMed2001

Selective neurodegeneration, without neurofibrillary tangles, in a mouse model of Niemann-Pick C disease.

The BALB/c mouse model of Niemann-Pick type C (NPC) disease exhibits neuropathological similarities to the human condition. There is an age-related cerebral atrophy, demyelination of the corpus callosum, and degeneration of cerebellar Purkinje cells in the NPC mouse. In human NPC, many cortical and subcortical neurons contain neurofibrillary tangles, which are thought by some investigators to play an important role in the neurodegenerative process. The purpose of the present study was to determine whether neurodegeneration occurs in the NPC mouse, in brain regions other than the cerebellum and whether the degeneration is related to the presence of neurofibrillary tangles. Using light microscopic methods with immunohistochemistry, electron microscopy, and cell counting methods, 11-week-old NPC(+/+) and NPC(-/-) animals were examined. In the NPC(-/-) mice, there were 96% fewer Purkinje cells, 28% fewer neurons in the prefrontal cortex, 20% fewer neurons in the thalamus, and 63% fewer glial cells in the corpus callosum. On the other hand, previous studies indicate normal numbers of neurons and glial cells in these same neuroanatomical regions in young NPC(-/-) mice. There were normal numbers of cholinergic neurons in sections assessed in the striatum and basal forebrain in the 11-week-old animals and no evidence of neurofibrillary tangles within cells. The present data indicate that both neurons and glial cells die in the NPC mouse but that all cells are not equally vulnerable. There was no evidence for neurofibrillary tangles in the NPC mouse, and therefore the degenerative process in the mouse is unrelated to the neurofibrillary tangle.

Animals↗

PubMed2000

Laminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer's disease. Correlations with the amyloid load and the density of tau-positive neurofibrillary tangles.

Presenilin 1 has been shown to be mutated in a high proportion of cases of familial Alzheimer's disease. Immunoreactive epitopes of the protein have been found mainly in neurones devoid of neurofibrillary tangles - an observation that has led to the conclusion that presenilin 1 could have a protective role. In this study, the relationship between deposits of Abeta peptide (both the 40 and 42 isoforms), tau positive neurofibrillary tangles and presenilin 1-positive neuronal profiles were analysed in three cases of presenilin 1 mutation, four cases of sporadic Alzheimer's disease and five controls. Immunohistochemistry was performed in a sample from the supramarginal gyrus. The proportion of volume occupied by the Abeta1-40 and Abeta1-42 deposits (amyloid load) was evaluated by a point-counting technique. Tau-positive neurofibrillary tangles, and presenilin 1-positive neuronal profiles were directly counted. The location of the lesions in the thickness of the cortex was recorded. The density of PS1-positive neuronal profiles in Alzheimer's disease cases was lower than in the controls. The deficit was significant only in the upper layers of the cortex. The density of presenilin 1 neuronal profiles was negatively correlated with Abeta1-40 and Abeta1-42 loads, and with the density of tau-positive neurofibrillary tangles. Multivariate analysis showed that the Abeta1-42 load was the best determinant of the decrease in presenilin 1-positive neuronal profiles. Presenilin 1-positive neurones appear to be lost rather than protected in the course of Alzheimer disease.

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PubMed1986

Fluorescence activated cell sorting (FACS) as a separation method for neurofibrillary tangles in Alzheimer's disease.

We have developed a fluorescence cell sorting (FACS) method for the separation of neurofibrillary tangles from post-mortem brain from cases of Alzheimer's disease and Down's syndrome. Neurofibrillary tangles in brain homogenate were selectively labelled with the fluorescent dye congo red. Using FACS the tangles were separated from other tissue components on the basis of fluorescence and forward-angle light scatter to give a fraction highly enriched in tangles, which were identified by light and crossed polarisation microscopy. Tangles were not observed in a comparison fraction, collected at the same time, of weakly fluorescent particles of similar size to the tangles. Thus FACS provides a non-denaturing method for obtaining preparations of neurofibrillary tangles for purposes of further analysis.

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PubMed1979

Ultrastructure of neurofibrillary tangles in progressive supranuclear palsy.

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.

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PubMed1993

Nonisotopic in situ hybridization of amyloid beta protein precursor in Alzheimer's disease: expression in neurofibrillary tangle bearing neurons and in the microenvironment surrounding senile plaques.

