RESUMEN
BACKGROUND: The neuropathology of Parkinson's disease (PD) associated with leucine-rich repeat kinase 2 (LRRK2) mutations (LRRK2-PD) is heterogeneous and varies with the type of mutation. There are only a few studies evaluating seeding aggregation assays to detect α-synuclein (α-syn) in patients with LRRK2-PD. OBJECTIVE: We aimed to investigate whether α-syn real-time quaking induced conversion (RT-QuIC) is a sensitive biomarker of synucleinopathy in LRRK2-PD. METHODS: We studied α-syn RT-QuIC in brain tissue and postmortem ventricular cerebrospinal fluid (CSF) of LRRK2-PD cases with and without Lewy-type pathology. RESULTS: The accuracy of α-syn RT-QuIC in substantia nigra and CSF samples of patients with LRRK2-PD was 100%. The test also obtained 100% sensitivity to detect misfolded α-syn in substantia nigra of cases with idiopathic PD and was negative in the substantia nigra of all the control brains without Lewy-type pathology. CONCLUSIONS: Substantia nigra and ventricular CSF RT-QuIC discriminates with high sensitivity and specificity LRRK2 cases with Lewy-type pathology from those without it. RT-QuIC assay could be of particular interest in the selection of cases for clinical trials in this genetic form of PD. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Enfermedad de Parkinson , Sinucleinopatías , Humanos , Enfermedad de Parkinson/genética , alfa-Sinucleína/metabolismo , Cuerpos de Lewy/patología , Encéfalo/patología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/genéticaRESUMEN
Importance: Sporadic Creutzfeldt-Jakob disease (sCJD) is a rapidly lethal disease. Rapid, accurate diagnosis is imperative for epidemiological surveillance and public health activities to exclude treatable differentials and facilitate supportive care. In 2017, the International CJD Surveillance Network diagnostic criteria were revised to incorporate cortical ribboning on magnetic resonance imaging and the real-time quaking-induced conversion (RT-QuIC) assay, developments that require multicenter evaluation. Objective: To evaluate the accuracy of revised diagnostic criteria through the retrospective diagnosis of autopsy-confirmed cases (referred to as in-life diagnosis). Design, Setting, and Participants: This diagnostic study used a 3-year clinicopathological series using all cases of autopsy-confirmed sCJD and a noncase group with alternative neuropathological diagnoses from national surveillance centers in the United Kingdom, France, Germany, and Italy. Data were collected from January 2017 to December 2019 and analyzed from January 2020 to November 2021. Main Outcomes and Measures: Sensitivity and specificity of revised diagnostic criteria and diagnostic investigations. Secondary analyses assessing sCJD subgroups by genotype, pathological classification, disease duration, and age. Results: A total of 501 sCJD cases and 146 noncases were included. Noncase diagnoses included neurodegenerative diseases, autoimmune encephalitis, and cerebral insults such as anoxia. Participants in the sCJD cases cohort were younger (mean [SD] age, 68.8 [9.8] years vs 72.8 [10.9] years; P < .001) and had longer median (IQR) disease duration (118 [74.8-222.3] days vs 85 [51.5-205.5] days; P = .002); sex ratios were equivalent (253 [50.5%] male cases vs 74 [50.7%] male noncases). Sensitivity of revised criteria in in-life diagnosis (450 of 488 [92.2%] diagnoses; 95% CI, 89.5%-94.4%) was increased compared with prior criteria (378 of 488 [77.5%] diagnoses; 95% CI, 73.5%-81.1%; P < .001), while specificity (101 of 125 [80.8%] diagnoses; 95% CI, 72.8%-87.3%) was unchanged (102 of 125 [81.6%] diagnoses; 95% CI, 73.7%-88.0%; P > .99). Among 223 cases and 52 noncases with the full panel of investigations performed, sensitivity of revised criteria (97.8%; 95% CI, 94.9%-99.3%) was increased compared with prior criteria (76.2%; 95% CI, 70.1%-81.7%; P < .001) while specificity was unchanged (67.3%; 95% CI, 52.9%-79.7% vs 69.2%; 95% CI, 54.9%-81.3%; P > .99). In 455 cases and 111 noncases, cortical ribboning was 67.9% sensitive (95% CI, 63.4%-72.2%) and 86.5% specific (95% CI, 78.7%-92.2%). In 274 cases and 77 noncases, RT-QuIC was 91.6% sensitive (95% CI, 87.7%-94.6%) and 100% specific (95% CI, 96.2%-100%). Investigation sensitivity varied with genetic and pathological features, disease duration, and age. Conclusions and Relevance: This diagnostic study demonstrated significantly improved sensitivity of revised sCJD diagnostic criteria with unaltered specificity. The revision has enhanced diagnostic accuracy for clinical care and surveillance.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Técnicas de Diagnóstico Neurológico/normas , Vigilancia de la Población/métodos , Anciano , Autopsia , Femenino , Francia , Alemania , Humanos , Italia , Imagen por Resonancia Magnética , Masculino , Estudios Retrospectivos , Sensibilidad y Especificidad , Reino UnidoRESUMEN
