Lesions akin to transmissible spongiform encephalopathy in the brains of rats inoculated with immature cerebellum

Summary 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.Preliminary results of this work were included in a paper read at the 28th meeting of the Deutsche Gesellschaft für Neuropathologie und Neuroanatomie in October 1983 [3]. The work is dedicated to the memory of Herbert Butler (James) Parry 1912–1980     

Drug therapy in human and experimental transmissible spongiform encephalopathy

During the past 30 years, over 60 different chemical compounds have been used to treat experimental animals infected with transmissible spongiform encephalopathies (TSE), including a wide variety of anti-infectious agents, immunomodulating drugs, and chemicals interacting with the lympho-reticular system. Some compounds achieved a prolongation of the incubation period, but this effect decreased or disappeared when they were administered at or near the onset of symptomatic disease. Recent in vitro and tissue culture studies support earlier speculation about the importance of a chemical structure containing both water-soluble and lipid-soluble components, evidently as a means of interaction with the misfolded membrane-bound 'prion' protein. A number of compounds shown to eliminate the protein (or infectivity) in TSE-infected tissue cultures are the subject of ongoing studies in animals, and are under consideration for human drug trials. As with other recalcitrant infections, combinations of drugs with different modes of action are likely to be necessary for any effective therapy. Also, very recent work in developing antibodies that can neutralize in vitro infection (and, in conjunction with genetic engineering, in vivo infection) has renewed interest in the strategies of both active and passive immunization.     

Spontaneous mutations in the prion protein gene causing transmissible spongiform encephalopathy

We analyzed the prion protein gene (PRNP) region in patients with transmissible spongiform encephalopathy associated with the PRNP D178N mutation. The results suggest that the D178N chromosomes had independent origins in each affected pedigree or apparently sporadic case. A de novo spontaneous PRNP mutation was observed. We provide evidence that hereditary and apparently sporadic transmissible spongiform encephalopathy cases associated with the D178N mutation result from multiple recurrent mutational events.     

The phenotypic expression of different mutations in transmissible human spongiform encephalopathy.

Clinical, pathological, and experimental transmission characteristics are reviewed for each of the known mutations in the amyloid precursor gene (PRNP) associated with familial spongiform encephalopathies. All mutation groups show an earlier age at onset and longer duration of illness than sporadic disease, and more or less distinctive patterns of illness can be recognized for each mutation, although much variability may occur even among affected members of the same family. Experimental transmission of disease has been accomplished for most of the mutations, with shortened incubation periods in the inoculated animals that parallel the earlier age at onset of human illness in these cases, implying a shortened pre-clinical phase of disease rather than an earlier 'infecting event'. Mutations thus not only predispose to spongiform encephalopathy, but also accelerate its pathogenetic tempo and influence its phenotypic expression.     

Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice

Catechol-O-methyltransferase (COMT) catalyses the O-methylation of compounds having a catechol structure and its main function involves the elimination of biologically active or toxic catechols and their metabolites. By means of homologous recombination in embryonic stem cells, a strain of mice has been produced in which the gene encoding the COMT enzyme is disrupted. We report here the levels of catecholamines and their metabolites in striatal extracellular fluid in these mice as well as in homogenates from different parts of the brain, under normal conditions and after acute levodopa administration. In immunoblotting studies, COMT-knockout mice had no COMT protein in brain or kidney tissues but the amounts of catecholamine synthesizing and other metabolizing enzyme proteins were normal. Under normal conditions, COMT deficiency does not appear to affect significantly brain dopamine and noradrenaline levels in spite of relevant changes in their metabolites. This finding is consistent with previous pharmacological studies with COMT inhibitors and confirms the pivotal role of synaptic reuptake processes and monoamine oxidase-dependent metabolism in terminating the actions of catecholamines at nerve terminals. In contrast, when COMT-deficient mice are challenged with l-dihydroxyphenylalanine, they show an extensive accumulation of 3,4-dihydroxyphenylacetic acid and dihydroxyphenylglycol and even dopamine, revealing an important role for COMT under such situations. Notably, in some cases these changes appear to be Comt gene dosage-dependent, brain-region specific and sexually dimorphic. Our results may have implications for improving the treatment of Parkinson's disease and for understanding the contribution of the natural variation in COMT activity to psychiatric phenotypes.     

