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      Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI)

      systematic-review
      , , , , , ,
      Cochrane Dementia and Cognitive Improvement Group
      The Cochrane Database of Systematic Reviews
      John Wiley & Sons, Ltd

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          Abstract

          Background

          According to the latest revised National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (now known as the Alzheimer's Association) (NINCDS‐ADRDA) diagnostic criteria for Alzheimer's disease dementia of the National Institute on Aging and Alzheimer Association, the confidence in diagnosing mild cognitive impairment (MCI) due to Alzheimer's disease dementia is raised with the application of biomarkers based on measures in the cerebrospinal fluid (CSF) or imaging. These tests, added to core clinical criteria, might increase the sensitivity or specificity of a testing strategy. However, the accuracy of biomarkers in the diagnosis of Alzheimer’s disease dementia and other dementias has not yet been systematically evaluated. A formal systematic evaluation of sensitivity, specificity, and other properties of plasma and CSF amyloid beta (Aß) biomarkers was performed.

          Objectives

          To determine the accuracy of plasma and CSF Aß levels for detecting those patients with MCI who would convert to Alzheimer's disease dementia or other forms of dementia over time.

          Search methods

          The most recent search for this review was performed on 3 December 2012. We searched MEDLINE (OvidSP), EMBASE (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science and Conference Proceedings (ISI Web of Knowledge), PsycINFO (OvidSP), and LILACS (BIREME). We also requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies (managed by the Cochrane Renal Group).

          No language or date restrictions were applied to the electronic searches and methodological filters were not used so as to maximise sensitivity.

          Selection criteria

          We selected those studies that had prospectively well defined cohorts with any accepted definition of cognitive decline, but no dementia, with baseline CSF or plasma Aß levels, or both, documented at or around the time the above diagnoses were made. We also included studies which looked at data from those cohorts retrospectively, and which contained sufficient data to construct two by two tables expressing plasma and CSF Aß biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's dementia diagnosis, for example the NINCDS‐ADRDA or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) criteria.

          Data collection and analysis

          We screened all titles generated by the electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. We assessed the identified full papers for eligibility and extracted data to create standard two by two tables. Two independent assessors performed quality assessment using the QUADAS‐2 tool. Where data allowed, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary receiver operating characteristic (ROC) curve.

          Main results

          Alzheimer's disease dementia was evaluated in 14 studies using CSF Aß 42. Of the 1349 participants included in the meta‐analysis, 436 developed Alzheimer’s dementia. Individual study estimates of sensitivity were between 36% and 100% while the specificities were between 29% and 91%. Because of the variation in assay thresholds, we did not estimate summary sensitivity and specificity. However, we derived estimates of sensitivity at fixed values of specificity from the model we fitted to produce the summary ROC curve. At the median specificity of 64%, the sensitivity was 81% (95% CI 72 to 87). This equated to a positive likelihood ratio (LR+) of 2.22 (95% CI 2.00 to 2.47) and a negative likelihood ratio (LR–) of 0.31 (95% CI 0.21 to 0.48).

          The accuracy of CSF Aß 42 for all forms of dementia was evaluated in four studies. Of the 464 participants examined, 188 developed a form of dementia (Alzheimer’s disease and other forms of dementia).The thresholds used were between 209 mg/ml and 512 ng/ml. The sensitivities were between 56% and 75% while the specificities were between 47% and 76%. At the median specificity of 75%, the sensitivity was estimated to be 63% (95% CI 22 to 91) from the meta‐analytic model. This equated to a LR+ of 2.51 (95% CI 1.30 to 4.86) and a LR– of 0.50 (95% CI 0.16 to 1.51).

          The accuracy of CSF Aß 42 for non‐Alzheimer's disease dementia was evaluated in three studies. Of the 385 participants examined, 61 developed non‐Alzheimer's disease dementia. Since there were very few studies and considerable variation between studies, the results were not meta‐analysed. The sensitivities were between 8% and 63% while the specificities were between 35% and 67%.

          Only one study examined the accuracy of plasma Aß 42 and the plasma Aß 42/Aß 40 ratio for Alzheimer's disease dementia. The sensitivity of 86% (95% CI 81 to 90) was the same for both tests while the specificities were 50% (95% CI 44 to 55) and 70% (95% CI 64 to 75) for plasma Aß 42 and the plasma Aß 42/Aß 40 ratio respectively. Of the 565 participants examined, 245 developed Alzheimer’s dementia and 87 non‐Alzheimer's disease dementia.

          There was substantial heterogeneity between studies. The accuracy of Aß 42 for the diagnosis of Alzheimer's disease dementia did not differ significantly (P = 0.8) between studies that pre‐specified the threshold for determining test positivity (n = 6) and those that only determined the threshold at follow‐up (n = 8). One study excluded a sample of MCI non‐Alzheimer's disease dementia converters from their analysis. In sensitivity analyses, the exclusion of this study had no impact on our findings. The exclusion of eight studies (950 patients) that were considered at high (n = 3) or unclear (n = 5) risk of bias for the patient selection domain also made no difference to our findings.

          Authors' conclusions

          The proposed diagnostic criteria for prodromal dementia and MCI due to Alzheimer's disease, although still being debated, would be fulfilled where there is both core clinical and cognitive criteria and a single biomarker abnormality. From our review, the measure of abnormally low CSF Aß levels has very little diagnostic benefit with likelihood ratios suggesting only marginal clinical utility. The quality of reports was also poor, and thresholds and length of follow‐up were inconsistent. We conclude that when applied to a population of patients with MCI, CSF Aß levels cannot be recommended as an accurate test for Alzheimer's disease.

          Plain language summary

          Proteins in blood and cerebrospinal fluids for early prediction of developing Alzheimer’s disease or other dementia in people with cognitive problems

          The numbers of people with dementia and other cognitive problems are increasing globally. A diagnosis of the pre‐dementia phase of disease is recommended but there is no agreement on the best approach. A range of tests have been developed which healthcare professionals can use to assess people with poor memory or cognitive impairment. In this review, however, we have found that measuring protein in cerebrospinal fluid (CSF amyloid beta (Aβ 40) or CSF Aβ 42), as a single test, lacks the accuracy to identify those patients with mild cognitive impairment who would develop Alzheimer's disease dementia or other forms of dementia.

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          Author and article information

          Contributors
          c.ritchie@imperial.ac.uk
          Journal
          Cochrane Database Syst Rev
          Cochrane Database Syst Rev
          14651858
          10.1002/14651858
          The Cochrane Database of Systematic Reviews
          John Wiley & Sons, Ltd (Chichester, UK )
          1469-493X
          10 June 2014
          June 2014
          5 June 2014
          : 2014
          : 6
          : CD008782
          Affiliations
          Imperial College London London UK
          University of Cambridge deptInstitute of Public Health Forvie Site Robinson Way Cambridge UK CB2 0SR
          University of Oxford deptRadcliffe Department of Medicine Room 4401c (4th Floor) John Radcliffe Hospital, Headington Oxford UK OX3 9DU
          University of Birmingham deptPublic Health, Epidemiology and Biostatistics Edgbaston Birmingham UK B15 2TT
          University of Western Australia deptWestern Australian Centre for Health & Ageing ‐ WACHA Crawley Perth Western Australia Australia 6014
          Imperial College Medical School London UK
          Article
          PMC6465069 PMC6465069 6465069 CD008782.pub4 CD008782
          10.1002/14651858.CD008782.pub4
          6465069
          24913723
          226a7512-12df-4bc4-b139-732cd2dde1dc
          Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
          History
          Categories
          Diagnosis
          Diagnosis
          Mental health
          Neurology

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