Pre-analytical and analytical factors influencing Alzheimer's disease cerebrospinal fluid biomarker variability

Fourier, Anthony; Portelius, Erik; Zetterberg, Henrik; Blennow, Kaj; Quadrio, Isabelle; Perret‐Liaudet, Armand

doi:10.1016/j.cca.2015.05.024

Cited by 70 publications

(55 citation statements)

References 51 publications

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“…Surprisingly, although huge efforts have been carried out in the study of preanalytical and analytical conditions affecting biomarker outcomes [28][29][30][31] and consensus guidelines have been reported [12,32], just a few studies have reported the performance of a given set of samples in different laboratories, particularly in the case of aSyn [25,[33][34][35][36]. Furthermore, among these studies, some of them are limited by using low numbers of cases, whereas others did not study the performance of the assays on their diagnostic context.…”

Section: Discussionmentioning

confidence: 99%

Interlaboratory validation of cerebrospinal fluid α‐synuclein quantification in the diagnosis of sporadic Creutzfeldt‐Jakob disease

Kruse

Heslegrave

Gupta

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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Introduction Cerebrospinal fluid α-synuclein level is increased in sporadic Creutzfeldt-Jakob disease cases. However, the clinical value of this biomarker remains to be established. In this study, we have addressed the clinical validation parameters and the interlaboratory reproducibility by using an electrochemiluminescent assay. Methods Cerebrospinal fluid α-synuclein was quantified in a total of 188 sporadic Creutzfeldt-Jakob disease and non–Creutzfeldt-Jakob-disease cases to determine sensitivity and specificity values and lot-to-lot variability. Two round robin tests with 70 additional cases were performed in six independent laboratories. Results A sensitivity of 93% and a specificity of 96% were achieved in discriminating sporadic Creutzfeldt-Jakob disease. No differences were detected between lots. The mean interlaboratory coefficient of variation was 23%, and the intralaboratory coefficient of variations ranged 2.70%–11.39%. Overall, 97% of samples were correctly diagnosed. Discussion The herein validated α-synuclein assay is robust, accurate, and reproducible in identifying Creutzfeldt-Jakob disease cases. Thus, it is ready for implementation in the clinical practice to support the diagnosis of Creutzfeldt-Jakob disease.

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Section: Discussionmentioning

confidence: 99%

Interlaboratory validation of cerebrospinal fluid α‐synuclein quantification in the diagnosis of sporadic Creutzfeldt‐Jakob disease

Kruse

Heslegrave

Gupta

et al. 2018

Alz & Dem Diag Ass & Dis Mo

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“…different CSF collection and processing procedures, repeated freeze-thaw cycles, prolonged or inaccurate storage of samples) and has been shown for other CSF analytes (for review, see ref. 55). …”

Section: Discussionmentioning

confidence: 99%

Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis

Lugert

Kremer

Jagasia

et al. 2017

Sci Rep

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Adult hippocampal neurogenesis is a remarkable form of brain plasticity through which new neurons are generated throughout life. Despite its important roles in cognition and emotion and its modulation in various preclinical disease models, the functional importance of adult hippocampal neurogenesis in human health has not been revealed because of a lack of tools for monitoring adult neurogenesis in vivo. Therefore, we performed an unbiased proteomics screen to identify novel proteins expressed during neuronal differentiation using a human neural stem cell model, and we identified the proteoglycan Glypican-2 (Gpc2) as a putative secreted marker of immature neurons. Exogenous Gpc2 binds to FGF2 and inhibits FGF2-induced neural progenitor cell proliferation. Gpc2 is enriched in neurogenic regions of the adult brain. Its expression is increased by physiological stimuli that increase hippocampal neurogenesis and decreased in transgenic models in which neurogenesis is selectively ablated. Changes in neurogenesis also result in changes in Gpc2 protein level in cerebrospinal fluid (CSF). Gpc2 is detectable in adult human CSF, and first pilot experiments with a longitudinal cohort indicate a decrease over time. Thus, Gpc2 may serve as a potential marker to monitor adult neurogenesis in both animal and human physiology and disease, warranting future studies.

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“…Other challenges include variability in measured values due to pre-analytical and analytical factors, and the lack of consensus on cut-off values [98]. However, it is feasible that CSF tau could be used to assess target engagement of tau-targeted drugs [174, 363].…”

Section: Tau Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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Pre-analytical and analytical factors influencing Alzheimer's disease cerebrospinal fluid biomarker variability

Cited by 70 publications

References 51 publications

Interlaboratory validation of cerebrospinal fluid α‐synuclein quantification in the diagnosis of sporadic Creutzfeldt‐Jakob disease

Interlaboratory validation of cerebrospinal fluid α‐synuclein quantification in the diagnosis of sporadic Creutzfeldt‐Jakob disease

Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis

Current state of Alzheimer’s fluid biomarkers

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