title: Association of cerebrospinal fluid prion protein levels and the distinction between Alzheimer disease and Creutzfeldt-Jakob disease.
abstract: OBJECTIVE
  Although typical forms of Alzheimer disease (AD) and Creutzfeldt-Jakob disease (CJD) are clinically distinguishable, atypical AD phenotypes may pose a diagnostic challenge. The major biological diagnostic biomarker for identifying CJD, 14-3-3 protein in cerebrospinal fluid (CSF), unfortunately lacks specificity when confronting a rapid dementia presentation.
  
  
  OBJECTIVE
  To assess the relevance of total CSF prion protein (t-PrP) levels in the differential biological diagnosis between atypical AD phenotypes and CJD.
  
  
  METHODS
  A retrospective study in an autopsy-confirmed cohort of 82 patients was performed to evaluate the relevance of CSF t-PrP to distinguish 30 definite cases of AD from 52 definite cases of CJD. Next, CSF t-PrP concentration was measured in a cohort of 104 patients including 55 patients with probable AD, 26 with probable sporadic CJD, and 23 control patients for whom 14-3-3 protein, total tau, phosphorylated tau 181 (P-tau181), and Aβ1-42 were available. We investigated 46 patients diagnosed as having probable AD who presented atypical phenotypes. A diagnosis strategy was proposed to classify atypical AD phenotypes with suspicion of CJD based on a decision tree combining CSF biomarkers.
  
  
  METHODS
  We determined CSF t-PrP levels for all patients. We calculated the ratio of total tau and P-tau181 and determined the diagnostic accuracy of each biomarker alone or in combination. We calculated the misclassification rate for each biomarker that corresponded to the percentage of patients within the group of atypical AD phenotypes wrongly classified as CJD.
  
  
  RESULTS
  In patients with CJD, CSF t-PrP concentrations were decreased compared with control participants and patients with AD. When considering the differential diagnosis of CJD compared with atypical AD phenotypes, CSF t-PrP determination reached 82.1% sensitivity and 91.3% specificity. The misclassification rate of atypical AD phenotypes decreased from 43.5%, obtained when using the CSF 14-3-3 protein determination alone, to only 4.3% when calculating the ratio total tau/(P-tau181 × t-PrP). The proposed classification tree permitted correct classification of 98.4% of the patients.
  
  
  CONCLUSIONS
  For unusual phenotypes of AD, especially cases presenting with a biological ambiguity suggesting CJD, determination of CSF t-PrP levels increased diagnostic accuracy. The use of CSF t-PrP levels may be beneficial in clinical practice in addition to the current classic biomarkers.
authors.affiliation: Hospices Civils de Lyon, Lyon 1 University, Hôpital des Charpennes, Center for Memory Resources and Research, Villeurbanne, France2Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Biochemistry, Neurochemistry Unit, Lyon, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Dorey
authors.affiliation: Lyon University, Lyon Neuroscience Research Center, Lyon, France4Centre Hospitalier Universitaire de Limoges, Department of Biochemistry and Molecular Genetics, University of Limoges Medical School, Limoges, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Tholance
authors.affiliation: Hospices Civils de Lyon, Lyon 1 University, Hôpital Neurologique, Department of Neurology, Bron Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Vighetto
authors.affiliation: Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Biochemistry, Neurochemistry Unit, Lyon, France6Lyon 1 University, Lyon Neuroscience Research Center, Bron Cedex, France.
authors.forename: Armand
authors.initials: A
authors.lastname: Perret-Liaudet
authors.affiliation: AJ Roboscreen GmbH, Leipzig, Germany.
authors.forename: Ingolf
authors.initials: I
authors.lastname: Lachman
authors.affiliation: Hospices Civils de Lyon, Lyon 1 University, Hôpital des Charpennes, Center for Memory Resources and Research, Villeurbanne, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Krolak-Salmon
authors.affiliation: AJ Roboscreen GmbH, Leipzig, Germany.
authors.forename: Uta
authors.initials: U
authors.lastname: Wagner
authors.affiliation: Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Hanne
authors.initials: H
authors.lastname: Struyfs
authors.affiliation: Biobank and Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Peter P
authors.initials: PP
authors.lastname: De Deyn
authors.affiliation: Laboratory of Human Histology-CRPP, Institute of Pharmacy-CHU, Liège, Belgium.
authors.forename: Benaissa
authors.initials: B
authors.lastname: El-Moualij
authors.affiliation: Laboratory of Human Histology-CRPP, Institute of Pharmacy-CHU, Liège, Belgium.
authors.forename: Willy
authors.initials: W
authors.lastname: Zorzi
authors.affiliation: Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Pathology and Neuropathology, Bron Cedex, France.
authors.forename: David
authors.initials: D
authors.lastname: Meyronet
authors.affiliation: Hospices Civils de Lyon, Lyon 1 University, Hôpital des Charpennes, Center for Memory Resources and Research, Villeurbanne, France11Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Pathology and Neuropathology, Bron Cedex, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Streichenberger
authors.affiliation: Reference Center for Biological Markers of Dementia, Laboratory of Neurochemistry and Behavior, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Engelborghs
authors.affiliation: Institute of Neurology, Medical University of Vienna, and Austrian Reference Center for Human Prion Diseases, Vienna, Austria.
authors.forename: Gabor G
authors.initials: GG
authors.lastname: Kovacs
authors.affiliation: Hospices Civils de Lyon, Groupement Hospitalier Est, Department of Biochemistry, Neurochemistry Unit, Lyon, France6Lyon 1 University, Lyon Neuroscience Research Center, Bron Cedex, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Quadrio
mesh_terms: D048948:14-3-3 Proteins / Q000134:cerebrospinal fluid; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011328:Prions / Q000134:cerebrospinal fluid*; D012189:Retrospective Studies
chemical_list: D048948:14-3-3 Proteins; D015415:Biomarkers; D011328:Prions