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Topographic analysis was performed on the distribution of argyrophilic inclusions in hippocampal neurones of patients with Pick's dementia. A semiautomated scanning stage microscope linked potentiometrically to an XY pen recorder permitted the plotting of cytoarchitectonic "scattergrams" from the sequentially screened hippocampal formations. The density of Pick body-bearing nerve cells per cubic mm. of (pyramidal) cortex was quantified by measuring the area of each of six "zones" with a digitizer and programmable calculator. The ranking orders of relative severity showed that neurones in Rose's H1 field, the adjacent subiculum, and the entorhinal cortex are severely involved; that H2 and the presubiculum are less afflicted; and that the endplate is the least affected of all. The similarity of these predilections to those already demonstrated for Hirano bodies, granulovacuoles and neurofibrillary tangles in Alzheimer's disease suggests that a specific neurotransmitter defect may also underlie the dementia of Pick's disease.

Paired helical filaments, pathologically changed components of the cytoskeleton of human nerve cells, are demonstrated by a specific silver staining technique, immunostaining and electron microscopy. Accumulations of these filaments are found in the telencephalic cortex of old-aged individuals and patients suffering from Alzheimer's disease. Apart from neurofibrillary tangles and neuritic plaques, paired helical filaments are encountered in neuropil threads. At this third location, pathological filaments occur in small and inconspicuous profiles scattered throughout both allocortical and isocortical areas. The pattern of distribution and packing density of neuropil threads varies between different cortical areas and layers.

Alzheimer's neurofibrillary tangles, Lewy bodies and chromatolytic neurons were found in the brain at autopsy of a 28-year-old male with pyramidal and extrapyramidal signs, and severe dementia of 7-year duration prior to his death. Review of histological material showed generalized changes involving both cortical and subcortical structures. These changes were characterized by the presence of neurofibrillary myelin in long tracts and in subcortical regions. The neurofibrillary tangles were mostly composed of Alzheimer's paired helical filaments (PHF), PHF were immunostained with both polyclonal and monoclonal antibodies to PHF and the microtubule-associated protein tau. Some Lewy bodies were immunolabelled with monoclonal antibodies to PHF. To the best of our knowledge it is the first reported case of a young adult-form of dementia with extensive formation of neurofibrillary changes and Lewy bodies.

Isolated paired helical filaments (PHF) of Alzheimer's disease and senile dementia of the Alzheimer type (AD/SDAT) were studied by negative stain techniques and electron microscopy (EM). The helical structure of the PHF was confirmed by tilt analysis of negatively stained isolated PHF. A substructure of four protofilaments, each 3-5 nm in diameter, was also observed. A comparison of PHF substructure, neurofilaments and microtubules, revealed no similarity among the three structures.

Neurofilaments were isolated from desheathed and minced segments of rat peripheral nerve by osmotic shock into 0.01 M Tris-HCI buffer, pH 7.2. Freshly isolated neurofilaments were observed to undergo disassembly by progressive fragmentation upon exposure of dilute tissue extracts to this buffer. Low- and high-speed centrifugations of these tissue extracts separated membranous and particulate constituents and produced a progressive enrichment of 68,000-dalton polypeptide band in successive supernates, as determined by analyses of soluble proteins by SDS-polyacrylamide electrophoresis. The final high-speed supernatant fractions (S3) of nerve extracts, which were predominantly composed of 68,000-dalton polypeptide, were used to raise a specific experimental antisera in rabbits. Utilizing techniques of immune electron microscopy, experimental rabbit antisear was shown to contain antibodies against neurofilaments. Intact neurofilaments isolated from rat nerves and attached to carbon-coated grids became decorated when exposed to experimental rabbit antisera or purified gamma globulin (IgG) derivatives. The decoration of neurofilaments closely resembled the IgG coating seen in immune electron microscopy. Antibody absorption techniques were used to identify the biochemical constituency of neurofilamentous antigenic determinants. The decoration of neurofilament by experimental IgG was not altered by additions of tubulin or bovine serum albumin, but was prevented by additions of S3 fractions as well as the 68,000-dalton polypeptide of this fraction which was eluted and recovered from polyacrylamide gels. These findings are indicative that a 68,000-dalton polypeptide is a constituent subunit of rat peripheral nerve neurofilaments.

