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CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment

Mattsson, Niklas; Zetterberg, Henrik; Hansson, Oskar LU ; Andreasen, Niels; Parnetti, Lucilla; Jonsson, Michael; Herukka, Sanna-Kaisa; van der Flier, Wiesje M.; Blankenstein, Marinus A. and Ewers, Michael, et al. (2009) In JAMA: the journal of the American Medical Association 302(4). p.385-393
Abstract
Context 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) (A beta 42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. Design, Setting, and Participants 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,... (More)
Context 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) (A beta 42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. Design, Setting, and Participants 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. Main Outcome Measures Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF A beta 42, 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 A beta 42 assay in particular had considerable intersite variability. Patients who developed AD had lower median A beta 42 (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, 1211420 ng/L for A beta 42; 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 A beta 42, 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 A beta 42/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 A beta 42, 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. JAMA. 2009;302(4):385-393 (Less)
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JAMA: the journal of the American Medical Association
volume
302
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4
pages
385 - 393
publisher
American Medical Association
external identifiers
  • wos:000268139200021
  • scopus:67651204382
ISSN
1538-3598
language
English
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2584ff8e-b83b-46be-b8dd-a8a258dc43ff (old id 1461554)
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2009-08-31 11:00:19
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@article{2584ff8e-b83b-46be-b8dd-a8a258dc43ff,
  abstract     = {Context 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) (A beta 42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. Design, Setting, and Participants 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. Main Outcome Measures Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF A beta 42, 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 A beta 42 assay in particular had considerable intersite variability. Patients who developed AD had lower median A beta 42 (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, 1211420 ng/L for A beta 42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P &lt; .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for A beta 42, 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 A beta 42/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 A beta 42, 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. JAMA. 2009;302(4):385-393},
  author       = {Mattsson, Niklas and Zetterberg, Henrik and Hansson, Oskar and Andreasen, Niels and Parnetti, Lucilla and Jonsson, Michael and Herukka, Sanna-Kaisa and van der Flier, Wiesje M. and Blankenstein, Marinus A. and Ewers, Michael and Rich, Kenneth and Kaiser, Elmar and Verbeek, Marcel and Tsolaki, Magda and Mulugeta, Ezra and Rosen, Erik and Aarsland, Dag and Visser, Pieter Jelle and Schroeder, Johannes and Marcusson, Jan and de Leon, Mony and Hampel, Harald and Scheltens, Philip and Pirttilae, Tuula and Wallin, Anders and Jonhagen, Maria Eriksdotter and Minthon, Lennart and Winblad, Bengt and Blennow, Kaj},
  issn         = {1538-3598},
  language     = {eng},
  number       = {4},
  pages        = {385--393},
  publisher    = {American Medical Association},
  series       = {JAMA: the journal of the American Medical Association},
  title        = {CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment},
  volume       = {302},
  year         = {2009},
}