Cochrane dementia group turns 21—older and (slightly) wiser

This invited editorial describes the achievements of the last 21 years of the Cochrane Dementia and Cognitive Improvement Group (DR Quinn is the coordinating editor of the group)

Are methodological quality and completeness of reporting associated with citation-based measures of publication impact? A secondary analysis of a systematic review of dementia biomarker studies

Objective: To determine whether methodological and reporting quality are associated with surrogate measures of publication impact in the field of dementia biomarker studies. Methods: We assessed dementia biomarker studies included in a previous systematic review in terms of methodological and reporting quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) and Standards for Reporting of Diagnostic Accuracy (STARD), respectively. We extracted additional study and journal-related data from each publication to account for factors shown to be associated with impact in previous research. We explored associations between potential determinants and measures of publication impact in univariable and stepwise multivariable linear regression analyses. Outcome measures: We aimed to collect data on four measures of publication impact: two traditional measures—average number of citations per year and 5-year impact factor of the publishing journal and two alternative measures—the Altmetric Attention Score and counts of electronic downloads. Results: The systematic review included 142 studies. Due to limited data, Altmetric Attention Scores and electronic downloads were excluded from the analysis, leaving traditional metrics as the only analysed outcome measures. We found no relationship between QUADAS and traditional metrics. Citation rates were independently associated with 5-year journal impact factor (β=0.42; p<0.001), journal subject area (β=0.39; p<0.001), number of years since publication (β=-0.29; p<0.001) and STARD (β=0.13; p<0.05). Independent determinants of 5-year journal impact factor were citation rates (β=0.45; p<0.001), statement on conflict of interest (β=0.22; p<0.01) and baseline sample size (β=0.15; p<0.05). Conclusions: Citation rates and 5-year journal impact factor appear to measure different dimensions of impact. Citation rates were weakly associated with completeness of reporting, while neither traditional metric was related to methodological rigour. Our results suggest that high publication usage and journal outlet is not a guarantee of quality and readers should critically appraise all papers regardless of presumed impact

Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the diagnosis of dementia within community dwelling populations

