| 1. |
- Mattsson, Niklas, 1979, et al.
(författare)
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The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers.
- 2011
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Ingår i: Alzheimer's & dementia : the journal of the Alzheimer's Association. - : Wiley. - 1552-5279. ; 7:4
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Tidskriftsartikel (refereegranskat)abstract
- The cerebrospinal fluid (CSF) biomarkers amyloid β (Aβ)-42, total-tau (T-tau), and phosphorylated-tau (P-tau) demonstrate good diagnostic accuracy for Alzheimer's disease (AD). However, there are large variations in biomarker measurements between studies, and between and within laboratories. The Alzheimer's Association has initiated a global quality control program to estimate and monitor variability of measurements, quantify batch-to-batch assay variations, and identify sources of variability. In this article, we present the results from the first two rounds of the program.
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| 2. |
- Verberk, Inge M.W., et al.
(författare)
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Combination of plasma amyloid beta(1-42/1-40)and glial fibrillary acidic protein strongly associates with cerebral amyloid pathology
- 2020
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Ingår i: Alzheimer's Research and Therapy. - : Springer Science and Business Media LLC. - 1758-9193. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Blood-based biomarkers for Alzheimer's disease (AD) might facilitate identification of participants for clinical trials targeting amyloid beta (Abeta) accumulation, and aid in AD diagnostics. We examined the potential of plasma markers Abeta(1-42/1-40), glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) to identify cerebral amyloidosis and/or disease severity. Methods: We included individuals with a positive (n = 176: 63 ± 7 years, 87 (49%) females) or negative (n = 76: 61 ± 9 years, 27 (36%) females) amyloid PET status, with syndrome diagnosis subjective cognitive decline (18 PET+, 25 PET-), mild cognitive impairment (26 PET+, 24 PET-), or AD-dementia (132 PET+). Plasma Abeta(1-42/1-40), GFAP, and NfL were measured by Simoa. We applied two-way ANOVA adjusted for age and sex to investigate the associations of the plasma markers with amyloid PET status and syndrome diagnosis; logistic regression analysis with Wald's backward selection to identify an optimal panel that identifies amyloid PET positivity; age, sex, and education-adjusted linear regression analysis to investigate associations between the plasma markers and neuropsychological test performance; and Spearman's correlation analysis to investigate associations between the plasma markers and medial temporal lobe atrophy (MTA). Results: Abeta(1-42/1-40) and GFAP independently associated with amyloid PET status (p = 0.009 and p < 0.001 respectively), and GFAP and NfL independently associated with syndrome diagnosis (p = 0.001 and p = 0.048 respectively). The optimal panel identifying a positive amyloid status included Abeta(1-42/1-40) and GFAP, alongside age and APOE (AUC = 88% (95% CI 83-93%), 82% sensitivity, 86% specificity), while excluding NfL and sex. GFAP and NfL robustly associated with cognitive performance on global cognition and all major cognitive domains (GFAP: range standardized β (sβ) = - 0.40 to - 0.26; NfL: range sβ = - 0.35 to - 0.18; all: p < 0.002), whereas Abeta(1-42/1-40) associated with global cognition, memory, attention, and executive functioning (range sβ = 0.22 - 0.11; all: p < 0.05) but not language. GFAP and NfL showed moderate positive correlations with MTA (both: Spearman's rho> 0.33, p < 0.001). Abeta(1-42/1-40) showed a moderate negative correlation with MTA (Spearman's rho = - 0.24, p = 0.001). Discussion and conclusions: Combination of plasma Abeta(1-42/1-40) and GFAP provides a valuable tool for the identification of amyloid PET status. Furthermore, plasma GFAP and NfL associate with various disease severity measures suggesting potential for disease monitoring.
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| 3. |
- Hansson, Oskar, et al.
(författare)
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The Alzheimer's Association international guidelines for handling of cerebrospinal fluid for routine clinical measurements of amyloid β and tau
- 2021
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 17:9, s. 1575-1582
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Tidskriftsartikel (refereegranskat)abstract
- The core cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers amyloid beta (Aβ42 and Aβ40), total tau, and phosphorylated tau, have been extensively clinically validated, with very high diagnostic performance for AD, including the early phases of the disease. However, between-center differences in pre-analytical procedures may contribute to variability in measurements across laboratories. To resolve this issue, a workgroup was led by the Alzheimer's Association with experts from both academia and industry. The aim of the group was to develop a simplified and standardized pre-analytical protocol for CSF collection and handling before analysis for routine clinical use, and ultimately to ensure high diagnostic performance and minimize patient misclassification rates. Widespread application of the protocol would help minimize variability in measurements, which would facilitate the implementation of unified cut-off levels across laboratories, and foster the use of CSF biomarkers in AD diagnostics for the benefit of the patients.
