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The etiology of Alzheimer disease (AD) is unknown. To investigate the transmissibility of AD, the buffy coat of the blood from 11 relatives of AD patients, including 2 with suspicious or early signs of AD, was inoculated intracerebrally into hamsters. In these pilot experiments, 5 individuals produced histologically documented spongiform encephalopathy on primary passage in recipient hamsters. Material from 3 of these positives was serially transmitted in a second passage. The histological alterations observed in the brains of positive hamsters were similar to those seen in experimental Creutzfeldt-Jakob disease (CJD). These transmission results raise the intriguing possibility that CJD-like agents may be involved in at least some forms of AD.

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A 32-year-old man with rapidly progressive dementia, pyramidal signs, myoclonic jerks and dystonic movements died following brain biopsy. neuropathological examination revealed minimal neuronal loss accompanied by mild spongiform change and astrocytic reaction. Numerous plaques and neurofibrillary tangles composed of paired helical filaments dominated the ultrastructural picture. This patient had features of both Creutzfeldt-Jakob disease and Alzheimer's disease, providing additional support for the existence of an overlap between these disorders.

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Brains of normal controls and patients with primary degenerative dementia were investigated for choline acetyltransferase (ChAT) activity in the frontal, temporal and parietal cortex, hippocampus, amygdala and thalamus. A few patients with Alzheimer's disease were unusual as the cholinergic marker was unaffected, except in the amygdala. Other patients with dementia and undiagnosed neurodegenerative disorder had elevated cortical ChAT activity. The interpretations offered are: (a) the syndrome of dementia and Alzheimer pathologic change precedes significant loss of cortical cholinergic innervation; (b) denervation in dementia can occur early in olfactory areas, exemplified here by the amygdala; (c) dementia is associated with the loss of non-cholinergic structure. An indication of structures involved was given by loss of a marker of excitatory amino acid-releasing neurones.

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Guinea pigs were inoculated intracerebrally with cerebrospinal fluid (CSF) and/or brain tissue suspensions from 8 patients with Creutzfeldt-Jakob disease (CJD) and with CSF from 2 patients with Alzheimer's disease. After a very long incubation period (over 360-420 days) a serially transmissible experimental disease appeared in the guinea pigs inoculated with CSF from 5 of the CJD patients, with either CSF or brain suspension from one CJD patient and with brain suspensions from the remaining 2 CJD patients. The disease was characterized by tremor, ataxia, convulsions and morphopathological lesions, such as spongiform change, glial hyperplasia and vacuolation of the neurons. Inoculations of CSF from the two Alzheimer's disease cases gave negative results.

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Mice inoculated intracerebrally before the age of 5 days with homogenates of autopsied brain tissue from patients with Creutzfeldt-Jakob (C-J), Alzheimer's, or Pick's diseases showed highly significant decreases in life span when compared with sham-inoculated control mice. With C-J disease there was strong indication of horizontal transmission of the agent to uninoculated mice caged with the inoculated mice. While the results with C-J disease were not unexpected in view of the known infectious etiology of the disease, the results obtained with Alzheimer's and Pick's diseases suggest that previously undetermined infectious or toxic agents may be associated with these two diseases, which currently have unresolved etiologies. Mice inoculated with autopsied brain tissue from patients with multiple sclerosis or subacute sclerosing panencephalitis had life spans similar to those of the control mice.

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Despite extensive chemical, epidemiological, histopathological and pharmacological investigations of Alzheimer's disease (AD), its etiology remains elusive. This article describes studies supporting a rationale for exploring a transmissible slow viral etiology of at least some forms of AD. To date, a major limitation in these studies has been reliance upon induction of AD histopathology as the outcome measure of successful transmission. Future studies should consider novel outcome measures for the detection of successful, although histopathologically inapparent, transmissible infection. In addition, the need to inoculate a diverse variety of rationally selected, potential hosts is stressed.

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Ample justification exists on clinical, pathologic, and biologic grounds for considering a similar pathogenesis for AD and the spongiform virus encephalopathies. However, the crux of the comparison rests squarely on results of attempts to transmit AD to experimental animals, and these results have not as yet validated a common etiology. Investigations of the biologic similarities between AD and the spongiform virus encephalopathies proceed in several laboratories, and our own observation of inoculated animals will be continued in the hope that incubation periods for AD may be even longer than those of CJD.

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We have analysed the familial occurrence of Creutzfeldt-Jakob disease (CJD) in 27 families selected from a total of 73 families. Fifteen per cent of all cases of CJD have a family history of disease consistent with autosomal dominant transmission. The onset of disease in familial cases is significantly earlier than in sporadic cases. A maternal effect was not found, nor was there evidence for prenatal vertical transmission of the virus. Temporal and spatial separations between affected members demonstrates that incubation periods ranging at least from one to four decades are to be expected. Affected siblings tend to die at the same age, and not at the same time, which is consistent with some form of vertical transmission (either prenatal or early postnatal), assuming rather uniform incubation periods. CJD occurred in four families in members related by marriage, evidence in favour of horizontal or common source transmission in occasional cases. The familial occurrence of CJD and Alzheimer's disease (AD) were compared using data on 52 families with AD. The age at death and duration of disease in familial AD is greater than in familial CJD. Familial AD also occurs in a pattern of autosomal dominant transmission, without maternal effect. There were four families with AD in which one or more members died from CJD. There were an additional 17 families with AD in which one or more members presented with clinical features resembling CJD. Although virus causing an experimental spongiform encephalopathy was isolated from the brain of two cases of familial AD, most cases of sporadic and familial AD tested failed to cause disease when brain tissue was inoculated into nonhuman primates. The precise mechanism of spread of the virus in familial CJD remains unknown. The results of the present study are consistent with the hypothesis of a genetically inherited susceptibility to infection which is acquired in early infancy or childhood. Other proposed mechanisms such as prenatal vertical transmission or a common environmental source of infection seem less likely.

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Nonhuman primates were inoculated intracerebrally with brain tissue from 52 patients with confirmed Alzheimer disease (AD) in order to investigate the possibility of an infectious etiology. Animals inoculated with brain tissue from two patients with familial AD developed a spongiform encephalopathy that was indistinguishable from Creutzfeldt-Jakob disease (CJD). Seventeen other cases of AD on test for more than 50 months failed to produce similar changes, and 33 cases have not been incubating for a sufficient period of time to ascertain the presence of a transmissible agent. The initial transmission of spongiform encephalopathy with brain tissue from the two familial cases of AD has not been reproduced and the association between AD and an infectious agent has not yet been demonstrated with any reasonable degree of certainty. The frequent overlap of clinical symptoms of AD and CJD, and the occurrence of cases of CJD and AD in the same families indicate the need for continuing research on the relationship between the two diseases.

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Recent studies suggest that some cases of familial Alzheimer's disease may be associated with a transmissible dementia. Animal experiments show that presymptomatic carriers of "slow virus" agents can transmit disease. Because of these findings, we have extended the precautions previously delineated to include those at risk of acquiring transmissible dementia, specifically, to the descendants of those affected with familial Alzheimer's disease or familial Creutzfeldt-Jakob's disease. Blood donation from such persons may pose a danger, because transmissible spongioform encephalopathy has been passed from animal to animal by blood serum and by the WBC layer of frozen whole blood.

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