We have made a histological study of the cerebral cortex and hippocampus from 59 consecutively autopsied subjects, aged 51-102 years, prospectively assessed for the presence and extent (or absence) of dementia. Counts were obtained of the numbers of argyrophilic plaques and neurofibrillary tangles in each area examined. In demented patients without evidence of cerebrovascular disease, a highly significant correlation was found between the presence and severity of dementia and the number of neurofibrillary tangles in the cerebral cortex. A significant but much weaker and inconstant correlation was obtained between the presence and severity of dementia and the number of argyrophilic plaques present in the cortex. The temporal lobe cortex and hippocampus were the areas most severely affected by the increased neurofibrillary tangle formation in senile dementia due to Alzheimer's disease.

Degenerative changes in the substantia nigra and ventral tegmental area were investigated in 104 cases of Alzheimer's disease and 13 cases of Down's syndrome. Frequencies of tangles in three groups of patients with Alzheimer's disease were 86%, 44% and 46% (54% overall) respectively. About half of those with tangles, but no Lewy bodies, had excess nigral cell loss, and 16% had moderate or severe neuronal fallout, but none had a Parkinsonian syndrome. Cases with nigral tangles were younger, tended to have more hippocampal and cortical tangles and plaques, and lower activities of cortical choline acetyltransferase. In most cases of Alzheimer's disease degeneration in nigral and tegmental areas was greater than controls, and tangles were evenly distributed. All the cases of Down's syndrome had tangles in the nigra and eight showed mild cell loss. Mild degenerative changes accompanied by tangles in the substantia nigra and ventral tegmental area are common in Alzheimer's disease, but severe cell loss is rare. When a Parkinsonian syndrome occurs in Alzheimer's disease it is likely to be due to Lewy body pathology.

Biopsy fragments from the frontal cortex of one patient with SSPE were studied with ultrastructural methods. Special attention was given to the presence of neurofibrillary tangles observed in all cortical layers. These tangles were composed either of filaments with a diameter of 10 -- 12 nm or of paired helical filaments 22 -- 24 nm at their widest and periodically reduced to 10 nm about every 80 nm. These tangles were observed in all cortical layers, while those formed by single filaments were only visualized in layer 3. The simultaneous appearance of both types of tangles in the same patient suggests that they may be chemically related, which is in keeping with recent chemical data concerning the nature of the neurofilament protein subunit.

Neurofibrillar methods stain a class of horizontal cells in the cat retina which are shown to be identical with the A-type horizontal cell of Golgi-staining. Thus all of the A-type cells of a single retina can be observed. On this basis the changes in density and dendritic field size of A-type horizontal cells with respect to retinal eccentricity were measured. The decrease in density from centre to periphery is balanced by a corresponding increase in size of the dendritic field. Consequently each retinal point--independent of retinal position--is covered by the dendritic fields of three of four A-type horizontal cells. The nuclei and nucleoli of B-type horizontal cells could also be recognized in neurofibrillar-stained material and thus their distribution was determined. The density ratio B-type: A-type is 2.8 +/- 0.4 and does not vary much from the centre to the periphery of the retina. Each retinal point is also covered by four B-type horizontal cells. Thus a single cone can contact a maximum of eight horizontal cells. The rate of density decrease from centre to periphery is closely similar in cones and horizontal cells but greater in ganglion cells.

A young cat had signs of tetraparesis that progressed to tetraplegia within a few weeks. Clinically, there was lower motor neuron disease with areflexia and muscle atrophy in all limbs. Degeneration of the motor neurons in the spinal cord was seen on histological examination. Ultrastructurally, the degeneration of nerve cells was characterized by abnormal proliferation of neurofilaments. These findings were compared to other motor neuron diseases and neurofibrillary accumulations in man and animals.

