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PubMed1995

Neurons, intracellular and extracellular neurofibrillary tangles in subdivisions of the hippocampal cortex in normal ageing and Alzheimer's disease.

Unaffected neurons, intracellular neurofibrillary tangles (I-NFTs) and extracellular NFTs (E-NFTs) in six normal subjects and six patients with Alzheimer's disease (AD) were morphometrically evaluated in eight subdivisions of the hippocampal cortex, using the Gallyas silver impregnation technique modified by the application of hematoxylin and eosin. The subdivisions examined included CA1-4, prosubiculum (PRO), subiculum and presubiculum (PRE), parasubiculum (PARA) and the entorhinal cortex (ENT). In the AD patients, the number of unaffected neurons in ENT, CA1, PRO and PARA was significantly decreased to one-quarter to two-thirds of that of the normal aged subjects. These four subdivisions in the AD patients had a greater number of both I- and E-NFTs. There were no significant differences in the total number of unaffected neurons, I- and ENTs between the AD patients and normal aged subjects for all the subdivisions. These findings suggest that neuronal loss in the hippocampal cortex in AD is almost entirely due to NFT formation. Furthermore, with regards to neuronal loss and NFT formation, there were two different subdivision groups in the AD patients. One group was composed of severely affected subdivisions (ENT, CA1, PRO and Para) and was distinct from the other group which was composed of mildly affected subdivisions (CA4, CA3, CA2 and PRE). Each subdivision in the normal aged subjects belonged to the mildly affected group as seen in the AD patients. These findings indicate that both neuronal loss and NFT formation associated with normal ageing and with AD are not only quantitatively but also qualitatively different.

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PubMedDate not supplied

The topographical and neuroanatomical distribution of neurofibrillary tangles and neuritic plaques in the cerebral cortex of patients with Alzheimer's disease.

The distribution of neurofibrillary tangles (NFTs) and neuritic plaques (NPs) was mapped in 39 cortical areas of 11 brains of patients with Alzheimer's disease (AD). Whole hemisphere blocks were embedded in polyethylene glycol (Carbowax), sectioned coronally, and stained with thioflavin S and thionin. The densities of NFTs and NPs were assessed using a numerical rating scale for each area. Scores were grouped by type of cortex and by lobe for statistical analysis. Highly significant differences were obtained. For example, limbic periallocortex and allocortex had more NFTs than any other type of cortex. In descending order, the density of NFTs was as follows: periallocortex (area 28) greater than allocortex (subiculum/CA1 zones of hippocampal formation, area 51) greater than corticoid areas (accessory basal nucleus of amygdala, nucleus basalis of Meynert) greater than proisocortex (areas 11, 12, 24, 23, anterior insula, 38, 35) greater than nonprimary association cortex (32, 46, superior temporal sulcus, 40, 39, posterior parahippocampal cortex, 37, 36) greater than primary sensory association cortex (7, 18, 19, 22, 21, 20) greater than agranular cortex (44-5, 8, 6, 4) greater than primary sensory cortex (41-2, 3-1-2, 17). The laminar distribution of NFTs tended to be selective, involving primarily layers III and V of association areas and layers II and IV of limbic periallocortex. There were far more NFTs in both limbic and temporal lobes than in frontal, parietal, and occipital lobes. In general, NPs were more evenly distributed throughout the cortex, with the exceptions of limbic periallocortex and allocortex, which had notably fewer NPs than other cortical areas. Temporal and occipital lobes had the highest NP densities, limbic and frontal lobes had the lowest, and parietal lobe was intermediate. No significant left-right hemispheric differences for NFT or NP densities were found across the population, and there was no relationship between duration of illness and densities of NFTs or NPs. The regional and laminar distribution of NFTs (and, to a lesser degree, that of NPs) suggests a consistent pattern of vulnerability within the cerebral cortices that seems correlated to the hierarchies of cortico-cortical connections. The higher-order association cortices, especially those in the anterior and ventromedial sectors of temporal lobe, are the most vulnerable, while other cortices appear less vulnerable to a degree commensurate with their connectional "distance" (i.e., synapses removed) from the limbic areas.

