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Seminars in Neurology Sep 2013Prion diseases are a group of diseases caused by abnormally conformed infectious proteins, called prions. They can be sporadic (Jakob-Creutzfeldt disease [JCD]), genetic... (Review)
Review
Prion diseases are a group of diseases caused by abnormally conformed infectious proteins, called prions. They can be sporadic (Jakob-Creutzfeldt disease [JCD]), genetic (genetic JCD, Gerstmann-Sträussler-Scheinker, and familial fatal insomnia), or acquired (kuru, variant JCD, and iatrogenic JCD). The clinical features associated with each form of prion disease, the neuroimaging findings, cerebrospinal fluid markers, and neuropathological findings are reviewed. Sporadic JCD is the most common form of human prion disease, and will be discussed in detail. Genetic prion diseases are caused by mutations in the prion-related protein gene (PRNP), and they are classified based on the mutation, clinical phenotype, and neuropathological features. Acquired prion diseases fortunately are becoming rarer, as awareness of transmission risk has led to implementation of measures to prevent such occurrences, but continued surveillance is necessary to prevent future cases. Treatment and management issues are also discussed.
Topics: Humans; Prion Diseases
PubMed: 24234356
DOI: 10.1055/s-0033-1359314 -
Journal of Perioperative Practice Jul 2008Prion diseases present unique challenges to healthcare facilities, both in the care and treatment of patients. A significant cause for concern is in the routine... (Review)
Review
Prion diseases present unique challenges to healthcare facilities, both in the care and treatment of patients. A significant cause for concern is in the routine reprocessing of medical devices used on patients and how disease transmission can be prevented on the reuse of devices. Investigations have shown that prion disease can be transmitted on medical devices, which can be a concern given the long incubation times associated with these diseases and that guidelines to control transmission only really apply in a small number of known or at risk cases. It is only recently that medical device-associated cleaning, disinfection and sterilization technologies have been investigated and the results of these studies are summarized in this report. The evidence would suggest that many simple decontamination steps can be applied to dramatically reduce the risks to patients, but the research has also given some surprises. Overall, it is reasonable to expect that standard precautions will be able to be applied both today as well as in the future to reduce the risk of prion disease transmission as well as the many other human pathogen concerns, although this may mean changes in some of our practices.
Topics: Cross Infection; Disinfection; Disposable Equipment; Drug Resistance, Viral; Equipment Contamination; Equipment Reuse; Forecasting; Humans; Infection Control; Operating Room Nursing; Practice Guidelines as Topic; Prion Diseases; Risk Factors; Risk Reduction Behavior; Sterilization; Surgical Instruments; United Kingdom
PubMed: 18710129
DOI: 10.1177/175045890801800706 -
Antioxidants & Redox Signaling Jun 2010Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several... (Review)
Review
Imbalance of brain metal homeostasis and associated oxidative stress by redox-active metals like iron and copper is an important trigger of neurotoxicity in several neurodegenerative conditions, including prion disorders. Whereas some reports attribute this to end-stage disease, others provide evidence for specific mechanisms leading to brain metal dyshomeostasis during disease progression. In prion disorders, imbalance of brain-iron homeostasis is observed before end-stage disease and worsens with disease progression, implicating iron-induced oxidative stress in disease pathogenesis. This is an unexpected observation, because the underlying cause of brain pathology in all prion disorders is PrP-scrapie (PrP(Sc)), a beta-sheet-rich conformation of a normal glycoprotein, the prion protein (PrP(C)). Whether brain-iron dyshomeostasis occurs because of gain of toxic function by PrP(Sc) or loss of normal function of PrP(C) remains unclear. In this review, we summarize available evidence suggesting the involvement of oxidative stress in prion-disease pathogenesis. Subsequently, we review the biology of PrP(C) to highlight its possible role in maintaining brain metal homeostasis during health and the contribution of PrP(Sc) in inducing brain metal imbalance with disease progression. Finally, we discuss possible therapeutic avenues directed at restoring brain metal homeostasis and alleviating metal-induced oxidative stress in prion disorders.
Topics: Animals; Humans; Oxidation-Reduction; Prion Diseases; Prions
PubMed: 19803746
DOI: 10.1089/ars.2009.2628 -
The Biochemical Journal Jan 2011One of the major current challenges to both medicine and neuroscience is the treatment of neurodegenerative diseases, which pose an ever-increasing medical, social and... (Review)
Review
One of the major current challenges to both medicine and neuroscience is the treatment of neurodegenerative diseases, which pose an ever-increasing medical, social and economic burden in the developed world. These disorders, which include Alzheimer's, Huntington's and Parkinson's diseases, and the rarer prion diseases, are separate entities clinically but have common features, including aggregates of misfolded proteins and varying patterns of neurodegeneration. A key barrier to effective treatment is that patients present clinically with advanced, irreversible, neuronal loss. Critically, mechanisms of neurotoxicity are poorly understood. Prevention of neuronal loss, ideally by targeting underlying pathogenic mechanisms, must be the aim of therapy. The present review describes the rationale and experimental approaches that have allowed such prevention, rescuing neurons in mice with prion disease. This rescue cured animals of a rapidly fatal neurodegenerative condition, resulting in symptom-free survival for their natural lifespan. Early pathological changes were reversed; behavioural, cognitive and neurophysiological deficits were recovered; and there was no neuronal loss. This was achieved by targeting the central pathogenic process in prion disease rather than the presumed toxic species, first by proof-of-principle experiments in transgenic mice and then by treatment using RNA interference for gene knockdown. The results have been a new therapeutic target for prion disease, further insight into mechanisms of prion neurotoxicity and the discovery of a window of reversibility in neuronal damage. Furthermore, the work gives rise to new concepts for treatment strategies for other neurodegenerative disorders, and highlights the need for clinical detection of early neuronal dysfunction, so that similar early rescue can also be achieved for these disorders.