The intratumorous distribution of catecholaminergic tumour cells and S100 protein-positive elements of 8 neuroblastomas, 8 ganglioneuroblastomas and 2 ganglioneuromas were studied using catecholamine fluorescence and immunohistochemical staining, respectively. The elements of catecholamine fluorescence were observed in all tumour specimens, even in urinary VMA-negative cases, but the patterns of distribution were not uniform. Catecholamine fluorescence was observed in both tumour cell bodies and neurofibres, and the appearance of the latter but not that of the former correlated with the histological grade of differentiation, thereby suggesting the occurrence of catecholaminergic differentiation within the tumour. S100 protein-positive elements also correlated with the histological differentiation, and were distributed mostly in the area where the catecholamine-containing neurofibres were located. The possible correlation between catecholaminergic differentiation and the appearance of S100 protein-positive elements in neuroblastoma requires close attention.

Neurofibrillary tangles composed of paired helical filaments were found in a human ganglioglioma. This is the first reported occurrence of neurofibrillary tangles in a neoplasm. These tangles were visible light microscopically with hematoxylin-eosin and Bodian's stains. They were confirmed as neurofibrillary tangles with Congo red staining under polarized light and with thioflavine S fluorescence. Untrastructurally, the tangles were composed of 10-nm filaments twisted in a helix with 80 nm between constructions. Thus, neoplastic proliferation does not preclude production of paired helical filaments. Cells grew from explants of this tumor, but no paired helical filaments were found in the cells examined. Two other gangliogliomas and normal brain tissue studies by the same procedures did not show paired helical filaments. Gangliogliomas that contain neurofibrillary tangles provide an alternative source of abnormal filaments for analysis.

Neurofibrillary tangles (NFTs) are one of the main pathological hallmarks of Alzheimer's disease or senile dementia, and are seen in the cerebral cortex and some other nuclei in the central nervous system (CNS). No NFTs have been reported in the human peripheral nervous system, although NFTs were recognized in the dorsal root ganglion of the aged rodents. We report here the presence of NFTs in the upper cervical ganglia (UCGs), but not in the stellate nor in the celiac ganglia, of an elderly patient, who was not demented and had only minimal senile changes in the CNS. Immunohistochemically the antibodies to microtubule-associated protein 2, paired helical filaments and ubiquitin stained positively the NFTs in the UCGs. On electron microscopic examination a periodical twisted pattern of the filaments was identified; these findings suggest that the NFTs of the UCGs have just the same properties as those of the cerebral cortex. This is the first report of the demonstration of NFTs in the peripheral ganglia and might contribute to the study of mechanism of NFT production.

Experimental structural alterations were studied in neurofilaments isolated from rat peripheral nerve. Structural alterations were induced in vitro by prolonged incubations of neurofilament-rich fractions in 0.1 M KCl prior to fixation and examination of neurofilaments by negative staining techniques. Neurofilaments appeared to retain their structural integrity during the first week of incubation. Subsequently, a progressive reduction in the numbers of intact neurofilaments coincided with the increasing appearance of neurofilamentous breakdown products. During the period of neurofilament breakdown, an increasing number of altered neurofilaments were observed. These abnormal neurofilaments were characterized primarily by axial enlargements with diameters frequently occurring in the 150-200 A range but measuring up to 250 A. Enlarged neurofilaments also showed a greater irregularity of their lateral margins and less ridigity in their linear course. A striking feature of enlarged neurofilaments was their tendency to display twisting deformations along their longitudinal axes. Twists occurred most frequently along neurofilaments of greatest diameter. The largest abnormal neurofilaments reveal multiple periodic twists, sometimes occurring at 800-1000 A intervals. These enlarged and twisted neurofilaments resembled the abnormal filaments described in neurofibrillary tangles and plaques. The demonstration of neurofilament plasticity as well as the resemblance of neurofilaments deformed in vitro to the abnormal filamentous structures of neurofibrillary tangles and plaques has led to the suggestion that the latter structures may be derived from alterations of normally-formed neurofilaments. Furthermore, it is proposed that the enlarged and twisted filaments of neurofibrillary pathology may arise from alterations in the turnover of neurofilaments or, more specifically, from deficiencies in the degradative processes by which these organelles are broken down.

