The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

Hansson, Oskar; Mikulskis, Alvydas; Fagan, Anne M.; Teunissen, Charlotte E.; Zetterberg, Henrik; Vanderstichele, Hugo; Molinuevo, José Luís; Shaw, Leslie M.; Vandijck, Manu; Verbeek, Marcel M.; Savage, Mary J.; Mattsson, Niklas; Lewczuk, Piotr; Batrla, Richard; Rutz, Sandra; Dean, Robert A.; Blennow, Kaj

doi:10.1016/j.jalz.2018.05.008

Cited by 100 publications

(119 citation statements)

References 161 publications

(141 reference statements)

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“…However, specific cutoff points for CSF biomarkers differ between these studies, and several methodological differences can explain these discrepancies. First, preanalytical conditions, such as the type of collection and storage tubes, are different between studies, and these factors are known to have a great impact on the absolute values of CSF biomarkers, especially for A β 1‐42 . Second, some analytical particularities for each immunoassay and platform used in these studies (specificity of the antibodies, time of incubation) result in diverse CSF biomarker measures.…”

Section: Discussionmentioning

confidence: 99%

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Alcolea

Pegueroles

Muñoz

et al. 2019

Ann Clin Transl Neurol

125

137

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Objective To determine the cutoffs that optimized the agreement between 18F‐Florbetapir positron emission tomography (PET) and Aβ1‐42, Aβ1‐40, tTau, pTau and their ratios measured in cerebrospinal fluid (CSF) on the LUMIPULSE G600II instrument, we quantified the levels of these four biomarkers in 94 CSF samples from participants of the Sant Pau Initiative on Neurodegeneration (SPIN cohort) using the Lumipulse G System with available 18F‐Florbetapir imaging. Methods Participants had mild cognitive impairment (n = 35), AD dementia (n = 12), other dementias or neurodegenerative diseases (n = 41), or were cognitively normal controls (n = 6). Levels of Aβ1‐42 were standardized to certified reference material. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with 18F‐Florbetapir PET and evaluated concordance between markers of the amyloid category. Results Aβ1‐42, tTau and pTau (but not Aβ1‐40) and the ratios with Aβ1‐42 had good diagnostic agreement with 18F‐Florbetapir PET. As a marker of amyloid pathology, the Aβ1‐42/Aβ1‐40 ratio had higher agreement and better correlation with amyloid PET than Aβ1‐42 alone. Interpretation CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging in a clinical setting with heterogeneous presentations of neurological disorders. Combination of Aβ1‐42 with Aβ1‐40 increases the agreement between markers of amyloid pathology.

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Section: Discussionmentioning

confidence: 99%

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Alcolea

Pegueroles

Muñoz

et al. 2019

Ann Clin Transl Neurol

125

137

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“…Although this strategy led to reasonable results, it does not allow for conclusions on the origin of observed variances. Potentially, differences in preanalytical protocols between the centres could be causative for the observed discrepancies, as the impact of preanalytical factors on biomarker levels is acknowledged well in research and assay manufacturer's instructions for standard AD markers in CSF and for immune markers in blood samples (though barely investigated for immune markers in CSF) . This would indicate that standardization and characterization of preanalytical confounders is of importance not only for the routinely used amyloid or tau isoforms but also for several immune markers frequently studied in CSF.…”

Section: Discussionmentioning

confidence: 99%

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Brosseron¹,

Kolbe²,

Santarelli³

et al. 2020

Alzheimer's & Dementia

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Introduction: Multiple immunity biomarkers have been suggested as tracers of neuroinflammation in neurodegeneration. This study aimed to verify findings in cerebrospinal fluid (CSF) samples of Alzheimer's disease (AD) and Parkinson's disease (PD) subjects from the network of the European, Innovative Medicines Initiative-funded project AETIONOMY.Methods: A total of 227 samples from the studies/centres AETIONOMY, ICEBERG, and IDIBAPS were used to analyse 21 selected immunity biomarkers in CSF. Results were compared to data of an independent cohort of 399 subjects previously published.Results: Immunity markers were predominantly and reproducibly associated with pathological levels of tau isoforms, but also with amyloid levels, aging, sex, APOE genotype, and center-specific factors.Discussion: Immunity biomarker levels in CSF reflect molecular and cellular pathology rather than diagnosis in neurodegenerative disorders. Assay standardization and stratification for age and other covariates could improve the power of such markers in clinical applications or intervention studies targeting immune responses in neurodegeneration.

