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1.
BMC Neurol ; 24(1): 92, 2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38468258

RESUMO

BACKGROUND: Human prion diseases (HPDs) are fatal neurodegenerative disorders characterized by abnormal prion proteins (PrPSc). However, the detection of prion seeding activity in patients with high sensitivity remains challenging. Even though real-time quaking-induced conversion (RT-QuIC) assay is suitable for detecting prion seeding activity in a variety of specimens, it shows lower accuracy when whole blood, blood plasma, and blood-contaminated tissue samples are used. In this study, we developed a novel technology for the in vitro amplification of abnormal prion proteins in HPD to the end of enabling their detection with high sensitivity known as the enhanced quaking-induced conversion (eQuIC) assay. METHODS: Three antibodies were used to develop the novel eQUIC method. Thereafter, SD50 seed activity was analyzed using brain tissue samples from patients with prion disease using the conventional RT-QUIC assay and the novel eQUIC assay. In addition, blood samples from six patients with solitary prion disease were analyzed using the novel eQuIC assay. RESULTS: The eQuIC assay, involving the use of three types of human monoclonal antibodies, showed approximately 1000-fold higher sensitivity than the original RT-QuIC assay. However, when this assay was used to analyze blood samples from six patients with sporadic human prion disease, no prion activity was detected. CONCLUSION: The detection of prion seeding activity in blood samples from patients with sporadic prion disease remains challenging. Thus, the development of alternative methods other than RT-QuIC and eQuIC will be necessary for future research.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Proteínas Priônicas , Doenças Priônicas/diagnóstico , Doenças Priônicas/metabolismo , Encéfalo/metabolismo , Plasma/metabolismo , Síndrome de Creutzfeldt-Jakob/diagnóstico
2.
Nat Commun ; 15(1): 2112, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459071

RESUMO

Prion diseases are a group of rapidly progressing neurodegenerative disorders caused by the misfolding of the endogenous prion protein (PrPC) into a pathogenic form (PrPSc). This process, despite being the central event underlying these disorders, remains largely unknown at a molecular level, precluding the prediction of new potential outbreaks or interspecies transmission incidents. In this work, we present a method to generate bona fide recombinant prions de novo, allowing a comprehensive analysis of protein misfolding across a wide range of prion proteins from mammalian species. We study more than 380 different prion proteins from mammals and classify them according to their spontaneous misfolding propensity and their conformational variability. This study aims to address fundamental questions in the prion research field such as defining infectivity determinants, interspecies transmission barriers or the structural influence of specific amino acids and provide invaluable information for future diagnosis and therapy applications.


Assuntos
Doenças Priônicas , Príons , Animais , Príons/metabolismo , Proteínas Priônicas/genética , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Mamíferos/metabolismo , Dobramento de Proteína
3.
Sci Rep ; 14(1): 6294, 2024 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-38491063

RESUMO

Real-time quaking-induced conversion assay (RT-QuIC) exploits templating activity of pathogenic prion protein for ultrasensitive detection of prions. We have utilized second generation RT-QuIC assay to analyze matching post-mortem cerebrospinal fluid and skin samples of 38 prion disease patients and of 30 deceased neurological controls. The analysis of cerebrospinal fluid samples led to 100% sensitivity and 100% specificity, but some samples had to be diluted before the analysis to alleviate the effect of present RT-QuIC inhibitors. The analysis of the corresponding skin samples provided 89.5% sensitivity and 100% specificity. The median seeding dose present in the skin was one order of magnitude higher than in the cerebrospinal fluid, despite the overall fluorescent signal of the skin samples was comparatively lower. Our data support the use of post-mortem cerebrospinal fluid for confirmation of prion disease diagnosis and encourage further studies of the potential of skin biopsy samples for intra-vitam prion diseases´ diagnostics.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/metabolismo , Doenças Priônicas/diagnóstico , Pele/metabolismo , Proteínas Priônicas , Bioensaio , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquidiano
5.
Science ; 383(6689): 1284-1289, 2024 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-38513035

RESUMO

Can the course of fatal prion diseases be changed by removing the protein before it goes bad?


