Meta-Review of CSF Core Biomarkers in Alzheimer’s Disease: The State-of-the-Art after the New Revised Diagnostic Criteria

Abstract

Background: Current research criteria for Alzheimer’s disease (AD) include cerebrospinal fluid (CSF) biomarkers into the diagnostic algorithm. However, spreading their use to the clinical routine is still questionable.Objective: To provide an updated, systematic and critical review on the diagnostic utility of the CSF core biomarkers for AD.Data sources: MEDLINE, PreMedline, EMBASE, PsycInfo, CINAHL, Cochrane Library, and CRD.Eligibility criteria: (1a) Systematic reviews with meta-analysis; (1b) Primary studies published after the new revised diagnostic criteria; (2) Evaluation of the diagnostic performance of at least one CSF core biomarker.Results: The diagnostic performance of CSF biomarkers is generally satisfactory. They are optimal for discriminating AD patients from healthy controls. Their combination may also be suitable for mild cognitive impairment (MCI) prognosis. However, CSF biomarkers fail to distinguish AD from other forms of dementia.Limitations: (1) Use of clinical diagnosis as standard instead of pathological postmortem confirmation; (2) variability of methodological aspects; (3) insufficiently long follow-up periods in MCI studies; and (4) lower diagnostic accuracy in primary care compared with memory clinics.Conclusion: Additional work needs to be done to validate the application of CSF core biomarkers as they are proposed in the new revised diagnostic criteria. The use of CSF core biomarkers in clinical routine is more likely if these limitations are overcome. Early diagnosis is going to be of utmost importance when effective pharmacological treatment will be available and the CSF core biomarkers can also be implemented in clinical trials for drug development.

On the early diagnosis of Alzheimer's Disease from multimodal signals: A survey

“…Aˇ40 is also present in the literature but no significant differences have been found for AD patients [63], and sometimes ratios between both Aˇ species have also been computed, suggesting that it has potential for both for distinguishing AD patients from healthy subjects and to predict AD in people suffering from MCI [60,[63][64][65]. CSF total tau, as well as some specific tau epitopes (p-tau231, p-tau181 and p-tau199), have been found to increase in AD [34,66] and some researches also affirm its predictability from MCI to AD [60,67]. The ratio of tau-epitopes to Aˇ42, in agreement with the precedent results, have also been found to be predictors of AD in MCI patients [67].…”

“…Aˇ42 is probably the most typical CSF measurement in AD detection, and in the majority of the cases decreased values have been found in AD patients compared to healthy subjects [34]. Aˇ40 is also present in the literature but no significant differences have been found for AD patients [63], and sometimes ratios between both Aˇ species have also been computed, suggesting that it has potential for both for distinguishing AD patients from healthy subjects and to predict AD in people suffering from MCI [60,[63][64][65].…”

“…Amyloid plaques refer to the deposits of beta-amyloid (ˇA) protein fragments, which are accumulated between the neurons and NFT to the deposits of tau protein fragments which are piled up inside the neurons [22]. The accumulation of ˇA on the brain is considered a necessary but not sufficient condition to produce the clinical symptoms of MCI and dementia [34]. The presence of these plaques and tangles is eventually accompanied by the damage and death of neurons [3], and in fact, one of the most favourable hypothesis about the origin of AD nowadays is the abnormal deposition of these proteins [35][36][37].…”

“…Thus, scientists have made the hypothesis that the accumulation of Aˇ plaques on the brain involves a decrease in CSF Aˇ42 levels and that this can be already appreciated in the asymptomatic period. CSF tau levels are also known to increase, but it is not clear if this happens after the Aˇ accumulation starts [62] or both processes start independently [34], thus, the pathophysiological process of tau might be precedent to the one of Aˇ.…”

“…"Numerous studies on CSF biomarkers for AD have been published during the last years, however frequently providing contradictory and inconclusive results" [34]. Furthermore, many of these biomarkers are not unique to AD disease but to other types of dementia.…”