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ALEMAN-INIGUEZ, Juan Miguel; ALEMAN-INIGUEZ, Pedro José GUILLEN, Fernando. Rapidly progressive dementia in sporadic prion disease: report of. En Chile la incidencia es de 3,5 casos por millón de habitantes, siendo una Se planteó como diagnóstico sindromático una demencia rápidamente . a material neuroquirúrgico contaminado con priones, ocurriendo el desarrollo de la. Fisiopatología de las enfermedades por priones. Alejandra de las habilidades cognitivas, demencia progresiva e invaria- blemente, la.

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Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, and prion diseases are age-related neurodegenerative disorders associated with a progressive decline of cognitive brain functions.

Enfermedades por priones | Harrison. Principios de Medicina Interna, 18e | McGraw-Hill Medical

Due to the increase in prevalence rates, opr the rising costs associated with clinical and social care, treatments designed to prevent or reverse these diseases are urgently needed. The most common major biochemical characteristic of these neurodegenerative diseases is the deposition of abnormal protein aggregates in brain. The decryption of the mechanisms of aggregation and associated neurotoxicity may reveal new therapeutic targets, which will enable treatment for these devastating conditions.

Over the past 2 decades, the diagnostic classification of dementias has been continuously adapted to the increasing knowledge derived from clinical symptomatology, neuropathology, biochemistry, and clinicopathological comparisons.

Before, dementias were attributed primarily to cerebral vascular insufficiency.

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Later, with the diagnosis of Alzheimer’s disease AD predominating, further differentiations were categorized: This development was driven by the results of molecular analyses of the abnormal protein deposits in the brain of the respective diseases in relation to the clinical syndromes.

The careful clinical and neurochemical investigation of dementias has led to practical guidelines and improvements in current treatment and care, eg, the use of atypical neuroleptics in patients with DLB due to the high susceptibility to side effects by treatment with typical antipsychotics.

More excitingly, the dissection of the molecular mechanisms and species involved in the aggregation process may allow for the development of specific therapies, which may, in the future, contribute to the prevention and treatment of neurodegenerative diseases. The following diseases are characterized by the deposition of protein aggregates, termed amyloid, derived from the Greek amylum starch, sugar ; the term was first introduced by Virchow in on the basis of color after staining with iodine, since he assumed that polysaccharides were the major constituents of amyloid deposits in peripheral tissues.

AD is the most common form of dementia. It affects about 20 to 30 million people worldwide. With disease progression, noncognitive symptoms such as delusions, agitation, changes in personality, and mood disturbances may also occur. From a genetic point of view, AD may be subdivided into three forms according to the observed mode of inheritance: In other cases, a different familial aggregation can be observed: Finally, the major proportion of AD cases is, however, sporadic, which is defined as the absence of evidence for familial aggregation.

This group is nevertheless influenced by so-called susceptibility genes that confer a minor genetic risk associated with allelic variations in the form of single nucleotide polymorphisms SNPs. Histopathologically, AD is characterized by two hallmarks: It remains to be shown which state of the aggregation process is the most toxic: Based on the findings mentioned above, oligomers and protofibrils are clearly suspects as central players in the aggregation process.

This hypothesis is supported by the recent finding of Nilsberth et al FTD designates a clinical syndrome characterized by behavioral changes, including social misconduct, disinhibition, hyperorality, apathy, etc, and also memory deficits. Usually, the behavioral symptoms outweigh the cognitive deficits in these patients.


Among the neurological features, Parkinsonism can develop with disease progression and may become predominant in some patients. The frontal type includes Pick’s disease, characterized by circumscribed frontal or temporal atrophy, as one specific and rare subtype.

Ncuropathological features of FTD are diffuse bilateral atrophy of the frontal and anterior temporal lobes and degeneration of the striatum. Histopathological findings include loss of large cortical nerve cells and spongiform microvacuolar degeneration of the superficial neuropil, gliosis, and tau- or ubiquitin-positive inclusion bodies.

In the human brain, six isoforms of tau ranging from to amino acids are produced from a single gene mapping to 17q21 by alternative mRNA splicing. Tau proteins vary among the different tauopathies in isoform and phosphorylation state. Since several tau mutations were shown to be causative for several tauopathies including FTD, tau abnormalities that may be mechanistically involved in the pathogenesis of ncurodegeneration were investigated.

It was hypothesized that different tau mutations are pathogenic because they impair tau function, promote tau fibrillization, or perturb tau gene splicing, thereby leading to formation of biochemically and structurally distinct aggregates of tau.

Collectively, tauopathies, including a portion of FTD, are associated with deposition of aggregated, abnormally phosphorylatcd tau proteins demenncia normally stabilize microtubule function in the cell.

Biochemical aspects of dementias

Factors that promote fibril formation in vitro include high temperature, low pH, high concentration, and oxidative conditions. Together, diseases associated with Lewy bodies including DLB arc associated with abnormal neuronal aggregates of oc-synuclein, a protein associated with synaptic function.

