PMCA-generated prions from the olfactory mucosa of patients with Fatal Familial Insomnia cause prion disease in mice.

Background: Fatal Familial Insomnia (FFI) is a genetic prion disease caused by the D178N mutation in the prion protein gene (PRNP) in coupling phase with methionine at PRNP 129. In 2017, we have shown that the olfactory mucosa (OM) collected from FFI patients contained traces of PrPSc detectable by Protein Misfolding Cyclic Amplification (PMCA). Methods: In this work, we have challenged PMCA-generated products obtained from OM and brain homogenate of FFI patients in BvPrP-Tg407 transgenic mice expressing the bank vole prion protein to test their ability to induce prion pathology. Results: All inoculated mice developed mild spongiform changes, astroglial activation, and PrPSc deposition mainly affecting the thalamus. However, their neuropathological alterations were different from those found in the brain of BvPrP-Tg407 mice injected with raw FFI brain homogenate. Conclusions: Although with some experimental constraints, we show that PrPSc present in OM of FFI patients is potentially infectious. Funding: This work was supported in part by the Italian Ministry of Health (GR-2013-02355724 and Ricerca Corrente), MJFF, ALZ, Alzheimer's Research UK and the Weston Brain Institute (BAND2015), and Euronanomed III (SPEEDY) to FM; by the Spanish Ministerio de Economía y Competitividad (grant AGL2016-78054-R [AEI/FEDER, UE]) to JMT and JCE; AM-M was supported by a fellowship from the INIA (FPI-SGIT-2015-02).

Clinical Features and Sleep Analysis of Chinese Patients with Fatal Familial Insomnia.

This study aimed to examine clinical features, sleep, abnormal sleep-wake transition and non-sleep disturbances as well as lab tests in Chinese fatal familial insomnia (FFI) subjects. Patients with confirmed clinical and laboratory diagnosis of FFI have been retrospectively reviewed. The clinical features and the results of the complementary tests, including polysomnography (PSG), brain imaging and genetic analysis, were used. Two male and three female patients were recruited in this study. Three of the five patients had more comprehensive family medical records. The most typical clinical manifestations in all 5 patients were sleep disturbances, including insomnia, laryngeal stridor, sleep breath disturbance, and sleep-related involuntary movements. PSG of all these five cases showed reduction in total sleep time, sleep fragmentation, abnormal short non-rapid eye movement - rapid eye movement (REM) cycling, REM sleep reduction or loss, and REM sleep instruction in wakefulness. Patient 2's emission tomography scan demonstrated a reduction in glucose uptake in the left thalamus and bilateral inferior parietal lobe. In summary, Chinese FFI patients are typically characterized by organic sleep related symptoms, rapidly progressive dementia and sympathetic symptoms. We propose that structural damages in the thalamus and cortex are mostly responsible for clinical manifestations of FFI.

Insomnio y muerte de Marilyn Monroe. Parte II: muerte / No disponible

Objetivo: Evaluar las circunstancias de la muerte de Marilyn Monroe (MM) desde un punto de vista médico, e intentar reconstruir el tratamiento prescrito para su insomnio crónico. Material y métodos: Documentación original de la investigación policial y médico-forense sobre su muerte, recetas de medicamentos y otros documentos de interés, testimonios directos de los testigos principales y valoración de conflictos de intereses. Resultados: MM falleció la noche del sábado 4 de agosto de 1962 a causa de una sobredosis de fármacos hipnóticos. Existió una divergencia entre la investigación policial, que valoró la muerte como accidental, y la forense, que prevaleció, y que la clasificó de "probable suicidio". Este dictamen se apoyó en una "autopsia psicológica", externa a la investigación oficial, llevada a cabo por especialistas en salud mental relacionados profesionalmente con el Dr. Greenson, psiquiatra de MM y fuente principal de esta investigación, la cual ignoró los hallazgos policiales. Parece probable que sus médicos mintieran sobre la hora y circunstancias de la muerte y retrasaran el aviso a la policía, que el cuerpo fuera cambiado de posición durante ese tiempo y que se intentara justificar la presencia de una cantidad de pentobarbital que no figuraba en ninguna parte. El Dr. Engelberg prescribió al menos diez fármacos psicoactivos en los dos últimos meses de vida de MM, aunque después lo negaría. Las conclusiones de la investigación forense parecen contaminadas por un problema de corporativismo médico. El tratamiento prescrito para el insomnio fue inadecuado, incluso para los estándares de la época (AU)

Objective: To evaluate the circumstances of Marilyn Monroe’s death from a medical perspective, and to try to reconstruct the treatment prescribed to her for chronic insomnia. Material and methods. Original documents from the police and forensic investigations on her death, drug prescriptions and other valuable documents, direct accounts from the main witnesses and assessment of conflicts of interest. Results. MM died on the night of August 4, 1962 from an overdose of hypnotic drugs. There was a divergence between the police investigation, which labelled the death as accidental, and the forensic one, which prevailed and described it as a ‘probable suicide’. This opinion relied on a ‘psychological autopsy,’ external to the official investigation, carried out by mental health specialists professionally related to Dr. Greenson, MM’s psychiatrist and the major source for this investigation, which ignored police findings. It seems likely that her doctors lied about the hour and circumstances of her death, and delayed the call to the police, that the position of the body was changed during this time, and that they tried to justify the presence of an unaccounted for quantity of pentobarbital. Dr. Engelberg prescribed al least ten different psychoactive drugs during the last two months of MM’s life, although he would later deny it. The conclusions of the forensic investigation seem contaminated by a problem of medical corporatism. The treatment prescribed for insomnia was inadequate, even for the period standards (AU)

An overview of human prion diseases.

Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrP(C). They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrP(C) and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.

Genetic Creutzfeldt-Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis.

Human prion diseases are a group of rare neurodegenerative disorders characterized by the conversion of the constitutively expressed prion protein, PrP(C), into an abnormally aggregated isoform, called PrP(Sc). While most people who develop a prion disease have no identifiable cause and a few acquire the disease through an identified source of infection, about 10-15% of patients are affected by a genetic form and carry either a point mutation or an insertion of octapeptide repeats in the prion protein gene. Prion diseases show the highest extent of phenotypic heterogeneity among neurodegenerative disorders and comprise three major disease entities with variable though overlapping phenotypic features: Creutzfeldt-Jakob disease (CJD), fatal insomnia and the Gerstmann-Sträussler-Scheinker syndrome. Both CJD and fatal insomnia are fully transmissible diseases, a feature that led to the isolation and characterization of different strains of the agent or prion showing distinctive clinical and neuropathological features after transmission to syngenic animals. Here, we review the current knowledge of the effects of the pathogenic mutations linked to genetic CJD and fatal familial insomnia on the prion protein metabolism and physicochemical properties, the disease phenotype and the strain characteristics. The data derived from studies in vitro and from those using cell and animal models are compared with those obtained from the analyses of the naturally occurring disease. The extent of phenotypic variation in genetic prion disease is analyzed in comparison to that of the sporadic disease, which has recently been the topic of a systematic and detailed characterization.

[Sleep disorders in prion diseases]. / Patología del sueño en las enfermedades priónicas.

Prion diseases are a group of encephalopathies with neurodegenerative changes caused by an altered protein named prion whose characteristic datum is transmissibility. In most cases they occur in a sporadic form although a group of them are familial associated with mutations in the gene of the prion protein. Genetic polymorphism seems to determine the different family variants. One of the most enigmatic and unusual is Fatal Familial Insomnia (FFI), a hereditary disorder characterised by loss of physiological sleep with oneiric stupor, autonomic and motor hyperactivity, and motor anomalies. The polysomnography of this entity reflects an inability to produce the physiological pattern of NREM and REM sleep, as well as hormonal and vegetative circadian fluctuations; the transition from wakefulness to sleep is markedly altered with the early disappearance sleep spindles. The hypothesis of the origin of these disorders is thalamic neuronal loss, especially in the anterior and dorsomedial nuclei, described in the neuropathology of these patients; besides PET reveals hypofunction of thalamic nuclei, centres responsible for controlling wakefulness-sleep. In Creutzfeldt-Jakob disease the wake-sleep disorders are not considered characteristic; nonetheless, frequent alterations have been found in the electroencephalographic registers of sleep. Besides thalamic neurodegeneration, there could be common etiopathogenic mechanisms in prion diseases in relation to the biological function of the prion protein.

The expanding universe of prion diseases.

Prions cause fatal and transmissible neurodegenerative disease. These etiological infectious agents are formed in greater part from a misfolded cell-surface protein called PrP(C). Several mammalian species are affected by the diseases, and in the case of "mad cow disease" (BSE) the agent has a tropism for humans, with negative consequences for agribusiness and public health. Unfortunately, the known universe of prion diseases is expanding. At least four novel prion diseases--including human diseases variant Creutzfeldt-Jakob disease (vCJD) and sporadic fatal insomnia (sFI), bovine amyloidotic spongiform encephalopathy (BASE), and Nor98 of sheep--have been identified in the last ten years, and chronic wasting disease (CWD) of North American deer (Odocoileus Specis) and Rocky Mountain elk (Cervus elaphus nelsoni) is undergoing a dramatic spread across North America. While amplification (BSE) and dissemination (CWD, commercial sourcing of cervids from the wild and movement of farmed elk) can be attributed to human activity, the origins of emergent prion diseases cannot always be laid at the door of humankind. Instead, the continued appearance of new outbreaks in the form of "sporadic" disease may be an inevitable outcome in a situation where the replicating pathogen is host-encoded.

Human and animal spongiform encephalopathies are the result of chronic autoimmune attack in the CNS: a novel medical theory supported by overwhelming experimental evidence.

Spongiform encephalopathies, also called "prion diseases", are fatal degenerative diseases of the central nervous system which can occur in animals (such as the "mad cow disease" in cattle) and also in humans. This paper presents a novel medical theory concerning the pathogenic mechanisms for various human and animal spongiform encephalopathies. It is hypothesized that various forms of prion diseases are essentially autoimmune diseases, resulting from chronic autoimmune attack of the central nervous system. A key step in the pathogenic process leading towards the development of spongiform encephalopathies involves the production of specific autoimmune antibodies against the disease-causing prion protein (PrPsc) and possibly other immunogenic macromolecules present in the brain. As precisely explained in this paper, the autoimmune antibodies produced against PrPsc are responsible for the conversion of the normal cellular prion protein (PrPc) to PrPsc, for the accumulation of PrPsc in the brain and other peripheral tissues, and also for the initiation of an antibody-mediated chronic autoimmune attack of the central nervous system neurons, which would contribute to the development of characteristic pathological changes and clinical symptoms associated with spongiform encephalopathies. The validity and correctness of the proposed theory is supported by an overwhelming body of experimental observations that are scattered in the biomedical literature. In addition, the theory also offers practical new strategies for early diagnosis, treatment, and prevention of various human and animal prion diseases.