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| 4. |
- Mattsson, Niklas, 1979, et al.
(författare)
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Reference measurement procedures for Alzheimer's disease cerebrospinal fluid biomarkers: definitions and approaches with focus on amyloid β42.
- 2012
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Ingår i: Biomarkers in medicine. - : Future Medicine Ltd. - 1752-0371 .- 1752-0363. ; 6:4, s. 409-17
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Tidskriftsartikel (refereegranskat)abstract
- Cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) are increasingly used in clinical settings, research and drug trials. However, their broad-scale use on different technology platforms is hampered by the lack of standardization at the level of sample handling, determination of concentrations of analytes and the absence of well-defined performance criteria for in vitro diagnostic or companion diagnostic assays, which influences the apparent concentration of the analytes measured and the subsequent interpretation of the data. There is a need for harmonization of CSF AD biomarker assays that can reliably, across centers, quantitate CSF biomarkers with high analytical precision, selectivity and stability over long time periods. In this position paper, we discuss reference procedures for the measurement of CSF AD biomarkers, especially amyloid β42 and tau. We describe possible technical approaches, focusing on a selected reaction monitoring mass spectrometry assay as a candidate reference method for quantification of CSF amyloid β42.
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| 5. |
- Mollenhauer, Brit, et al.
(författare)
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A user's guide for α-synuclein biomarker studies in biological fluids: Perianalytical considerations.
- 2017
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Ingår i: Movement disorders : official journal of the Movement Disorder Society. - : Wiley. - 1531-8257. ; 32:8, s. 1117-1130
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Forskningsöversikt (refereegranskat)abstract
- Parkinson's disease biomarkers are needed to increase diagnostic accuracy, to objectively monitor disease progression and to assess therapeutic efficacy as well as target engagement when evaluating novel drug and therapeutic strategies. This article summarizes perianalytical considerations for biomarker studies (based on immunoassays) in Parkinson's disease, with emphasis on quantifying total α-synuclein protein in biological fluids. Current knowledge and pitfalls are discussed, and selected perianalytical variables are presented systematically, including different temperature of sample collection and types of collection tubes, gradient sampling, the addition of detergent, aliquot volume, the freezing time, and the different thawing methods. We also discuss analytical confounders. We identify gaps in the knowledge and delineate specific areas that require further investigation, such as the need to identify posttranslational modifications of α-synuclein and antibody-independent reference methods for quantification, as well as the analysis of potential confounders, such as comorbidities, medication, and phenotypes of Parkinson's disease in larger cohorts. This review could be used as a guideline for future Parkinson's disease biomarker studies and will require regular updating as more information arises in this growing field, including new technical developments as they become available. In addition to reviewing best practices, we also identify the current technical limitations and gaps in the knowledge that should be addressed to enable accurate and quantitative assessment of α-synuclein levels in the clinical setting. © 2017 International Parkinson and Movement Disorder Society.
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| 6. |
- Mollenhauer, Brit, et al.
(författare)
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Antibody-based methods for the measurement of α-synuclein concentration in human cerebrospinal fluid - method comparison and round robin study.
- 2019
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Ingår i: Journal of neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 149:1, s. 126-138
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Tidskriftsartikel (refereegranskat)abstract
- α-Synuclein is the major component of Lewy bodies and a candidate biomarker for neurodegenerative diseases in which Lewy bodies are common, including Parkinson's disease and dementia with Lewy bodies. A large body of literature suggests that these disorders are characterized by reduced concentrations of α-synuclein in cerebrospinal fluid (CSF), with overlapping concentrations compared to healthy controls and variability across studies. Several reasons can account for this variability, including technical ones, such as inter-assay and inter-laboratory variation (reproducibility). We compared four immunochemical methods for the quantification of α-synuclein concentration in 50 unique CSF samples. All methods were designed to capture most of the existing α-synuclein forms in CSF ('total' α-synuclein). Each of the four methods showed high analytical precision, excellent correlation between laboratories (R2 0.83-0.99), and good correlation with each other (R2 0.64-0.93), although the slopes of the regression lines were different between the four immunoassays. The use of common reference CSF samples decreased the differences in α-synuclein concentration between detection methods and technologies. Pilot data on an immunoprecipitation mass spectrometry (IP-MS) method isalso presented. Our results suggest that the four immunochemical methods and the IP-MS method measure similarforms of α-synuclein and that a common reference materialwould allow harmonization of results between immunoassays.