Brain histamine turnover enhanced by footshock

When footshock was given to mice at 15-s intervals for 30–120 min, there was a significant increase in the brain level of the tele-methyl-histamine (t-MH), a predominant metabolite of brain histamine (HA). This footshock-induced elevation of the t-MH level also occurred in mice pretreated with pargyline but not in mice pretreated with metoprine. The footshock facilitated the HA depletion induced by α-fluoromethylhistidine. These results suggest that footshock increases the brain HA turnover.     

Prion protein immunohistochemical staining in the brains of monkeys with transmissible spongiform encephalopathy

Prion protein (PrP) immunohistochemical staining of the brains of common marmosets (Callithrix jacchus) with experimental transmissible spongiform encephalopathy is described. The monkeys ( n =17) had been injected, intracerebrally, 17–49  months previously with homogenates of brain tissue taken post mortem from a cow with BSE ( n =2 monkeys), a sheep with natural scrapie ( n =2 monkeys), human cases of growth hormone related Creutzfeldt–Jakob disease (CJD) ( n =2 monkeys), sporadic CJD ( n =5 monkeys), or Gerstmann–Sträussler–Scheinker disease (GSS) ( n =4 monkeys), or from monkeys with spongiform encephalopathy resulting from injection with brain tissue from these last two cases ( n =1 monkey from each case). Only diffuse PrP-staining was seen in monkeys injected with CJD-material whereas more aggregated deposits of PrP were seen in monkeys injected with BSE-, scrapie-and GSS-brain tissue. There were no patterns of staining specific to the brains injected with BSE-material that could be used to identify the origin of that inoculum. BSE-and scrapie-injected monkey brains could be distinguished from each other because in BSE-injected monkey brain the spongiform vacuolation was largely confined to subcortical structures whereas in scrapie-injected monkey brain the spongiform vacuolation was also prominent in the neocortex. The patterns of PrP deposition differed markedly between those seen in monkey brains injected with BSE-material or CJD-material, but the patterns of PrP staining seen in monkey brains injected with BSE-material were also seen in monkey brains injected with scrapie-or GSS-material. Overall there was a correlation between the length of the incubation period and the amount of aggregated PrP-staining, but no correlation between the neuropathological picture and the clinical presentation of neurological signs.     

Cell death and autophagy in prion diseases (transmissible spongiform encephalopathies)

Neuronal autophagy, like apoptosis, is one of the mechanisms of programmed cell death. In this review, we summarize current information about autophagy in naturally occurring and experimentally induced scrapie, Creutzfeldt-Jakob disease and Gerstmann-Str?ussler-Scheinker syndrome against the broad background of neural degenerations in transmissible spongiform encephalopathies (TSEs). Typically a sequence of events is observed: from a part of the neuronal cytoplasm sequestrated by concentric arrays of double membranes (phagophores); through the enclosure of the cytoplasm and membrane proliferation; to a final transformation of the large area of the cytoplasm into a collection of autophagic vacuoles of different sizes. These autophagic vacuoles form not only in neuronal perikarya but also in neurites and synapses. On the basis of ultrastructural studies, we suggest that autophagy may play a major role in transmissible spongiform encephalopathies and may even participate in the formation of spongiform change.     

Subacute spongiform encephalopathy (Creutzfeldt-Jakob disease) with amyloid angiopathy.

A case is reported of Creutzfeldt-Jakob disease associated with amyloid infiltration of cerebral vessels. The duration of progressive dementia was only 4 months. Neuritic plaques were not a feature of the pathology. This report emphasises the association of spongiform encephalopathy with the presence of amyloid in the brain.     

