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PubMed1988

Correlation of phosphorus-31 magnetic resonance spectroscopy and morphologic findings in Alzheimer's disease.

Senile plaques (SPs), especially, and neurofibrillary tangles are important pathologic markers for the diagnosis of Alzheimer's disease (AD), but neither is pathognomonic for AD. We hypothesize that elevations in levels of phosphomonoesters, precursors of membrane phospholipids, occur early in the pathogenesis of AD and precede the appearance of SPs. In contrast, elevations in levels of phosphodiesters, breakdown products of phospholipids, reflect degeneration of neural membranes and will correlate with the appearance of SPs. Correlative phosphorus-31 magnetic resonance spectroscopy and morphologic studies conducted to test this hypothesis disclosed that elevations in levels of phosphomonoesters had a negative correlation with the numbers of SPs, and elevations in levels of phosphodiesters had a positive correlation with the numbers of SPs. No correlations were observed for either membrane parameter and neurofibrillary tangles. These findings support our hypothesis and suggest that aberrations in the synthesis of membrane phospholipids are early metabolic events in the pathogenesis of AD.

Aged↗
PubMed1988

Familial Alzheimer's disease with myoclonus and 'spongy change'.

"Spongy change," or vacuolar change, was observed in the neocortex of temporal and frontal lobes in four of 27 patients with clinical and pathologic characteristics of Alzheimer's disease. All four cases had the autosomal dominant form of the disease, and aside from severe dementia, all developed myoclonus and became mute before death. The degeneration observed was unlike that seen in Creutzfeldt-Jakob disease because it lacked astrocytosis and had a different distribution of lesions. Moreover, the abundance of neurofibrillary changes and senile plaques was consistent with Alzheimer's disease. None of the other 23 cases were familial, and none developed myoclonus or mutism; three of them had minor vacuolation limited to the temporal lobe. The four cases with severe spongy change described are the first, to our knowledge, in which vacuolar or spongy change has been associated with the familial form of Alzheimer's disease.

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PubMed1989

A brain regional analysis of morphologic and cholinergic abnormalities in Alzheimer's disease.

In the brains of 21 patients with Alzheimer's disease (AD) and 10 nondemented controls, senile plaques (SPs), neurofibrillary tangles (NFTs), and three indexes of cholinergic function were quantified in the middle frontal (MF) and superior temporal (ST) cortex, the entorhinal cortex (HEN), and the prosubiculum (HPR) of the hippocampus. Control brains contained few SPs without preferential distribution in any of the brain regions examined, while NFTs were found almost exclusively in the HPR. In brains from patients with AD, an inverse relationship of SPs and NFTs was found in the brain regions examined; SPs were preferentially in the neocortex and NFTs preferentially in the hippocampus. The specific activities of choline acetyltransferase and acetylcholinesterase were reduced in all regions examined, while no significant change in the density of muscarinic binding sites was observed in any region. Numerous NFTs were associated with an earlier age at onset, while the presence of SPs was related to the cholinergic deficit in AD. Earlier-onset (less than 67 years) AD was also associated with a qualitative difference in the regional distribution of NFTs compared with cases with a later onset. In the latter group, most NFTs were observed in the hippocampus, a distribution pattern similar to that observed with normal aging. In AD cases with an earlier onset, NFTs were more globally distributed in the neocortex and allocortex.

Acetylcholinesterase↗
PubMed1989

Lateralization of brain morphologic and cholinergic abnormalities in Alzheimer's disease.

The extent of left-right asymmetry in the densities of senile plaques and neurofibrillary tangles and the levels of the cholinergic enzymes choline acetyltransferase and acetylcholinesterase were quantified in the middle frontal and superior temporal cerebral cortex, entorhinal cortex, and prosubiculum of the hippocampus from 21 patients who died with Alzheimer's disease. Morphologic lesions were more asymmetrically distributed than deficits in the cholinergic enzymes. Neither cerebral hemisphere showed consistently higher densities of senile plaques and neurofibrillary tangles, or lower levels of choline acetyltransferase and acetylcholinesterase. Deficits in the cholinergic enzymes tended to colateralize, while asymmetries of senile plaques and neurofibrillary tangles did not. Finally, left-right asymmetry in the density of senile plaques diminished with increasing neuropathologic severity, while similar evidence for diminishing left-right asymmetry of neurofibrillary tangle density or cholinergic enzyme activity with increasing severity was not found.