BACKGROUND AND PURPOSE: Creutzfeldt-Jakob disease (CJD) is lethal and transmissible. We assessed the impact of the COVID-19 pandemic on UK CJD surveillance. We hypothesized that (i) disruptions prolonged diagnostic latency; (ii) autopsy rates declined; and (iii) COVID-19 infection negatively affected diagnosis, care, and survival. METHODS: We retrospectively investigated the first year of the pandemic, using the preceding year as a comparator, quantifying numbers of individuals assessed by the UK National CJD Research & Surveillance Unit for suspected CJD, time to diagnosis, disease duration, and autopsy rates. We evaluated the impact of COVID-19 status on diagnosis, care, and survival in CJD. RESULTS: A total of 148 individuals were diagnosed with CJD in the pandemic (from a total of 166 individuals assessed) compared to 141 in the comparator (from 145 assessed). No differences were identified in disease duration or time to diagnosis. Autopsy rates were unchanged. Twenty individuals had COVID-19; 60% were symptomatic, and 10% had severe disease. Disruptions in diagnosis and care were frequently identified. Forty percent of COVID-19-positive individuals died; however, COVID-19 status did not significantly alter survival duration in CJD. CONCLUSIONS: The COVID-19 pandemic has not impacted UK CJD case ascertainment or survival, but diagnostic evaluation and clinical care of individuals have been affected.
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COVID-19 , Síndrome de Creutzfeldt-Jakob , COVID-19/epidemiología , Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/epidemiología , Humanos , Pandemias , Atención al Paciente , Estudios Retrospectivos , SARS-CoV-2 , Reino Unido/epidemiologíaRESUMEN
BACKGROUND: Isolated rapid-eye-movement (REM) sleep behaviour disorder (IRBD) can be part of the prodromal stage of the α-synucleinopathies Parkinson's disease and dementia with Lewy bodies. Real-time quaking-induced conversion (RT-QuIC) analysis of CSF has high sensitivity and specificity for the detection of misfolded α-synuclein in patients with Parkinson's disease and dementia with Lewy bodies. We investigated whether RT-QuIC could detect α-synuclein in the CSF of patients with IRBD and be used as a biomarker of prodromal α-synucleinopathy. METHODS: In this longitudinal observational study, CSF samples were obtained by lumbar puncture from patients with video polysomnography-confirmed IRBD recruited at a specialised sleep disorders centre in Barcelona, Spain, and from controls free of neurological disease. CSF samples were stored until analysed using RT-QuIC. After lumbar puncture, participants were assessed clinically for neurological status every 3-12 months. Rates of neurological disease-free survival were estimated using the Kaplan-Meier method. Disease-free survival rates were assessed from the date of lumbar puncture to the date of diagnosis of any neurodegenerative disease, or to the last follow-up visit for censored observations. FINDINGS: 52 patients with IRBD and 40 healthy controls matched for age (p=0·20), sex (p=0·15), and duration of follow-up (p=0·27) underwent lumbar puncture between March 23, 2008, and July 16, 2017. The CSF α-synuclein RT-QuIC assay was positive in 47 (90%) patients with IRBD and in four (10%) controls, resulting in a sensitivity of 90·4% (95% CI 79·4-95·8) and a specificity of 90·0% (95% CI 76·9-96·0). Mean follow-up from lumbar puncture until the end of the study (July 31, 2020) was 7·1 years (SD 2·8) in patients with IRBD and 7·7 years (2·9) in controls. During follow-up, 32 (62%) patients were diagnosed with Parkinson's disease or dementia with Lewy bodies a mean 3·4 years (SD 2·6) after lumbar puncture, of whom 31 (97%) were α-synuclein positive at baseline. Kaplan-Meier analysis showed that patients with IRBD who were α-synuclein negative had lower risk for developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8, and 10 years of follow-up than patients with IRBD who were α-synuclein positive (log-rank test p=0·028; hazard ratio 0·143, 95% CI 0·019-1·063). During follow-up, none of the controls developed an α-synucleinopathy. Kaplan-Meier analysis showed that participants who were α-synuclein negative (ie, five patients with IRBD plus 36 controls) had lower risk of developing Parkinson's disease or dementia with Lewy bodies at 2, 4, 6, 8 and 10 years after lumbar