Comparison of spongiform lesions in experimental scrapie and rabies in skunks

Summary Striped skunks were inoculated intracerebrally with the scrapie agent (suspension of brain from a naturally infected Suffolk sheep) or intramuscularly with street rabies virus (suspension of salivary glands from naturally infected skunks). Those given the scrapie agent developed clinical signs of weakness, posterior ataxia, and emaciation after incubation periods of 8 to 23 months. Those inoculated with rabies virus developed clinical signs of rabies (aggressive behavior, hyperexcitability, ataxia and paralysis) after incubation periods of 20 to 62 days. The gross lesions in the brains of the skunks given the scrapie agent consisted of marked atrophy of the thalamus and moderate atrophy of the cerebrum. No gross lesions occurred in the rabid skunks. Histologically, the type of spongiform lesion in rabies was the same as that in scrapie. However, spongiform change of rabies infected brains was less extensive (only rarely affected the basal ganglia, hippocampus or hypothalamus) than that of brains infected with the scrapie agent and was characterized by fewer numbers of small vacuoles (as a proportion of total number of vacuoles) than occurred in scrapie spongiform change.     

The effect of methamphetamine on histamine release in the rat hypothalamus

Abstract In the present study, the effect of methamphetamine (MAP) on histamine (HA) release measured by in vivo brain microdialysis in the rat hypothalamus was investigated. Administration of MAP (3 mg/kg) significantly increase HA release from 40 to 160 min after the injection. This finding suggests that a moderate dose of MAP activates the hypothalamic HA neuron system, which may be related to effects of MAP on intrinsic biological rhythms.     

Nuclear inclusions in subacute spongiform encephalopathy

Summary Type A inclusions were observed in glial cells from necropsy material from a case of subacute spongiform encephalopathy. Their origin and aetiological significance are obscure.

---

Zusammenfassung Kerneinschlüsse vom Typ A wurden in Gliazellen eines Autopsiefalles von subakuter spongiöser Encephalopathie beobachtet. Ihre Genese und ätiologische Bedeutung sind unklar.

     

How do neurons degenerate in transmissible spongiform encephalopathies?

Neuroaxonal dystrophy is a feature of neuronal degeneration encountered in all subacute spongiform virus encephalopathies including scrapie and Creutzfeldt-Jakob disease (CJD). By immunohistochemical techniques, the accumulation of 200 kDa neurofilament protein was demonstrated in affected neurites in human CJD. These neurites exhibited the ultrastructural features of dystrophic neurites encountered in other neurodegenerative disorders, particularly Alzheimer's disease. These findings support the hypothesis that impairment of slow axoplasmic transport is a common pathogenetic mechanism for CJD and many other neurodegenerative conditions.     

Brain magnetic resonance spectroscopy in episodic hepatic encephalopathy

Brain magnetic resonance (MR) study has shown metabolic abnormalities and changes in water distribution of the brain tissue that may relate to the pathogenesis of hepatic encephalopathy (HE). We designed a study to investigate the disturbances in brain water and metabolites during episodic HE using a 3-T MR scanner. Cirrhotic patients with different grades of HE underwent MR during hospitalization (n=18). The MR was repeated at 6 weeks'' follow-up (n=14). The results were compared with those of a group of healthy volunteers (n=8). During episodic HE, brain diffusion-weighted imaging showed a high apparent diffusion coefficient (ADC) (12% to 14%) that decreased during follow-up (−1% to −4%). These disturbances were accompanied by high glutamine (581%), low choline (−31%), and low myo-inositol (−86%) peaks on MR spectroscopy. In overt HE, patients showed high glutamine that decreased during follow-up (−22%). In addition, these patients exhibited a rise in plasma S100 beta and enlargement of brain white-matter lesions. In conclusion, several disturbances detected by MR support the presence of impaired brain water homeostasis during episodic HE. Although astrocytes have a major role in this condition, brain edema during episodic HE may be extracellular and does not appear to be directly responsible for the development of neurologic manifestations.