Immunoelectron-microscopic demonstration of NACP/alpha-synuclein-epitopes on the filamentous component of Lewy bodies in Parkinson's disease and in dementia with Lewy bodies.

We examined brains from Parkinson's disease and from dementia with Lewy bodies (LBs) by using antibodies to NACP/alpha-synuclein. Immunohistochemically, all of the antibodies against the amino-terminal region, NAC domain, and carboxyl-terminal region of NACP labeled not only LBs, pale bodies (PBs), and dystrophic neurites, but also fine thread-like structures in the neuronal perikarya (perikaryal threads) in the hypothalamus and brainstem nuclei. On electron microscopy, immunoreactive products were found to label the 9 to 12 nm-thick filamentous component (LB-filaments) of LBs, PBs, and perikaryal threads. The NACP-immunoreactive perikaryal threads, consisting of small bundles of LB-filaments and randomly oriented LB-filaments, presumably represent an initial stage of LB- or PB-formation. The present study indicates that the entire molecule of NACP is involved in the neuronal filament-aggregating processes of LB disorders.

Cellular co-localization of phosphorylated tau- and NACP/alpha-synuclein-epitopes in lewy bodies in sporadic Parkinson's disease and in dementia with Lewy bodies.

The precursor of the non-Abeta-component of Alzheimer's disease (AD) amyloid (NACP, alpha-synuclein) aggregates into insoluble filaments of Lewy bodies (LBs) in Parkinson's disease (PD) and dementia with LBs (DLB). The microtubule-associated protein tau is an integral component of filaments of neurofibrillary tangles (NFTs). NFTs are occasionally found in brains of PD and DLB; however, the presence of NFTs or tau-epitopes within LB-containing neurons is rare. Double-immunofluorescence study and peroxidase-immunohistochemical study in serial sections, performed to examine the co-localization of tau- and NACP-epitopes in the brainstem of PD and DLB, demonstrated that four different epitopes of tau including phosphorylation-dependent and independent ones were present in a minority of LBs, but more often than previously considered. A tau (tau2)-epitope was localized to filaments in the outer layers of brainstem-type LBs by immunoelectron microscopy. Therefore, we conclude that tau is incorporated into filaments in certain LBs. Extensive investigation has enabled us to classify this co-localization into four types: type 1, LBs with ring-shaped tau-immunoreactivity; type 2, LBs surrounded by NFTs; type 3, NACP- and tau-immunoreactive filamentous and granular masses; and type 4, NACP- and tau-immunoreactive dystrophic neurites. This study raises a new question whether aggregation and hyperphosphorylation of tau in PD and DLB are triggered by the collapse of intraneuronal organization of microtubules due to NACP-filament aggregation in neuronal perikarya and axons.

Corticonigral degeneration with neuronal achromasia presenting with primary progressive aphasia: ultrastructural and immunocytochemical studies.

We describe a clinico-pathological variant of a degenerative disorder involving Broca's, Wernicke's, and supplementary motor areas, which presented as primary progressive aphasia, dysarthria, bucco-facial apraxia, and hearing loss as initial symptoms, followed by organic personality changes. Postmortem examination revealed severe focal atrophy of the cerebral convolutions in the frontal operculum, superior frontal gyrus, and superior and transverse temporal gyri in addition to diffuse atrophy of the frontal and temporal lobes in both hemispheres. Microscopical examination revealed argyrophilic neuronal inclusions (ANIs) in the neuronal perikarya and presynaptic terminal throughout the central nervous system, as well as neuronal loss and swollen chromatolytic neurons in the affected cortices. Neocortical ANIs showed a positive immunoreaction with an anti-tau antibody but only a weak reaction with an anti-ubiquitin antibody immunohistochemically. Ultrastructurally, neocortical ANIs consisted of 15-nm thick smooth-surfaced tubules and tubules with constrictions at 120-150-nm intervals; thus they were different from the typical paired helical filaments of the 80-nm interval constrictions observed in the subiculum. ANIs were also found in the basal ganglia, brain stem nuclei, and cervical cord. Accordingly, ANIs appear distinct from neurofibrillary tangles (NFTs) of progressive supranuclear palsy, NFTs of Alzheimer-type dementia, and Pick bodies. The authors consider that this case fits the histopathological criteria of corticonigral degeneration with neuronal achromasia except for the unusual extension to the temporal lobes.

Static bone cavity of the mandible: Computed tomography findings with histopathologic correlation.

