Detection of 14‐3‐3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt‐Jakob disease

Zerr, Inga; Bodemer, Monika; Gefeller, Olaf; Otto, Markus; Poser, S.; Wiltfang, Jens; Windl, Otto; Kretzschmar, Hans A.; Weber, Thomas K.

doi:10.1002/ana.410430109

Cited by 412 publications

(270 citation statements)

References 35 publications

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“…If similar changes are detectable in more easily accessible biospecimens, including CSF and plasma, 14‐3‐3 phosphorylation has the potential as a biomarker for neurodegeneration. Measurement of 14‐3‐3s in CSF has been used clinically as a diagnostic biomarker for Creutzfeldt‐Jakob Disease (CJD), although recent studies have demonstrated that the specificity for CJD is lower than initially thought 48, 49, 50, 51. However, this body of research has demonstrated that 14‐3‐3 measurements in CSF are reliable and stable in patients, and can help with diagnosis in the right clinical context 48, 49.…”

Section: Discussionmentioning

confidence: 99%

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

McFerrin

Chi

Cutter

et al. 2017

Ann Clin Transl Neurol

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ObjectiveThe highly conserved 14‐3‐3 proteins interact with key players involved in Parkinson's disease (PD) and other neurodegenerative disorders. We recently demonstrated that 14‐3‐3 phosphorylation is increased in PD models and that increased 14‐3‐3 phosphorylation reduces the neuroprotective effects of 14‐3‐3 proteins. Here, we investigated whether 14‐3‐3 phosphorylation is altered in postmortem brains from control, PD, Alzheimer's Disease (AD), Alzheimer's with Lewy Bodies (ADLB), Dementia with Lewy Bodies (DLB), and Progressive Supranuclear Palsy (PSP) subjects at three conserved sites: serine 58 (S58), serine 185 (S185), and serine 232 (S232).MethodsS58, S185, and S232 phosphorylation was measured by western blot analysis of Triton X‐100 soluble and insoluble fractions from postmortem temporal cortex.ResultsThe ratio of soluble phospho‐S232 to insoluble phospho‐S232 was reduced by 32%, 60%, 37%, and 52% in PD, AD, ADLB, and DLB, respectively. S185 and S58 phosphorylation were mildly elevated in the soluble fraction in DLB. We also noted a dramatic reduction in soluble pan 14‐3‐3 levels by ~35% in AD, ADLB, and DLB. Lower ratios of soluble to insoluble S232 phosphorylation (pointing to higher insoluble pS232) correlated with lower soluble pan 14‐3‐3 levels, suggesting that S232 phosphorylation may promote insolubilization of 14‐3‐3s. The phospho‐S232 ratio and soluble pan 14‐3‐3 levels correlated with clinical and pathological severity.InterpretationThese data reveal dysregulation of 14‐3‐3 proteins in neurodegeneration associated with Lewy body or Alzheimer pathology. S232 phosphorylation may drive insolubilization of 14‐3‐3s and thus contribute to the pathophysiology in neurodegenerative disorders associated with Lewy body or Alzheimer pathology.

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Section: Discussionmentioning

confidence: 99%

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

McFerrin

Chi

Cutter

et al. 2017

Ann Clin Transl Neurol

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“…CSF proteins evaluation: 14-3-3, Ab42, t-tau, p-tau and S-100b CSF samples, collected in sterile polypropylene tubes, were centrifuged at 2,500 rpm for 5 min, aliquoted and stored at -80°C until analysis. Immunodetection of protein 14-3-3 in CSF was done as described previously [42], with minor modifications. Briefly, CSF proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and detection was carried out by incubation with mouse anti-14-3-3 beta monoclonal antibody (sc-1657, Santa Cruz Biotechnology, USA) followed by horseradish peroxidaseconjugated anti-mouse immunoglobulin (DakoCytomation, Denmark).…”

Section: Sample Characterizationmentioning

confidence: 99%

“…Immunodetection of protein 14-3-3 in CSF was originally demonstrated to have a high sensitivity and specificity for sCJD [19,42] and has, therefore, been included by the World Health Organization (WHO) in the diagnostic criteria for probable disease [41]. However, this view has been challenged by findings of poor specificity [6,7] and low sensitivity in autopsy-proven sCJD cases [11].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