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PubMed1996

Improved selectivity and sensitivity in the visualization of neurofibrillary tangles, plaques and neuropil threads.

Stain sensitivity is a key factor in estimating the frequency of plaques and neurofibrillary tangles in Alzheimer's disease (AD), making it essential that the sensitivity and selectivity of detection methods for identifying these lesions is maximized. Several new, improved techniques have recently been described, although these methods have not been compared quantitatively with those techniques currently recommended for use in standardized diagnostic protocols. In the present study, eight different stains were examined for their selectivity and sensitivity in detecting plaques and tangles in serial tissue sections from AD and control brains. Techniques compared were immunohistochemistry for tau and beta-amyloid, thioflavin S, nickel peroxidase method, and four silver impregnation techniques (Gallyas silver iodide, Campbell-Switzer-Martin, Garvey's modified Bielschowsky and methenamine silver methods). Among these eight staining techniques, the nickel peroxidase proved the most reliable method for the demonstration of the histopathological lesions of AD. This method labels all morphological types of plaques and tangles within a single tissue section, and provides several advantages for the analysis of lesion progression and distribution.

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PubMed1988

Human antibodies to neurofibrillary tangles and astrocytes in Alzheimer's disease.

Multiple B cell lines established by Epstein-Barr viral transformation from six patients with Alzheimer's disease (AD) and six age-matched controls were screened immunocytochemically for their reactivities with AD and normal brains as well as to cell lines such as HeLa, fibroblasts and neuroblastoma. A higher incidence of reactivity with neurofibrillary tangles in situ was found among the cell lines from AD patients (23/866) in comparison with those from normals (6/803). Three cell lines from a patient with a definitive neuropathological diagnosis of AD were shown to secrete antibodies preferentially reactive with astrocytes in the grey matter of AD brain and one cell line from a normal elderly individual was shown to specifically react with neurofibrillary tangles and plaque neurites. These four antibodies were not reactive with normal brains or cell lines. These unique human antibodies may be useful in the diagnosis of AD and offer clues to its pathogenesis.

Alzheimer Disease↗

PubMed1995

Ganglioglioma with neurofibrillary tangles (NFTs): neoplastic NFTs share antigenic determinants with NFTs of Alzheimer's disease.

A cerebral ganglioglioma contained abundant neurofibrillary tangles (NFTs) of the paired helical filament (PHF) type. The NFTs in the tumor were argyrophilic and Congo red and thioflavin-S positive. Immunohistochemically, the NFTs were reactive with antibodies to phosphorylated neurofilament protein, PHF/tau and ubiquitin. The demonstration in the neoplasm of abnormally phosphorylated and ubiquitinated cytoskeletal components, similar in morphology and in immunoreactivity to those seen in NFTs of Alzheimer's disease, suggest that similar pathogenetic mechanisms may operate in both conditions.

Adult↗

PubMedDate not supplied

Neurofibrillary tangles in the peripheral sympathetic ganglia of non-Alzheimer elderly individuals.

AIM AND METHODS: To clarify whether neurofibrillary tangle (NFT) formation in the peripheral nervous system is related to that in the central nervous system (CNS), we examined the sympathetic and spinal ganglia from 20 patients with Alzheimer's disease (AD), 8 with progressive supranuclear palsy (PSP), and 100 non-demented individuals, all older than 60 years of age. RESULTS: NFTs were found in the sympathetic ganglia in two elderly (72- and 84-year-old) individuals without AD pathology. Ultrastructurally, these NFTs were composed of paired helical filaments which showed positive immunohistochemical staining with antibodies against ubiquitin and phosphorylation-dependent and -independent epitopes of tau protein. They were identical to those observed in the CNS. No NFTs were detected in the sympathetic or spinal ganglia in AD and PSP patients. CONCLUSIONS: These findings indicate that NFTs in the peripheral ganglia are uncommon and develop independently of the neurofibrillary pathology that occurs in the CNS.

