Cerebrospinal fluid amyloid-β 42/40 ratio in clinical setting of memory centers: a multicentric study

Abstract

IntroductionThe cerebrospinal fluid (CSF) biomarkers amyloid-β (Aβ), tau and phosphorylated tau (p-tau181) are now used for the diagnosis of Alzheimer’s disease (AD). Aβ40 is the most abundant Aβ peptide isoform in the CSF, and the Aβ 42/40 ratio has been proposed to better reflect brain amyloid production. However, its additional value in the clinical setting remains uncertain.MethodsA total of 367 subjects with cognitive disorders who underwent a lumbar puncture were prospectively included at three French memory centers (Paris-North, Lille and Montpellier; the PLM Study). The frequency of positive, negative and indeterminate CSF profiles were assessed by various methods, and their adequacies with the diagnosis of clinicians were tested using net reclassification improvement (NRI) analyses.ResultsOn the basis of local optimum cutoffs for Aβ42 and p-tau181, 22% of the explored patients had indeterminate CSF profiles. The systematic use of Aβ 42/40 ratio instead of Aβ42 levels alone decreased the number of indeterminate profiles (17%; P = 0.03), but it failed to improve the classification of subjects (NRI = −2.1%; P = 0.64). In contrast, the use of Aβ 42/40 ratio instead of Aβ42 levels alone in patients with a discrepancy between p-tau181 and Aβ42 led to a reduction by half of the number of indeterminate profiles (10%; P < 0.001) and was further in agreement with clinician diagnosis (NRI = 10.5%; P = 0.003).ConclusionsIn patients with a discrepancy between CSF p-tau181 and CSF Aβ42, the assessment of Aβ 42/40 ratio led to a reliable biological conclusion in over 50% of cases that agreed with a clinician’s diagnosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-015-0114-5) contains supplementary material, which is available to authorized users.

Conflicting cerebrospinal fluid biomarkers and progression to dementia due to Alzheimer’s disease

“…In line with a number of previous reports [17–19], but in contrast to others [8, 9, 34, 35], approximately half of the MCI cases in our study had conflicting CSF biomarker constellations. This discrepancy in the frequency of patients with conflicting CSF biomarker results could be possibly attributed to differences in study design.…”

“…A further shortcoming of the study is the collection of some early CSF samples into inappropriate tubes at the ADNI sites. Although the error was corrected rapidly and despite the relatively limited exposure time to any inappropriate CSF collection tube, this error could embody a source of bias because the use of different collection tubes increases intra-laboratory variability [34, 56–58]. Moreover, we did not take into account imaging biomarker data.…”

Extracellular vesicle-associated Aβ mediates trans-neuronal bioenergetic and Ca2+-handling deficits in Alzheimer’s disease models

“…However, the Aβ42/Aβ40 ratio was significantly higher in EVs compared to the fluids from which they were isolated. These findings are of interest with regards to AD pathogenesis as the Aβ42/Aβ40 ratio has been found to be a more reliable biomarker for AD than Aβ42 or Aβ40 alone 44 . Moreover, mixtures of Aβ42 and Aβ40 with a higher Aβ42/Aβ40 ratio aggregate more vigorously and are more neurotoxic than mixtures with a low Aβ42/Aβ40 ratio 45,46 .…”

Detection of Plasma Biomarkers Using Immunomagnetic Reduction: A Promising Method for the Early Diagnosis of Alzheimer’s Disease

“…The ac magnetic signal from the sample is detected by the pick-up coil and is transmitted to the flux coupling component.

Fig. 3Configuration of the single-channel high-Tc SQUID ac magnetosusceptometer for IMR measurement [44]

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