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CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment.
JAMA 2009; 302(4):385-93JAMA

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) (Abeta42), 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 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+Show Affiliations

Institute of Neuroscience and Physiology, Department of Neurochemistry and Psychiatry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden. niklas.mattsson@neuro.gu.seNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19622817

Citation

Mattsson, Niklas, et al. "CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment." JAMA, vol. 302, no. 4, 2009, pp. 385-93.
Mattsson N, Zetterberg H, Hansson O, et al. CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA. 2009;302(4):385-93.
Mattsson, N., Zetterberg, H., Hansson, O., Andreasen, N., Parnetti, L., Jonsson, M., ... Blennow, K. (2009). CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA, 302(4), pp. 385-93. doi:10.1001/jama.2009.1064.
Mattsson N, et al. CSF Biomarkers and Incipient Alzheimer Disease in Patients With Mild Cognitive Impairment. JAMA. 2009 Jul 22;302(4):385-93. PubMed PMID: 19622817.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. AU - Mattsson,Niklas, AU - Zetterberg,Henrik, AU - Hansson,Oskar, AU - Andreasen,Niels, AU - Parnetti,Lucilla, AU - Jonsson,Michael, AU - Herukka,Sanna-Kaisa, AU - van der Flier,Wiesje M, AU - Blankenstein,Marinus A, AU - Ewers,Michael, AU - Rich,Kenneth, AU - Kaiser,Elmar, AU - Verbeek,Marcel, AU - Tsolaki,Magda, AU - Mulugeta,Ezra, AU - Rosén,Erik, AU - Aarsland,Dag, AU - Visser,Pieter Jelle, AU - Schröder,Johannes, AU - Marcusson,Jan, AU - de Leon,Mony, AU - Hampel,Harald, AU - Scheltens,Philip, AU - Pirttilä,Tuula, AU - Wallin,Anders, AU - Jönhagen,Maria Eriksdotter, AU - Minthon,Lennart, AU - Winblad,Bengt, AU - Blennow,Kaj, PY - 2009/7/23/entrez PY - 2009/7/23/pubmed PY - 2009/7/30/medline SP - 385 EP - 93 JF - JAMA JO - JAMA VL - 302 IS - 4 N2 - 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) (Abeta42), 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 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. SN - 1538-3598 UR - https://www.unboundmedicine.com/medline/citation/19622817/CSF_biomarkers_and_incipient_Alzheimer_disease_in_patients_with_mild_cognitive_impairment_ L2 - https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2009.1064 DB - PRIME DP - Unbound Medicine ER -