The clinical value of fluid biomarkers for dementia diagnosis
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We read with interest the Article by Bob Olsson and colleagues1 examining CSF and blood biomarkers for the diagnosis of Alzheimer's disease. Olsson and colleagues recommend the use of the CSF biomarkers total tau, phosphorylated tau, amyloid β42, and neurofilament light protein in the diagnosis of Alzheimer's disease and mild cognitive impairment.1 By contrast, Cochrane reviews2 , 3 based on similar studies have concluded that there is not sufficient evidence to support the routine use of CSF amyloid β or PET in the diagnosis of mild cognitive impairment due to Alzheimer's disease and other dementias. This discrepancy in interpreting the evidence base for diagnostic technologies can only serve to create variations in practice and confusion for both doctors and their patients. Although the use of biomarkers as diagnostic criteria for Alzheimer's disease might be valuable in research, concerns have been raised about the premature use of such criteria beyond the research setting.4 There is no doubt that many of the changes in CSF and blood biomarkers are associated with Alzheimer's disease and mild cognitive impairment, but such associations by themselves might be inadequate to demonstrate clinical usefulness. Establishment of clinical usefulness requires the use of thresholds for positive and negative results and standard accuracy metrics such as sensitivity, specificity, and likelihood ratios.5 Alternative measures such as correlations or ratios of blood biomarker concentrations in patients and controls might be important to indicate the potential value of a marker in the research phase, but these studies do not provide information about how the test will perform in a typical clinical setting. In clinical practice, patients requiring further testing will not be those with established Alzheimer's disease or cognitively healthy controls.5 The use of such widely differing groups in accuracy studies will result in spectrum bias and does not provide evidence of the performance of the test in a true clinical setting. More definitive evidence from studies done in consecutive series of presenting patients (even if this series includes people with a range of diagnoses) is needed before these biomarkers can be recommended for routine clinical use.5 The true value of the use of a diagnostic test in practice should relate to its benefit for the patient, in terms of outcomes such as quality of life. Even if biomarkers are proven to be highly accurate in diagnosing Alzheimer's disease, the probable patient benefit should still be considered. The value of testing for a diagnosis of mild cognitive impairment, while important for research advances, can be questioned given the uncertain balance between the benefits and harms of a diagnosis while a treatment is not available. This might be particularly important in tests with impressive sensitivity but inadequate specificity, leading to a large number of false positive diagnoses in patients who might never develop dementia. Some researchers, enthusiastic about promising results for diagnostic tests in a common and debilitating disease, might be frustrated by the requirement for more definitive evidence of the accuracy of diagnostic tests before routine use. However, improvements in clinical practice will only come with more consistent interpretation of evidence before recommendations for adopting new technologies are made. LF is an Editor for The Cochrane Dementia and Cognitive Improvement Group. SD was previously employed conducting health technology assessments for the Medical Services Advisory Committee, who make recommendations for public funding of diagnostic technologies through Medicare in Australia. All authors were involved in development of clinical practice guidelines for dementia in Australia.
© 2016 Elsevier Ltd. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/