Dataset Information

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging.

ABSTRACT:

Background

?-amyloid (A?) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology.

Methods

Using automated Elecsys® assays (Roche Diagnostics) for A? (1-42) (A?42), A? (1-40) (A?40), total tau (tTau) and phosphorylated tau (181P) (pTau), we examined CSF samples from 202 participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing cohort, to demonstrate the concordance with pathological AD via PET imaging.

Results

Ratios A?42/A?40, tTau/A?42 and pTau/A?42 had higher receiver operator characteristic-area under the curve (all 0.94), and greater concordance with A?-PET (overall percentage agreement ~?90%), compared with individual biomarkers.

Conclusion

Strong concordance between CSF biomarkers and A?-PET status was observed overall, including for cognitively normal participants, further strengthening the association between these markers of AD neuropathological burden for both developmental research studies and for use in clinical trials.

SUBMITTER: Doecke JD

PROVIDER: S-EPMC7110644 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Publications

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging.

Doecke James D JD Ward Larry L Burnham Samantha C SC Villemagne Victor L VL Li Qiao-Xin QX Collins Steven S Fowler Christopher J CJ Manuilova Ekaterina E Widmann Monika M Rainey-Smith Stephanie R SR Martins Ralph N RN Masters Colin L CL

Alzheimer's research & therapy 20200331 1

<h4>Background</h4>β-amyloid (Aβ) positron emission tomography (PET) imaging is currently the only Food and Drug Administration-approved method to support clinical diagnosis of Alzheimer's disease (AD). However, numerous research studies support the use of cerebrospinal fluid (CSF) biomarkers, as a cost-efficient, quick and equally valid method to define AD pathology.<h4>Methods</h4>Using automated Elecsys® assays (Roche Diagnostics) for Aβ (1-42) (Aβ42), Aβ (1-40) (Aβ40), total tau (tTau) and p ...[more]

PMID: 32234072

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Project description:Importance:Visual assessment of amyloid positron emission tomographic (PET) images has been approved by regulatory authorities for clinical use. Several immunoassays have been developed to measure ?-amyloid (A?) 42 in cerebrospinal fluid (CSF). The agreement between CSF A?42 measures from different immunoassays and visual PET readings may influence the use of CSF biomarkers and/or amyloid PET assessment in clinical practice and trials. Objective:To determine the concordance between CSF A?42 levels measured using 5 different immunoassays and visual amyloid PET analysis. Design, Setting, and Participants:The study included 262 patients with mild cognitive impairment or subjective cognitive decline from the Swedish BioFINDER (Biomarkers for Identifying Neurodegenerative Disorders Early and Reliably) cohort (recruited from September 1, 2010, through December 31, 2014) who had undergone flutemetamol F 18 ([18F]flutemetamol)-labeled PET. Levels of CSF A?42 were analyzed using the classic INNOTEST and the newer modified INNOTEST, fully automated Lumipulse (FL), EUROIMMUN (EI), and Meso Scale Discovery (MSD) assays. Concentrations of CSF A? were assessed using an antibody-independent mass spectrometry-based reference measurement procedure. Main Outcomes and Measures:The concordance of CSF A?42 levels and A?42:A?40 and A?42:tau ratios with visual [18F]flutemetamol PET status. Results:Of 262 participants (mean [SD] age, 70.9 [5.5] years), 108 were women (41.2%) and 154 were men (58.8%). The mass spectrometry-derived A?42 values showed higher correlations with the modified A?42-INNOTEST (r?=?0.97), A?42-FL (r?=?0.93), A?42-EI (r?=?0.93), and A?42-MSD (r?=?0.95) assays compared with the classic A?42-INNOTEST assay (r?=?0.88; P???.01). The signal in the classic A?42-INNOTEST assay was partly quenched by recombinant A?1-40 peptide. However, the classic A?42-INNOTEST assay showed better concordance with visual [18F]flutemetamol PET status (area under the receiver operating characteristic curve [AUC], 0.92) compared with the newer assays (AUCs, 0.87-0.89; P???.01). The accuracies of the newer assays improved significantly when A?42:A?40 (AUCs, 0.93-0.95; P???.01), A?42 to total tau (T-tau) (AUCs, 0.94; P???.05), or A?42 to phosphorylated tau (P-tau) (AUCs, 0.94-0.95; P???.001) ratios were used. A combination of the A?42:A?40 ratio and T-tau or P-tau level did not improve the accuracy compared with the ratio alone. Conclusions and Relevance:Concentrations of CSF A?42 derived from the new immunoassays (modified INNOTEST, FL, EI, and MSD) may correlate better with the antibody-independent mass spectrometry-based reference measurement procedure and may show improved agreement with visual [18F]flutemetamol PET assessment when using the A?42:A?40 or A?42:tau ratios. These findings suggest the benefit of implementing the CSF A?42:A?40 or A?42:tau ratios as a biomarker of amyloid deposition in clinical practice and trials.