Assuntos
Doenças Priônicas , Príons , Humanos , Doenças Priônicas/metabolismo
6.
J Phys Chem Lett ; 15(8): 2117-2122, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38363235

RESUMO

The misfolding of the α-helical cellular prion protein into a self-propagating ß-rich aggregated form is a key pathogenic event in fatal and transmissible neurodegenerative diseases collectively known as prion diseases. Herein, we utilize the interfacial properties of liquid crystals (LCs) to monitor the lipid-membrane-induced conformational switching of prion protein (PrP) into ß-rich amyloid fibrils. The lipid-induced conformational switching resulting in aggregation occurs at the nanomolar protein concentration and is primarily mediated by electrostatic interactions between PrP and lipid headgroups. Our LC-based methodology offers a potent and sensitive tool to detect and delineate molecular mechanisms of PrP misfolding mediated by lipid-protein interactions at the aqueous interface under physiological conditions.


Assuntos
Cristais Líquidos , Doenças Priônicas , Príons , Humanos , Proteínas Priônicas/química , Príons/química , Príons/metabolismo , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Peptídeos beta-Amiloides , Amiloide/química , Lipídeos , Dobramento de Proteína
7.
Transfusion ; 64 Suppl 1: S4-S18, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38394039
8.
Nat Rev Dis Primers ; 10(1): 14, 2024 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-38424082

RESUMO

Prion diseases share common clinical and pathological characteristics such as spongiform neuronal degeneration and deposition of an abnormal form of a host-derived protein, termed prion protein. The characteristic features of prion diseases are long incubation times, short clinical courses, extreme resistance of the transmissible agent to degradation and lack of nucleic acid involvement. Sporadic and genetic forms of prion diseases occur worldwide, of which genetic forms are associated with mutations in PRNP. Human to human transmission of these diseases has occurred due to iatrogenic exposure, and zoonotic forms of prion diseases are linked to bovine disease. Significant progress has been made in the diagnosis of these disorders. Clinical tools for diagnosis comprise brain imaging and cerebrospinal fluid tests. Aggregation assays for detection of the abnormally folded prion protein have a clear potential to diagnose the disease in peripherally accessible biofluids. After decades of therapeutic nihilism, new treatment strategies and clinical trials are on the horizon. Although prion diseases are relatively rare disorders, understanding their pathogenesis and mechanisms of prion protein misfolding has significantly enhanced the field in research of neurodegenerative diseases.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Animais , Bovinos , Humanos , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Síndrome de Creutzfeldt-Jakob/patologia , Proteínas Priônicas/metabolismo , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Encéfalo/patologia
10.
BMC Genomics ; 25(1): 177, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355406

RESUMO

BACKGROUND: Prion diseases, also known as transmissible spongiform encephalopathies (TSEs) remain one of the deleterious disorders, which have affected several animal species. Polymorphism of the prion protein (PRNP) gene majorly determines the susceptibility of animals to TSEs. However, only limited studies have examined the variation in PRNP gene in different Nigerian livestock species. Thus, this study aimed to identify the polymorphism of PRNP gene in Nigerian livestock species (including camel, dog, horse, goat, and sheep). We sequenced the open reading frame (ORF) of 65 camels, 31 village dogs and 12 horses from Nigeria and compared with PRNP sequences of 886 individuals retrieved from public databases. RESULTS: All the 994 individuals were assigned into 162 haplotypes. The sheep had the highest number of haplotypes (n = 54), and the camel had the lowest (n = 7). Phylogenetic tree further confirmed clustering of Nigerian individuals into their various species. We detected five non-synonymous SNPs of PRNP comprising of G9A, G10A, C11G, G12C, and T669C shared by all Nigerian livestock species and were in Hardy-Weinberg Equilibrium (HWE). The amino acid changes in these five non-synonymous SNP were all "benign" via Polyphen-2 program. Three SNPs G34C, T699C, and C738G occurred only in Nigerian dogs while C16G, G502A, G503A, and C681A in Nigerian horse. In addition, C50T was detected only in goats and sheep. CONCLUSION: Our study serves as the first to simultaneously investigate the polymorphism of PRNP gene in Nigerian livestock species and provides relevant information that could be adopted in programs targeted at breeding for prion diseases resistance.


