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Developments in clinical testing of cerebrospinal fluid biomarkers of Alzheimer’s disease in the UK
Author(s) -
Keshavan Ashvini,
Chapman Miles D.,
Hart Melanie,
Lunn Michael P.,
Zetterberg Henrik,
Schott Jonathan M.
Publication year - 2021
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.055946
Subject(s) - concordance , medicine , cohort , cerebrospinal fluid , disease , point of care testing , biomarker , prospective cohort study , pathology , biochemistry , chemistry
Background Guidance from the UK National Institute for Health and Care Excellence now incorporates CSF biomarkers in certain circumstances when a diagnosis of Alzheimer’s disease (AD) is considered. To improve testing speed and reliability, we validated the fully‐automated Lumipulse platform against existing Innotest ELISAs, by measuring amyloid‐β 1‐42 and 1‐40 (Aβ42 and Aβ40), tau and phospho‐tau181 (p‐tau181), and deriving cut‐points for reporting all routine clinical tests in the UK. Method In a prospectively‐collected cognitive clinic cohort, 56 samples were tested using Innotest ELISAs for Aβ42 and total tau, and the Lumipulse platform for Aβ42 and Aβ40. The Lumipulse Aβ42/Aβ40 cut‐point that gave the best concordance with an Innotest definition of AD‐like CSF (Aβ42<630 pg/ml and tau/Aβ42≥0.88) was selected and compared to values derived in the Insight 46 cohort by concordance with 18F‐florbetapir PET (Keshavan et al. 2020, Alz Dem (Amst.) doi:10.1002/dad2.12097). A subset of 20 samples from the clinic cohort assayed on both platforms for p‐tau181, and a further 42 samples from routine clinical testing, were also examined for concordance of Lumipulse p‐tau181 with Aβ42/Aβ40. Result A Lumipulse Aβ42/Aβ40 cut‐point of 0.065 gave 95% sensitivity and 89% specificity for distinguishing AD‐like from non‐AD‐like CSF (area under the curve (AUC) 0.959). Applying this cut‐point to data from Insight 46, where the Lumipulse Aβ42/Aβ40 AUC for amyloid PET was 0.966, yielded 85% sensitivity and 94‐96% specificity. Innotest and Lumipulse measurements of p‐tau181 were highly correlated (r=0.897, β=1.261, intercept=‐1.001). Applying the manufacturer's recommended Lumipulse p‐tau181 cut‐point of 56.5 pg/ml to the clinical samples gave 72% sensitivity and 86% specificity for distinguishing those with Lumipulse Aβ42/Aβ40≤0.065. Conclusion Clinical testing of AD CSF biomarkers in the UK has now moved to the Lumipulse platform, reducing the result turnaround time from 20‐25 to 10 working days. As certified reference materials for each biomarker become available, future cut‐point refinements may allow for standardisation across laboratories and even countries.