Acetylcholinesterase↗
PubMed1990

The natural history of dementia in Down's syndrome.

In a prospective longitudinal study with death as the end point in 17 middle-aged patients with Down's syndrome, dementia was clinically diagnosed in 15 patients, by means of careful observations in daily circumstances. Autopsies were performed in 10 cases: 8 demented patients and 2 nondemented patients. Neuropathologically, Alzheimer-type abnormalities were demonstrated in 9 patients, both demented and nondemented, and combined Alzheimer-type abnormalities with infarctions were demonstrated in 1 patient. In the 14 demented patients who did not show evidence of cerebrovascular or systemic vascular disease, dementia had an early onset and was rapidly progressive (mean age at onset, 51.3 years in the moderately retarded patients and 52.6 years in the severely retarded patients; mean duration of symptoms, respectively, 4.9 and 5.2 years). Cognitive and behavioral decline corresponded to symptoms of dementia of the Alzheimer's type in patients without Down's syndrome, but often were not recognized early. In the present group of patients, there was a remarkably high incidence of gait and speech deterioration. Also, the incidence of epileptic seizures and myoclonus was about eightfold, as compared with dementia of the Alzheimer's type in patients without Down's syndrome.

Brain↗
PubMed1991

Neuropathologic and neurochemical correlates of psychosis in primary dementia.

Neuropathologic and neurochemical correlates of psychosis were determined using brain tissue from 27 autopsy-confirmed cases of Alzheimer's disease. The densities of senile plaques and neurofibrillary tangles were determined in the middle frontal and superior temporal cortex, the prosubiculum, and the entorhinal cortex of the hippocampus. The concentrations of norepinephrine, dopamine, and serotonin, the metabolites of these biogenic amines, and the specific activity of choline acetyltransferase were also determined in these four cortical regions as well as in the substantia nigra, thalamus, amygdala, and caudate nucleus. Psychosis was associated with significantly increased densities of senile plaques and neurofibrillary tangles in the prosubiculum and middle frontal cortex, respectively, with trends toward increased densities of these lesions in the other areas examined. This finding is consistent with the increased rate of cognitive decline that accompanies this behavioral disorder. Psychosis was also associated with the relative preservation of norepinephrine in the substantia nigra, with trends in this direction for five of the remaining seven brain regions examined, and a significant reduction of serotonin in the prosubiculum that was accompanied by trends toward reduced levels of serotonin and 5 hydroxyindoleacetic acid in the remaining regions. The profile of neuropathologic and neurochemical changes associated with psychosis is distinct from that previously reported for major depression in the context of primary dementia.

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PubMed1991

Expression of 'Alzheimer antigens' in cultured skin fibroblasts.

When cultured skin fibroblasts were exposed to culture conditions designed to favor the expression of neuronal antigens, cells from each of 19 patients with Alzheimer's disease reacted immunocytochemically with antibodies to paired helical filaments, Alz-50, or both compared with only a small fraction of cells from 19 identically treated age-matched control cultures. Immunoblots confirmed the presence of soluble material reacting with Alz-50 antibody in the Alzheimer fibroblasts. Ultrastructurally, fascicles of 10-nm filaments were seen that occasionally twisted around each other, but no structures were seen that were identical to paired helical filaments. Thus, cultured skin fibroblasts from patients with Alzheimer's disease developed greater immunocytochemical reactivity with antibodies raised to paired helical filaments than did fibroblasts from control subjects, when cultured under the specified conditions.

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PubMed1987

Age and histopathologic heterogeneity in Alzheimer's disease. Evidence for subtypes.

In support of heterogeneity in Alzheimer's disease (AD), the existence of clinical and biologic subtypes has been claimed. We have investigated this claim by a statistical analysis of the relationships between the number of neurons in nucleus locus ceruleus (nLC), cortical levels of neurotransmitters, number of cortical plaques and tangles, and age. We separated AD patients into two groups: AD-1, with a less severe loss of nLC neurons; and AD-2, with a greater loss. The AD-2 cases were associated with less choline acetyltransferase activity, smaller concentrations of somatostatin and norepinephrine, and more plaques and tangles in the cerebral cortex. Although the mean age at death was less and the duration of dementia was greater in AD-2 patients than in AD-1 patients, the differences in these age-related variables were not significant. Further evidence of heterogeneity came from discriminant function analyses based on nLC neuronal counts and age at death. These findings, suggesting two subtypes of AD, suggest heterogeneity.