Assuntos
Doenças Priônicas , Príons , Scrapie , Animais , Cavalos/genética , Ovinos/genética , Cães , Príons/genética , Príons/metabolismo , Proteínas Priônicas/genética , Polimorfismo de Nucleotídeo Único , Gado/genética , Fases de Leitura Aberta , Filogenia , Camelus/genética , Doenças Priônicas/genética , Doenças Priônicas/veterinária , Cabras/genética , Cabras/metabolismo , Scrapie/genética
11.
PLoS One ; 19(2): e0298095, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38394123

RESUMO

The PINK1/Parkin pathway of mitophagy has been implicated in the pathogenesis of Parkinson's disease. In prion diseases, a transmissible neurodegenerative disease caused by the misfolded and infectious prion protein (PrPSc), expression of both PINK1 and Parkin are elevated, suggesting that PINK1/Parkin mediated mitophagy may also play a role in prion pathogenesis. Using mice in which expression of either PINK1 (PINK1KO) or Parkin (ParkinKO) has been ablated, we analyzed the potential role of PINK1 and Parkin in prion pathogenesis. Prion infected PINK1KO and ParkinKO mice succumbed to disease more rapidly (153 and 150 days, respectively) than wild-type control C57Bl/6 mice (161 days). Faster incubation times in PINK1KO and ParkinKO mice did not correlate with altered prion pathology in the brain, altered expression of proteins associated with mitochondrial dynamics, or prion-related changes in mitochondrial respiration. However, the expression level of mitochondrial respiration Complex I, a major site for the formation of reactive oxygen species (ROS), was higher in prion infected PINK1KO and ParkinKO mice when compared to prion infected control mice. Our results demonstrate a protective role for PINK1/Parkin mitophagy during prion disease, likely by helping to minimize ROS formation via Complex I, leading to slower prion disease progression.


Assuntos
Doenças Neurodegenerativas , Doenças Priônicas , Príons , Camundongos , Animais , Mitofagia , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Doenças Priônicas/genética
12.
ACS Chem Neurosci ; 15(5): 898-908, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38407017

RESUMO

Protein misfolding has been extensively studied in the context of neurodegenerative disorders and systemic amyloidoses. Due to misfolding and aggregation of proteins being highly heterogeneous and generating a variety of structures, a growing body of evidence illustrates numerous ways how the aggregates contribute to progression of diseases such as Alzheimer's disease, Parkinson's disease, and prion disorders. Different misfolded species of the same protein, commonly referred to as strains, appear to play a significant role in shaping the disease clinical phenotype and clinical progression. The distinct toxicity profiles of various misfolded proteins underscore their importance. Current diagnostics struggle to differentiate among these strains early in the disease course. This review explores the potential of spectral fluorescence approaches to illuminate the complexities of protein misfolding pathology and discusses the applications of advanced spectral methods in the detection and characterization of protein misfolding disorders. By examining spectrally variable probes, current data analysis approaches, and important considerations for the use of these techniques, this review aims to provide an overview of the progress made in this field and highlights directions for future research.


Assuntos
Amiloidose , Doenças Neurodegenerativas , Doenças Priônicas , Deficiências na Proteostase , Humanos , Fluorescência , Deficiências na Proteostase/metabolismo , Amiloidose/metabolismo , Doenças Priônicas/metabolismo , Doenças Neurodegenerativas/metabolismo , Dobramento de Proteína
13.
BMJ Case Rep ; 17(2)2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388201

RESUMO

Variably protease-sensitive prionopathy (VPSPr) is a recently characterised rare subtype of sporadic prion disease, mainly affecting individuals with valine homozygosity at codon 129 in the prion protein gene, with only seven methionine homozygote cases reported to date. This case presents clinical, neuropathological and biochemical features of the eighth VPSPr case worldwide with methionine homozygosity at codon 129 and compares the features with the formerly presented cases.The patient, a woman in her 70s, presented with cognitive decline, impaired balance and frequent falls. Medical history and clinical presentation were suggestive of a rapidly progressive dementia disorder. MRI showed bilateral thalamic hyperintensity. Cerebrospinal fluid real-time quaking-induced conversion was negative, and the electroencephalogram was unremarkable. The diagnosis was established through post-mortem pathological examinations. VPSPr should be suspected in rapidly progressive dementia lacking typical features or paraclinical results of protein misfolding diseases.