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PubMedDate not supplied

Glycogen synthase kinase 3 alteration in Alzheimer disease is related to neurofibrillary tangle formation.

Highly phosphorylated tau protein is the main component of paired helical filaments (PHF), which comprise the neurofibrillary tangles (NFT) in some neurons of patients with Alzheimer disease (AD). Glycogen synthase kinase 3 (GSK3) phosphorylates tau in vitro at several sites also found to be phosphorylated in PHF-tau; tau is phosphorylated at these sites in both AD and normal control (NC) brains, although the extent of phosphorylation is far greater in tau from AD. If GSK3 levels are increased in AD, then tau phosphorylation and perhaps PHF formation may occur. To quantify GSK3, blots of AD and NC brain supernatant and particulate fractions were probed with antibodies to GSK3. In particulate fractions of AD compared to NC, GSK3 alpha immunoreactivity did not increase, but in fact, decreased 40%, and GSK3 beta immunoreactivity decreased 30%. GSK3 alpha and GSK3 beta levels correlated well with each other. GSK3 levels correlated negatively with numbers of NFT.

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PubMed1989

Gerstmann-Sträussler-Scheinker disease. II. Neurofibrillary tangles and plaques with PrP-amyloid coexist in an affected family.

Azzarelli et al reported an Indiana kindred affected by a hereditary disorder, characterized clinically by ataxia, parkinsonism, and dementia. Recently, we studied neuropathologically the 3rd and 4th cases that came to autopsy among the patients of this family. As in 2 patients examined previously, amyloid plaques were widespread throughout the cerebrum and the cerebellum, whereas neurofibrillary tangles were numerous in the cerebral cortex, the hippocampus, and the substantia innominata. Amyloid plaques were not recognized by polyclonal antibodies against the Alzheimer's disease amyloid A4 protein, but did contain epitopes recognized by antibodies against a prion protein. Spongiform changes were occasionally observed and were mild. Our findings indicate that this familial disorder is a form of or is related to Gerstmann-Sträussler-Scheinker disease. The consistent presence of numerous neurofibrillary tangles may be important in differentiating a distinct subgroup of patients with familial Gerstmann-Sträussler-Scheinker disease, and indicates that a disturbance of the cytoskeleton might be part of the neuronal pathology of Gerstmann-Sträussler-Scheinker disease.

Amyloid↗

PubMed1992

Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.

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PubMedDate not supplied

Senile dementia of the neurofibrillary tangle type: a comparison with Alzheimer's disease.

A subset of senile dementia, 'senile dementia (SD) of the neurofibrillary tangle (NFT) type' (SD-NFT), is characterized by numerous NFTs in the hippocampal region and absence or scarcity of senile plaques throughout the brain. To elucidate the pathogenesis of SD-NFT in comparison with Alzheimer's disease (AD), we investigated the hippocampal lesions and analyzed the tau gene. The hippocampal regions from 5 patients with SD-NFT were neuropathologically evaluated in comparison with AD and nondemented control subjects. The tau gene was analyzed in 3 patients with SD-NFT. The densities of NFTs in the CA1/subiculum and entorhinal cortex of SD-NFT were significantly higher than those in AD. However, hippocampal atrophy, neuronal and synaptic loss, and astrocytic and microglial proliferation in SD-NFT were significantly mild compared with AD. There was no significant difference between SD-NFT and AD in the immunoreactivities of NFTs with different anti-tau antibodies. No mutation was found in the tau gene from the SD-NFT patients. Our results indicate that the neurodegenerative process with NFT formation of the hippocampal region in SD-NFT would be different from that in AD.

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PubMed2005

Is there a spatial association between senile plaques and neurofibrillary tangles in Alzheimer's disease?

