Structural and functional neuroimaging in human prion diseases.

INTRODUCTION: Prion diseases are neurodegenerative disorders resulting from the accumulation of a misfolded isoform of the cellular prion protein (PrPc). They can occur as acquired, sporadic, or hereditary forms. Although prion diseases show a wide range of phenotypic variations, pathological features and clinical evolution, they are all characterised by a common unfavourable course and a fatal outcome. REVIEW SUMMARY: Some variants, such as kuru, have practically disappeared, while others, for example the variant Creutzfeldt-Jakob (vCJD) or those attributable to iatrogenic causes, are still in force and pose a challenge to current medicine. There are no definitive pre-mortem diagnostic tests, except for vCJD, where a tonsil biopsy detects 100% of the cases. For this reason, diagnostic criteria dependent on statistical probability have had to be created. These require complementary examinations, such as an electroencephalogram (EEG) or the detection of 14-3-3 protein in cerebrospinal fluid (CSF). Only the pulvinar sign in magnetic resonance imaging (MRI) has been included as a vCJD diagnostic criterion. The present review discusses neuroimaging findings for each type of prion disease in patients with a definitive histopathological diagnosis. CONCLUSIONS: The aim is to define the usefulness of these complementary examinations as a tool for the diagnosis of this family of neurodegenerative diseases.

A history of kuru.

Kuru is placed in its geographic and linguistic setting in the Eastern Highlands of Papua New Guinea. The epidemic of kuru has declined over the period 1957 to 2005 from more than 200 deaths a year to 1 or none. Since transmission of the kuru prion agent through the mortuary practice of transumption ceased by the early 1960s, the continuation of the epidemic into the present century demonstrates the long incubation periods that are possible in human prion diseases. Several histories of kuru are portrayed, from the different perspectives of the Fore people, of the scientists striving to elucidate the disease, of those engaged in research on prions, and of humans confronting the implications of kuru-like epidemics in the remote past. Kuru has connections to bovine spongiform encephalopathy through intraspecies recycling. The influence of host genetics on the incubation period in kuru may help to predict the shape of the still ongoing epidemic of variant Creutzfeldt-Jakob disease.

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.

The human spongiform encephalopathies.

The spongiform encephalopathies are comprised of kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straüssler syndrome. These diseases are compared, and their causes, effects, and treatments are given.

The diagnosis of human prion diseases.

Prion diseases present a wide spectrum of clinical and neuropathological features. In this review, clinical and neuropathological findings are summarized along with criteria for the diagnosis of the molecular-phenotypic subtypes of sporadic Creutzfeldt-Jakob disease (CJD), familial CJD, new variant CJD, iatrogenic CJD, Gerstmann-Straussler-Scheinker disease, fatal familial insomnia and kuru.

Gerstmann-Sträussler-Scheinker disease with A117V mutation in a second French-Alsatian family.

We report a kindred of French/Alsatian origin with symptoms of Gerstmann-Sträussler-Scheinker disease over 3 generations. In the propositus, cerebellar signs and memory disturbance were the presenting features, followed by other neurological manifestations. Biopsy of the cerebral cortex showed numerous multicentric and "kuru"-type amyloid plaques that on immuno-light and electron microscopy stained with antibody to prion protein. Molecular genetic analysis revealed an A117V mutation in the open reading frame of the prion protein gene. Questions as to pathology and spread of this mutation are discussed.

Notes on the history of the prion diseases. Part I.

The astute observation by William Hadlow, an American veterinary neuropathologist of the similarity between the histopathology of kuru, an obscure disease of the primitive tribe in New Guinea, and scrapie of sheep, was the first clue to the etiology of the transmissible spongiform encephalopathies (TSE). The knowledge that scrapie was transmissible but only after an unusually long incubation period, that the causative agent was highly resistant to heat and formalin, and that it seemed to be able to replicate in the absence of nucleic acid, eventually led to the discovery of the prion by Stanley Pruisner and the still controversial protein-only hypothesis of etiology of the TSE.

[Gerstmann-Sträussler-Scheinker disease. Pathologal and genetic study]. / Maladie de Gerstmann-Sträussler-Scheinker. Etude pathologique et généalogique.

Gerstmann-Sträussler-Scheinker's disease is a familial spongiform encephalopathy whose pathological hallmark is the existence--especially in the cerebellum--of numerous amyloid plaques. We report here the third clinicopathological case in a French family. Brain tissue from one of its members--initially described as familial Creutzfeldt-Jakob's disease--has been reported as successfully inoculated to monkeys. We present the currently accumulating data favouring the hypothesis of a common etiology for familial Creutzfeldt-Jakob's disease and Gerstmann-Sträussler-Scheinker's disease. The familial characteristics, resulting in different durations of incubation and evolution, could lead to different clinical and histological expressions.

[Familial presenile dementia: Gerstmann-Sträussler-Scheinker's syndrome (author's transl)]. / Démence pré-sénile familiale: syndrome de Gerstmann-Sträussler-Scheinker.

