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Abstract JAMA 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 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 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. Results: 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%. Conclusions: 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. JAMA. 2009;302(4):385-393.. Numerous studies have now shown that cerebrospinal fluid (CSF) levels of β-amyloid 42 (Aβ42) are, on average, decreased in individuals with dementia of the Alzheimer type and that levels of total tau as well as phosphorylated forms of tau (phosphorylated at position threonine 181 [p-tau181] and 231 [p-tau231]) are increased compared with those in age-matched controls.1 In addition, studies have shown that these molecules alone, and to a greater extent when combined, are strongly predictive of the conversion of individuals with mild cognitive impairment (MCI) to dementia of the Alzheimer type.2 Interestingly and importantly, the same markers are also predictive of conversion from being cognitively normal to having MCI/very mild dementia.3-5 Because it is now clear that the pathology of Alzheimer disease (AD), including amyloid plaques, neurofibrillary tangles, neuronal and synaptic loss, and inflammation, begin accumulating in the brain for as long as 10 to 20 years prior to the onset of clinical signs and symptoms of AD, identification of antecedent biomarkers that are predictive of cognitive decline will be critical in identifying individuals for entry into clinical trials and ultimately for deciding who should receive disease-modifying treatments. Such strategies are likely essential, as the amount of brain injury in those with even MCI who have underlying AD pathology is already substantial.6-8 While it is clear that CSF Aβ42, tau, and p-tau are good diagnostic and prognostic markers for AD, most studies assessing these markers have been single site or relatively small. In a recent issue of JAMA, Mattsson and colleagues studied 750 individuals with MCI, 529 with AD, and 304 controls at 12 sites, all but one of which were in Europe. As in smaller, mostly single-site studies, the researchers found that CSF Aβ42, total tau, and p-tau181 were both alone, and to a greater extent together, predictive of conversion from MCI to AD. For example, the Aβ42:p-tau181 ratio identified those who converted from MCI to AD during a minimum of a 2-year period with a sensitivity of 83%, specificity of 72%, a positive likelihood ratio of 3.0, and a negative likelihood ratio of 0.24. These data, along with numerous other studies in the literature, confirm the biological relevance of these markers as well as their potential usefulness in identifying individuals for entry into clinical trials. However, there are hurdles to overcome before widespread clinical use of these assays will be a reality. First, it will be critical that disease-modifying treatments be identified. Once this is accomplished, the findings from Mattsson et al highlight several important technical and standardization issues that need to be addressed. For example, in the large study by Mattsson et al, the samples were stored for anywhere from 1 to 17 years prior to analysis. Some samples were frozen immediately after CSF was obtained, others not for 3 hours. While many archived samples were analyzed at 1 site, samples from 4 centers (n = 409) were not. A subset of these samples were assayed at a central site and then values were readjusted for intercenter variation, which in some cases was large. Some CSF samples were assessed with an enzyme-linked immunosorbent assay (Innotest), others were measured with Luminex x-MAP technology (Innogenetics, Zwijndrecht, Belgium). Values were adjusted to allow comparison between these tests. While these assays are both very sensitive and accurate, a previous study comparing these methods showed that total tau and p-tau181 correlated well on both the Innotest and x-MAP assays, whereas the correlation of Aβ42 measurements between assays was not nearly as strong.9 Thus, there are many possible reasons why the results from this multisite study revealed that CSF Aβ42, total tau, and p-tau were not quite as predictive of clinical progression as the results from previous single-site studies. It is very encouraging, however, that despite all these caveats, the results from the study were so overwhelmingly positive. As the authors suggest, there are several steps that need to be taken to standardize the measurements of these CSF markers if they are going to be used around the world, ultimately for clinical use. First, collection and storage procedures for CSF need to be uniform. Second, it would be useful if everyone used the same standardized assay along with appropriate external control programs to assist in standardization if all samples are not run at the same site. Recent efforts by the Alzheimer Disease Neuroimaging Initiative have begun to show the power of this approach for these markers.10 In addition, it seems likely that fluid and imaging biomarkers in addition to CSF Aβ42 and tau will be useful for the identification of individuals at high risk of developing AD. How these other markers and tests will be used will need to be carefully sorted out. It is exciting that certain CSF biomarkers are now established as having the potential to be powerful tools to assist in the quest for treatments and hopefully, in the not too distant future, prevention of AD. Correspondence: Dr Holtzman, Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, Box 8111, St Louis, MO 63110 (email@example.com). Financial Disclosure: Dr Holtzman is a cofounder of C2N Diagnostics LLC. References 1. Sunderland TLinker GMirza N et al. Decreased β-amyloid1-42 and increased tau levels in cerebrospinal fluid of patients with Alzheimer disease [erratum published in JAMA. 2007;298(13):1516]. JAMA 2003;289 (16) 2094- 2103PubMedGoogle ScholarCrossref 2. Hansson OZetterberg HBuchhave PLondos EBlennow KMinthon L Association between CSF biomarkers and incipient Alzheimer's disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5 (3) 228- 234PubMedGoogle ScholarCrossref 3. Fagan AMRoe CMXiong CMintun MAMorris JCHoltzman DM Cerebrospinal fluid tau/β-amyloid42 ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol 2007;64 (3) 343- 349PubMedGoogle ScholarCrossref 4. Li GSokal IQuinn JF et al. CSF tau/Aβ42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology 2007;69 (7) 631- 639PubMedGoogle ScholarCrossref 5. Gustafson DRSkoog IRosengren LZetterberg HBlennow K Cerebrospinal fluid β-amyloid 1-42 concentration may predict cognitive decline in older women. J Neurol Neurosurg Psychiatry 2007;78 (5) 461- 464PubMedGoogle ScholarCrossref 6. Morris JCPrice JL Pathologic correlates of nondemented aging, mild cognitive impairment, and early-stage Alzheimer's disease. J Mol Neurosci 2001;17 (2) 101- 118PubMedGoogle ScholarCrossref 7. Fagan AMHead DShah AR et al. Decreased cerebrospinal fluid Aβ42 correlates with brain atrophy in cognitively normal elderly. Ann Neurol 2009;65 (2) 176- 183PubMedGoogle ScholarCrossref 8. Fagan AMMintun MAMach RH et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Aβ42 in humans. Ann Neurol 2006;59 (3) 512- 519PubMedGoogle ScholarCrossref 9. Olsson AVanderstichele HAndreasen N et al. Simultaneous measurement of β-amyloid(1-42), total tau, and phosphorylated tau (Thr181) in cerebrospinal fluid by the xMAP technology. Clin Chem 2005;51 (2) 336- 345PubMedGoogle ScholarCrossref 10. Shaw LMVanderstichele HKnapik-Czajka M et al. Alzheimer's Disease Neuroimaging Initiative, Cerebrospinal fluid biomarker signature in Alzheimer's disease neuroimaging initiative subjects. Ann Neurol 2009;65 (4) 403- 413PubMedGoogle ScholarCrossref
Archives of Neurology – American Medical Association
Published: Dec 1, 2009
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