OBJECTIVE: To test the hypothesis that the clusters of senile plaques (SP) and neurofibrillary tangles (NFT) in patients with Alzheimer's disease (AD) are spatially associated as predicted by the 'Amyloid Cascade Hypothesis'. METHODS: The spatial association between the SP and NFT was studied in the cerebral cortex and hippocampus in six cases of sporadic Alzheimer's disease (AD) using contingency tables. The coefficient C7 was used as an index of spatial association while chi-square with correction for continuity was used as a test of significance. RESULTS: In the brain regions analysed, values of C7 were in the range -0.31 to +0.32 but a statistically significant spatial association between SP and NFT was present in only 8/39 (21%) regions. The degree of spatial association between the SP and NFT was similar in different brain regions and did not vary with apolipoprotein e genotype of the patient. However, the magnitude of C7 in a region was positively correlated with the density of the NFT and with the total density of SP and NFT but not with the density of SP alone. CONCLUSION: There was little evidence that SP and NFT were spatially associated except in brain areas with high densities of lesions. The data support the hypothesis that SP and NFT are distributed relatively independently in the cerebral cortex and hippocampus and therefore, could be distinct phenomena in AD.

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PubMed2002

Distribution of basal ganglia lesions in diffuse neurofibrillary tangles with calcification: a clinicopathological study of five autopsy cases.

We investigated five Japanese autopsy cases of diffuse neurofibrillary tangles with calcification (DNTC), both clinically and pathologically, and examined the degree and distribution of the basal ganglia lesions, especially in the amygdala, striatum, pallidum, and substantia nigra. The lesions in the amygdala, striatum, and pallidum were classified into three categories (mild, moderate, and severe). The lesions in the substantia nigra were qualitatively judged, compared with normal controls. Severe dementia was observed in four cases neuropathologically showing pronounced neuronal loss in the cerebral cortex, but one case without neuronal loss in the cerebral cortex showed mild memory disturbance. Extrapyramidal signs were evident in three cases. Obvious neuronal loss in the substantia nigra with the presence of Lewy bodies was noticed in four cases. Basal ganglia lesions in all five cases were uniform: the amygdala showed severe to moderate lesions, the caudate nucleus moderate to slight lesions, and the putamen and pallidum slight lesions to normal. Furthermore, the lesions in the amygdala were more prominent in the basolateral group than in the corticomedial group, inconsistent with those in the amygdala of Alzheimer's disease. Moderate lesions were evident in the basolateral group of the amygdala in the case without neuronal loss in the cerebral cortex. In DNTC, the degree and distribution of the basal ganglia lesions, except for nigral lesions, were analogous to those found in Pick's disease with Pick bodies. These clinicopathological findings may contribute to the elucidation of the clinicopathological hallmarks in this disorder.

Age of Onset↗

PubMed1989

Reappraisal of neurofibrillary tangles. Immunohistochemical, ultrastructural, and immunoelectron microscopical studies.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1982

Senile dementia of Alzheimer type: astroglial reaction to extracellular neurofibrillary tangles in the hippocampus. An immunocytochemical and electron-microscopic study.

Two types of Alzheimer neurofibrillary tangles may be found in the hippocampus in senile dementia of the Alzheimer type. Besides classical flame-shaped intraneuronal tangles, there are less compact tangles representing extracellular remnants of destroyed neurons with neurofibrillary change. Strong immunoreactivity for glial fibrillary acidic protein (GFA) was found in the second type of tangles, which was due to penetration of fine processes of fibrous astrocytes into bundles of paired helical filaments (PHF). PHF appear to be a strong stimulus for astrocytic reaction when they are not segregated from the neuropil by the neuronal cell membrane.

Aged↗

PubMed1994

Non-Alzheimer neurofibrillary tangles show beta-amyloid-like immunoreactivity.

As well as being a neuropathological hallmark of Alzheimer's disease (AD), neurofibrillary tangles (NFT) are present in the brain in a number of other neurodegenerative conditions. beta-Amyloid (beta/A4) plaque formation is a central event in AD, although recent reports indicate that beta/A4, and its precursor protein (beta APP), are also associated with AD NFT. Using an antibody to a beta APP epitope overlapping the beta/A4 region, we demonstrate that immunoreactivity is found in extracellular NFT in Niemann-Pick disease, Hallervorden-Spatz disease, progressive supranuclear palsy and subacute sclerosing panencephalitis. These NFT were not labelled with a beta/A4 antibody which recognizes plaque beta/A4 in AD, which supports the proposal that beta/A4 can exist in different conformations. Our results also imply a common mechanism of NFT development in different neurodegenerative conditions, including those not normally associated with substantial beta/A4 deposition or beta APP involvement.