puncture than participants who were α-synuclein positive (ie, 47 patients with IRBD plus four controls; log-rank test p<0·0001; hazard ratio 0·024, 95% CI 0·003-0·177). INTERPRETATION: In patients with IRBD, RT-QuIC detects misfolded α-synuclein in the CSF with both sensitivity and specificity of 90%, and α-synuclein positivity was associated with increased risk of subsequent diagnosis of Parkinson's disease or dementia with Lewy bodies. Detection of α-synuclein in the CSF represents a potential prodromal marker of Parkinson's disease and dementia with Lewy bodies. If these findings are replicated in additional cohorts, detection of CSF α-synuclein by RT-QuIC could be used to enrich IRBD cohorts in neuroprotective trials, particularly when assessing interventions that target α-synuclein. FUNDING: Department of Health and Social Care Policy Research Programme, the Scottish Government, and the Weston Brain Institute.
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Trastorno de la Conducta del Sueño REM/líquido cefalorraquídeo , alfa-Sinucleína/líquido cefalorraquídeo , Anciano , Sistemas de Computación , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Enfermedad por Cuerpos de Lewy/etiología , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/etiología , Polisomnografía , Síntomas Prodrómicos , Trastorno de la Conducta del Sueño REM/complicaciones , Medición de Riesgo , Sensibilidad y Especificidad , Punción EspinalRESUMEN
RT-QuIC is a shaking-based cyclic amplification technique originally developed in the prion field to detect minute amounts of scrapie prion protein (PrPSc). In this study, we applied the RT-QuIC assay to investigate a-synuclein (a-syn) seeding activity in brains of Dementia with Lewy Body (DLB) patients and in brains of G2-3 transgenic mice expressing human a-syn with A53T mutation. The results show that a-syn seeding activity varies between patients with detectable dilutions ranging from 10-3 to 10-8 dilutions of brain tissue and is stable under exposures to the cycles of freezing, thawing and sonication. A53T a-syn aggregates from G2-3 transgenic mice greatly favoured A53T recombinant human a-syn as substrates in comparison to wild-type a-syn, suggesting that conformations for wild-type a-syn to be able to adopt are not compatible with that of A53T aggregates from G2-3.
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Bioensayo/métodos , Encéfalo/patología , Enfermedad por Cuerpos de Lewy/complicaciones , Enfermedad por Cuerpos de Lewy/diagnóstico , Sinucleinopatías/complicaciones , Sinucleinopatías/diagnóstico , alfa-Sinucleína/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Humanos , Ratones Transgénicos , Persona de Mediana Edad , Mutación/genética , alfa-Sinucleína/genéticaRESUMEN
Sporadic Creutzfeldt-Jakob disease (sCJD) is a transmissible, rapidly progressive and fatal neurodegenerative disease. The transmissible agent linked to sCJD is composed of the misfolded form of the host-encoded prion protein. The combination of histopathological and biochemical analyses has allowed the identification and sub-classification of six sCJD subtypes. This classification depends on the polymorphic variability of codon 129 of the prion protein gene and the PrPres isotype, and appears to be associated with neuropathological and clinical features. Currently, sCJD subtyping is only fully achievable post mortem. However, a rapid and non-invasive method for discriminating sCJD subtypes in vita would be invaluable for the clinical management of affected individuals, and for the selection of participants for clinical trials. The CSF analysis by Real Time Quaking Induced Conversion (RT-QuIC) reaction is the most sensitive and specific ante mortem sCJD diagnostic test available to date, and it is used by a number of laboratories internationally. RT-QuIC takes advantage of the natural replication mechanisms of prions by template-induced misfolding, employing recombinant prion protein as reaction substrate. We asked whether epitope mapping, of the RT-QuIC reaction products obtained from seeding RT-QuIC with brain and CSF samples from each of the six molecular subtypes of sCJD could be employed to distinguish them and therefore achieve in vita sCJD molecular subtyping. We found that it is possible to distinguish the RT-QuIC products generated by sCJD biological samples from the ones generated by spontaneous conversion in the negative controls, but that different sCJD subtypes generate very similar, if not identical RT-QuIC reaction products. We concluded that whilst RT-QuIC has demonstrable diagnostic value it has limited prognostic value at this point in time.
