Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging

Doecke, James D.; Ward, Larry D.; Burnham, Samantha; Villemagne, Victor L.; Li, Qiao Xin; Collins, Steven J.; Fowler, Christopher; Manuilova, Ekaterina; Widmann, Monika; Rainey-Smith, Stephanie R.; Martins, Ralph N.; Masters, Colin L.

doi:10.1186/s13195-020-00595-5

Cited by 45 publications

(84 citation statements)

References 35 publications

(43 reference statements)

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“…In comparison, optimal cut-offs for describing Aβ-PET-positivity have been reported in the range from 977-1100 pg/mL for Aβ 1-42 , 213-242 pg/ml for t-tau, and 19-21 pg/ml for p-tau181. [7][8][9] The strong agreement between our neuropathology analysis and these in-vivo biomarker studies may be explained by the excellent accuracy of Aβ-PET for the detection of Aβ pathology, 24 further supporting the generalisability of Elecsys CSF cut-offs across different research settings.…”

Section: Discussionsupporting

confidence: 70%

“…Specifically, to date, there exists no neuropathologic validation of the fully automated Elecsys-derived Aβ and tau biomarker measurements, and currently recommended cut-offs for these standardised measures are based on concordance studies with Aβ-PET or clinical criteria. [7][8][9][10]23 In this study, we examined ante-mortem Elecsys-derived CSF biomarkers in relation to AD neuropathology assessed at autopsy in the same individuals. In preliminary analyses on a smaller subset of participants we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL).…”

Section: Introductionmentioning

confidence: 99%

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Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

et al. 2021

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Objective:To study cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) analyzed by fully automated Elecsys immunoassays in comparison to neuropathologic gold standards, and compare their accuracy to plasma phosphorylated tau (p-tau181) measured using a novel Simoa method.Methods:We studied ante-mortem Elecsys-derived CSF biomarkers in 45 individuals who underwent standardized post-mortem assessments of AD and non-AD neuropathologic changes at autopsy. In a subset of 26 participants, we also analysed ante-mortem levels of plasma p-tau181 and neurofilament light (NfL). Reference biomarker values were obtained from 146 amyloid-PET-negative healthy controls (HC).Results:All CSF biomarkers clearly distinguished pathology-confirmed AD dementia (N=27) from HC (AUCs=0.86-1.00). CSF total-tau (t-tau), p-tau181, and their ratios with Aβ1-42, also accurately distinguished pathology-confirmed AD from non-AD dementia (N=8; AUCs=0.94-0.97). In pathology-specific analyses, intermediate-to-high Thal amyloid phases were best detected by CSF Aβ1-42 (AUC[95% CI]=0.91[0.81-1]), while intermediate-to-high CERAD neuritic plaques and Braak tau stages were best detected by CSF p-tau181 (AUC=0.89[0.79-0.99] and 0.88[0.77-0.99], respectively). Optimal Elecsys biomarker cut-offs were derived at 1097/229/19 pg/ml for Aβ1-42, t-tau, and p-tau181. In the plasma subsample, both plasma p-tau181 (AUC=0.91[0.86-0.96]) and NfL (AUC=0.93[0.87-0.99]) accurately distinguished pathology-confirmed AD (N=14) from HC. However, only p-tau181 distinguished AD from non-AD dementia cases (N=4; AUC=0.96[0.88-1.00]), and showed a similar, though weaker, pathologic specificity for neuritic plaques (AUC=0.75[0.52-0.98]) and Braak stage (AUC=0.71[0.44-0.98]) as CSF p-tau181.Conclusions:Elecsys-derived CSF biomarkers detect AD neuropathologic changes with very high discriminative accuracy in-vivo. Preliminary findings support the use of plasma p-tau181 as an easily accessible and scalable biomarker of AD pathology.Classification of Evidence:This study provides Class II evidence that fully-automated CSF t-tau and p-tau181measurements discriminate between autopsy-confirmed Alzheimer's disease and other dementias.