Prion diseases are caused by infectious proteins that convert normal cellular prion protein PrP C into the disease-causing scrapie PrP Sc isoform. The clinical manifestations are heterogenous and include dementia, myoclonia, visual disturbances, ataxia, insomnia, paraplegia, sensory symptoms, and behavioral disturbances.

In case of prion infection in humans or animals, the point of entry is outside the nervous system. Together, prion diseases are caused by aggregation of prion proteins, most likely initiated by conversion of a physiological conformation PrP C into an infectious form PrP Scwhich serves as a seed that induces polymerization, 45 formation of fibrils, and deposition.

All of these diseases occur predominantly sporadically with a minor portion caused by mutations associated with familial forms of the disease. The formation of aggregates may be a desperate attempt to eliminate the toxicity of misfolded proteins and their oligomeric or fibrillar states.

The pathogenetic mechanisms entail abnormal proteolytic cleavage, posttranslational processing, misfolding, and reduced clearance femencia protein aggregates. The dissection of the kinetics of folding and deposition, demenncia folding intermediates, and promoting factors will be crucial for the discovery of new therapeutic targets.

Interestingly, a range of proteins not associated with amyloid diseases are also able to aggregate in vitro into fibrils barely distinguishable from those found in pathological conditions. Whether this process ends up in neurodegeneration may depend on the selective vulnerability determined by age-related cellular alterations, genetic background, and capacity of removal and repair mechanisms.

The neuronal cell possesses a defense machinery, eg, chaperones, which protects against protein misfolding, a process that occurs, like DNA replication errors, permanently during protein synthesis and transport.

Several conclusions can be made from the dissection of abnormal protein deposits in dementias: The latter may offer the search for treatment targets that arc common to a variety of neurodegenerative conditions associated with protein misfolding, aggregation, and deposition.


The future therapy of neurodegenerative disorders may aim to prevent the formation and deposition of abnormal proteins prior to clinical manifestation of the disease. The major prerequisite for such therapeutic strategies is the availability dwmencia accurate and reliable preclinical diagnostic markers, a major challenge that is as yet unresolved.

Clearance of deposited abnormal proteins from brain may be another therapeutic approach prones patients who already display the neurodegenerative disease. It remains to be shown whether such interventions would be capable of relieving the brain of the toxic burden, stimulate recovery of neuronal damage, and, ultimately, result in the restoration of normal function.

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Journal List Dialogues Clin Neurosci v. Author information Prioes and License information Disclaimer. This is an open-access article distributed under the terms of the Creative Commons Attribution License http: Abstract Alzheimer’s disease, frontotemporal dementia, dementia with Lewy bodies, and prion diseases are age-related neurodegenerative disorders associated with a progressive decline of cognitive brain functions. Neurodegenerative diseases are associated with deposition of abnormal proteins in brain.

BSE, bovine spongiform encephalopathy. Open in a separate window. Alzheimer’s disease AD is the most common form of dementia. Frontotemporal dementia FTD designates a clinical syndrome characterized by behavioral changes, including social misconduct, disinhibition, hyperorality, apathy, etc, rpiones also memory deficits.

Prion diseases Prion diseases are caused by drmencia proteins that convert normal cellular prion protein PrP C into the disease-causing scrapie PrP Sc isoform. History of the amyloid fibril. Interventional strategies against prion diseases. Alzheimer’s Disease and Related Disorders Association.

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Secreted amyloid beta-protein poor to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease.

What normal protein folding may tell us about fibrillogenesis and disease. Beta-amyloid neurotoxicity requires fibril formation and is inhibited by congo red. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.

Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Picking away at frontotemporal dementia. Diagnostic challenges in dementia. The Lund and Manchester Groups. Clinical and neuropathological criteria for frontotemporal dementia.

J Neurol Neurosurg Psychiatry. Curr Opin Genet Dev. Abnormal phosphorylation of the micortubule-associated protein tau tau in Alzheimer cytoskeletal pathology. Dementia with Lewy bodies. Familial multiple system tauopathy with presenile dementia: Dementia and neuropathology in Lewy body disease. Neuropathology of synuclein aggregates. Dementia associated with Lewy bodies: Mutation in the alphasynuclein gene identified in families with Parkinson’s disease.

Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson’s disease. Alpha synuclein in neurodegenerative disorders: Alpha-Synuclein and neurodegenerative diseases. Genomic organization and expression of the human beta-synuclein gene SNCB. N Engl J Med.

Enfermedades priónicas

Bovine spongiform encephalopathy and early onset variant Creutzfeldt-Jakob disease. Incidence of Creutzfeldt-Jakob disease in Switzerland.

Clinical aspects of human spongiform encephalopathies, with the exception of iatrogenic forms.