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Síndrome de Creutzfeldt-Jakob/etiología , Síndrome de Creutzfeldt-Jakob/metabolismo , Endopeptidasas/inmunología , Mapeo Epitopo , Biomarcadores , Encéfalo/metabolismo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Humanos , Proteínas Priónicas/metabolismo , Priones/metabolismo , Proteolisis , Proteínas Recombinantes/metabolismoRESUMEN
A reliable biomarker is needed for accurate and early differentiation between Parkinson disease and the various forms of atypical parkinsonism. We used a novel real-time quaking-induced conversion (RT-QuIC) assay to detect α-synuclein (α-syn) aggregates in cerebrospinal fluid (CSF) of 118 patients with parkinsonism of uncertain clinical etiology and 52 controls. Diagnostic accuracy to distinguish α-synucleinopathies from non-α-synucleinopathies and controls was 84% (sensitivity = 75%, specificity = 94%, area under the curve = 0.84, 95% confidence interval = 0.78-0.91, p < 0.0001, positive predictive value = 93%). CSF α-syn RT-QuIC could be a useful diagnostic tool to help clinicians differentiate α-synucleinopathies from other forms of parkinsonism when the clinical picture is uncertain. Ann Neurol 2019;85:777-781.
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Trastornos Parkinsonianos/líquido cefalorraquídeo , Trastornos Parkinsonianos/diagnóstico , alfa-Sinucleína/líquido cefalorraquídeo , Anciano , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Diagnóstico Diferencial , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) can be difficult, but the real-time quaking-induced conversion (RT-QuIC) assays have made a considerable impact on its clinical diagnosis. This technique exploits the ability of the misfolded pathological form of prion protein (PrPSc) found in cerebrospinal fluid (CSF) to induce conversion of normal PrP to the misfolded form, which subsequently aggregates. The formation of these aggregates of misfolded PrP is monitored in real time using fluorescent dyes. The current sensitivity of CSF RT-QuIC undertaken at the UK National CJD Research & Surveillance Unit is 92% and the specificity is 100%. The interpretation of the RT-QuIC traces is affected by the presence of raised CSF red and white cells counts and elevated total protein concentrations. We recommend that CSF samples for RT-QuIC analysis are clear and colourless with a white cell count of <10 x10^6/L and have a total protein concentration of <1 g/L.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Imagen Óptica/métodos , Proteínas PrPSc/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Humanos , Sensibilidad y EspecificidadRESUMEN
A patient with a heterozygous variant of Creutzfeldt-Jakob disease (CJD) with a methionine/valine genotype at codon 129 of the prion protein gene was recently reported. Using an ultrasensitive and specific protein misfolding cyclic amplification-based assay for detecting variant CJD prions in cerebrospinal fluid, we discriminated this heterozygous case of variant CJD from cases of sporadic CJD.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/metabolismo , Metionina/metabolismo , Proteínas Priónicas/metabolismo , Valina/metabolismo , Síndrome de Creutzfeldt-Jakob/genética , Genotipo , Humanos , Proteínas Priónicas/genética , Deficiencias en la Proteostasis/diagnóstico , Deficiencias en la Proteostasis/metabolismo , Sensibilidad y EspecificidadRESUMEN
Protein amplification techniques exploit the ability of PrPTSE to induce a conformational change in prion protein (PrP) in a continuous fashion, so that the small amount of PrPTSE found in tissues and biologic fluids in prion diseases can be amplified to a point where they are detectable by conventional laboratory techniques. The most widely used protein aggregation assays are protein misfolding cyclic amplification assay (PMCA) and real-time quaking-induced conversion (RT-QuIC). These assays have been used extensively in both animal and human prion disease in studies ranging from the development of diagnostics, understanding disease transmission potential, to investigating mechanisms underlying neurodegeneration. In human prion disease, cerebrospinal fluid (CSF) RT-QuIC analysis has been shown to be a highly sensitive and specific test for sporadic Creutzfeldt-Jakob disease (sCJD) and has now been included in the diagnostic criteria. It is also a useful investigation for some genetic forms of prion disease where other cerebrospinal fluid tests may be negative. PMCA shows great potential for the diagnosis of variant CJD (vCJD) and has the ability to distinguish vCJD from sCJD, which may become increasingly important with emergence of a patient with neuropathologically confirmed vCJD associated with PRNP codon129MV, which indicates that a new wave of vCJD cases is likely and that these may be difficult to distinguish from sCJD.
