Towards a unified protocol for handling of CSF before β-amyloid measurements

Janelidze, Shorena; Stomrud, Erik; Brix, Britta; Hansson, Oskar

doi:10.1186/s13195-019-0517-9

Cited by 46 publications

(53 citation statements)

References 40 publications

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“…Beyond these biological factors, sampling and storage procedures may also affect biomarker levels, and thereby influence reproducibility for both blood-based and CSF-based biomarker 43,44 . For example, CSF Aβ42 is hydrophobic and especially sensitive for variations in pre-analytical handling, and may be affected by the type of tubes used for CSF sampling and storage, as well as freeze-thaw procedures 45 .…”

Section: Factors Affecting Reproducibilitymentioning

confidence: 99%

Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies

et al. 2020

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Biomarkers have revolutionized scientific research on neurodegenerative diseases, in particular Alzheimer’s disease, transformed drug trial design, and are also increasingly improving patient management in clinical practice. A few key cerebrospinal fluid biomarkers have been robustly associated with neurodegenerative diseases. Several novel biomarkers are very promising, especially blood-based markers. However, many biomarker findings have had low reproducibility despite initial promising results. In this perspective, we identify possible sources for low reproducibility of studies on fluid biomarkers for neurodegenerative diseases, with a focus on Alzheimer’s disease. We suggest guidelines for researchers and journal editors, with the aim to improve reproducibility of findings.

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Section: Factors Affecting Reproducibilitymentioning

confidence: 99%

Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies

et al. 2020

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“…However, only 8 samples were tested and thus the significance of small variations could have been hindered by the limited sample size. Similar considerations can be done also for the more recent works of Le Bastard et al [9] and Janelidze et al [33], in which, together with other preanalytical factors, the impact of freezing was tested for Aβ42, ptau, and t-tau and for Aβ40, Aβ42, and Aβ42/Aβ40 ratio, respectively, on 10 samples by ELISAs. In our experiments, by using aliquots originating from 58 distinct patients, small but significant systematic differences were observed for Aβ40, Aβ42/Aβ40, p-tau, and t-tau between fresh and frozen samples, while a non-significant decreased value of Aβ42 was also measured.…”

Section: Discussionmentioning

confidence: 74%

Measurement of CSF core Alzheimer disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

et al. 2020

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Background Cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau), and total-tau (t-tau) represent core biomarkers of Alzheimer disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work. Methods Fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after 1-month deep freezing (− 80 °C). As an automated platform, we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes. Results In fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%), and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42. These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau. Nevertheless, the Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples. Conclusions Small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau, and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cutoffs for fresh and frozen samples are required, larger, multi-center investigations are needed.

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“…However, only 8 samples were tested and thus the signi cance of small variations could have been hindered by the limited sample size. Similar considerations can be done also for the more recent works of Le Bastard et al [9] and Janelidze et al [33], in which, together with other preanalytical factors, the impact of freezing was tested for Aβ42, p-tau and t-tau and for Aβ40, Aβ42 and Aβ42/Aβ40 ratio, respectively on 10 samples by ELISAs. In our experiments, by using aliquots originating from 58 distinct patients, small but signi cant systematic differences were observed for Aβ40, Aβ42/Aβ40, p-tau and t-tau between fresh and frozen samples, while a non-signi cant decreased value of Aβ42 was also measured.…”

Section: Discussionmentioning

confidence: 75%

Measurement of CSF core Alzheimer Disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

Bellomo

Cataldi

Paciotti

et al. 2020

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Abstract Background: cerebrospinal fluid (CSF) amyloid-beta (Aβ) 42/40 ratio, threonine-181-phosphorylated-tau (p-tau) and total-tau (t-tau) represent core biomarkers of Alzheimer Disease (AD). The recent availability of automated platforms has represented a significant achievement for reducing the pre-analytical variability of these determinations in clinical setting. With respect to classical manual ELISAs, these platforms give us also the possibility to measure any single sample and to get the result within approximately 30 min. So far, reference values have been calculated from measurements obtained in frozen samples. In this work, we wanted to check if the values obtained in fresh CSF samples differ from those obtained in frozen samples, since this issue is mandatory in routine diagnostic work.Methods: fifty-eight consecutive CSF samples have been analyzed immediately after lumbar puncture and after one-month deep freezing (-80°C). As automated platform we used Lumipulse G600-II (Fujirebio Inc.). Both the fresh and the frozen aliquots were analyzed in their storage tubes. Results: in fresh samples, a mean increase of Aβ40 (6%), Aβ42 (2%), p-tau (2%) and t-tau (4%) was observed as compared to frozen samples, whereas a slight decrease was observed for Aβ42/Aβ40 ratio (4%), due to the higher deviation of Aβ40 in fresh samples compared to Aβ42.These differences are significant for Aβ40, Aβ42/Aβ40 ratio, p-tau and t-tau. Nevertheless, Aβ42/Aβ40 ratio showed a lower variability (smaller standard deviation of relative differences) with respect to Aβ42. With respect to the AD profile according to the A/T/(N) criteria for AD diagnosis, no significant changes in classification were observed when comparing results obtained in fresh vs frozen samples. Conclusions: small but significant differences have been found for Aβ40, Aβ42/Aβ40 ratio, p-tau and t-tau in fresh vs frozen samples. Importantly, these differences did not imply a modification in the A/T/(N) classification system. In order to know if different cut-offs for fresh and frozen samples are required, larger, multi-center investigations are needed.

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Towards a unified protocol for handling of CSF before β-amyloid measurements

Cited by 46 publications

References 40 publications

Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies

Increasing the reproducibility of fluid biomarker studies in neurodegenerative studies

Measurement of CSF core Alzheimer disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

Measurement of CSF core Alzheimer Disease biomarkers for routine clinical diagnosis: do fresh vs frozen samples differ?

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