PURPOSE: To review computed tomography (CT) findings of histopathologically examined static bone cavities in order to determine whether an additional pathogenesis may play a role in this disease. MATERIAL AND METHODS: Four patients with histopathologically examined static bone cavities were included in this retrospective study. Location, appearance of bone remodeling, tissue characteristics, and contrast enhancement of the cavity were assessed on CT images. CT findings were then compared with the histopathological findings. RESULTS: Static bone cavity was found in the lingual molar region in three patients and in the lingual cuspid region of the mandible in one patient. Both fatty and soft tissues were present in the cavities of all four patients. Attenuation of the soft tissue in the cavities was found to be different from that of the submandibular gland. The soft tissue showed enhancement with contrast-enhanced CT in three patients. For all patients, the histopathologic content of the static bone cavity included fat, soft tissue, and abnormal vasculature. The thickened vein wall in the abnormal vasculature was observed. Aberrant tissue of the submandibular gland was not found in any of the static bone cavities. CONCLUSION: Contrast enhancement of the soft tissue on the contrast-enhanced CT images suggests the presence of vasculature in the cavities. Histopathological examination confirmed the presence of fatty tissue and dilated abnormal vessels, and the absence of salivary gland tissue in the cavities. These findings show that vascular structures are prominent in tissues found in static bone cavities.

Ultrastructure of 6-aminonicotinamide (6-AN)-induced lesions in the central nervous system of rats. III. Alterations of the spinal gray matter lesion with aging.

Following a single i.p. injection of 6-AN (10 mg/kg), the anterior horn cells of 20- and 25-month-old rats increased more in size and recovered slower from chromatolytic changes than those of 3-month-old rats. Neurofilamentous hyperplasia of the perikarya was more prominent in aged rats; proliferated neurofilaments were arranged in thick parallel bundles. In the acute stage, reactive and degenerative changes of glial and mesenchymal elements were more conspicuous in 3-month-old rats; however, they disappeared by day 14 with prominent proliferation of hypertrophic astrocytes. The older rats showed less intensity and slower progression of these changes; sponginess and swelling of the astrocytic cytoplasm were still observed at day 14. Our results suggest that these age-dependent changes in the response to neurotoxins are not only induced on the neuron without mitotic phenomena after birth, but also on neuroglial cells. Furthermore, an alteration or reduction in the support of the neuron augments its intensified and delayed susceptibility to neurotoxins.

Extracellular or ghost Pick bodies and their lack of tau immunoreactivity: a histological, immunohistochemical and electron microscopic study.

Histological, immunohistochemical, and electron microscopic evidence of an extracellular, or ghost Pick body has been found in the granular cell layer and, rarely, in the pyramidal cell layer of the hippocampus of an autopsy case of Pick's disease. The ghost Pick body appeared as a blurred, weak argyrophilic mass in the neuropil, and it was composed of accumulated fibrillary structures, 13 nm in diameter, intermingled with glial filament bundles. These ghost Pick bodies did not react with anti-tau and anti-ubiquitin antibodies, but did react weakly with anti-glial fibrillary acidic protein antibody, whereas intracytoplasmic Pick bodies were strongly immunolabeled with anti-tau but only weakly with anti-ubiquitin antibodies. These results suggest that the Pick body is discharged into the neuropil after destruction of the mother neuron, loses its immunoreactivity to certain tau and ubiquitin antibodies during this process (thereby inducing a glial reaction) and remains in the neuropil as a ghost Pick body.

Ultrastructure of 6-aminonicotinamide (6-AN)-induced lesions in the central nervous system of rats. II. Alterations of the nervous susceptibility with aging.

Lesions in the CNS induced by 6-aminonicotinamide (6-AN) presented a spongy state of the gray matter and neuronal chromatolysis. With aging of the experimental animals the lesions extended from the phylogenetically early developed structures to those developed later, i.e., from spinal gray matter, dentate nuclei, and brain stem nuclei through limbic structures and striatum to the cerebral cortex. Changes of the neurons were more prominent with aging. Lesions in the CNS of rats at the age, corresponding to the involutional period in the human, were similar to those of Creutzfeldt-Jakob disease (C-J) disease) in the presenile age. In recent years, the resemblance between C-J disease and pellagra encephalopathy had been noted by several authors, and they resemble the lesions caused by 6-AN, an antimetabolite of nicotinamide used in our experiment. This evidence, therefore, has led to the hypothesis that dysfunction of NAD(H)- or NADP(H)-dependent enzymes in the CNS of the aged, even if not the primary cause, may be one possible pathogenetic factor of C-J disease.

Neuropathologic changes in suckling and weanling rats with pyrithiamine-induced thiamine deficiency.

