CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment
Niklas Mattsson, MD; Henrik Zetterberg, MD, PhD; Oskar Hansson, MD, PhD; Niels Andreasen, MD, PhD; Lucilla Parnetti, MD, PhD; Michael Jonsson, MD; Sanna-Kaisa Herukka, PhD; Wiesje M. van der Flier, PhD; Marinus A. Blankenstein, PhD; Michael Ewers, PhD; Kenneth Rich, MD; Elmar Kaiser, MD; Marcel Verbeek, PhD; Magda Tsolaki, MD, PhD; Ezra Mulugeta, PhD; Erik Rosén, PhD; Dag Aarsland, MD, PhD; Pieter Jelle Visser, MD, PhD; Johannes Schröder, MD, PhD; Jan Marcusson, MD, PhD; Mony de Leon, MD, PhD; Harald Hampel, MD, PhD; Philip Scheltens, MD, PhD; Tuula Pirttilä, MD, PhD; Anders Wallin, MD, PhD; Maria Eriksdotter Jönhagen, MD; Lennart Minthon, MD, PhD; Bengt Winblad, MD, PhD; Kaj Blennow, MD, PhD
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.
To determine the diagnostic accuracy of CSF β-amyloid1-42 (Aβ42), 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 Aβ42, T-tau, and P-tau for identifying incipient AD.
During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The Aβ42 assay in particular had considerable intersite variability. Patients who developed AD had lower median Aβ42 (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 Aβ42; 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 Aβ42, 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 Aβ42/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%.
This multicenter study found that CSF Aβ42, 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.
Holtzman DM. Cerebrospinal Fluid β-Amyloid 42, Tau, and P-tau: Confirmation Now Realization. Arch Neurol. 2009;66(12):1552–1553. doi:10.1001/archneurol.2009.270
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