Establishing In-House Cutoffs of CSF Alzheimer's Disease Biomarkers for the AT(N) Stratification of the Alzheimer Center Barcelona Cohort
Por:
Orellana, A, Garcia-Gonzalez, P, Valero, S, Montrreal, L, de Rojas, I, Hernandez, I, Rosende-Roca, M, Vargas, L, Tartari, JP, Antonio, EED, Bojaryn, U, Narvaiza, L, Alarcon-Martin, E, Alegret, M, Alcolea, D, Lleo, A, Tarraga, L, Pytel, V, Cano, A, Marquie, M, Boada, M, Ruiz, A
Publicada:
1 jul 2022
Resumen:
Background: Clinical diagnosis of Alzheimer's disease (AD) increasingly incorporates CSF biomarkers. However, due to the intrinsic variability of the immunodetection techniques used to measure these biomarkers, establishing in-house cutoffs defining the positivity/negativity of CSF biomarkers is recommended. However, the cutoffs currently published are usually reported by using cross-sectional datasets, not providing evidence about its intrinsic prognostic value when applied to real-world memory clinic cases. Methods: We quantified CSF A beta 1-42, A beta 1-40, t-Tau, and p181Tau with standard INNOTEST (R) ELISA and Lumipulse G (R) chemiluminescence enzyme immunoassay (CLEIA) performed on the automated Lumipulse G600II. Determination of cutoffs included patients clinically diagnosed with probable Alzheimer's disease (AD, n = 37) and subjective cognitive decline subjects (SCD, n = 45), cognitively stable for 3 years and with no evidence of brain amyloidosis in 18F-Florbetaben-labeled positron emission tomography (FBB-PET). To compare both methods, a subset of samples for A beta 1-42 (n = 519), t-Tau (n = 399), p181Tau (n = 77), and A beta 1-40 (n = 44) was analyzed. Kappa agreement of single biomarkers and A beta 1-42/A beta 1-40 was evaluated in an independent group of mild cognitive impairment (MCI) and dementia patients (n = 68). Next, established cutoffs were applied to a large real-world cohort of MCI subjects with follow-up data available (n = 647). Results: Cutoff values of A beta 1-42 and t-Tau were higher for CLEIA than for ELISA and similar for p181Tau. Spearman coefficients ranged between 0.81 for A beta 1-40 and 0.96 for p181TAU. Passing-Bablok analysis showed a systematic and proportional difference for all biomarkers but only systematic for A beta 1-40. Bland-Altman analysis showed an average difference between methods in favor of CLEIA. Kappa agreement for single biomarkers was good but lower for the A beta 1-42/A beta 1-40 ratio. Using the calculated cutoffs, we were able to stratify MCI subjects into four AT(N) categories. Kaplan-Meier analyses of AT(N) categories demonstrated gradual and differential dementia conversion rates (p = 9.815(-27)). Multivariate Cox proportional hazard models corroborated these findings, demonstrating that the proposed AT(N) classifier has prognostic value. AT(N) categories are only modestly influenced by other known factors associated with disease progression. Conclusions: We established CLEIA and ELISA internal cutoffs to discriminate AD patients from amyloid-negative SCD individuals. The results obtained by both methods are not interchangeable but show good agreement. CLEIA is a good and faster alternative to manual ELISA for providing AT(N) classification of our patients. AT(N) categories have an impact on disease progression. AT(N) classifiers increase the certainty of the MCI prognosis, which can be instrumental in managing real-world MCI subjects.
Filiaciones:
Orellana, A:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Garcia-Gonzalez, P:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Valero, S:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Montrreal, L:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
de Rojas, I:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Hernandez, I:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Rosende-Roca, M:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Vargas, L:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Tartari, JP:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Antonio, EED:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Bojaryn, U:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Narvaiza, L:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Alarcon-Martin, E:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Alegret, M:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Alcolea, D:
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Univ Autonoma Barcelona, St Pau Memory Unit, Dept Neurol, Hosp Santa Creu & St Pau,Biomed Res Inst St Pau, Barcelona 08029, Spain
Lleo, A:
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Univ Autonoma Barcelona, St Pau Memory Unit, Dept Neurol, Hosp Santa Creu & St Pau,Biomed Res Inst St Pau, Barcelona 08029, Spain
Tarraga, L:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Pytel, V:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Cano, A:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Marquie, M:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Boada, M:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
Ruiz, A:
Univ Int Catalunya UIC, Ace Alzheimer Ctr Barcelona, Barcelona 08029, Spain
Biomed Res Networking Ctr Neurodegenerat Dis CIBE, Madrid 28031, Spain
gold, Green Published
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