Topics: Animals; Disease-Free Survival; Mice; Neurons; Neuroprotective Agents; Prion Diseases; RNA Interference; Remission Induction
PubMed: 21158739
DOI: 10.1042/BJ20101323 -
The American Journal of Psychiatry Mar 2014The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression.... (Review)
Review
The prion diseases are rare neurodegenerative conditions that cause complex and highly variable neuropsychiatric syndromes, often with remarkably rapid progression. Prominent behavioral and psychiatric symptoms have been recognized since these diseases were first described. While research on such symptoms in common dementias has led to major changes in the way these symptoms are managed, evidence to guide the care of patients with prion disease is scarce. The authors review the published research and draw on more than 10 years' experience at the U.K. National Prion Clinic, including two large prospective clinical research studies in which more than 300 patients with prion disease have been followed up from diagnosis to death, with detailed observational data gathered on symptomatology and symptomatic treatments. The authors group behavioral and psychiatric symptoms into psychotic features, agitated features, and mood disorder and describe their natural history, showing that they spontaneously improve or resolve in many patients and are short-lived in many others because of rapid progression of global neurological disability. Diagnostic category, disease severity, age, gender, and genetic variation are or may be predictive factors. The authors review the observational data on pharmacological treatment of these symptoms in the U.K. clinical studies and make cautious recommendations for clinical practice. While nonpharmacological measures should be the first-line interventions for these symptoms, the authors conclude that there is a role for judicious use of pharmacological agents in some patients: antipsychotics for severe psychosis or agitation; benzodiazepines, particularly in the late stages of disease; and antidepressants for mood disorder.
Topics: Humans; Mood Disorders; Prion Diseases; Psychomotor Agitation; Psychotic Disorders; Psychotropic Drugs
PubMed: 24585329
DOI: 10.1176/appi.ajp.2013.12111460 -
Acta Neurobiologiae Experimentalis 2004Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns... (Review)
Review
Prion diseases are widely recognized for their transmissibility, and it is this feature that has been studied most extensively. In recent years, public health concerns over the transmission of animal forms of prion disease, such as bovine spongiform encephalopathy and chronic wasting disease, to humans has only augmented the notion that prion diseases are primarily infectious. Yet within the spectrum of human prion diseases, often overlooked is the fact that the overwhelming majority of cases are age-dependent sporadic, or inherited processes. Closer examination of the pathophysiological processes involved in prion disease further indicates a neurodegenerative, rather than infectious disease. Indeed, the age requirement, the numerous kindreds carrying point mutations in an amyloidogenic protein, the copper binding properties of the amyloidogenic protein, the evidence of free radical damage, the presence of polymorphisms that influence disease susceptibility, the formation of amyloid plaques, and in some cases the presence of neurofibrillary pathology, are features common to both prion disease and Alzheimer's disease. Therefore, while transmissibility will continue to be a major subject of prion disease research, we suspect that further characterization of its pathophysiological mechanisms will only substantiate the notion that prion disease is fundamentally a neurodegenerative process.
Topics: Alzheimer Disease; Humans; Prion Diseases
PubMed: 15190676
DOI: 10.55782/ane-2004-1487 -
Rinsho Shinkeigaku = Clinical Neurology May 2010Prion disease develops when normal prion proteins change into transmissible abnormal prion proteins and the converted proteins accumulate in the brain. The Japanese... (Review)
Review
Prion disease develops when normal prion proteins change into transmissible abnormal prion proteins and the converted proteins accumulate in the brain. The Japanese Creutzfeldt-Jakob Disease (CJD) Surveillance Committee has identified 1320 patients with prion diseases in the 10 years since 1999 (classified into 3 types: sporadic, 77.2%; hereditary, 16.7%; and environmentally acquired, 6.1%). Compared with patients in other countries, a relatively larger number of Japanese patients characteristically have dura mater graft-associated CJD and hereditary prion diseases. All the environmentally acquired cases, except 1 case of variant CJD, were acquired from dura grafts. Although most patients were diagnosed with a classical subtype of sporadic CJD (sCJD), whose features include rapidly progressing dementia, myoclonus, hyperintensity in the cerebral cortex and basal ganglia in diffusion-weighted magnetic resonance imaging, and periodic synchronous discharge in electroencephalography, the number of cases with atypical symptoms, such as MM2 (0.8%), MV2 (0.2%), VV1 (0%), and VV2 (0.2%) subtypes of sCJD cases, was not negligible. Appropriate diagnosis should be made based on clinical features, neuroradiological findings, CSF findings (14-3-3 and total tau proteins), and genetic analysis of polymorphisms. Hereditary prion diseases are classified into 3 major phenotypes: familial CJD (fCJD); Gerstmann-Straeussler-Scheinker disease (GSS), which mainly presents as spinocerebellar ataxia; and fatal familial insomnia. Many mutations of the prion protein gene have been identified, but V180I (fCJD), P102L (GSS), and E200K (fCJD) mutations were the most common among the fCJD cases in Japan. Without a family history, genetic testing is necessary to distinguish even seemingly "sporadic" CJD from fCJD. Accurate diagnosis is important for clarification of the pathological process, prevention of secondary infection, and also psychological support.