Pregnant and nursing Wistar rats were fed a thiamine-deficient diet, and their offspring were injected daily with pyrithiamine. The pathologic lesions in the suckling rats were examined at different times of development. There were distinct changes at 22 days of age, by which time the rats are weaned, and the morphogenesis of the cerebellum is almost completed. Before 22 days of age, there were no pathologic changes except for scattered petechial hemorrhages in the brain. After 22 days of age, acute pathologic changes were observed, in decreasing order of severity, in the vestibular nuclei, inferior olivary nuclei, mammillary body, periventricular gray matter, thalamus, and quadrigeminal plates. The initial changes were swelling of post-synaptic dendrites and distension of the periaxonal space of myelinated axons in the parenchyma and ring-shaped hemorrhages in the perivascular space. Pyrithiamine injections into the offspring of rats fed a thiamine-deficient diet probably induce disturbance of the electrolyte permeability of the neuronal excitable membrane, resulting in swelling of this element. These changes were followed by the filtration of erythrocytes and plasma into the parenchyma and astrocytic swelling, which may be a secondary effect of neuronal changes on the brain vascular permeability.

Ultrastructural characterization of the tau-immunoreactive tubules in the oligodendroglial perikarya and their inner loop processes in progressive supranuclear palsy.

Coiled bodies and interfascicular threads are conspicuous white matter abnormalities of brains of patients with progressive supranuclear palsy (PSP). Both structures are argyrophilic and immunoreactive for the microtubule-binding protein tau. This report concerns the ultrastructural localization of interfascicular threads and their relationship to coiled bodies in five PSP patients. We showed for the first time that abnormal tubules with a 13- to 15-nm diameter and fuzzy outer contours were the common structures of coiled bodies in the oligodendroglial perikarya and of interfascicular threads. Moreover, the tubules were immunolabeled by anti-tau antibodies. The abnormal tau-positive tubules of interfascicular threads were located in the inner loop of the myelin sheath. Our study further indicated that the thread-like structures in the white matter comprised, at least in part, oligodendroglial processes, and that they were also present in gray matter. We consider that the formation of coiled bodies in the perikarya and of interfascicular threads represents a common cytoskeletal abnormality of the oligodendroglia of PSP patients. Moreover, even though the white matter alterations of PSP resemble those of corticobasal degeneration, there are certain ultrastructural differences in the abnormal oligodendroglial tubules of the two diseases.

NACP/alpha-synuclein and tau constitute two distinctive subsets of filaments in the same neuronal inclusions in brains from a family of parkinsonism and dementia with Lewy bodies: double-immunolabeling fluorescence and electron microscopic studies.

The co-localization of NACP/alpha-synuclein and tau epitopes was examined in the brain stem and hippocampal formation in two patients from a family of autosomal dominant parkinsonism and dementia with Lewy bodies (LBs) without two reported missense mutations in the NACP gene. Double-labeling immunofluorescence study revealed that some brain stem LBs, cortical LBs, pale bodies, Lewy-related neurites, and neurofibrillary tangles expressed both NACP epitopes and the PHF tau AT8 epitope. Double-immunolabeling electron microscopy demonstrated that the NACP antibody selectively labeled 9- to 13-nm-thick straight filaments (LB filaments), whereas AT8 recognized twisted tubules with 80-to 100-nm-interval constrictions in the same neuronal inclusions. We show that NACP and tau aggregate into different filamentous components even if both proteins are incorporated into the same inclusions.

Argyrophilic tau-positive twisted and non-twisted tubules in astrocytic processes in brains of Alzheimer-type dementia: an electron microscopical study.

This report concerns pathological astrocytic tubular structures (astrocytic tubules, As-Tbs) that coexist with glial filaments in astrocytic processes in brains with presenile-onset Alzheimer-type dementia. The formation of As-Tbs appears to be related to the duration of disease and the intensity of Alzheimer histopathology. In three cases in which the disease was of extremely long duration, As-Tbs were found in the frontal and temporal neocortices, the temporal pole and the hippocampus using electron microscopy, whereas they were not found in two cases with a long, but not extremely long, illness duration. As-Tbs were almost exclusively found in the highly devastated neuropil, and we could not find them in regions of moderate neuronal degeneration despite intensive inspection. As reported previously, some As-Tbs was seen adjacent to extracellular neurofibrillary tangles (NFTs) and in perivascular astrocytes. Our novel finding is that they can exist independently from these, in the highly devastated neuropil. Two types of As-Tbs were observed, twisted tubules with periodic constrictions at 50- to 80-nm intervals and non-twisted tubules where no constrictions were seen but which had a 15-nm fuzzy outer contour. They were positively stained by anti-human tau antibody, an antibody that does not recognize extracellular NFTs. Thus, it is most likely that As-Tbs are not the sequestration of extracellular NFTs, and that they are of astrocytic origin. Moreover, As-TBs showed argyrophilia. As-TBs appear indistinguishable from dystrophic neurites under the light microscope. The present data suggest that they may be more widely distributed in the damaged cerebral neuropil than previously thought.