Synaptic density was quantitated in the cerebral cortex and subiculum of rabbits with experimental neurofibrillary changes. Animals were subjected to subcutaneous injection of aluminum tartrate for 90 days, and synapses stained with ethanolic phosphotungstic acid were analyzed in animals killed 100, 200, or 300 days postinjection with aluminum tartrate. A significant difference was found in synaptic density between animals injected with aluminum tartrate and their age-matched controls. This difference was a result of a low synaptic density present in animals killed 200 or 300 days postinjection of aluminum tartrate. In contrast, animals killed 100 days postinjection revealed the same synaptic density as their control. The data suggest that the synaptic depopulation associated with experimental neurofibrillary changes is a gradual process, and such changes are demonstrable only long after the initial appearance of neurofibrillary changes.

Muscle spindles in the tenuissimus muscle of the cat were studied between 12 and 168 h after cutting or freezing the nerve to this muscle. Degenerative changes in sensory and motor nerve terminals on intrafusal muscle fibres were observed using the electron microscope. Comparisons were made with spindles from unoperated or sham-operated cats. The earliest degenerative changes were seen in sensory and motor terminals at 20-24 h after the lesion. No nerve endings were seen by 114 h after denervation. The most consistent initial signs of degeneration were: (1) the presence of abnormal mitochondria and dense bodies in sensory terminals, and (2) a decrease in the number and clumping of synaptic vesicles combined with an increase in glycogen and neurofilaments in motor endings. Intrafusal fibres participate in the removal of degenerating sensory endings. Schwann cells phagocytose degenerating motor terminals. The disappearance of nerve terminals precedes the complete degeneration of preterminal myelinated fibres within the muscle spindle.

Periodic synchronous discharges were consistently observed in a 68-year-old man with a four-year history of progressive dementia. Pathological examination revealed diffuse atrophy of the brain with remarkable dilatation of the temporal horns. Histologically there were severe changes of Alzheimer's disease and diffuse Lewy bodies (LB), either typical or less distinctive ones without clear halos. Cerebellar LB were also observed in the cerebellum. Four types of abnormal intraneuronal filamentous structures were observed: neurofibrillary tangles, accumulated neurofilaments, thick linear structures studded with ribosome-like dense granules, and fuzzy, thin filaments similar to, but generally wider than, a neurofilament.

The ultrastructure of neurofibrillary tangles of Alzheimer's disease was analyzed by computerized digital processing of electron micrographs. Processing of the electron micrographs consists of four steps: digitizing the electron micrograph, Fourier transformation, noise filtering and inverse Fourier transformation and Laplacian operation. In the present study, we have confirmed that neurofibrillary tangles are composed of a pair of helical filaments (PHF), which appear characteristically as an unbranched rigid structure. The periodicity of PHF is 78 nm on the diffractogram. The dimensions of PHF obtained by our analysis, although basically similar to those described earlier by other investigators using conventional techniques, more precisely defines its structural conformation. We have also demonstrated that the spatial relationship of two filaments appears symmetrical after two-way tilting of the specimen about the axis of rotation. Our observations emphasize the importance of digital image processing as an effective tool for structural analytical research in biology and medicine.

In order to substantiate the hypothesis of a cholinergic matrix for neuritic plaque formation in Alzheimer's disease (AD), the relationship between the loss of cholinergic neurons in the basal forebrain and formation of neuritic plaques in the cerebral cortex was studied in 5 cases of neuropathologically verified AD. Quantitative evaluation of the number of neuritic plaques in the cerebral cortex as calculated from 6 areas showed a strong correlation with the loss of neurons in the nucleus basalis of Meynert (NbM). This finding indicates that changes in cortical cholinergic innervation which arise from the neurons of the NbM are an important feature in the pathogenesis of neuritic plaques.