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“…However, specific cutoff points for CSF biomarkers differ between these studies, and several methodological differences can explain these discrepancies. First, pre-analytical conditions, such as the type of collection and storage tubes, are different between studies, and these factors are known to have a great impact on the absolute values of CSF biomarkers, especially for Aβ1-42 [31,32]. Second, some analytical particularities for each immunoassay and platform used in these studies (specificity of the antibodies, In our study, we additionally included patients with other dementias or neurodegenerative diseases, which might reflect more realistically the application of biomarkers in daily clinical practice.…”

Section: Discussionmentioning

confidence: 99%

Agreement between ¹⁸F-Florbetapir PET imaging and cerebrospinal fluid Aβ1-42, Aβ1-40, tTau and pTau measured on the LUMIPULSE G fully automated platform

Alcolea

Pegueroles

Muñoz

et al. 2018

Preprint

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INTRODUCTION: The development of fully automated immunoassay platforms has improved the technical reliability of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease. METHODS:We quantified Aβ1-42, Aβ1-40, tTau and pTau levels using the Lumipulse G System in 94 CSF samples from participants of the SPIN cohort with available 18 F-Florbetapir imaging. Amyloid scans were assessed visually and through automated quantification. We determined the cutoffs of CSF biomarkers that optimized their agreement with 18 F-Florbetapir PET and evaluated concordance between markers of the amyloid category.RESULTS: Aβ1-42, tTau and pTau (but not Aβ1-40) and the ratios with Aβ1-42 had good diagnostic agreement with 18 F-Florbetapir PET. As a marker of amyloid pathology, the Aβ1-42/Aβ1-40 ratio had higher agreement and better correlation with amyloid PET than Aβ1-42 alone.DISCUSSION: CSF biomarkers measured with the Lumipulse G System show good agreement with amyloid imaging. Combination of Aβ1-42 with Aβ1-40 increases the agreement between markers of amyloid pathology.

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The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

Abstract: A unified CSF handling protocol is recommended to reduce preanalytical variability and facilitate comparison of CSF biomarkers across studies and laboratories. In future, experiments should use a gold standard with fresh CSF collected in low binding tubes.

Cited by 100 publications

References 161 publications

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Agreement between ¹⁸F-Florbetapir PET imaging and cerebrospinal fluid Aβ1-42, Aβ1-40, tTau and pTau measured on the LUMIPULSE G fully automated platform

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The impact of preanalytical variables on measuring cerebrospinal fluid biomarkers for Alzheimer's disease diagnosis: A review

Abstract: A unified CSF handling protocol is recommended to reduce preanalytical variability and facilitate comparison of CSF biomarkers across studies and laboratories. In future, experiments should use a gold standard with fresh CSF collected in low binding tubes.

Cited by 100 publications

References 161 publications

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Agreement of amyloid PET and CSF biomarkers for Alzheimer's disease on Lumipulse

Multicenter Alzheimer's and Parkinson's disease immune biomarker verification study

Agreement between 18F-Florbetapir PET imaging and cerebrospinal fluid Aβ1-42, Aβ1-40, tTau and pTau measured on the LUMIPULSE G fully automated platform

Contact Info

Product

Resources

About

Agreement between ¹⁸F-Florbetapir PET imaging and cerebrospinal fluid Aβ1-42, Aβ1-40, tTau and pTau measured on the LUMIPULSE G fully automated platform