Assuntos
Síndrome de Creutzfeldt-Jakob , Demência , Doenças Priônicas , Príons , Feminino , Humanos , Príons/genética , Príons/metabolismo , Proteínas Priônicas/genética , Proteínas Priônicas/metabolismo , Metionina/genética , Metionina/metabolismo , Homozigoto , Encéfalo/patologia , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia , Demência/genética , Racemetionina/metabolismo , Códon/genética , Códon/metabolismo , Peptídeo Hidrolases/genética , Peptídeo Hidrolases/metabolismo , Síndrome de Creutzfeldt-Jakob/patologia
14.
Science ; 383(6680): eadn9424, 2024 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-38236962

RESUMO

My first encounter with prion diseases dates to 1986. As a clinical resident in neuropathology, I was tasked with performing autopsies of patients who died of mysterious brain diseases. In his early 60s, my patient had developed a form of dementia that progressed at a terrifyingly rapid pace and eventually led to his death. I sampled the patient's brain and processed it for histological examination. The microscope revealed an eerie landscape of destruction. All that was left in the patient's cortex were astrocytes and microglia, and the few remaining neurons showed extensive vacuolation of their bodies and processes. Such blazing destruction of the brain was indicative of just one diagnosis: Creutzfeldt-Jakob disease, a spongiform encephalopathy caused by enigmatic infectious agents called prions.


Assuntos
Doenças Priônicas , Príons , Humanos , Córtex Cerebral/patologia , Síndrome de Creutzfeldt-Jakob/história , Doenças Priônicas/história , Príons/história
15.
Acta Neuropathol ; 147(1): 17, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38231266

RESUMO

Definitive diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) relies on the examination of brain tissues for the pathological prion protein (PrPSc). Our previous study revealed that PrPSc-seeding activity (PrPSc-SA) is detectable in skin of sCJD patients by an ultrasensitive PrPSc seed amplification assay (PrPSc-SAA) known as real-time quaking-induced conversion (RT-QuIC). A total of 875 skin samples were collected from 2 cohorts (1 and 2) at autopsy from 2-3 body areas of 339 cases with neuropathologically confirmed prion diseases and non-sCJD controls. The skin samples were analyzed for PrPSc-SA by RT-QuIC assay. The results were compared with demographic information, clinical manifestations, cerebrospinal fluid (CSF) PrPSc-SA, other laboratory tests, subtypes of prion diseases defined by the methionine (M) or valine (V) polymorphism at residue 129 of PrP, PrPSc types (#1 or #2), and gene mutations in deceased patients. RT-QuIC assays of the cohort #1 by two independent laboratories gave 87.3% or 91.3% sensitivity and 94.7% or 100% specificity, respectively. The cohort #2 showed sensitivity of 89.4% and specificity of 95.5%. RT-QuIC of CSF available from 212 cases gave 89.7% sensitivity and 94.1% specificity. The sensitivity of skin RT-QuIC was subtype dependent, being highest in sCJDVV1-2 subtype, followed by VV2, MV1-2, MV1, MV2, MM1, MM1-2, MM2, and VV1. The skin area next to the ear gave highest sensitivity, followed by lower back and apex of the head. Although no difference in brain PrPSc-SA was detected between the cases with false negative and true positive skin RT-QuIC results, the disease duration was significantly longer with the false negatives [12.0 ± 13.3 (months, SD) vs. 6.5 ± 6.4, p < 0.001]. Our study validates skin PrPSc-SA as a biomarker for the detection of prion diseases, which is influenced by the PrPSc types, PRNP 129 polymorphisms, dermatome sampled, and disease duration.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/genética , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Biomarcadores
16.
Brain ; 147(1): 240-254, 2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-37669322

RESUMO

A common pathological denominator of various neurodegenerative diseases is the accumulation of protein aggregates. Neurotoxic effects are caused by a loss of the physiological activity of the aggregating protein and/or a gain of toxic function of the misfolded protein conformers. In transmissible spongiform encephalopathies or prion diseases, neurodegeneration is caused by aberrantly folded isoforms of the prion protein (PrP). However, it is poorly understood how pathogenic PrP conformers interfere with neuronal viability. Employing in vitro approaches, cell culture, animal models and patients' brain samples, we show that misfolded PrP can induce aggregation and inactivation of TAR DNA-binding protein-43 (TDP-43). Purified PrP aggregates interact with TDP-43 in vitro and in cells and induce the conversion of soluble TDP-43 into non-dynamic protein assemblies. Similarly, mislocalized PrP conformers in the cytosol bind to and sequester TDP-43 in cytosolic aggregates. As a consequence, TDP-43-dependent splicing activity in the nucleus is significantly decreased, leading to altered protein expression in cells with cytosolic PrP aggregates. Finally, we present evidence for cytosolic TDP-43 aggregates in neurons of transgenic flies expressing mammalian PrP and Creutzfeldt-Jakob disease patients. Our study identified a novel mechanism of how aberrant PrP conformers impair physiological pathways by cross-seeding.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Animais , Humanos , Proteínas de Ligação a DNA , Mamíferos/metabolismo , Doenças Priônicas/metabolismo , Proteínas Priônicas , Príons/metabolismo
17.
J Neurol ; 271(1): 263-273, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37689591