Project description:BackgroundIn vivo, high cerebral amyloid-β load has been associated with (i) reduced concentrations of Aβ42 in cerebrospinal fluid and (ii) increased retention using amyloid-β positron emission tomography. Although these two amyloid-β biomarkers generally show good correspondence, ~ 10-20% of cases have discordant results. To assess the consequences of having discordant amyloid-β PET and CSF biomarkers on clinical features, biomarkers, and longitudinal cognitive trajectories.MethodsWe included 768 patients (194 with subjective cognitive decline (SCD), 127 mild cognitive impairment (MCI), 309 Alzheimer's dementia (AD), and 138 non-AD) who were categorized as concordant-negative (n = 315, 41%), discordant (n = 97, 13%), or concordant-positive (n = 356, 46%) based on CSF and PET results. We compared discordant with both concordant-negative and concordant-positive groups on demographics, clinical syndrome, apolipoprotein E (APOE) ε4 status, CSF tau, and clinical and neuropsychological progression.ResultsWe found an increase from concordant-negative to discordant to concordant-positive in rates of APOE ε4 (28%, 55%, 70%, Z = - 10.6, P < 0.001), CSF total tau (25%, 45%, 78%, Z = - 13.7, P < 0.001), and phosphorylated tau (28%, 43%, 80%, Z = - 13.7, P < 0.001) positivity. In patients without dementia, linear mixed models showed that Mini-Mental State Examination and memory composite scores did not differ between concordant-negative (β [SE] - 0.13[0.08], P = 0.09) and discordant (β 0.08[0.15], P = 0.15) patients (Pinteraction = 0.19), while these scores declined in concordant-positive (β - 0.75[0.08] patients (Pinteraction < 0.001). In patients with dementia, longitudinal cognitive scores were not affected by amyloid-β biomarker concordance or discordance. Clinical progression rates from SCD to MCI or dementia (P = 0.01) and from MCI to dementia (P = 0.003) increased from concordant-negative to discordant to concordant-positive.ConclusionsDiscordant cases were intermediate to concordant-negative and concordant-positive patients in terms of genetic (APOE ε4) and CSF (tau) markers of AD. While biomarker agreement did not impact cognition in patients with dementia, discordant biomarkers are not benign in patients without dementia given their higher risk of clinical progression.

Project description:BackgroundWe aimed to investigate the tau biomarker discrepancies of Alzheimer's disease (AD) using plasma tau phosphorylated at threonine 181 (p-tau181), cerebrospinal fluid (CSF) p-tau181, and AV1451 positron emission tomography (PET).MethodsIn the Alzheimer's Disease Neuroimaging Initiative, 724 non-demented participants were categorized into plasma/CSF and plasma/PET groups. Demographic and clinical variables, amyloid-β (Aβ) burden, flortaucipir-PET binding in Braak regions of interest (ROIs), longitudinal changes in clinical outcomes, and conversion risk were compared.ResultsAcross different tau biomarker groups, the proportion of participants with a discordant profile varied (plasma+/CSF- 15.6%, plasma-/CSF+ 15.3%, plasma+/PET- 22.4%, and plasma-/PET+ 6.1%). Within the plasma/CSF categories, we found an increase from concordant-negative to discordant to concordant-positive in the frequency of Aβ pathology or cognitive impairment, rates of cognitive decline, and risk of cognitive conversion. However, the two discordant categories (plasma+/CSF- and plasma-/CSF+) showed comparable performances, resulting in similarly reduced cognitive capacities. Regarding plasma/PET categories, as expected, PET-positive individuals had increased Aβ burden, elevated flortaucipir retention in Braak ROIs, and accelerated cognitive deterioration than concordant-negative persons. Noteworthy, discordant participants with normal PET exhibited reduced flortaucipir uptake in Braak stage ROIs and slower rates of cognitive decline, relative to those PET-positive. Therefore, individuals with PET abnormality appeared to have advanced tau pathological changes and poorer cognitive function, regardless of the plasma status. Furthermore, these results were found only in individuals with Aβ pathology.ConclusionsOur results indicate that plasma and CSF p-tau181 abnormalities associated with amyloidosis occur simultaneously in the progression of AD pathogenesis and related cognitive decline, before tau-PET turns positive.

Project description:BackgroundAlzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability in diverse ethnic groups are necessary for their use in clinics and clinical trials. With lack of cutoffs from fully automated immunoassay platforms in diverse races, the aim of this study is to evaluate the clinical utility of CSF AD biomarkers from the Lumipulse fully automated immunoassay based on ?-amyloid (A?) positron emission tomography (PET) status comparing with these from two manual immunoassays, in Koreans.MethodsAmong 331 Korean participants enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD, 139 (29 CN, 58 SCD, 29 MCI, and 23 AD) provided CSF and 271 underwent baseline amyloid PET (n?=?128 with overlapping CSF and A?-PET, and 143 without CSFs). Three annual cognitive and neuropsychiatric function tests were conducted. A?42, A?40, total-tau, and phosphorylated-tau181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with A?-PET, was evaluated.ResultsCognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN>SCD>MCI>AD. Biomarker levels among immunoassays were strongly intercorrelated. We determined the A?-PET status in a subgroup without CSF (n?=?143), and then when we applied CSF biomarker cutoffs determined based on the A?-PET status, the CSF biomarkers (cutoffs of 642.1?pg/mL for A?42, 0.060 for A?42/A?40, 0.315 for t-tau/A?42, and 0.051 for p-tau/A?42, respectively) showed good agreement with A?-PET (overall AUC ranges of 0.840-0.898). Use of the A?-PET-based CSF cutoffs showed excellent diagnostic discrimination between AD and CN (A?42, A?42/A?40, t-tau/A?42, and p-tau/A?42) with overall AUC ranges of 0.876-0.952. During follow-up, participants with AD-like CSF signature determined by A?-PET-based cutoffs from Lumipulse showed rapid progression of cognitive decline in 139 subjects, after adjustment for potential confounders, compared with those with a normal CSF signature.ConclusionCSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with A?-PET in Koreans. The Korean-specific A?-PET-based CSF biomarker cutoffs measured by the Lumipulse assay strongly predicts progression of cognitive decline. The clinical utility of CSF biomarkers from fully-automated immunoassay platforms should be evaluated in larger, more diverse cohorts.

Dataset Information

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging.

Background

Methods

Results

Conclusion

Publications

Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging.

Similar Datasets

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