<b>Background</b><p></p> Various tools exist for initial assessment of possible dementia with no consensus on the optimal assessment method. Instruments that use collateral sources to assess change in cognitive function over time may have particular utility. The most commonly used informant dementia assessment is the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE).<p></p> A synthesis of the available data regarding IQCODE accuracy will help inform cognitive assessment strategies for clinical practice, research and policy.<p></p> <b>Objectives</b><p></p> Our primary objective was to determine the diagnostic accuracy of the informant based questionnaire IQCODE, for detection of all cause (undifferentiated) dementia in community-dwelling adults with no previous cognitive assessment. We sought to describe the accuracy of IQCODE (the index test) against a clinical diagnosis of dementia (the reference standard).<p></p> Our secondary objective was to describe the effect of heterogeneity on the summary estimates. We were particularly interested in the traditional 26-item scale versus the 16-item short form; and language of administration. We explored the effect of varying the threshold IQCODE score used to define 'test positivity'.<p></p> <b>Search methods</b><p></p> We searched the following sources on 28 January 2013: ALOIS (Cochrane Dementia and Cognitive Improvement Group), MEDLINE (OvidSP), EMBASE (OvidSP), PsycINFO (OvidSP), BIOSIS Previews (ISI Web of Knowledge), Web of Science with Conference Proceedings (ISI Web of Knowledge), LILACS (BIREME). We also searched sources relevant or specific to diagnostic test accuracy: MEDION (Universities of Maastrict and Leuven); DARE (York University); ARIF (Birmingham University). We used sensitive search terms based on MeSH terms and other controlled vocabulary.<p></p> <b>Selection criteria</b><p></p> We selected those studies performed in community settings that used (not necessarily exclusively) the IQCODE to assess for presence of dementia and, where dementia diagnosis was confirmed, with clinical assessment. Our intention with limiting the search to a 'community' setting was to include those studies closest to population level assessment. Within our predefined community inclusion criteria, there were relevant papers that fulfilled our definition of community dwelling but represented a selected population, for example stroke survivors. We included these studies but performed sensitivity analyses to assess the effects of these less representative populations on the summary results.<p></p> <b>Data collection and analysis</b><p></p> We screened all titles generated by the electronic database searches and abstracts of all potentially relevant studies were reviewed. Full papers were assessed for eligibility and data extracted by two independent assessors. For quality assessment (risk of bias and applicability) we used the QUADAS 2 tool. We included test accuracy data on the IQCODE used at predefined diagnostic thresholds. Where data allowed, we performed meta-analyses to calculate summary values of sensitivity and specificity with corresponding 95% confidence intervals (CIs). We pre-specified analyses to describe the effect of IQCODE format (traditional or short form) and language of administration for the IQCODE.<p></p> <b>Main results</b><p></p> From 16,144 citations, 71 papers described IQCODE test accuracy. We included 10 papers (11 independent datasets) representing data from 2644 individuals (n = 379 (14%) with dementia). Using IQCODE cut-offs commonly employed in clinical practice (3.3, 3.4, 3.5, 3.6) the sensitivity and specificity of IQCODE for diagnosis of dementia across the studies were generally above 75%.<p></p> Taking an IQCODE threshold of 3.3 (or closest available) the sensitivity was 0.80 (95% CI 0.75 to 0.85); specificity was 0.84 (95% CI 0.78 to 0.90); positive likelihood ratio was 5.2 (95% CI 3.7 to 7.5) and the negative likelihood ratio was 0.23 (95% CI 0.19 to 0.29).<p></p> Comparative analysis suggested no significant difference in the test accuracy of the 16 and 26-item IQCODE tests and no significant difference in test accuracy by language of administration. There was little difference in sensitivity across our predefined diagnostic cut-points.<p></p> There was substantial heterogeneity in the included studies. Sensitivity analyses removing potentially unrepresentative populations in these studies made little difference to the pooled data estimates. The majority of included papers had potential for bias, particularly around participant selection and sampling. The quality of reporting was suboptimal particularly regarding timing of assessments and descriptors of reproducibility and inter-observer variability.<p></p> <b>Authors' conclusions</b><p></p> Published data suggest that if using the IQCODE for community dwelling older adults, the 16 item IQCODE may be preferable to the traditional scale due to lesser test burden and no obvious difference in accuracy. Although IQCODE test accuracy is in a range that many would consider 'reasonable', in the context of community or population settings the use of the IQCODE alone would result in substantial misdiagnosis and false reassurance. Across the included studies there were issues with heterogeneity, several potential biases and suboptimal reporting quality

Machine learning reduced workload for the Cochrane COVID-19 Study Register: development and evaluation of the Cochrane COVID-19 Study Classifier

BACKGROUND: This study developed, calibrated and evaluated a machine learning (ML) classifier designed to reduce study identification workload in maintaining the Cochrane COVID-19 Study Register (CCSR), a continuously updated register of COVID-19 research studies. METHODS: A ML classifier for retrieving COVID-19 research studies (the 'Cochrane COVID-19 Study Classifier') was developed using a data set of title-abstract records 'included' in, or 'excluded' from, the CCSR up to 18th October 2020, manually labelled by information and data curation specialists or the Cochrane Crowd. The classifier was then calibrated using a second data set of similar records 'included' in, or 'excluded' from, the CCSR between October 19 and December 2, 2020, aiming for 99% recall. Finally, the calibrated classifier was evaluated using a third data set of similar records 'included' in, or 'excluded' from, the CCSR between the 4th and 19th of January 2021. RESULTS: The Cochrane COVID-19 Study Classifier was trained using 59,513 records (20,878 of which were 'included' in the CCSR). A classification threshold was set using 16,123 calibration records (6005 of which were 'included' in the CCSR) and the classifier had a precision of 0.52 in this data set at the target threshold recall >0.99. The final, calibrated COVID-19 classifier correctly retrieved 2285 (98.9%) of 2310 eligible records but missed 25 (1%), with a precision of 0.638 and a net screening workload reduction of 24.1% (1113 records correctly excluded). CONCLUSIONS: The Cochrane COVID-19 Study Classifier reduces manual screening workload for identifying COVID-19 research studies, with a very low and acceptable risk of missing eligible studies. It is now deployed in the live study identification workflow for the Cochrane COVID-19 Study Register

Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) for the early diagnosis of dementia across a variety of healthcare settings

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To determine the diagnostic accuracy of the informant based questionnaire IQCODE in a population free from dementia for the delayed diagnosis of dementia

CSF tau and the CSF tau/ABeta ratio for the diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

BACKGROUND: Research suggests that measurable change in cerebrospinal fluid (CSF) biomarkers occurs years in advance of the onset of clinical symptoms (Beckett 2010). In this review, we aimed to assess the ability of CSF tau biomarkers (t-tau and p-tau) and the CSF tau (t-tau or p-tau)/ABeta ratio to enable the detection of Alzheimer's disease pathology in patients with mild cognitive impairment (MCI). These biomarkers have been proposed as important in new criteria for Alzheimer's disease dementia that incorporate biomarker abnormalities. OBJECTIVES: To determine the diagnostic accuracy of 1) CSF t-tau, 2) CSF p-tau, 3) the CSF t-tau/ABeta ratio and 4) the CSF p-tau/ABeta ratio index tests for detecting people with MCI at baseline who would clinically convert to Alzheimer's disease dementia or other forms of dementia at follow-up. SEARCH METHODS: The most recent search for this review was performed in January 2013. We searched MEDLINE (OvidSP), Embase (OvidSP), BIOSIS Previews (Thomson Reuters Web of Science), Web of Science Core Collection, including Conference Proceedings Citation Index (Thomson Reuters Web of Science), PsycINFO (OvidSP), and LILACS (BIREME). We searched specialized sources of diagnostic test accuracy studies and reviews. We checked reference lists of relevant studies and reviews for additional studies. We contacted researchers for possible relevant but unpublished data. We did not apply any language or data restriction to the electronic searches. We did not use any methodological filters as a method to restrict the search overall. SELECTION CRITERIA: We selected those studies that had prospectively well-defined cohorts with any accepted definition of MCI and with CSF t-tau or p-tau and CSF tau (t-tau or p-tau)/ABeta ratio values, documented at or around the time the MCI diagnosis was 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 those biomarker results by disease status. Moreover, studies were only selected if they applied a reference standard for Alzheimer's disease 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, and the full papers for eligibility. Two independent assessors performed data extraction and quality assessment. 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: In total, 1282 participants with MCI at baseline were identified in the 15 included studies of which 1172 had analysable data; 430 participants converted to Alzheimer's disease dementia and 130 participants to other forms of dementia. Follow-up ranged from less than one year to over four years for some participants, but in the majority of studies was in the range one to three years. Conversion to Alzheimer's disease dementia The accuracy of the CSF t-tau was evaluated in seven studies (291 cases and 418 non-cases).The sensitivity values ranged from 51% to 90% while the specificity values ranged from 48% to 88%. At the median specificity of 72%, the estimated sensitivity was 75% (95% CI 67 to 85), the positive likelihood ratio was 2.72 (95% CI 2.43 to 3.04), and the negative likelihood ratio was 0.32 (95% CI 0.22 to 0.47).Six studies (164 cases and 328 non-cases) evaluated the accuracy of the CSF p-tau. The sensitivities were between 40% and 100% while the specificities were between 22% and 86%. At the median specificity of 47.5%, the estimated sensitivity was 81% (95% CI: 64 to 91), the positive likelihood ratio was 1.55 (CI 1.31 to 1.84), and the negative likelihood ratio was 0.39 (CI: 0.19 to 0.82).Five studies (140 cases and 293 non-cases) evaluated the accuracy of the CSF p-tau/ABeta ratio. The sensitivities were between 80% and 96% while the specificities were between 33% and 95%. We did not conduct a meta-analysis because the studies were few and small. Only one study reported the accuracy of CSF t-tau/ABeta ratio.Our findings are based on studies with poor reporting. A significant number of studies had unclear risk of bias for the reference standard, participant selection and flow and timing domains. According to the assessment of index test domain, eight of 15 studies were of poor methodological quality.The accuracy of these CSF biomarkers for 'other dementias' had not been investigated in the included primary studies. Investigation of heterogeneity The main sources of heterogeneity were thought likely to be reference standards used for the target disorders, sources of recruitment, participant sampling, index test methodology and aspects of study quality (particularly, inadequate blinding).We were not able to formally assess the effect of each potential source of heterogeneity as planned, due to the small number of studies available to be included. AUTHORS' CONCLUSIONS: The insufficiency and heterogeneity of research to date primarily leads to a state of uncertainty regarding the value of CSF testing of t-tau, p-tau or p-tau/ABeta ratio for the diagnosis of Alzheimer's disease in current clinical practice. Particular attention should be paid to the risk of misdiagnosis and overdiagnosis of dementia (and therefore over-treatment) in clinical practice. These tests, like other biomarker tests which have been subject to Cochrane DTA reviews, appear to have better sensitivity than specificity and therefore might have greater utility in ruling out Alzheimer's disease as the aetiology to the individual's evident cognitive impairment, as opposed to ruling it in. The heterogeneity observed in the few studies awaiting classification suggests our initial summary will remain valid. However, these tests may have limited clinical value until uncertainties have been addressed. Future studies with more uniformed approaches to thresholds, analysis and study conduct may provide a more homogenous estimate than the one that has been available from the included studies we have identified