A similar affection has developed in eight members from four generations of a family living in the Alsace. The disease is characterized by the onset of a pyramidal, pseudobulbar syndrome and dementia during the third or fourth decade of life. The outcome is fatal after a mean period of three years. Cerebral biopsies in three cases have demonstrated multicentric amyloid plaques differing from senile plaques. Clinical and pathological findings are similar to those currently reported in the literature as being typical of Gerstmann-Sträussler-Scheinker's syndrome. The affection appears as a separate entity: the multicentric plaques, clinical symptomatology, pyramidal or pseudobulbar, cerebellar syndromes, usually preceding dementia, age of onset, course, and familial character or the disorder distinguish it among presenile dementias. Its clinical profile and course are very similar to that of familial cases of Alzheimer's disease, some of which are probably cases of Gerstmann-Strässler-Scheinker's syndrome. Transmission to animals, though inconstant, places it within the group of transmissible dementias among kuru, Creutzfeldt-Jakob's, and familial forms of Alzheimer's disease. The familial nature of the affection and the variability of clinical and pathological features in the same family illustrate the complex relationships between hosts and pathogenic agents in the clinicopathological expression of a disease.

[Prions, infections and confusions in the "transmissible" spongiform encephalopathies. The other evidence-based science. III. Review]. / Priones, infecciones y confusiones en las encefalopatías espongiformes "trasmisibles". Ciencia basada en la otra evidencia III. Revisión.

There are some neurological disorders with a pathological hallmark called spongiosis which include Creutzfeld-Jakob disease and its new variant, the Gertsmann-Straussler-Scheinker Syndrome and the Fatal Familial Insomnia in humans; and Scrapie and Bovine Spongiform Encephalopathy, among others, in animals. The etiological agent has been considered either transmissible or hereditary or both. Curiously, this agent has no nucleic acids, is impossible to filter, is resistant to inactivation by chemical means, has not been cultured and is unobservable at electron microscopy. All of these facts have led to some researches to claim that these agents are similar to viruses appearing in computers. However, after almost fifty years of research, is still not possible to explain why and how such elements produce the diseases commented about. On the contrary, during these years have been possible to know that these entities called slow viral infections, transmissible amyloidosis, transmissible dementia, transmissible spongiform encephalopathies or prion diseases appear in individuals with genetical predispositions exposed to several worldwide immunological stressors. The possibility that prions are the consequence and not the cause of these diseases in animals and man is day by day more reliable, and supports the suggestion that a systematic intoxication due to pesticides as well as mycotoxin ingestion, produced mainly by different molds such as Aspergillus, Penicillium or Fusarium, seem to be the true etiology of these neurodegenerative disorders.

[Human prion diseases]. / Prionkrankheiten beim Menschen.

The interest in prion diseases, particularly the Creutzfeldt-Jakob type (CJD), rose dramatically in the last years for two reasons. 1) The general public wants to know whether eating beef may cause CJD. Discovering the new variant Creutzfeldt-Jakob disease (nvCJD) and experimental evidence that nvCJD and bovine spongiforme encephalopathy (BSE) are caused by the same prion strain make this idea probable. 2) Infectiologists and Neuroscientists recognise a model disease for a new infectious principle in that the same disease may occur as being inherited as well as transmitted. Additionally, it might allow new insights into the possible aetiologies of neurodegenerative disease.

[Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Part I]. / Choroba Creutzfeldta-Jakoba i inne pasazowalne encefalopatie gabczaste czlowieka. Czesc I.

In the first part of this work the main problems of prion diseases--also called transmissible cerebral amyloidoses (TCA) or subacute (transmissible) encephalopathies (SSE, TSE)--and clinical symptoms of Creutzfeldt-Jakob disease are presented. Some problems of neuropathology of Creutzfeldt-Jakob disease and basic informations about other human prion diseases will be presented in the second part. The growth of the interest in prion diseases during last years is caused by the problem of bovine spongiform encephalopathy (BSE or "mad cow disease") and its transmission into a human. The new variant of Creutzfeldt-Jakob disease (nvCJD) has appeared. Prion diseases: Gerstmann-Sträussler-Scheinker syndrome (GSS), kuru, fatal familial insomnia (FFI) and particularly the most frequent of them--Creutzfeldt-Jakob disease (CJD)--have nonspecific, sometimes variable clinical (psychopathological and neurological) symptoms. The imaging, EEG, cerebrospinal fluid tests and other laboratory tests are not specific either and their diagnostic value is limited. Neuropathological studies are needed but their interpretation is often difficult. The only certain diagnostic marker for TSE is the presence of PrP(Sc), the prion protein, which is presently believed to be a direct cause for all transmissible cerebral amyloidoses (TCA).

Kuru.

Theis report discusses problems involved in the diagnosis of kuru. The gentic and epidemiological pattern is also reviewed. This reveals a continuing overall reduction in kuru incidence with the disappearance of juvenile cases and increasing age of male kuru patients a reduction in the age of female cases. The significance of these trends in relation to the transmission of kuru is discussed.