RESUMO

Inherited prion diseases caused by two- to twelve-octapeptide repeat insertions (OPRIs) in the prion protein gene (PRNP) show significant clinical heterogeneity. This study describes a family with two new cases with a 4-OPRI mutation and two asymptomatic mutation carriers. The pooled analysis summarizes all cases reported in the literature to date and describes the relation between survival, age of onset, number of OPRI and codon 129 polymorphism. MEDLINE and Google Scholar were queried from database inception up to December 31, 2022. Age of onset was compared per number of OPRI and per codon 129 polymorphism using the Kruskal-Wallis and Wilcoxon-Mann-Whitney tests, respectively. Disease duration was modeled non-parametrically by a Kaplan-Meier model and semi-parametrically by a Cox model. This study comprised 164 patients. Lower number of OPRI and presence of valine (cis-V) versus methionine (cis-M) on codon 129 were associated with an older age of onset (P < 0.001 and P = 0.025, respectively) and shorter disease duration (P < 0.001 and P = 0.003, respectively). Within patients with 5- or more OPRI codon cis-V remained significantly associated with a shorter disease duration. Codon 129 homozygosity versus heterozygosity was not significantly associated with age of onset or disease duration (P = 0.076 and P = 0.409, respectively). This study summarized the largest cohort of patients with two- to twelve-OPRI to date. Lower number of OPRI and codon 129 cis-V is associated with an older age of onset and shorter disease duration, while homozygosity or heterozygosity on codon 129 was not.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Humanos , Príons/genética , Príons/metabolismo , Proteínas Priônicas/genética , Doenças Priônicas/genética , Doenças Priônicas/metabolismo , Mutação , Códon/genética
18.
Brain ; 147(2): 649-664, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37703312

RESUMO

The unfolded protein response (UPR) is rapidly gaining momentum as a therapeutic target for protein misfolding neurodegenerative diseases, in which its overactivation results in sustained translational repression leading to synapse loss and neurodegeneration. In mouse models of these disorders, from Alzheimer's to prion disease, modulation of the pathway-including by the licensed drug, trazodone-restores global protein synthesis rates with profound neuroprotective effects. However, the precise nature of the translational impairment, in particular the specific proteins affected in disease, and their response to therapeutic UPR modulation are poorly understood. We used non-canonical amino acid tagging (NCAT) to measure de novo protein synthesis in the brains of prion-diseased mice with and without trazodone treatment, in both whole hippocampus and cell-specifically. During disease the predominant nascent proteome changes occur in synaptic, cytoskeletal and mitochondrial proteins in both hippocampal neurons and astrocytes. Remarkably, trazodone treatment for just 2 weeks largely restored the whole disease nascent proteome in the hippocampus to that of healthy, uninfected mice, predominantly with recovery of proteins involved in synaptic and mitochondrial function. In parallel, trazodone treatment restored the disease-associated decline in synapses and mitochondria and their function to wild-type levels. In conclusion, this study increases our understanding of how translational repression contributes to neurodegeneration through synaptic and mitochondrial toxicity via depletion of key proteins essential for their function. Further, it provides new insights into the neuroprotective mechanisms of trazodone through reversal of this toxicity, relevant for the treatment of neurodegenerative diseases via translational modulation.