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Síndrome de Creutzfeldt-Jakob/diagnóstico , Síndrome de Creutzfeldt-Jakob/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Proteínas Priónicas/genética , Encéfalo/metabolismo , Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/metabolismo , Humanos , Proteínas Priónicas/metabolismo , Deficiencias en la Proteostasis/complicacionesRESUMEN
We have developed a novel real-time quaking-induced conversion RT-QuIC-based assay to detect alpha-synuclein aggregation in brain and cerebrospinal fluid from dementia with Lewy bodies and Parkinson's disease patients. This assay can detect alpha-synuclein aggregation in Dementia with Lewy bodies and Parkinson's disease cerebrospinal fluid with sensitivities of 92% and 95%, respectively, and with an overall specificity of 100% when compared to Alzheimer and control cerebrospinal fluid. Patients with neuropathologically confirmed tauopathies (progressive supranuclear palsy; corticobasal degeneration) gave negative results. These results suggest that RT-QuiC analysis of cerebrospinal fluid is potentially useful for the early clinical assessment of patients with alpha-synucleinopathies.
RESUMEN
Many human neurodegenerative diseases are associated with hyperphosphorylation and widespread intra-neuronal and glial associated aggregation of the microtubule associated protein tau. In contrast, animal tauopathies are not reported with only senescent animals showing inconspicuous tau labelling of fine processes albeit significant tau aggregation may occur in some experimental animal disease. Since 1986, an idiopathic neurological condition of adult cattle has been recognised in the UK as a sub-set of cattle slaughtered as suspect bovine spongiform encephalopathy cases. This disorder is characterised by brainstem neuronal chromatolysis and degeneration with variable hippocampal sclerosis and spongiform change. Selected cases of idiopathic brainstem neuronal chromatolysis (IBNC) were identified from archive material and characterised using antibodies specific to several tau hyperphosphorylation sites or different isoforms of the tau microtubule binding region. Labelling was also carried out for alpha synuclein, ubiquitin, TDP43, Aß 1-42, Aß 1-40. Widespread tau labelling was identified in all IBNC brains examined and with each of seven tau antibodies recognising different hyperphosphorylated sites. Labelling with each antibody was associated with dendrites, neuronal perikarya and glia. Thus IBNC is a sporadic, progressive neurological disease predominantly affecting aged cattle that occurs throughout the UK and is associated with hyperphosphorylation of tau, a rare example of a naturally-occurring tauopathy in a non-primate species. Secondary accumulation of alpha synuclein and ubiquitin was also present. The neuropathology does not precisely correspond with any human tauopathy. The cause of IBNC remains undetermined but environmental factors and exposure to agrochemicals needs to be considered in future aetiological investigations.
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Enfermedades de los Bovinos/epidemiología , Enfermedades de los Bovinos/etiología , Tauopatías/veterinaria , Animales , Encéfalo/metabolismo , Encéfalo/patología , Bovinos , Encefalopatía Espongiforme Bovina/epidemiología , Encefalopatía Espongiforme Bovina/etiología , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Incidencia , Neuroglía/metabolismo , Neuronas/metabolismo , Isoformas de Proteínas , Reino Unido/epidemiología , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismoRESUMEN
OBJECTIVES: Delirium is associated with an increased risk of long-term cognitive decline, suggesting the possibility of concurrent central nervous system (CNS) injury. S100B is a putative biomarker of CNS injury and elevated serum levels in delirium have been reported. Here we hypothesize that delirium is associated with raised concentrations of cerebrospinal fluid (CSF) S100B. METHODS: Forty-five patients with hip fracture aged over 60 and awaiting surgery under spinal anesthesia were assessed for delirium pre- and post-operatively. CSF S100B levels were measured in samples collected at the onset of surgery. RESULTS: Participants with pre-operative delirium (N = 8) had elevated Log10 CSF S100B (mean: -0.156; SD: 0.238) compared with those without delirium (mean: -0.306; SD: 0.162), Student's t-test t = 2.18, df = 43, p = 0.035. CONCLUSIONS: This study provides preliminary evidence of elevated CSF S100B in current delirium, consistent with findings in serum and with other studies showing elevated S100B in the presence of diverse forms of CNS injury.
