title: CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
abstract: BACKGROUND
  Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted.
  
  
  OBJECTIVE
  To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (Abeta42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI.
  
  
  METHODS
  The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia.
  
  
  METHODS
  Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF Abeta42, T-tau, and P-tau for identifying incipient AD.
  
  
  RESULTS
  During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Abeta42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Abeta42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 121-1420 ng/L for Abeta42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for Abeta42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%.
  
  
  CONCLUSIONS
  This multicenter study found that CSF Abeta42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures.
authors.affiliation: Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. niklas.mattsson@neuro.gu.se
authors.forename: Niklas
authors.initials: N
authors.lastname: Mattsson
authors.forename: Henrik
authors.initials: H
authors.lastname: Zetterberg
authors.forename: Oskar
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authors.lastname: Hansson
authors.forename: Niels
authors.initials: N
authors.lastname: Andreasen
authors.forename: Lucilla
authors.initials: L
authors.lastname: Parnetti
authors.forename: Michael
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authors.lastname: Jonsson
authors.forename: Sanna-Kaisa
authors.initials: SK
authors.lastname: Herukka
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
authors.forename: Marinus A
authors.initials: MA
authors.lastname: Blankenstein
authors.forename: Michael
authors.initials: M
authors.lastname: Ewers
authors.forename: Kenneth
authors.initials: K
authors.lastname: Rich
authors.forename: Elmar
authors.initials: E
authors.lastname: Kaiser
authors.forename: Marcel
authors.initials: M
authors.lastname: Verbeek
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Ezra
authors.initials: E
authors.lastname: Mulugeta
authors.forename: Erik
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authors.lastname: Rosén
authors.forename: Dag
authors.initials: D
authors.lastname: Aarsland
authors.forename: Pieter Jelle
authors.initials: PJ
authors.lastname: Visser
authors.forename: Johannes
authors.initials: J
authors.lastname: Schröder
authors.forename: Jan
authors.initials: J
authors.lastname: Marcusson
authors.forename: Mony
authors.initials: M
authors.lastname: de Leon
authors.forename: Harald
authors.initials: H
authors.lastname: Hampel
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.forename: Tuula
authors.initials: T
authors.lastname: Pirttilä
authors.forename: Anders
authors.initials: A
authors.lastname: Wallin
authors.forename: Maria Eriksdotter
authors.initials: ME
authors.lastname: Jönhagen
authors.forename: Lennart
authors.initials: L
authors.lastname: Minthon
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D003072:Cognition Disorders / Q000134:cerebrospinal fluid*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010769:Phosphothreonine; D012680:Sensitivity and Specificity; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D010769:Phosphothreonine