title: Plasma and cerebrospinal fluid amyloid beta for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).
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.
  
  
  OBJECTIVE
  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.
  
  
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  Alzheimer's disease dementia was evaluated in 14 studies using CSF Aß42. 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 Aß42 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 Aß42 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 Aß42 and the plasma Aß42/Aß40 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 Aß42 and the plasma Aß42/Aß40 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 Aß42 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.
  
  
  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.
authors.affiliation: Imperial College London, London, UK.
authors.forename: Craig
authors.initials: C
authors.lastname: Ritchie
authors.forename: Nadja
authors.initials: N
authors.lastname: Smailagic
authors.forename: Anna H
authors.initials: AH
authors.lastname: Noel-Storr
authors.forename: Yemisi
authors.initials: Y
authors.lastname: Takwoingi
authors.forename: Leon
authors.initials: L
authors.lastname: Flicker
authors.forename: Sam E
authors.initials: SE
authors.lastname: Mason
authors.forename: Rupert
authors.initials: R
authors.lastname: McShane
mesh_terms: D000544:Alzheimer Disease / Q000175:diagnosis*; D016229:Amyloid beta-Peptides / Q000097:blood / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D060825:Cognitive Dysfunction / Q000175:diagnosis*; D003704:Dementia / Q000175:diagnosis; D018450:Disease Progression; D006801:Humans; D010446:Peptide Fragments / Q000097:blood / Q000134:cerebrospinal fluid*; D012680:Sensitivity and Specificity
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)