(11)C-PIB-PET for the early diagnosis of Alzheimer's disease dementia and other dementias in people with mild cognitive impairment (MCI).

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, the confidence in diagnosing mild cognitive impairment (MCI) due to Alzheimer's disease dementia is raised with the application of imaging biomarkers. 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 the sensitivity, specificity, and other properties of positron emission tomography (PET) imaging with the (11)C-labelled Pittsburgh Compound-B ((11)C-PIB) ligand was performed. OBJECTIVES: To determine the diagnostic accuracy of the (11)C- PIB-PET scan for detecting participants with MCI at baseline who will clinically convert to Alzheimer's disease dementia or other forms of dementia over a period of time. SEARCH METHODS: The most recent search for this review was performed on 12 January 2013. 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 studies that had prospectively defined cohorts with any accepted definition of MCI with baseline (11)C-PIB-PET scan. In addition, we only selected studies that applied a reference standard for Alzheimer's dementia diagnosis for example NINCDS-ADRDA or Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria. DATA COLLECTION AND ANALYSIS: We screened all titles generated by electronic database searches. Two review authors independently assessed the abstracts of all potentially relevant studies. The identified full papers were assessed for eligibility and data were extracted to create two by two tables. Two independent assessors performed quality assessment using the QUADAS 2 tool. We used the hierarchical summary receiver operating characteristic (ROC) model to produce a summary ROC curve. MAIN RESULTS: Conversion from MCI to Alzheimer's disease dementia was evaluated in nine studies. The quality of the evidence was limited. Of the 274 participants included in the meta-analysis, 112 developed Alzheimer's dementia. Based on the nine included studies, the median proportion converting was 34%. The studies varied markedly in how the PIB scans were done and interpreted.The sensitivities were between 83% and 100% while the specificities were between 46% and 88%. Because of the variation in thresholds and measures of (11)C-PIB amyloid retention, we did not calculate summary sensitivity and specificity. Although subject to considerable uncertainty, to illustrate the potential strengths and weaknesses of (11)C-PIB-PET scans we estimated from the fitted summary ROC curve that the sensitivity was 96% (95% confidence interval (CI) 87 to 99) at the included study median specificity of 58%. This equated to a positive likelihood ratio of 2.3 and a negative likelihood ratio of 0.07. Assuming a typical conversion rate of MCI to Alzheimer's dementia of 34%, for every 100 PIB scans one person with a negative scan would progress and 28 with a positive scan would not actually progress to Alzheimer's dementia.There were limited data for formal investigation of heterogeneity. We performed two sensitivity analyses to assess the influence of type of reference standard and the use of a pre-specified threshold. There was no effect on our findings. AUTHORS' CONCLUSIONS: Although the good sensitivity achieved in some included studies is promising for the value of (11)C-PIB-PET, given the heterogeneity in the conduct and interpretation of the test and the lack of defined thresholds for determination of test positivity, we cannot recommend its routine use in clinical practice.(11)C-PIB-PET biomarker is a high cost investigation, therefore it is important to clearly demonstrate its accuracy and standardise the process of the (11)C-PIB diagnostic modality prior to it being widely used

Montreal Cognitive Assessment for the diagnosis of Alzheimer's disease and other dementias.