Topics: Aged; Animals; Female; Genetic Counseling; Humans; Japan; Magnetic Resonance Angiography; Male; Middle Aged; Mutation; Prion Diseases; Prions; Secondary Prevention; Social Support
PubMed: 20535976
DOI: 10.5692/clinicalneurol.50.287 -
Microscopy Research and Technique Jul 2001Gliosis is one of the hallmarks of the prion diseases. Prion diseases are fatal neurodegenerative conditions of low incidence made famous by both the hypothesis that a... (Review)
Review
Gliosis is one of the hallmarks of the prion diseases. Prion diseases are fatal neurodegenerative conditions of low incidence made famous by both the hypothesis that a protein acts as the infectious agent without involvement of nucleic acid and the speculative idea that a disease of cattle, BSE, has spread to humans from the ingestion of prion-infected beef. Despite these unproved hypotheses, the aetiology of the prion diseases remains unsolved. The rapid degenerative course of the disease is preceded by a long incubation period with little or no symptoms. The rapid neurodegeneration in the disease follows from increased deposition of an abnormal isoform of a normal neuronal protein. Co-incident with the appearance of this abnormal protein is the activation of large numbers of microglia. Studies in cell culture with both the abnormal prion protein and a peptide-mimic suggest that neuronal degeneration occurs because of two concurrent effects. First, there is a reduction in neuronal resistance to toxic insults and, second, there is an increase in the production of toxic substances such as reactive oxygen species by microglia and a decrease in glutamate clearance by astrocytes. Microglia activated by the abnormal form of the prion protein also release cytokines, which stimulate changes in astrocytes such as proliferation. The implication of this is that microglia may play a major role in initiating the pathological changes in prion disease. This review discusses the role of microglia in these changes.
Topics: Animals; Humans; Mice; Microglia; Neurons; PrPSc Proteins; Prion Diseases
PubMed: 11455614
DOI: 10.1002/jemt.1122 -
Acta Neuropathologica Jan 2011Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification... (Comparative Study)
Comparative Study Review
Human prion diseases are associated with a range of clinical presentations and are classified by both clinicopathological syndrome and aetiology with sub-classification according to molecular criteria. Considerable experimental evidence suggests that phenotypic diversity in human prion disease relates in significant part to the existence of distinct human prion strains encoded by abnormal PrP isoforms with differing physicochemical properties. To date, however, the conformational repertoire of pathological isoforms of wild-type human PrP and the various forms of mutant human PrP has not been fully defined. Efforts to produce a unified international classification of human prion disease are still ongoing. The ability of genetic background to influence prion strain selection together with knowledge of numerous other factors that may influence clinical and neuropathological presentation strongly emphasises the requirement to identify distinct human prion strains in appropriate transgenic models, where host genetic variability and other modifiers of phenotype are removed. Defining how many human prion strains exist allied with transgenic modelling of potentially zoonotic prion strains will inform on how many human infections may have an animal origin. Understanding these relationships will have direct translation to protecting public health.
Topics: Animals; Animals, Genetically Modified; Disease Models, Animal; Humans; Prion Diseases; Prions; Protein Isoforms
PubMed: 20694796
DOI: 10.1007/s00401-010-0735-5 -
Chemosphere May 2012Prion diseases, including chronic wasting disease (CWD) and scrapie, can be transmitted via indirect environmental routes. Animals habitually ingest soil, and results... (Review)
Review
Prion diseases, including chronic wasting disease (CWD) and scrapie, can be transmitted via indirect environmental routes. Animals habitually ingest soil, and results from laboratory experiments demonstrate prions can bind to a wide range of soils and soil minerals, retain the ability to replicate, and remain infectious, indicating soil could serve as a reservoir for natural prion transmission and a potential prion exposure route for humans. Preliminary epidemiological modeling suggests soil texture may influence the incidence of prion disease. These results are supported by experimental work demonstrating variance in prion interactions with soil, including variance in prion soil adsorption and soil-bound prion replication with respect to soil type. Thus, local soil type may be a key determinant of prion incidence. Further experimental and epidemiological work is required to fully elucidate the dynamics of soil-mediated prion transmission, an effort that should lead to effective disease management and mitigation strategies.
Topics: Animals; Humans; Prion Diseases; Prions; Soil; Soil Pollutants
PubMed: 22265680
DOI: 10.1016/j.chemosphere.2011.12.076