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CSF Biomarkers and AD Prediction

In patients with mild cognitive impairment, CSF biomarkers helped predict who would develop Alzheimer disease.

Several reports have been made of the value of the CSF markers amyloid-beta_1-42 (Aβ[42]), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau) in predicting progression from mild cognitive impairment (MCI) to Alzheimer disease (AD). However, these studies have tended to either be small or involve only one investigation site. Now, researchers have conducted a large study of these biomarkers, including 750 patients with MCI seen at 12 centers in the U.S. and Europe. CSF was obtained at the time of MCI diagnosis, and subjects were followed longitudinally.

Over at least 2 years of follow-up, 271 participants with MCI were diagnosed with dementia caused by AD. Using cutoff scores developed from a separate group of healthy controls and patients with existing AD, the ratio of Aβ(42)/P-tau level combined with T-tau level yielded a sensitivity of 83%, specificity of 72%, positive predictive value of 62%, and negative predictive value of 88% for predicting conversion from MCI to AD-related dementia.

Comment: These findings add to those of another recent multicenter study showing that CSF Aβ(42), T-tau, and P-tau identify a group of MCI patients who are at increased risk for declining to dementia caused by AD (Ann Neurol 2009; 65:403). Early work with these CSF biomarkers focused on differentiating patients with AD from nondemented patients, but in that context, the clinical utility of CSF biomarkers beyond that of clinical diagnosis alone was limited. By contrast, the value in MCI is of enormous potential significance. Given the currently available interventions for AD, the main use of this combination of markers will be in clinical trials, not clinical practice. However, the field of Alzheimer therapeutics is turning to studies of patients with the earliest symptomatic manifestations of AD. Selective enrollment of MCI subjects with a higher probability of progressing to AD is a necessity for this trial design, and the CSF biomarkers studied here are strong candidates for use in participant selection.

— David Knopman, MD

Dr. Knopman is Professor of Neurology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN.

Published in Journal Watch Neurology September 15, 2009

Citation(s):

Mattsson N et al. CSF Biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 2009 Jul 22/29; 302:385.

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• Medline abstract (Free)

Petersen RC and Trojanowski JQ. Use of Alzheimer disease biomarkers: Potentially yes for clinical trials but not yet for clinical practice. JAMA 2009 Jul 22/29; 302:436.

• Original article (Subscription may be required)
• Medline abstract (Free)