L. A. Mattiace

Neuropathologic overlap of progressive supranuclear palsy, Pick's disease and corticobasal degeneration

Several neurodegenerative disorders contain tau-immunoreactive neuronal and glial inclusions throughout the cerebral cortex and brainstem. Although these diseases have been considered distinct clinicopathological entities, recent recognition of many neuropathological and clinical parallels has raised the question of overlap between the disorders. In addition, histopathological similarities sometimes complicate neuropathological diagnosis. To address these issues, we examined the morphology and differential distribution of pathologic lesions in three disorders: progressive supranuclear palsy, Picks disease, and corticobasal degeneration. We found considerable similarity in the anatomical regions affected by the three entities; however, semiquantitative analysis revealed differential anatomical susceptibility. Similarly, although overlap existed in the morphology of tau-immunoreactive inclusions, characteristic differences remained and may be useful in differential diagnosis. In particular, glial inclusions varied dramatically between the disorders. Despite significant overlap among the three neurodegenerative diseases examined, the morphological and regional differences suggest that each is a distinct pathophysiological entity

Diffuse lewy body disease: light and electron microscopic immunocytochemistry of senile plaques

SummaryThe nature of senile plaques (SP) in 27 cases of diffuse Lewy body disease (LBD) was investigated using immunocytochemistry and antibodies to beta amyloid protein synthetic peptides (BetaSP), ubiquitin (UBQ), paired helical filaments (PHF; Ab39) and a 68-kDa protein in Alzheimer brains (Alz50). Lewy bodies were present in widespread areas of the neocortex of all cases and were more easily detected with ubiquitin immunocytochemistry than with conventional stains. All cases had neocortical SP, but only six cases had neocortical neurofibrillary tangles (NFT). SP were very numerous in most cases and were usually “pale”, “diffuse” or “very primitive” plaques with thioflavin S fluorescent microscopy. SP in diffuse LBD were immunostained with BetaSP. Several cases had extensive amyloid angiopathy that was also immunoreactive with BetaSP. SP in diffuse LBD were characterized by amyloid deposits with few or no neuritic elements that could be detected with thioflavin S, Bielschowskys stain or double staining with BetaSP and Bodians silver stain. They differed from plaques in Alzheimers disease by lack of PHF-type neurites that could be stained with Ab39. In diffuse LBD, SP contained PHF-type neurites only in areas coexistent with NFT. Some SP had round, granular neurites that were immunoreactive with UBQ, but weakly argyrophilic with Bodians stain and nonfluorescent with thioflavin S. Diffuse LBD lacked significant neuritic change in the neuropil that could be detected with UBQ, Ab39 and Alz50. The latter finding is a characteristic feature that distinguishes Alzheimers disease from diffuse LBD.

Microglia in cerebellar plaques in Alzheimer's disease

SummaryCerebellar amyloid deposits in Alzheimers disease were studied by immunocytochemistry and with a series of antibodies that recognize human microglia, including anti-HLA-DR, LN-1, Leu-M5 and leukocyte common antigen. Microglia formed a dense reticular array throughout the cerebellum in areas with and without amyloid deposits. In areas with compact and reticular amyloid deposits, microglia had morphological features consistent with activation, such as cytoplasmic swelling and shortening and thickening of cell processes. In areas with diffuse amyloid deposits, microglia had delicate and highly ramified processes. Nevertheless, microglial cells or their processes were detected in association with amyloid deposits of all morphological types. These results raise the possibility that microglia may play a fundamental role in the pathogenesis of amyloid deposition in the cerebellum in Alzheimers disease.

Ubiquitin immunoelectron microscopy of dystrophic neurites in cerebellar senile plaques of Alzheimer's disease

SummarySenile plaques are present in the cerebellum of most Alzheimer patients. They are composed of beta-amyloid deposits lacking neurites detectable with immunocytochemistry for neurofilament, tau and paired helical filament proteins. Recent studies, however, have shown that cerebellar plaques usually contain round structures that are reactive with ubiquitin antibodies. In this immunoelectron microscopic study, the nature of these structures is explored. Ubiquitin-positive structures in cerebellar senile plaques were composed of degenerating neurites that contained membranous and vesicular dense bodies, but no paired helical filaments. A minority of the neurites contained finely granular material. Thus, cerebellar plaques are associated with neuritic degeneration, and the neurites in cerebellar plaques resemble dystrophic neurites in senile plaques of non-demented elderly subjects and subjects with non-Alzheimer dementias. They differ from some of the neurites in senile plaques in the neocortex in Alzheimers disease by the absence of paired helical filaments. These results suggest that the same mechanisms involved in the generation of dystrophic neurites in pathological aging are involved in generating dystrophic neurites in the cerebellum in Alzheimers discase.

