Transmission of Alpers' disease (chronic progressive encephalopathy) produces experimental Creutzfeldt-Jakob disease in hamsters.

We successfully and serially transmitted to outbred and inbred strains of hamsters the brain tissue of a 2 1/2-year-old girl with a chronic progressive encephalopathy (Alpers' disease) characterized postmortem as a spongiform encephalopathy. In all hamster strains we produced a spongiform encephalopathy. The light and ultrastructural changes in the brain of hamsters, as well as the clinical signs of experimental disease, are identical to those obtained in transmission experiments of human Creutzfeldt-Jakob disease (CJD). CJD infection may be more widespread than previously recognized and can be manifested in infancy.

Lesions akin to transmissible spongiform encephalopathy in the brains of rats inoculated with immature cerebellum. Their significance in the aetiology of these diseases.

Fourteen BD IX rats were inoculated intracerebrally with a homogenate prepared from the immature cerebellar cortex of 10-day-old rats, when synaptogenesis is at its peak in this species. Eight controls were inoculated with mature cerebellar cortex. Transient ultrastructural changes were observed between 2 and 23 weeks' incubation in those animals which had received an inoculum of immature cerebellum. These changes pointed to a re-activation of embryonic or neo-natal growth mechanisms and were identical to those occurring in kuru-inoculated spider monkeys. With longer incubation histopathological lesions such as intracytoplasmic vacuolation, chromatolysis and neuronophagia appeared in neurons of the brain stem reticular formation. Such features are common in all the spongiform encephalopathies. All controls were negative. It is suggested that the transmissible agent in these diseases might be the factor which influences the various stages of normal neuronal maturation. A hypothesis is developed which would reconcile the "infectious" character of these diseases with a genetic factor and explain the "unconventional" behaviour of the agent as well as the mode of its transmission.

[Development of laboratory diagnostic methods for slow infections of the human central nervous system caused by nonclassical viruses]. / Razrabotka metodov laboratornoi diagnostiki medlennykh infektsii tsentral'noi nervnoi sistemy cheloveka, vyzyvaemykh neklassicheskimi virusami.

The theoretical foundations of the laboratory diagnosis of Creutzfeldt-Jakob disease and amyotrophic leukospongiosis in living patients are discussed and practical diagnostic methods are proposed on the basis of the study of the biological properties of nonclassical viruses and the pathogenesis of slow infections of the central nervous system. The use of the retrobulbar method of infecting susceptible animals has permitted, besides a considerable decrease in the incubation period in modeling slow infections, the improvement of the in vivo biological test. Thus, as the result of the multiplication of non-classical viruses in the visual nerve and the retina, experimental animals develop retinopathy which can be detected 1.5-2.5 weeks after the animals are injected with the spinal fluid or blood taken from the patient under examination. To diagnose amyotrophic leukospongiosis, the in vitro biological test, based on the capacity of the causative agent for inducing a considerable (2- to 5-fold) increase in the mitotic activity of HEp-2 cells, has been developed. The comparative studies have shown the expediency of using the method for the detection of antibodies to nerve-fiber proteins as an additional test for the differential diagnosis of slow infections of the central nervous system.

[Reproduction of amyotrophic leukospongiosis in laboratory animals]. / Vosproizvedenie amiotroficheskogo leikospongioza u laboratornykh zhivotnykh.

Amyotrophic leukospongiosis (ALSP) was produced in laboratory animals: hamsters, rabbits, guinea pigs. Guinea pigs were found to be a most suitable laboratory model for the study of ALSP pathogenesis with the longest incubation period. The data are obtained verifying the role of previously isolated unconventional virus in the ALSP etiology.

Creutzfeldt-Jakob disease.

