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000164069 1001_ $$0P:(DE-2719)9000287$$aSchmitz, Matthias$$b0$$eFirst author$$udzne
000164069 245__ $$aDiagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases.
000164069 260__ $$aOxford$$bOxford Univ. Press$$c2022
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000164069 520__ $$aGenetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons. Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP. CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated. High sensitivity of the four biomarkers was detected for genetic Creutzfeldt-Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann-Sträussler-Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt-Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt-Jakob disease-E200K, Gerstmann-Sträussler-Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels. In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.
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000164069 650_7 $$2Other$$abiomarker
000164069 650_7 $$2Other$$acerebrospinal fluid
000164069 650_7 $$2Other$$adiagnostic marker
000164069 650_7 $$2Other$$agenetic prion diseases
000164069 650_7 $$2NLM Chemicals$$aBiomarkers
000164069 650_7 $$2NLM Chemicals$$aPrion Proteins
000164069 650_7 $$2NLM Chemicals$$aPrions
000164069 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000164069 650_2 $$2MeSH$$aBiomarkers: cerebrospinal fluid
000164069 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: diagnosis
000164069 650_2 $$2MeSH$$aCreutzfeldt-Jakob Syndrome: genetics
000164069 650_2 $$2MeSH$$aHumans
000164069 650_2 $$2MeSH$$aInsomnia, Fatal Familial: genetics
000164069 650_2 $$2MeSH$$aPrion Diseases: diagnosis
000164069 650_2 $$2MeSH$$aPrion Diseases: genetics
000164069 650_2 $$2MeSH$$aPrion Proteins: genetics
000164069 650_2 $$2MeSH$$aPrions: genetics
000164069 650_2 $$2MeSH$$aalpha-Synuclein
000164069 7001_ $$0P:(DE-2719)9000327$$aVillar-Piqué, Anna$$b1$$udzne
000164069 7001_ $$0P:(DE-2719)2812183$$aHermann, Peter$$b2$$udzne
000164069 7001_ $$aEscaramís, Geòrgia$$b3
000164069 7001_ $$aCalero, Miguel$$b4
000164069 7001_ $$aChen, Cao$$b5
000164069 7001_ $$aKruse, Niels$$b6
000164069 7001_ $$0P:(DE-2719)2810657$$aCramm, Maria$$b7$$udzne
000164069 7001_ $$aGolanska, Ewa$$b8
000164069 7001_ $$aSikorska, Beata$$b9
000164069 7001_ $$aLiberski, Pawel P$$b10
000164069 7001_ $$aPocchiari, Maurizio$$b11
000164069 7001_ $$0P:(DE-2719)9000182$$aLange, Peter$$b12$$udzne
000164069 7001_ $$aStehmann, Christiane$$b13
000164069 7001_ $$aSarros, Shannon$$b14
000164069 7001_ $$aMartí, Eulàlia$$b15
000164069 7001_ $$aBaldeiras, Inês$$b16
000164069 7001_ $$aSantana, Isabel$$b17
000164069 7001_ $$aŽáková, Dana$$b18
000164069 7001_ $$aMitrová, Eva$$b19
000164069 7001_ $$aDong, Xiao-Ping$$b20
000164069 7001_ $$aCollins, Steven$$b21
000164069 7001_ $$aPoleggi, Anna$$b22
000164069 7001_ $$aLadogana, Anna$$b23
000164069 7001_ $$0P:(DE-2719)9001340$$aMollenhauer, Brit$$b24$$udzne
000164069 7001_ $$aKovacs, Gabor G$$b25
000164069 7001_ $$aGeschwind, Michael D$$b26
000164069 7001_ $$aSánchez-Valle, Raquel$$b27
000164069 7001_ $$0P:(DE-2719)2000058$$aZerr, Inga$$b28$$udzne
000164069 7001_ $$0P:(DE-2719)2811280$$aLlorens Torres, Francesc Josep$$b29$$udzne
000164069 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awab350$$gVol. 145, no. 2, p. 700 - 712$$n2$$p700 - 712$$tBrain$$v145$$x0006-8950$$y2022
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