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Delirio/líquido cefalorraquídeo , Fracturas de Cadera/cirugía , Subunidad beta de la Proteína de Unión al Calcio S100/líquido cefalorraquídeo , Anciano , Anciano de 80 o más Años , Biomarcadores/líquido cefalorraquídeo , Delirio/complicaciones , Femenino , Fracturas de Cadera/complicaciones , Humanos , MasculinoRESUMEN
OBJECTIVE: Current cerebrospinal fluid (CSF) tests for sporadic Creutzfeldt-Jakob disease (sCJD) are based on the detection of surrogate markers of neuronal damage such as CSF 14-3-3, which are not specific for sCJD. A number of prion protein conversion assays have been developed, including real time quaking-induced conversion (RT-QuIC). The objective of this study is to investigate whether CSF RT-QuIC analysis could be used as a diagnostic test in sCJD. METHODS: An exploratory study was undertaken that analyzed 108 CSF samples from patients with neuropathologically confirmed sCJD or from control patients. Of the 108 CSF samples, 56 were from sCJD patients (30 female, 26 male; aged 31-84 years; mean age, 62.3 ± 13.5 years), and 52 were from control patients (26 female, 26 male; aged 43-84 years; mean age, 67.8 ± 10.4 years). A confirmatory group of 118 patients was subsequently examined that consisted of 67 cases of neuropathologically confirmed sCJD (33 female, 34 male; aged 39-82 years; mean age, 67.5 ± 9.0 years) and 51 control cases (26 female, 25 male; aged 36-87 years; mean age, 63.5 ± 11.6 years). RESULTS: The exploratory study showed that RT-QuIC analysis had a sensitivity of 91% and a specificity of 98% for the diagnosis of sCJD. These results were confirmed in the confirmatory study, which showed that CSF RT-QuIC analysis had a sensitivity and specificity of 87% and 100%, respectively. INTERPRETATION: This study shows that CSF RT-QuIC analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests.
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Proteínas 14-3-3/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/líquido cefalorraquídeo , Síndrome de Creutzfeldt-Jakob/diagnóstico , Priones/líquido cefalorraquídeo , Adulto , Anciano , Anciano de 80 o más Años , Animales , Encéfalo/metabolismo , Encéfalo/patología , Sistemas de Computación , Cricetinae , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sensibilidad y EspecificidadRESUMEN
Real-time quaking-induced conversion (RT-QuIC) is an assay in which disease-associated prion protein (PrP) initiates a rapid conformational transition in recombinant PrP (recPrP), resulting in the formation of amyloid that can be monitored in real time using the dye thioflavin T. It therefore has potential advantages over analogous cell-free PrP conversion assays such as protein misfolding cyclic amplification (PMCA). The QuIC assay and the related amyloid seeding assay have been developed largely using rodent-passaged sheep scrapie strains. Given the potential RT-QuIC has for Creutzfeldt-Jakob disease (CJD) research and human prion test development, this study characterized the behaviour of a range of CJD brain specimens with hamster and human recPrP in the RT-QuIC assay. The results showed that RT-QuIC is a rapid, sensitive and specific test for the form of abnormal PrP found in the most commonly occurring forms of sporadic CJD. The assay appeared to be largely independent of species-related sequence differences between human and hamster recPrP and of the methionine/valine polymorphism at codon 129 of the human PrP gene. However, with the same conditions and substrate, the assay was less efficient in detecting the abnormal PrP that characterizes variant CJD brain. Comparison of these QuIC results with those previously obtained using PMCA suggested that these two seemingly similar assays differ in important respects.