Adult↗

PubMed2001

Diffuse neurofibrillary tangles with calcification (a form of dementia): X-ray spectrometric evidence of lead accumulation in calcified regions.

Diffuse neurofibrillary tangles with calcification (DNTC) is a form of slowly progressive dementia in which no senile plaques are observed. The calcification is one of the most characteristic features of DNTC. We examined the elemental content of certain mineral deposits (lead, magnesium, phosphorus, calcium, iron, copper and zinc) in the calcified and non-calcified regions of eight cases of DNTC, five cases of Alzheimer's disease (AD) and in eight non-demented elderly controls. The study was performed using a combination of scanning electron microscopy and X-ray spectrometry on 10% formalin-fixed brain tissue. A marked abundance of calcium and phosphorus was observed in the calcified regions of DNTC and non-DNTC brains. Although no lead was observed in the non-calcified regions of DNTC and in non-DNTC brains, traces of lead were detected exclusively in the calcified regions of DNTC brains. The implications and possible significance of the lead accumulation in DNTC brains are discussed.

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PubMed1985

Nucleus raphe dorsalis in Alzheimer's disease: neurofibrillary tangles and loss of large neurons.

Diffuse serotonergic fibers are presumed to project to the telencephalon from the nucleus raphe dorsalis (NRD) of the midbrain, in a manner similar to the cholinergic projections from the nucleus basalis of Meynert (nbM) to the cerebral cortex. Neuropathological changes in both of these nuclei have been reported in Alzheimer's disease (AD). Although many morphometric studies of the nbM in AD have been documented, only one such study of the NRD has been conducted so far; it demonstrated a sixfold increase in neurofibrillary tangles in AD but no statistically significant difference in the number of neurons in patients with AD and age-matched controls. A study of the NRD utilizing different stains and wider anatomical boundaries is detailed in this report of 5 patients with AD and 7 age-matched controls. In AD the NRD showed 39 times more neurofibrillary tangles and the number and cell density of large neurons were reduced to 23% and 28%, respectively, of those in the controls. A small number of senile plaques were found in the NRD in all patients with AD but none were found in the controls.

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PubMed2004

Imaging beta-amyloid plaques and neurofibrillary tangles in the aging human brain.

The development of radioligands to image beta-amyloid (A beta) plaques and neurofibrillary tangles (NFTs) in vivo in the aging human brain is an important and active area of radiopharmaceutical design. When used in combination with positron emission tomography (Pet) or single photon emission computed tomography (spect), amyloid-imaging tracers could facilitate the evaluation of the efficacy of anti-amyloid therapies currently under intense development by many major pharmaceutical companies throughout the world. Amyloid-imaging agents could also serve as surrogate markers in early diagnosis and neuropathogenesis studies of Alzheimer's disease and other aging-related neurodegenerative disorders. In this review article, the design and biological evaluation of amyloid-imaging agents are discussed. The structures of these agents vary from large proteins and peptides such as radiolabeled A beta peptides and monoclonal antibodies to small molecules derived from Congo red, Chrysamine-G, thioflavin-T, and Acridine Orange. In vitro studies indicate that amyloid plaques contain multiple binding sites that can accommodate structurally diverse compounds, providing flexibility for radiopharmaceutical design of amyloid imaging agents. Compared to large biomolecules, small molecule radiotracers are often readily accessible through chemical synthesis and can display superior brain permeability. Several small molecule amyloid-imaging radioligands display high binding affinities to A beta and sufficient brain penetration for imaging studies. Recent studies demonstrate the feasibility of imaging amyloid plaques in vivo in human subjects with PET. Imaging NFTs, separately or in concert with A beta plaques, is not as far advanced as imaging A beta plaques and remains to be fully characterized and demonstrated.

Aging↗