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| 7. |
- Bjerke, Maria, 1977, et al.
(författare)
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Assessing the commutability of reference material formats for the harmonization of amyloid beta measurements.
- 2016
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Ingår i: Clinical chemistry and laboratory medicine : CCLM / FESCC. - : Walter de Gruyter GmbH. - 1437-4331 .- 1434-6621. ; 54:7, s. 1177-91
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The cerebrospinal fluid (CSF) amyloid-β (Aβ42) peptide is an important biomarker for Alzheimer's disease (AD). Variability in measured Aβ42 concentrations at different laboratories may be overcome by standardization and establishing traceability to a reference system. Candidate certified reference materials (CRMs) are validated herein for this purpose. METHODS: Commutability of 16 candidate CRM formats was assessed across five CSF Aβ42 immunoassays and one mass spectrometry (MS) method in a set of 48 individual clinical CSF samples. Promising candidate CRM formats (neat CSF and CSF spiked with Aβ42) were identified and subjected to validation across eight (Elecsys, EUROIMMUN, IBL, INNO-BIA AlzBio3, INNOTEST, MSD, Simoa, and Saladax) immunoassays and the MS method in 32 individual CSF samples. Commutability was evaluated by Passing-Bablok regression and the candidate CRM termed commutable when found within the prediction interval (PI). The relative distance to the regression line was assessed. RESULTS: The neat CSF candidate CRM format was commutable for almost all method comparisons, except for the Simoa/MSD, Simoa/MS and MS/IBL where it was found just outside the 95% PI. However, the neat CSF was found within 5% relative distance to the regression line for MS/IBL, between 5% and 10% for Simoa/MS and between 10% and 15% for Simoa/MSD comparisons. CONCLUSIONS: The neat CSF candidate CRM format was commutable for 33 of 36 method comparisons, only one comparison more than expected given the 95% PI acceptance limit. We conclude that the neat CSF candidate CRM can be used for value assignment of the kit calibrators for the different Aβ42 methods.
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| 8. |
- Petzold, Axel, et al.
(författare)
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Neurofilament ELISA validation
- 2010
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Ingår i: JOURNAL OF IMMUNOLOGICAL METHODS. - 0022-1759. ; 352:1-2, s. 23-31
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Tidskriftsartikel (refereegranskat)
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| 9. |
- Petzold, Axel, et al.
(författare)
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Neurofilament ELISA validation
- 2010
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Ingår i: JIM - Journal of Immunological Methods. - : Elsevier BV. - 0022-1759 .- 1872-7905. ; 352:1-2, s. 23-31
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Neurofilament proteins (Nf) are highly specific biomarkers for neuronal death and axonal degeneration. As these markers become more widely used, an inter-laboratory validation study is required to identify assay criteria for high quality performance. METHODS: The UmanDiagnostics NF-light (R)enzyme-linked immunoabsorbent assays (ELISA) for the neurofilament light chain (NfL, 68kDa) was used to test the intra-assay and inter-laboratory coefficient of variation (CV) between 35 laboratories worldwide on 15 cerebrospinal fluid (CSF) samples. Critical factors, such as sample transport and storage, analytical delays, reaction temperature and time, the laboratories' accuracy and preparation of standards were documented and used for the statistical analyses. RESULTS: The intra-laboratory CV averaged 3.3% and the inter-laboratory CV 59%. The results from the test laboratories correlated with those from the reference laboratory (R=0.60, p<0.0001). Correcting for critical factors improved the strength of the correlation. Differences in the accuracy of standard preparation were identified as the most critical factor. Correcting for the error introduced by variation in the protein standards improved the correlation to R=0.98, p<0.0001 with an averaged inter-laboratory CV of 14%. The corrected overall inter-rater agreement was subtantial (0.6) according to Fleiss' multi-rater kappa and Gwet's AC1 statistics. CONCLUSION: This multi-center validation study identified the lack of preparation of accurate and consistent protein standards as the main reason for a poor inter-laboratory CV. This issue is also relevant to other protein biomarkers based on this type of assay and will need to be solved in order to achieve an acceptable level of analytical accuracy. The raw data of this study is available online.
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| 10. |
- Shaw, Leslie M, et al.
(författare)
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Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI.
- 2011
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 121:5, s. 597-609
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Tidskriftsartikel (refereegranskat)abstract
- The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau(181)) and Aβ(1-42) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0-6.0% (5.3%) for CSF Aβ(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p-tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Aβ(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aβ(1-42) and for the ratio t-tau/Aβ(1-42) were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau(181) and Aβ(1-42), together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the "gold standard" for the diagnosis of definite AD in the near future.
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