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Encéfalo/patología , Síndrome de Creutzfeldt-Jakob/diagnóstico , Patología/métodos , Priones/análisis , Amiloide/análisis , Animales , Cricetinae , Humanos , Conformación Proteica , Pliegue de Proteína , Factores de TiempoRESUMEN
Viliuisk encephalomyelitis (VE) is a neurodegenerative disorder expressed as subacute meningo-encephalitis progressing to a more prolonged pan-encephalitic syndrome with a fatal outcome within 1 to 10 years. Some patients survive to a steady state of global dementia and severe spasticity that may last for over 20 years. Multiple micronecrotic foci surrounded by inflammatory infiltrates are observed throughout the cerebral cortex and other gray matter areas. Infectious etiology of VE is strongly suspected, but the causative agent has not been identified. We conducted a search for assays that might be helpful for VE diagnosis and established for the first time that the majority of patients with definite VE show evidence for intrathecal IgG synthesis correlating with the clinical manifestations of the disease. This indicates that the detection of oligoclonal IgG banding in the cerebrospinal fluid is a valuable diagnostic assay for VE. Implications of these findings for a possible etiology of VE are discussed.
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Encefalomielitis/inmunología , Inmunoglobulinas/metabolismo , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Western Blotting/métodos , Corteza Cerebral/patología , Encefalomielitis/sangre , Encefalomielitis/líquido cefalorraquídeo , Femenino , Humanos , Inmunoglobulinas/inmunología , Focalización Isoeléctrica/métodos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Bandas Oligoclonales , Valores de Referencia , Sensibilidad y EspecificidadRESUMEN
OBJECTIVE: To investigate whether serum S100B is suitable as a sensitive biomarker for early prediction of increased intracranial pressure and mortality rates after brain injury. DESIGN: A prospective, longitudinal study. SETTING: Neurosurgical intensive care unit. PATIENTS: Twenty-one patients with acute brain injury and 13 healthy controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed Glasgow Coma Scale score and pupil reaction on admission and quantified serum S100B (in-house enzyme-linked immunosorbent assay) and intracranial pressure on admission and the subsequent 6 days. Serum S100B concentrations on admission and day 1 were significantly higher in patients with fatal outcome (p <.05, p<.01, respectively), with a sensitivity of 100% and a specificity of 75-83%. Patients with high serum S100B on admission had an eight-fold and on day 1 a 12-fold increased relative risk of a fatal outcome. Subsequent serum S100B values predicted the development of high intracranial pressure in patients with traumatic brain injury (p <.01). Patients with high intracranial pressure on day 5 had an 11-fold and on day 6 a nine-fold increased risk of fatal outcome. CONCLUSIONS: Serum S100B is a sensitive biomarker for early prediction of the development of high intracranial pressure and fatal outcome following acute brain injury. Monitoring S100B concentrations could contribute to early detection of patients at risk of secondary increases in intracranial pressure and subsequent mortality. This would allow earlier targeting of therapy in selected patients.
Asunto(s)
Lesiones Encefálicas/sangre , Lesiones Encefálicas/mortalidad , Hipertensión Intracraneal/diagnóstico , Factores de Crecimiento Nervioso/sangre , Proteínas S100/sangre , Adulto , Biomarcadores , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión Intracraneal/sangre , Londres/epidemiología , Masculino , Persona de Mediana Edad , Proyectos Piloto , Pronóstico , Estudios Prospectivos , Riesgo , Subunidad beta de la Proteína de Unión al Calcio S100 , Sensibilidad y EspecificidadRESUMEN
A protein capture assay was used to measure 14-3-3 (-isoform) in the cerebrospinal fluid (CSF) of patients with either variant or sporadic Creutzfeldt-Jakob disease (CJD). The results were compared with those obtained using Western blotting. Elevated levels of 14-3-3 were found in 58% of variant CJD (vCJD) patients and 82% of sporadic CJD (spCJD) patients using the protein capture assay. Using a Western blotting technique, the presence of CSF 14-3-3 was detected in 58% of vCJD patients and in 89% of spCJD patients. When the results from the protein capture assay and the Western blot were combined, 14-3-3 was detected in 77% of vCJD patients and in 91% of spCJD patients. These results suggest that although analysis of CSF 14-3-3 is not as useful in vCJD as it is in the sporadic form of the disease, a combination of these two techniques results in increased sensitivity of 14-3-3 for the diagnosis of vCJD.