Proteins in cerebrospinal fluids (CSF) for early prediction of developing Alzheimer’s disease or other dementia in people with mild cognitive problems

Background

The numbers of people with dementia and other cognitive problems are increasing globally. A diagnosis of dementia at early stage 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, we have focused on the cerebrospinal fluid (CSF) diagnostic tests.

Review question

We reviewed the evidence about the accuracy of CSF tests in identifying those people presenting with mild cognitive impairment (MCI) who would develop Alzheimer’s disease dementia or other forms of dementia over a period of time.

Study characteristics

The evidence is current to January 2013. We included 15 studies containing a total of 1282 participants with MCI. The majority of studies (n = 9) were published between 2010 and 2013. The remaining six studies were published between 2004 and 2009. All of the included studies were conducted in Europe.

Study sizes varied and ranged from 15 to 231 participants.The mean (range) age of the youngest sample was 64 years (45 to 76) and the mean (standard deviation) age of the oldest sample was 73.4 (6.6) years.

Quality of the evidence

Our findings are based on studies with poor reporting, with a majority of studies at unclear risk of bias due to insufficient details given on how participants were selected and how the clinical diagnosis of dementia was established. According to the assessment of how the CSF tests were conducted and analysed, eight of 15 studies were of poor methodological quality.

Key findings

Below is a summary of key findings for the tests:

CSF t-tau test for conversion from MCI to Alzheimer’s disease dementia

The sensitivity values in seven individual studies ranged from 51% to 90% while the specificity values ranged from 48% to 88%. The statistical analysis of those studies showed that, at the fixed specificity of 72%, the estimated sensitivity was 77%, and, at the prevalence of 37%, the positive predictive value was 62% and the negative predictive value was 84%. Based on these results, on average 62 out of 100 people with MCI and a positive index test result would convert to Alzheimer's disease dementia but 38 would not; on average, 84 out of 100 people with MCI and with a negative index test result would not convert to Alzheimer's disease dementia, but 16 would.

CSF p-tau test for conversion from MCI to Alzheimer’s disease dementia

The sensitivity values in six individual studies ranged from 40% to 100% while the specificity values ranged from 22% to 86%. The statistical analysis of those studies showed that, at the fixed specificity of 48%, the estimated sensitivity was 81%, and, at the prevalence of 37%, the positive predictive value was 48% and the negative predictive value was 81%. Based on these results, on average 48 out of 100 people with MCI and with a positive index test result would convert to Alzheimer's disease dementia, but 52 would not; on average, 81 out of 100 people with MCI with a negative index test result would not convert to Alzheimer's disease dementia, but 19 would.

We found that the cerebrospinal fluid (CSF) diagnostic test, as a single test, lacks the accuracy to identify those people with mild cognitive impairment (MCI) who would develop Alzheimer’s disease dementia or other forms of dementia over a period of time. The data suggested that a negative CSF test, in people with MCI, almost indicates the absence of Alzheimer's disease as the cause of their clinical symptoms. However, a positive CSF test does not confirm the presence of Alzheimer's disease as the aetiology (cause) of their clinical symptoms.

There were methodological problems in the included studies that did not allow for a clear answer to the review question. The main limitations of the review were poor reporting in the included studies, lack of a widely accepted threshold of the CSF diagnostic tests in people with MCI, variability in length of follow-up, and the marked variation in CSF tests’ accuracy between the included studies.

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.

Read the full abstract...
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 strategy: 

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.

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