Age Factors↗
PubMed1998

Production of paired helical filament, tau-like proteins by PC12 cells: a model of neurofibrillary degeneration.

Neuron-like cells derived from a rat pheochromocytoma cell line (PC12) and differentiated with nerve growth factor produce a paired helical filament (PHF)-like antigen when they are subjected to heat shock (Wallace et al.: Mol Brain Res 19:149-155, 1993). It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies, which identify epitopes in the N- and C-terminal halves and the microtubule-binding domain of tau protein. The observed profile of immunoreactivity suggests the presence of full-length and C-terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy. The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy. Because differentiated PC12 cells pretreated with colcemid or Taxol prior to heat shock fail to exhibit perinuclear PHF-like immunoreactivity, the reported response to heat shock appears to require an intact system of intracellular microtubules. This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer's disease can be manipulated. The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and/or degeneration of PHF-tau in Alzheimer's disease.

Animals↗
PubMed1989

Duodenal gangliocytic paraganglioma with lymph node metastasis in a 17-year-old boy.

A case of duodenal gangliocytic paraganglioma (DGP) in a 17-year-old boy is presented. In this case a lymph node in the peripancreatic region was involved by a metastatic tumor. A review of the literature on DGP indicates that this case represents the youngest patient and is the second case of DGP with metastasis. Immunohistochemical staining for neuron-specific enolase (NSE), neurofilament (NF), pancreatic polypeptide, and somatostatin showed positive results for epithelioid and ganglion-like cells, whereas spindle cells showed immunoreactivities for S-100 protein, NSE, and NF. The histogenesis of DGP is discussed.

Adolescent↗
PubMed1999

Overexpression of four-repeat tau mRNA isoforms in progressive supranuclear palsy but not in Alzheimer's disease.

Perturbations in the microtubule-associated protein tau occur in several human neurodegenerative diseases. In Alzheimer's disease and progressive supranuclear palsy (PSP), tau proteins assemble into straight and paired helical filaments that form intraneuronal deposits of neurofibrillary tangles (NFTs). The mechanisms underlying the aberrant assembly of tau into NFTs is unknown. To determine whether alterations in the expression of the carboxyl-terminal variants of tau contribute to NFT formation, we analyzed tau mRNA isoform expression in select regions of control, Alzheimer's disease, and PSP brains. In Alzheimer's disease, there were no alterations in tau mRNA isoform expression. However, in PSP, the levels of tau mRNA isoforms containing four microtubule binding domains were increased in the brainstem but not the frontal cortex or cerebellum. The brainstem in PSP has extensive NFT pathology, whereas the frontal cortex and cerebellum are relatively spared, suggesting that alterations in tau mRNA isoform expression occur in NFT-vulnerable regions in this disease. An increase in the four-repeat tau mRNA may lead to an increase in four-repeat tau protein isoforms and may contribute to the formation of NFTs in PSP. A similar increase in four-repeat tau mRNA has been reported for mutations associated with frontotemporal dementia and parkinsonism linked to chromosome 17.

Aged↗
PubMed1988

Alzheimer's disease as an age-dependent disorder.

Alzheimer's disease is the most significant of the age-related diseases of the brain. The incidence of Alzheimer's at age 80 is twenty-fold that at age 60 years. In one study the incidence at age 80 surpassed that of stroke. Three major advances have occurred in regard to Alzheimer's disease: (1) clinical diagnosis has markedly improved and now approaches 90% accuracy; (2) understanding of the biology of Alzheimer's has increased with delineation of specific fibrous protein abnormalities and identification of the amyloid precursor gene and the gene linked to familial Alzheimer's, both genes being located on chromosome 21; and (3) there have been advances in the correlation of specific nerve cell involvement and neurotransmitter changes with physiological (position emission tomography), behavioural and neuropsychological manifestations.

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