Assuntos
Doença de Alzheimer , Doenças Neurodegenerativas , Doenças Priônicas , Príons , Trazodona , Camundongos , Animais , Príons/metabolismo , Proteoma/metabolismo , Proteoma/farmacologia , Trazodona/farmacologia , Trazodona/uso terapêutico , Trazodona/metabolismo , Doenças Priônicas/tratamento farmacológico , Doenças Priônicas/metabolismo , Doenças Neurodegenerativas/metabolismo , Sinapses/metabolismo , Doença de Alzheimer/metabolismo
19.
J Neurol ; 271(1): 446-456, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37755461

RESUMO

OBJECTIVE: The underlying pathology of autoimmune encephalitis is not well characterized due to the limited opportunities to study tissue specimens. Autopsy specimens available at prion surveillance centers from patients with suspected Creutzfeldt-Jakob disease offer a unique opportunity to study the pathology of autoimmune encephalitis. Our objective was to describe pathological findings of autoimmune encephalitis specimens submitted to the U.S. National Prion Disease Pathology Surveillance Center. METHODS: Pathology reports were obtained from the National Prion Center. Specimens negative for prion disease were screened for inflammatory pathology and those suggestive of autoimmune encephalitis were analyzed. Cases identified on autopsy were compared to institutional cases with fatal seronegative autoimmune encephalitis and available brain biopsy. RESULTS: Between 1998 and 2022, 7934 specimens were evaluated of which 2998 (38%) were negative for prion protein. Querying the database for alternative diagnoses of encephalitis/encephalopathy yielded 43 cases that were screened by an experienced neuropathologist yielding 14 (0.5%) cases consistent with autoimmune encephalitis. Most specimens showed diffuse inflammation involving the limbic system (86%), basal ganglia (86%), cortex (71%), diencephalon (71%), and in some cases the brainstem (43%) and cerebellum (43%). Lymphocytic inflammatory infiltrate was predominantly perivascular with parenchymal extension in 64%. Microglial activation/nodules were seen in 64% of cases. Neuronal loss was present only in 50%. Pathological findings were identical to biopsy specimens from our institutional cohort. DISCUSSION: Seronegative AE may have consistent pathology with diffuse or multifocal perivascular inflammation and microglial activation. Half the patients do not have neuronal loss suggesting a potential for neurological recovery. These findings are preliminary and require further confirmation.


Assuntos
Doenças Autoimunes do Sistema Nervoso , Síndrome de Creutzfeldt-Jakob , Encefalite , Doenças do Sistema Nervoso , Doenças Priônicas , Príons , Humanos , Encéfalo/patologia , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/patologia , Encefalite/patologia , Príons/metabolismo , Doenças do Sistema Nervoso/patologia , Doenças Autoimunes do Sistema Nervoso/patologia , Autopsia , Inflamação/metabolismo , Doenças Priônicas/metabolismo , Doenças Priônicas/patologia
20.
Brain Pathol ; 34(2): e13214, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37771100

RESUMO

Human prion diseases, including Creutzfeldt-Jakob disease (CJD), occur in sporadic, genetic, and acquired forms. Variant Creutzfeldt-Jakob disease (vCJD) first reported in 1996 in the United Kingdom (UK), resulted from contamination of food with bovine spongiform encephalopathy. There is a concern that UK national surveillance mechanisms might miss some CJD cases (including vCJD), particularly in the older population where other neurodegenerative disorders are more prevalent. We developed a highly sensitive protocol for analysing autopsy brain tissue for the misfolded prion protein (PrPSc ) associated with prion disease, which could be used to screen for prion disease in the elderly. Brain tissue samples from 331 donors to the Edinburgh Brain and Tissue Bank (EBTB), from 2005 to 2022, were analysed, using immunohistochemical analysis on fixed tissue, and five biochemical tests on frozen specimens from six brain regions, based on different principles for detecting PrPSc . An algorithm was established for classifying the biochemical results. To test the effectiveness of the protocol, several neuropathologically confirmed prion disease controls, including vCJD, were included and blinded in the study cohort. On unblinding, all the positive control cases had been correctly identified. No other cases tested positive; our analysis uncovered no overlooked prion disease cases. Our algorithm for classifying cases was effective for handling anomalous biochemical results. An overall analysis suggested that a reduced biochemical protocol employing only three of the five tests on only two brain tissue regions gave sufficient sensitivity and specificity. We conclude that this protocol may be useful as a UK-wide screening programme for human prion disease in selected brains from autopsies in the elderly. Further improvements to the protocol were suggested by enhancements of the in vitro conversion assays made during the course of this study.


Assuntos
Síndrome de Creutzfeldt-Jakob , Doenças Priônicas , Príons , Obtenção de Tecidos e Órgãos , Animais , Bovinos , Humanos , Idoso , Síndrome de Creutzfeldt-Jakob/epidemiologia , Doenças Priônicas/genética , Encéfalo/metabolismo , Príons/metabolismo
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