Four neocortical regions (frontal, parietal, temporal, occipital) of 44 cases were impregnated by a silver stain to show neuritic plaques and stained with Congo red to show amyloid plaques. In 11 cases with large numbers of argentophilic plaques these plaques decreased significantly with age while the reverse appeared to be true for the congophilic plaques. In the remaining 34 cases which had few argentophilic plaques the numbers of congophilic plaques increased significantly with age in the parietal and occipital regions. These results suggest that the neuritic component of senile plaques precedes the amyloid cores in their pathogenesis although a causative relationship is not implied.

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.

The degree of neurofibrillary tangle formation, granulovascuolar degeneration, and nerve cell loss was quantified in serial sections of the hippocampal formation from the brains of 5 adults dying with Down syndrome (monogolism). These morphometric results were compared with values obtained from a series of mentally normal elderly patients reported previously. Granulovacuolar change appeared to be related as much to patient age as to the existence of monogolism. By contrast, the number of Alzheimer neurofibrillary tangles and loss of pyramidal neurons from the hippocampus exceeded levels found in considerably older subjects and fell into the same range of severity as was noted in 8 patients with Alzheimer dementia. The neuron population in the hippocampus of Down syndrome patients may be only half the expected normal number for their decade. These quantitative similarities stimulate the search for a common pathogenetic mechanism underlying cerebral changes in monogolism and senile dementia of the Alzheimer type.

Lesions of the frontal and temporal neocortices and hippocampus typically found in Alzheimer's disease were looked for with the electron microscope in 119 autopsy cases whose ages ranged from 24-93 years. By light microscopy 11 of the cases over the age of 60 had large numbers of plaques and neurofibrillary tangles, whereas the remaining cases had few or none. From the age frequency distribution of the electron microscopic lesions in these two categories of cases amyloid fibrils and abnormal neurites, both components of plaques, were first seen at approximately the same time. This suggests that amyloid is unlikely to precede the neurites in their formation. The abnormal neurites were thought, due to the small numbers of synapses in their walls, to be largely derived from degenerating neuronal processes and not synaptic boutons.

Reviewing the literature since recognition of progressive supranuclear palsy (PSP) as a clinicopathological entity 20 years ago, the present state of knowledge is delineated. The etiology of PSP is still unknown. The clinical hallmarks are supranuclear palsy of vertical gaze, axial dystonia in extension and pseudobulbar palsy with marked dysarthria and dysphagia. Accessory features include subcortical dementia, mental, extrapyramidal, pyramidal and cerebellar symptoms. PSP is a disease of the presenium (average age at onset, 59.6 years) with a male preponderance (60% men). The onset is insidious with vague complaints of dysequilibrium (60%), mental changes (46%) and disturbed vision (21%), often preceding abnormal neurological findings. The important borderland and main differential diagnosis is parkinsonism. However, in PSP, responsiveness to antiparkinsonian agents is poor and progression is rapid and fatal within few years (average survival time, 5.7 years). Promising diagnostic tools at present include CT-scanning and neuro-otologic and -ophthalmologic examination. Neuropathological findings, confined to specific diencephalic, brainstem and cerebellar nuclei, include neurofibrillary tangles (ultrastructurally different from those seen in other CNS disorders), neuron loss and gliosis. The importance of research on neurocytochemistry, brain ultrastructure and immunology in the current investigation of PSP is outlined.

A loss of nerve cells from the nucleus basalis of Meynert and the locus caeruleus together with a reduction in nucleolar volume in surviving cells was measured in twenty-two patients with Alzheimer's disease who ranged in age from 48-92 years, and in six patients over 50 years of age with Down's syndrome who also showed extensive formation of senile plaques and neurofibrillary tangles within their cerebral cortex. When compared with age matched controls the severity of these changes was greatest in the younger patients with Alzheimer's disease, but this fell with age such that by 90 years the level of change in Alzheimer's disease approached that in old age alone. There were only slight differences in the extent of these pathological changes in those patients with Down's syndrome when compared with others of similar age with Alzheimer's disease. It is concluded that the presenile dementia of Alzheimer's disease, the senile dementia of Alzheimer type and Down's syndrome in middle age all form an age-related continuum of pathological change.