The historical aspects of spongiform encephalopathies, Creutzfeldt-Jakob disease (CJD) and kuru of man, as well as scrapie and transmissible mink encephalopathy, are outlined. Transmissions of these diseases to animal hosts are presented, with emphasis on CJD transmissions to guinea pigs, hamsters, and mice. The relationship of CJD to scrapie with reference to the pathological findings is discussed. In CJD the incubation period is cut in half in guinea pigs and hamsters in the second passage. The spongiform changes occurring in the neuropil are reviewed. These changes are related to the type of inoculum, e.g., there is more vacuolization after inoculation with brain, and less after inoculation with spleen. Spongiform changes are also dependent upon the route of inoculation; these are more severe in intracerebral inoculation compared to intraperitoneal inoculation. Viremia is present. Maternal transmission and lateral transmission are absent. No virus-like particles are detected, and no other organisms are visible by electron microscopy. Isolations of the causative agent and strains of the agent in spongiform encephalopathies remain elusive. The hypotheses concerning the nature of the agent are critically reviewed. Novel data on the production of tumors derived from CJD brains are presented. Tissue culture cells arising from such brains become permanent lines and are similar to neoplastic lines. When such CJD lines are injected subcutaneously into nude mice, malignant neoplasms are formed. No evidence of an infectious etiology in Alzheimer's disease exists. Reported similarities between this disease and CJD are reviewed. Animal models of CJD are useful for the investigation of dementias.

Sheep consumption: a possible source of spongiform encephalopathy in humans.

A fatal spongiform encephalopathy of sheep and goats (scrapie) shares many characteristics with Creutzfeldt-Jakob disease (CJD), a similar dementing illness of humans. To investigate the possibility that CJD is acquired by ingestion of contaminated sheep products, we collected information on production, slaughtering practices, and marketing of sheep in Pennsylvania. The study revealed that sheep were usually marketed before central nervous system signs of scrapie are expected to appear; breeds known to be susceptible to the disease were the most common breeds raised in the area; sheep were imported from other states including those with a high frequency of scrapie; use of veterinary services on the sheep farms investigated and, hence, opportunities to detect the disease were limited; sheep producers in the area knew little about scrapie despite the fact that the disease has been reported in the area, and animal organs including sheep organs were sometimes included in processed food. Therefore, it was concluded that in Pennsylvania there are some 'weak links' through which scrapie-infected animals could contaminate human food, and that consumption of these foods could perhaps account for spongiform encephalopathy in humans. The weak links observed are probably not unique to Pennsylvania.

Brain tissue from persons dying of Creutzfeldt-Jakob disease causes scrapie-like encephalopathy in goats.

Two goats became affected with an encephalopathy indistinguishable from scrapie 43 months after they were inoculated intracerebrally with 10% suspensions of brain from two persons dying of Creutzfeldt-Jakob disease. Although this observation does not establish the common identity of Creutzfeldt-Jakob disease virus and scrapie virus, it is thought to provide strong evidence of a close etiological relationship between the two diseases.

Human spongiform encephalopathies in marmoset monkeys (Saguinus sp.).

Brain homogenates (10% w/v) from five of seven kuru patients inoculated intracerebrally (i.c., 0.1 ml) into marmosets (Saguinus sp.) induced a rapidly progressive CNS disease 26, 31, 36, 76 and 94 months postinoculation. Serial marmoset passages of kuru were accomplished by i.c. inoculation of neonatal marmosets with brain homogenates from marmosets with experimentally induced kuru. The incubation periods ranged from 1.5 to 11 months (average 7.3) in 19 animals, 20-25 months in four animals and greater than 26 months in two animals. Symptoms and brain lesions of the induced disease were compatible with kuru as observed in humans and other nonhuman primates. Creutzfeldt-Jakob disease (CJD) has been induced by i.c. inoculation of marmosets with brain homogenates from two of four human CJD patients with incubation periods of 43 and 54 months and is in serial passage.

A transmissible subacute spongiform encephalopathy in a visitor to the eastern highlands of New Guinea.

A Caucasian male, clinically ill with a respiratory disease, visited the Eastern Highlands of New Guinea (endemic for kuru in the Fore people) and developed subacute spongiform encephalopathy (Jakob-Creutzfeldt disease) ten weeks later, from which he subsequently died. Brain material was inoculated intracranially into squirrel monkeys, and several of them developed a spongiform encephalopathy. Monkeys that received control material (normal brain) were normal. Electronmicroscopic features in affected brain tissue are described, and the question of a relationship between Jakob-Creutzfeldt disease and kuru is considered.