We have used nonisotopic in situ hybridization techniques with biotinylated junctional oligonucleotide probes to study expression of amyloid precursor protein (APP) 695 and 751 mRNA in the hippocampal formation of Alzheimer's disease. Both mRNAs are strongly expressed in neurons of the hippocampal formation, particularly in the dentate gyrus granule cells and the pyramidal neurons of CA3. The patterns of expression of neither APP695 nor APP751 mRNA correlate well with the stereotyped topography of neurofibrillary tangles or senile plaques, which occur primarily in CA1 and subiculum. We double-labeled in situ sections with immunohistochemical reagents for neurofibrillary tangles or senile plaques. Neurons that contain neurofibrillary tangles continue to express APP mRNA. The level of APP695 and APP751 was measured semiquantitatively by optical density measurements in neurons that were close to (within 25 microns) or father from a senile plaque (more than 100 microns). There was no increase in expression in neurons in the immediate microenvironment of senile plaques. Our results suggest that no major change in distribution or type of APP mRNA accompanies neurofibrillary tangle or senile plaque development.

Adult↗

PubMed1991

Demonstration of beta amyloid protein-containing neurofibrillary tangles in parkinsonism-dementia complex on Guam.

This report concerns the immunohistochemical demonstration of beta amyloid protein-containing neurofibrillary tangles (beta-NFTs) from patients with parkinsonism-dementia complex on Guam (PDC). Formalin-fixed paraffin-embedded tissue sections from the temporal lobe of nine PDC cases and the spinal cord of three were examined. An affinity-purified antibody to the N-terminal peptide sequence of beta amyloid protein was used. beta-NFTs were demonstrated in the temporal lobes of the three oldest individuals. Some senile plaques, probably a manifestation of ageing, were also seen. The beta-NFTs were most frequent in the entorhinal cortex. Senile plaques were invariably present in the vicinity of the beta-NFTs. Conversely, in the regions without senile plaques, even though numerous neurofibrillary tangles were identifiable with the modified Bielschowsky method, no beta-NFTs were seen. The density of beta-NFTs appeared to be proportional to that of senile plaques, none was seen in cases lacking senile plaques. No beta-NFTs were detected in the spinal cords. Our data suggest that beta-NFTs result from secondary beta amyloid deposition on certain neurofibrillary tangles.

Amyloid beta-Peptides↗

PubMed1987

Quantitative assessment of the density of neurofibrillary tangles and senile plaques in senile dementia of the Alzheimer type. Comparison of immunocytochemistry with a specific antibody and Bodian's protargol method.

Counts of neurofibrillary tangles and senile plaques were performed in two adjacent sections from the temporal lobe in 14 women aged over 75 years at death. The mental status of these cases had been prospectively assessed by the test score of Blessed, Tomlinson and Roth. They were either intellectually normal or had senile dementia of the Alzheimer type of various degrees of severity. The first section was silver-impregnated according to Bodian's method; the second one was immunolabeled with an antiserum raised against neurofibrillary tangles. Densities of neurofibrillary tangles and senile plaques evaluated by the two techniques were highly correlated but their means of differences and limits of agreement were large. The correlation with the clinical data was similar for the two methods. Both techniques can thus be used with the same accuracy in correlative studies but their results are not interchangeable without caution.

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PubMedDate not supplied

Oxidative posttranslational modifications in Alzheimer disease. A possible pathogenic role in the formation of senile plaques and neurofibrillary tangles.

The distinctive pathological lesions of Alzheimer disease (AD), senile plaques, and neurofibrillary tangles comprise aggregates of insoluble fibrillar protein. We and other investigators recently demonstrated that several mechanisms related to oxidative stress and free-radical reactions could play a crucial role in the pathogenesis of AD and, specifically, in the formation of senile plaques and neurofibrillary tangles (NFT).

Alzheimer Disease↗

PubMed1997

Neurofibrillary tangles in Gerstmann-Sträussler-Scheinker syndrome with the A117V prion gene mutation.

One patient of a French family with Gerstmann-Sträussler-Scheinker syndrome with the mutation in codon 117 of the prion protein (PrP) gene displayed unexpected neuritic degeneration around PrP plaques and numerous diffuse neurofibrillary tangles, whereas other members did not. The tau profile in this patient's brain was analysed and compared with one from another member of the Gerstmann-Sträussler-Scheinker family as well as with the Alzheimer's tau profile. A panel of well characterised antibodies against both normal tau protein and paired helical filaments-tau protein was used on immunoblots of brain proteins resolved by mono and two dimensional gels. The tau profile in the patient with Gerstmann-Sträussler-Scheinker syndrome without neurofibrillary tangles was normal. The tau profile from the patient with Gerstmann-Sträussler-Scheinker syndrome and neurofibrillary tangles was characterised by a hyperaggregation state of tau protein. This case illustrates the phenotypic heterogeneity of the GSS117 mutation not only from one family to another, but also between members of the same family. In this family, the presence of neurofibrillary tangles is still unexplained, but could be correlated with either the protracted duration of the disease or the old age of the patient.

Adult↗