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Section: Discussionsupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

et al. 2021

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“…Strong concordance has been observed between CSF markers (A␤ 42 , tau, and pTau181) and PET-A␤amyloid status, as measured by the Roche Elecsys and INNOtest assays [30,31]. A high correlation of CSF biomarkers on the AlzBio3 and EUROIMMUNE platforms has also been reported [101].…”

Section: Cerebrospinal Fluid Biomarkers: Aβ Tau Neurofilament Light Chainmentioning

confidence: 75%

“…CSF was tested routinely using the INNOTEST ® kit assay (Innogenetics, now Fujirebio Europe N.V., Ghent, Belgium) for Abeta 1-42 (A␤42), total tau (tTau) and phospho-tau 181 (pTau181), with thresholds for CSF biomarker positivity determined using a rank order approach (0.10 fractile for A␤ 42 and 0.90 fractile for tTau and pTau181) against a Pittsburgh Compound B (PiB) Standardized Uptake Value Ratio (SUVR) of 1.4 (or equivalent in other tracers) [30]. Participants with three or more collections of CSF have also been analyzed using automated Elecsys® assays (Roche Diagnostics) for A␤ 42 , A␤ 1-40 , tTau, and pTau181 [31].…”

Section: Cerebrospinal Fluid Samplesmentioning

confidence: 99%

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

Fowler¹,

Rainey‐Smith²,

Bird³

et al. 2021

ADR

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Background: The Australian Imaging, Biomarkers and Lifestyle (AIBL) Study commenced in 2006 as a prospective study of 1,112 individuals (768 cognitively normal (CN), 133 with mild cognitive impairment (MCI), and 211 with Alzheimer’s disease dementia (AD)) as an ‘Inception cohort’ who underwent detailed ssessments every 18 months. Over the past decade, an additional 1247 subjects have been added as an ‘Enrichment cohort’ (as of 10 April 2019). Objective: Here we provide an overview of these Inception and Enrichment cohorts of more than 8,500 person-years of investigation. Methods: Participants underwent reassessment every 18 months including comprehensive cognitive testing, neuroimaging (magnetic resonance imaging, MRI; positron emission tomography, PET), biofluid biomarkers and lifestyle evaluations. Results: AIBL has made major contributions to the understanding of the natural history of AD, with cognitive and biological definitions of its three major stages: preclinical, prodromal and clinical. Early deployment of Aβ-amyloid and tau molecular PET imaging and the development of more sensitive and specific blood tests have facilitated the assessment of genetic and environmental factors which affect age at onset and rates of progression. Conclusion: This fifteen-year study provides a large database of highly characterized individuals with longitudinal cognitive, imaging and lifestyle data and biofluid collections, to aid in the development of interventions to delay onset, prevent or treat AD. Harmonization with similar large longitudinal cohort studies is underway to further these aims.

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“…Therefore, standardized and accurate determination of Aβ in CU participants is particularly challenging when multiple methods to assess Aβ are used. Among other concerns, the use of both CSF Aβ42 and Aβ PET may be particularly troublesome with 81% overall agreement reported between CSF Aβ42 and PiB‐PET 90 . The possibility for bias is also introduced with the use of multiple Aβ PET tracers due to factors such as lack of standardization of acquisition protocols, tracer administration, and image processing and analysis 91 .…”

Section: Discussionmentioning

confidence: 99%

The search for a convenient procedure to detect one of the earliest signs of Alzheimer's disease: A systematic review of the prediction of brain amyloid status

Ashford

Veitch

Neuhaus

et al. 2021

Alzheimer's & Dementia

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Introduction Convenient, cost‐effective tests for amyloid beta (Aβ) are needed to identify those at higher risk for developing Alzheimer's disease (AD). This systematic review evaluates recent models that predict dichotomous Aβ. (PROSPERO: CRD42020144734). Methods We searched Embase and identified 73 studies from 29,581 for review. We assessed study quality using established tools, extracted information, and reported results narratively. Results We identified few high‐quality studies due to concerns about Aβ determination and analytical issues. The most promising convenient, inexpensive classifiers consist of age, apolipoprotein E genotype, cognitive measures, and/or plasma Aβ. Plasma Aβ may be sufficient if pre‐analytical variables are standardized and scalable assays developed. Some models lowered costs associated with clinical trial recruitment or clinical screening. Discussion Conclusions about models are difficult due to study heterogeneity and quality. Promising prediction models used demographic, cognitive/neuropsychological, imaging, and plasma Aβ measures. Further studies using standardized Aβ determination, and improved model validation are required.

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Elecsys CSF biomarker immunoassays demonstrate concordance with amyloid-PET imaging

Cited by 45 publications

References 35 publications

Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Associations of Fully Automated CSF and Novel Plasma Biomarkers With Alzheimer Disease Neuropathology at Autopsy

Fifteen Years of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study: Progress and Observations from 2,359 Older Adults Spanning the Spectrum from Cognitive Normality to Alzheimer’s Disease

The search for a convenient procedure to detect one of the earliest signs of Alzheimer's disease: A systematic review of the prediction of brain amyloid status

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