The most important morphological findings in dementia of Alzheimer type (DAT) are Alzheimer neurofibrillary tangles, senile plaques, amyloid angiopathy, granulovacuolar degeneration and Hirano bodies. The morphological and immunocytochemical findings in these changes are described, in particular those related to the pathological cytoskeleton. Their possible relationship to the disturbed synthesis of neurotransmitters recently demonstrated is considered, and their relevance for the clinical syndrome of dementia is discussed. Hypothetical etiologies (ageing per se, genetics, infection and chronic intoxication) are briefly mentioned.

Two immunocytochemical probes were used to specifically identify and localize heparan sulphate proteoglycans (HSPGs) in 17 cases of Alzheimer's disease (AD). A monoclonal (HK-102) and an affinity-purified polyclonal antibody, each recognizing specific domains on the protein core of a basement membrane-derived HSPG, localized HSPGs to the amyloid fibrils present in neuritic plaques (NPs) and congophilic angiopathy (CA) in the brains of Alzheimer's patients, with weak to no immunostaining in neurofibrillary tangles from the same tissues. HSPGs were also demonstrated in "primitive plaques," suggesting that their accumulation takes place during early stages of plaque development. Immunolocalization of HSPGs to subsets of astrocytes and neuronal cells, particularly those in close proximity to NPs and CA, suggested possible involvement of these two cell types in deposition of HS-PGs into the amyloidotic lesions. The current study not only identifies a new component (HSPGs) present in the amyloid deposits of NPs and CA but also suggests that astrocytes, neurons, or both may be involved in its deposition at these sites.

Instrumental neutron activation analysis procedures were used to determine the aluminum content of various brain regions in histologically verified Alzheimer disease (AD) and in controls. The grand mean aluminum level for 74 AD specimens was 0.372 +/- 0.058 microgram/gm and for 137 adult controls, 0.467 +/- 0.033 microgram/gm, both on a wet weight basis. No difference was found at the bulk sample level between AD and adult controls, corrected for age and sex, or when frontal, temporal, and hippocampal specimens were compared. Control specimens (infancy to 85 years) showed an increase in brain aluminum concentration with age. Comparison of freeze-dried to wet weight ratios of AD and controls revealed a small increase in water content in AD brains.

Two cases of presenile dementia were presented. Both showed "stehende Redensarten" and aphasia. Histopathologically, besides Pick features--temporal lobe atrophy, fibrillary gliosis of the temporal white matter and neuronal loss in the 2--3 cortical layers--, Alzheimer features--neurofibrillary tangles and granulo-vacuolar degeneration--were found in both cases. But no senile plaques were found. Pseudocalcerous deposits were observed in the cerebral cortex, basal ganglia and cerebellum. Atypical cases with both Pick's and Alzheimer's diseases in the literature were classified into four groups according to the extent of the features of each disease. Sensory aphasia, which is relatively unusual in Pick's disease, was correlated to the atrophy of left T1, and similar cases in the literature were reviewed.

Enriched fractions of "tangles" obtained from cases of Alzheimer's disease have been observed by negative staining and platinum: iridium shadowing, and also after treatment with sodium dodecyl sulfate and urea. Abnormal filaments with a 80-nm periodic constriction exhibited a substructure consisting of six protofilaments. They also showed a periodic right-handed twist. Some fibrils with a 160-nm periodic constriction were made up of four protofilaments. These features are discussed in view of known fibrous protein models, especially neurofilaments.

Autopsied human brains from three patients with senile dementia were studied for the effect of neurofibrillary tangles on neuronal RNA content. Nerve cell bodies were dissected out from the subiculum under the phase contrast microscope and were separated into two groups based on the presence or absence of neurofibrillary tangles within the perikaryon. It was found that the mean RNA content of the tangle-bearing cells was 28.61 pg, whereas that measured in nerve cell bodies considered as free from the tangles was 41.21 pg. Thus, a significant decrease in neuronal RNA content could be correlated to an excess accumulation of neurofibrillary tangles.

