Senile dementia of the Alzheimer type: possibility of infectious etiology in genetically susceptible individuals.

The concept that SDAT is caused by an infectious agent acting in a genetically susceptible host was approached from a number of standpoints. The similarities between SDAT and the transmissible encephalopathies are discussed. One of the areas of similarity is the influence of genetic background on the development and expression of both conditions. Evidence is presented showing that genetics plays a role in many cases of SDAT and that there are known genetically controlled phenomena, the incidence of which is positively correlated with SDAT. For human encephalopathies the genetics of CJD and GSS are detailed. In experimental systems with scrapie, the influence of genetic control, operating through both host and agent, on the outcome of infection with scrapie is described. The events controlled include length of incubation period, type of lesions and their distribution and intensity. In the context of the human diseases, scrapie provides a model for the known human encephalopathies and for SDAT.

Gerstmann-Sträussler-Scheinker disease. I. Extending the clinical spectrum.

We present the clinical findings in affected members of a large kindred with Gerstmann-Sträussler-Scheinker disease. Sixty-four patients exhibited progressive ataxia, dementia, and parkinsonian features. Inheritance appears to be autosomal dominant. Impaired smooth-pursuit eye movements, defective short-term memory, clumsiness of the hands, and ataxia of gait develop in the late 30s to early 60s. Eye movement abnormalities are characteristic of cerebellar dysfunction. Dementia progresses gradually over several years. Later, rigidity and bradykinesia appear and, at this stage, there is often psychosis or severe depression with rapid weight loss. Death occurs in 6 months to 2 years after onset of rigidity. Magnetic resonance imaging in 2 affected individuals showed cerebellar atrophy. There is decreased T2 signal in the basal ganglia, consistent with iron deposition.

Fragile X expression in Martin-Bell syndrome, intellectually normal individuals, and neoplasia, interpreted by a viral hypothesis.

We present data on fragile X expression in lymphocytes obtained from the following patients: a university student, an infertile couple, 6 of 22 prostatic cancer patients, a meningioma patient, and members of families with meningioma and familial gliomas. All patients were of normal intelligence. In addition, we report 3 cases of central nervous system (CNS) tumors in more typical fragile X families. We suggest that the fragile X expression as well as the clinical findings may be caused by a viral (or similar) infection. The virus may require a receptor protein coded by one allele of a gene on the X chromosome.

Slow virus infections.

Slow viruses produce diseases whose incubation periods range from several months to many years. Because of this long latency period, the lack of inflammation produced by these diseases and the lack of recoverable virus particles, it is only recently that the association has been made between the viruses and the diseases they cause. The detailed study of kuru, a neurologic affliction of a remote tribe of cannibals in New Guinea, was responsible for the synthesis of new and previously gathered information into a unified framework to explain not only kuru but other diseases as well. Since then, animal models, transmission experiments and histologic and biochemical studies have unveiled new links connecting viruses to previously obscure neurologic, neurophthalmic and ophthalmic entities.

Adult dementia: history, biopsy, pathology.

The historical events in the evolution of Alzheimer's disease are reviewed, including the initial description by Alois Alzheimer and the subsequent controversy regarding the nosological specificity of this entity. The similarity of senile dementia and Alzheimer's disease is emphasized. The basis for the modern concept of Alzheimer's disease as premature or accelerated aging is included in the review. The pathological correlates of the major categories of adult dementia have been described. The traditional criteria of neurofibrillary tangles and senile plaques have been re-evaluated using the current insight into these changes afforded by electron microscopy and biochemistry. The significance of amyloid has been described because it occurs within the senile plaque and also as the essential component of congophilic angiopathy. The new information regarding neuronal cell counts and the loss of choline acetyltransferase has been evaluated in terms of an indication of a pathogenic mechanism of Alzheimer's disease. The current understanding of normal pressure hydrocephalus, Creutzfeldt-Jakob disease, and multi-infarct dementia has been described. Brain biopsy in dementia has been described as having diagnostic, research, pathogenic, and prognostic value. The precautions involving the performance and handling of the biopsy have been stressed, particularly because these procedures involve conditions of possible slow virus etiology. The polemic for Alzheimer's disease as aging or slow virus infection has been summarized. At this time a consideration seems justified that Alzheimer's disease is an age-related, slow virus disease due to a hitherto unknown immune defect. Aging as an etiological agent must be clarified before Alzheimer's disease, in any form, can be considered to be an inevitable consequence of longevity.

Mechanisms and possible causes of Alzheimer's disease.

Alzheimer's disease has been found to be genetically transmitted. Structural changes in the disease include loss of neurons, specifically cholinergic and perhaps noradrenergic neurons. Functional connections among neurons are also lost. No cause has yet been determined, but slow viruses, autoimmune processes, and aluminum toxicity have been proposed.

[Virologic studies in patients with amyotrophic lateral sclerosis]. / Estudos virológicos em pacientes com esclerose lateral amiotrófica.

The effects of intracerebral inoculation of cerebrospinal fluid in mice from 9 patients with amyotrophic lateral sclerosis are reported. There were 704 animals inoculated. The results were considered positive when the animals presented difficulties in walking and equilibrating. Cases 1, 2, 6, 7 and 9 were positives in the first passage. In case 1, the positivity was reached from first to fourth passage and in case 6, to third passage. At sight of this results, the possibility of that disease to be caused by slow-virus is discussed.

[The role of maternal virus-specific cytotoxic T-lymphocytes in the immunopathology of congenital influenza infection in mice]. / Rol' materinskikh virusspetsificheskikh tsitotoksicheskikh T-limfotsitov v immunopatologii pri vrozhdennoi grippoznoi infektsii u myshei.

Using 51Cr isotope label it was demonstrated that a very low per cent of syngeneic lymphocytes derived from healthy donors and inoculated in the blood stream of uninfected or influenza virus-infected pregnant mice is found in fetuses before delivery. Similar results were obtained after inoculation of virus-specific cytotoxic lymphocytes (CTL) into uninfected pregnant mice. After inoculation into the blood stream of infected pregnant mice of virus-specific CTL their migration into fetuses before delivery increases, being most marked in 25-30% of mice. Intravenous inoculation of excess CTL (10(6) cells) to infected pregnant mice resulted in rapid development of signs of slow influenza infection in the progeny with typical clinical picture and histopathological lesions in organs and tissues. Large doses (10(7)-10(8) cells) of CTL inoculated into the blood stream cause higher reduction and death of fetuses and increase the rate of stillbirths. The role of maternal virus-specific CTL in the pathogenesis of experimental congenital and especially slow influenza infection is discussed.