et al. 2009

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The clinical diagnosis of sporadic CreutzfeldtJakob disease (sCJD) is difficult, and reliable markers are highly desired. In this work we assess the value of several cerebrospinal fluid (CSF) markers for sCJD diagnosis. Within the framework of the Portuguese Epidemiological Surveillance Program for Human Prion Diseases, CSF samples from 71 patients with clinically suspected sCJD, 30 definite sCJD and 41 non-CJD patients, were analysed for the presence of 14-3-3 protein. CSF levels of tau (t-tau), and phosphorylated tau (p-tau181), S-100b and b amyloid (Ab42) proteins were determined. The influence of clinical and genetic characteristics on CSF markers sensitivity was also evaluated. Protein 14-3-3 was detected in 29/30 sCJD patients and 9/41 non-CJD patients. Extremely elevated t-tau and S-100b protein levels were found in sCJD patients, while p-tau181 levels were only slightly elevated and Ab42 showed no differences compared to controls. 14-3-3 was the most sensitive parameter (97%), but its specificity was low (78%); sensitivity/specificity for other proteins were: S-100b-93/93%, t-tau-93/95%, with maximum accuracy being obtained by a combination of tests (14-3-3 combined with either t-tau or S-100b, or combining S-100b with t-tau/Ab42 or p-tau/t-tau ratios). The sensitivity of 14-3-3, as well as of p-tau181/t-tau ratio, was decreased in younger patients with long disease duration, with the PrP-2 isotype and MV genotype. Both 14-3-3, t-tau and S-100b are sensitive markers for sCJD, but 14-3-3 specificity seems to be lower in this special clinical setting of rapidly progressing dementias. We propose that in cases with a 14-3-3 weak positive result, or in young patients with long disease duration, a second CSF marker would be valuable for the diagnosis of sCJD.

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“…The 14-3-3 protein in the CSF has been reported to have a sensitivity between 85% and 96% and a specificity between 79% and 96%. As it may be present in other conditions such as viral encephalitis, metabolic encephalopathy and cerebral hemorrhages, the test is not appropriate as a general screening test for CJD, but is useful for diagnosis of truly suspect cases (14)(15)(16). In contrast to qualitative 14-3-3 test, ELISA immunoassay for the quantitative detection of tau protein in CSF has shown superior accuracy with less ambiguous results (17).…”

Section: Discussionmentioning

confidence: 99%

Positive 14-3-3 and tau proteins in a sporadic Creutzfeldt-Jakob disease case and a brief perspective of prion diseases in Colombia

Escandón-Vargas¹,

Zorrilla-Vaca²,

Corral-Prado³

2016

biomedica

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Prion diseases are rare neurodegenerative disorders occurring worldwide and affecting both humans and animals. Herein, we present the case of a patient diagnosed with definite sporadic CreutzfeldtJakob disease in Cali, Colombia. Besides neurological examination, 14-3-3 and tau proteins were valuable tools supporting the diagnosis. We also present a brief perspective of the prion diseases reported in Colombia to date. Although the incidence of prion diseases is unknown in Colombia, our literature review revealed that one case of scrapie in 1981 and 29 human sporadic cases of Creutzfeldt-Jakob disease have been documented and published in our country.Key words: Creutzfeldt-Jakob syndrome, prions, case reports. doi: http://dx.doi.org/10.7705/biomedica.v36i3.2729 Proteínas 14-3-3 y tau positivas en un caso de enfermedad esporádica de Creutzfeldt-Jakob y una breve reseña de las enfermedades priónicas en Colombia Las enfermedades priónicas son alteraciones neurodegenerativas raras que ocurren en todo el mundo y afectan tanto a humanos como a animales. En el presente artículo, se reporta un caso con diagnóstico confirmado de enfermedad esporádica de Creutzfeldt-Jakob. Además del examen neuropatológico, las proteínas 14-3-3 y tau fueron herramientas valiosas que ayudaron en el diagnóstico. También, se presenta una breve reseña de las enfermedades priónicas reportadas en Colombia hasta la fecha. Aunque en el país se desconoce la incidencia de las enfermedades priónicas, nuestra búsqueda en la literatura científica reveló informes publicados sobre un caso de tembladera de las ovejas (scrapie o encefalopatía espongiforme ovina) en 1981 y 29 casos esporádicos de Creutzfeldt-Jakob en el país.Palabras clave: síndrome de Creutzfeldt-Jakob, priones, informes de casos.

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Detection of 14‐3‐3 protein in the cerebrospinal fluid supports the diagnosis of Creutzfeldt‐Jakob disease

Cited by 412 publications

References 35 publications

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

Diagnostic value of CSF protein profile in a Portuguese population of sCJD patients

Positive 14-3-3 and tau proteins in a sporadic Creutzfeldt-Jakob disease case and a brief perspective of prion diseases in Colombia

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