A series of 22 cases of amyotrophic lateral sclerosis (ALS) and 22 controls have been assessed for the presence of neurofilamentous accumulations in axons and perikarya. Large axonal swellings were seen in the spinal cord of 12 controls and of 13 ALS cases. When they were present in ALS cases they tended to be much more numerous than in controls, and when they were not present in ALS cases there tended to be severe neuronal loss in the cord. Axonal swelling on lower motor neurons appears to be a significant feature of the pathology of ALS. Its implications in terms of etiology are unknown.

A report was made of an autopsied case of presenile dementia presenting the clinically characteristic symptoms of Alzheimer's disease and Pick's disease. The neuropathological findings were senile changes, namely, numerous senile plaques, neurofibrillary tangles, granulovacuolar degeneration and Pick bodies, etc., and numerous Lewy bodies in the brain stem and in the cerebral cortex. We studied mainly the ultrastructure of Lewy bodies in the cerebral cortex in this paper. The features of ultrastructural components of Lewy bodies presented types which might correspond to the various profiles of Lewy bodies observed by a light microscope. In addition, we studied the senile changes in the cerebral cortex ultrastructurally and considered that some relationship possibly existed between Lewy bodies and senile changes.

I have used Tau-1 and Tau-2, two monoclonal antibodies against tau protein, to study at the electron microscopic level the tau immunoreactivity in 8 cases with dementia of the Alzheimer type, using the peroxidase-antiperoxidase technique and formalin-fixed autopsy and biopsy brain tissues. In neurons and astrocytes, excessive amounts of tau immunoreactivity were noted in association with ribosomes. The Alzheimer's abnormal filaments in neurofibrillary tangles in neuronal perikarya, in senile plaques, and in a multitude of abnormal neuropil neurites were frequently stained intensely. However, many neurons contained either stained ribosomes only or stained ribosomes and unstained abnormal filaments both scattered and in neurofibrillary tangles. In all locations, the immunostained abnormal filaments were straight without appreciable periodic constrictions and, on cross-section, had a tubular appearance with stained walls, frequently demonstrable unstained lumens and an accentuation of staining intensity at the periphery. In addition, conventional electron microscopy showed that formalin-fixed and glutaraldehyde-fixed neurofibrillary tangles were made of compactly arranged straight filaments and loosely arranged paired helical filaments, whereas osmium tetroxide-fixed neurofibrillary tangles were made almost exclusively of paired helical filaments. These findings suggest that: (a) localization of excessive tau immunoreactivity with ribosomes might be the primary event and association of detectable tau immunoreactivity with already assembled filaments might be an epiphenomenon; and (b) the mode of fixation and subsequent preparatory procedures might alter the morphology of the Alzheimer's abnormal filaments.

In postmortem investigations of patients with dementia of Alzheimer type (AD/SDAT) (n = 14) the brain weight was significantly reduced when compared to controls (n = 16). In four AD/SDAT-brain parts investigated the concentrations of 5-hydroxy-tryptamine and noradrenaline were significantly reduced while 3-methoxy-4-hydroxyphenylglycol was significantly increased. In the caudate nucleus of the AD/SDAT-brains the concentrations of dopamine and homovanillic acid were significantly reduced. The activity of monoamine oxidase B was increased suggesting a proliferation of extra neuronal tissue in the AD/SDAT-brains. The activity of choline acetyl transferase was reduced in the four brain parts investigated, showing a general reduction in the acetylcholine system in the AD/SDAT-brains. The ganglioside concentration was significantly reduced suggesting a reduced density of nerve endings in the demented brains. The AD/SDAT-group was according to rating scales severely demented. Patients with an early onset of the dementia disease were more severely intellectually reduced and had more pronounced biochemical disturbances than those with a late onset of the dementia.