Glycation and microglial reaction in lesions of Alzheimer's disease

Single, double, and triple immunostaining of cryostat sections of elderly normal and Alzheimer disease (AD) brain was performed with monoclonal and polyclonal antibodies to advanced glycation end products (AGE). The sections were counterstained with thioflavin-S or with immunocytochemistry for A beta and also stained with markers for microglia. AGE-immunoreactivity was detected in senile plaques and neurofibrillary tangles (NFT). AGE immunoreactivity was most intense in dense or reticular amyloid deposits and extracellular NFT, while intracellular NFT and diffuse amyloid had less AGE immunoreactivity. This pattern of immunoreactivity was similar to that noted in previous studies with antibodies to apolipoprotein-E (apo-E). Therefore, double labeling with antibodies to apo-E and AGE was performed. AGE immunoreactivity colocalized to a very high degree with apo-E immunoreactivity, except that relatively more intense apo-E immunoreactivity was detected in amyloid deposits and more intense AGE immunoreactivity in NFT. The lesions that were immunostained with antibodies to AGE and apo-E were often, but not always, associated with a local microglial reaction. The results raise the possibility that apo-E or a fragment of apo-E may be glycated. Biochemical studies are needed to determine the extent of possible apo-E glycation in AD. The present results raise the possibility that glycation may serve as one of the signals for activation of microglia associated with amyloid deposits and extracellular NFT.

Ubiquitin-immunoreactive dystrophic neurites in Down's syndrome brains.

Ubiquitin-immunoreactivity was studied in Downs syndrome brains ranging in age from two days to sixty years. Numerous randomly distributed ubiquitin-immunoreactive dot-like structures in the white matter were shown to correspond to granular degeneration of myelin. Granular degeneration of myelin was first detected at age 21 and increased thereafter with age. Other larger and more coarsely granular ubiquitin-immunoreactive structures, most numerous in the middle and upper cortical layers, were consistent with dystrophic neurites. Immunoelectron microscopy demonstrated that the dystrophic neurites contained non-filamentous, membranous, dense bodies. In Downs syndrome, ubiquitin-immunoreactive dystrophic neurites were first detected at age six in the hippocampus, and were consistently more numerous in comparison to age-matched control subjects. In the presence of amyloid, either as diffuse or as compact deposits, ubiquitin-immunoreactive dystrophic neurites frequently formed aggregates consistent with senile plaques. Although apparently independent events, these data suggest that amyloid deposition is associated with local accentuation of ubiquitin-immunoreactive neuritic dystrophy. In addition, since dystrophic neurites appeared substantially earlier in the grey matter in Downs syndrome than in age-matched normals, this may be further evidence that selective aspects of aging are accelerated in Downs syndrome.

A case of Down's syndrome with diffuse Lewy body disease and Alzheimer's disease

Almost all Downs syndrome (DS) patients over the age of 35 to 40 years have histologic features of Alzheimers disease (AD). However, the presence of extrapyramidal features in up to 364 of these patients has no satisfactory pathologic explanation. We report an older patient with DS, dementia, and parkinsonian signs who showed pathologic changes of Parkinsons disease and cortical Lewy bodies in addition to AD. These parkinsonian changes may be related to chromosome 21 abnormalities.

Regional localization of the regulatory subunit (RIIβ) of the type II cAMP-dependent protein kinase in human brain

The distribution of the regulatory (RII beta) subunits of type II cAMP-dependent protein kinase in cortical and subcortical areas was examined in human control and Alzheimers disease (AD) brains. Four monoclonal antibodies generated against bovine brain RII, which cross-reacted with human brain RII beta, detected RII-immunoreactivity in pyramidal neurons of the hippocampus and frontal, occipital, parietal and superior temporal cortices and in non-pyramidal neurons of the amygdala and putamen. RII beta immunoreactivity was localized to neuronal perikarya, proximal dendrites and cell processes. With the exception of rare processes in the ventroposterior lateral nucleus, RII-immunoreactivity was not seen in the thalamus. Other areas lacking RII-immunoreactivity included the midbrain, caudate nucleus and globus pallidus. RII-immunoreactivity was not detected in endothelia or glia. Except for the neocortex, the distribution of RII beta immunoreactivity was the same in AD and non-demented control brains; however, cell bodies and their processes stained more intensely and uniformly in the neocortical regions of non-demented controls compared to AD. In the neocortex of AD, RII beta immunoreactivity was substantially decreased in the superior temporal and occipital cortices, but not in the frontal cortex. Our data suggest that RII subunits are regionally distributed in the human brain. RII-immunoreactivity was decreased in some regions of neocortex in AD, but it did not preferentially colocalize with neurofibrillary tangles (NFT), senile plaques, or neuropil threads.