BACKGROUND: Dementia is a progressive syndrome of global cognitive impairment with significant health and social care costs. Global prevalence is projected to increase, particularly in resource-limited settings. Recent policy changes in Western countries to increase detection mandates a careful examination of the diagnostic accuracy of neuropsychological tests for dementia. OBJECTIVES: To determine the diagnostic accuracy of the Montreal Cognitive Assessment (MoCA) at various thresholds for dementia and its subtypes. SEARCH METHODS: We searched MEDLINE, EMBASE, BIOSIS Previews, Science Citation Index, PsycINFO and LILACS databases to August 2012. In addition, we searched specialised sources containing diagnostic studies and reviews, including MEDION (Meta-analyses van Diagnostisch Onderzoek), DARE (Database of Abstracts of Reviews of Effects), HTA (Health Technology Assessment Database), ARIF (Aggressive Research Intelligence Facility) and C-EBLM (International Federation of Clinical Chemistry and Laboratory Medicine Committee for Evidence-based Laboratory Medicine) databases. We also searched ALOIS (Cochrane Dementia and Cognitive Improvement Group specialized register of diagnostic and intervention studies). We identified further relevant studies from the PubMed 'related articles' feature and by tracking key studies in Science Citation Index and Scopus. We also searched for relevant grey literature from the Web of Science Core Collection, including Science Citation Index and Conference Proceedings Citation Index (Thomson Reuters Web of Science), PhD theses and contacted researchers with potential relevant data. SELECTION CRITERIA: Cross-sectional designs where all participants were recruited from the same sample were sought; case-control studies were excluded due to high chance of bias. We searched for studies from memory clinics, hospital clinics, primary care and community populations. We excluded studies of early onset dementia, dementia from a secondary cause, or studies where participants were selected on the basis of a specific disease type such as Parkinson's disease or specific settings such as nursing homes. DATA COLLECTION AND ANALYSIS: We extracted dementia study prevalence and dichotomised test positive/test negative results with thresholds used to diagnose dementia. This allowed calculation of sensitivity and specificity if not already reported in the study. Study authors were contacted where there was insufficient information to complete the 2x2 tables. We performed quality assessment according to the QUADAS-2 criteria.Methodological variation in selected studies precluded quantitative meta-analysis, therefore results from individual studies were presented with a narrative synthesis. MAIN RESULTS: Seven studies were selected: three in memory clinics, two in hospital clinics, none in primary care and two in population-derived samples. There were 9422 participants in total, but most of studies recruited only small samples, with only one having more than 350 participants. The prevalence of dementia was 22% to 54% in the clinic-based studies, and 5% to 10% in population samples. In the four studies that used the recommended threshold score of 26 or over indicating normal cognition, the MoCA had high sensitivity of 0.94 or more but low specificity of 0.60 or less. AUTHORS' CONCLUSIONS: The overall quality and quantity of information is insufficient to make recommendations on the clinical utility of MoCA for detecting dementia in different settings. Further studies that do not recruit participants based on diagnoses already present (case-control design) but apply diagnostic tests and reference standards prospectively are required. Methodological clarity could be improved in subsequent DTA studies of MoCA by reporting findings using recommended guidelines (e.g. STARDdem). Thresholds lower than 26 are likely to be more useful for optimal diagnostic accuracy of MoCA in dementia, but this requires confirmation in further studies.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/14651858.CD010775.pub

AD-8 for diagnosis of dementia across a variety of healthcare settings

This is a protocol for a Cochrane Review (Diagnostic test accuracy). The objectives are as follows: To determine the diagnostic accuracy of the informant‐based questionnaire AD‐8, in detection of all‐cause (undifferentiated) dementia in adults. We will present data for each healthcare setting where AD‐8 may be employed (community; primary care; secondary care)

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

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 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. 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