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. 2023 Jul;19(7):2943-2955.
doi: 10.1002/alz.12907. Epub 2023 Jan 17.

Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study

Gemma Salvadó  1 , Victoria Larsson  1 , Karly A Cody  2 , Nicholas C Cullen  1 , Erin M Jonaitis  2   3 , Erik Stomrud  1   4 , Gwendlyn Kollmorgen  5 , Norbert Wild  5 , Sebastian Palmqvist  1   4 , Shorena Janelidze  1 , Niklas Mattsson-Carlgren  1   6   7 , Henrik Zetterberg  8   9   10   11   12 , Kaj Blennow  8   9 , Sterling C Johnson  2   3   13   14 , Rik Ossenkoppele  1   15 , Oskar Hansson  1   4
Affiliations

Optimal combinations of CSF biomarkers for predicting cognitive decline and clinical conversion in cognitively unimpaired participants and mild cognitive impairment patients: A multi-cohort study

Gemma Salvadó et al. Alzheimers Dement. 2023 Jul.

Abstract

Introduction: Our objective was determining the optimal combinations of cerebrospinal fluid (CSF) biomarkers for predicting disease progression in Alzheimer's disease (AD) and other neurodegenerative diseases.

Methods: We included 1,983 participants from three different cohorts with longitudinal cognitive and clinical data, and baseline CSF levels of Aβ42, Aβ40, phosphorylated tau at threonine-181 (p-tau), neurofilament light (NfL), neurogranin, α-synuclein, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), glial fibrillary acidic protein (GFAP), YKL-40, S100b, and interleukin 6 (IL-6) (Elecsys NeuroToolKit).

Results: Change of modified Preclinical Alzheimer's Cognitive Composite (mPACC) in cognitively unimpaired (CU) was best predicted by p-tau/Aβ42 alone (R2 ≥ 0.31) or together with NfL (R2 = 0.25), while p-tau/Aβ42 (R2 ≥ 0.19) was sufficient to accurately predict change of the Mini-Mental State Examination (MMSE) in mild cognitive impairment (MCI) patients. P-tau/Aβ42 (AUC ≥ 0.87) and p-tau/Aβ42 together with NfL (AUC ≥ 0.75) were the best predictors of conversion to AD and all-cause dementia, respectively.

Discussion: P-tau/Aβ42 is sufficient for predicting progression in AD, with very high accuracy. Adding NfL improves the prediction of all-cause dementia conversion and cognitive decline.

Keywords: BioFINDER; WADRC; WRAP; amyloid-β; cognitive decline; conversion to dementia; glial activation; inflammation; neurodegeneration; tau ratio.

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Conflict of interest statement

OH has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy/speaker fees from Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Fujirebio, Genentech, Novartis, Roche, and Siemens. GK and NW are employees of Roche Diagnostics. SP has served on scientific advisory boards and/or given lectures in symposia sponsored by Biogen, Eli Lilly, Geras Solutions, and Roche. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. SCJ previously served on an advisory board for Roche Diagnostics, and receives research funding from NIH and from Cerveau Technologies. COBAS, COBAS E and ELECSYS are trademarks of Roche. The Elecsys β-Amyloid (1-42) CSF assay, the Elecsys Phospo-Tau (181P) CSF assay and the Elecsys Total-Tau CSF assay are not approved for clinical use in the US. The NeuroToolKit robust prototype assays are for investigational purposes and are not approved for clinical use. GSB, VL, KAC, NCC, EMJ, ES, SJ, NMC and RO have nothing to disclose.

Figures

Figure 1.
Figure 1.. Cognitive change
Depiction of cognitive change over time per cohort and clinical group. Cognitive change in CU participants is shown with mPACC change (first column) while cognitive change in MCI patients is shown with MMSE (second column). Bold lines represent the predicted trajectory using the parsimonious model based on biomarkers levels at baseline. Green (red) lines represent participants with all biomarkers in the parsimonious model below (above) the mean at baseline. For the model with more than one biomarker included in the parsimonious model, the yellow line represents subjects with only one biomarker above the mean at baseline. Grey bands represent 95% confidence intervals. These lines are only for visualization purposes and represent the mean trajectory of the group of participants included in these artificial groups. Individual trajectories were calculated per each participant in the statistical model. Linear mixed models with random slope and intercept were used to construct the models. Biomarkers used in the parsimonious model in each case are detailed in the plots. Abbreviations: CU, cognitively unimpaired; MCI, mild cognitive impairment; MMSE, Mini-Mental State Examination; mPACC, modified Preclinical Alzheimer Cognitive Composite; WADRC, Wisconsin Alzheimer’s disease Research Center; WRAP, Wisconsin Registry for Alzheimer’s Prevention.
Figure 2.
Figure 2.. Clinical conversion
Depiction of ROC curves for basic, p-tau/aβ42 only and parsimonious models for predicting progression to AD or all-cause dementia. Models were created independently per clinical group at baseline (CU or MCI) and cohort (BioFINDER-1: [a], [c] and [e]; BioFINDER-2: [b], [d] and [f]; and WRAP & WADRC: [g]). Only scenarios with data available and more than 20 conversion cases are depicted. AUC[95%CI] are depicted for each model and case in the picture. Basic models only included covariates. Biomarkers included in the parsimonious models in each case are detailed in the figure. Covariates were included in all models and were: age, sex, APOE-ε4 carriership and time. Abbreviations: Aβ, amyloid-β; AD, Alzheimer’s disease; AUC, area under the curve; CI, confidence interval; CU, cognitively unimpaired; MCI, mild cognitive impairment; NfL, neurofilament light; Ng, neurogranin; p-tau; phosphorylated tau; ROC, receiver operating characteristic; WADRC, Wisconsin Alzheimer’s disease Research Center; WRAP, Wisconsin Registry for Alzheimer’s Prevention.
Figure 3.
Figure 3.. Kaplan-Meier survival curves for clinical conversion
Kaplan-Meier survival curves for each cohort and clinical group at baseline with conversion to Alzheimer’s dementia or all-cause dementia as outcome. Coloured lines depict different groups of individuals based on their baseline levels of selected biomarkers in the parsimonious models. Green (red) group line represents participants with all biomarkers in the parsimonious model below (above) the mean at baseline. For models with more than one biomarker included in the parsimonious model, yellow lines represent subjects with only one biomarkers above the mean at baseline. Coloured bands represent 95% confidence intervals and crosses represent censored data. These lines are only for visualization purposes and represent the mean trajectory of the group of participants included in these artificial groups. Individual trajectories were calculated per each participant in the statistical model. The total number of individuals in each group and timepoints are shown in the tables below the curves. Biomarkers used in the parsimonious model in each case are detailed in the plots. Abbreviations: Aβ, amyloid-β; CU, cognitively unimpaired; MCI, mild cognitive impairment; NfL, neurofilament light; Ng, neurogranin; p-tau; phosphorylated tau; WADRC, Wisconsin Alzheimer’s disease Research Center; WRAP, Wisconsin Registry for Alzheimer’s Prevention.
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References

    1. Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimer’s & Dementia 2018;14:535–62. 10.1016/j.jalz.2018.02.018. - DOI - PMC - PubMed
    1. Hansson O, Zetterberg H, Buchhave P, Londos E, Blennow K, Minthon L. Association between CSF biomarkers and incipient Alzheimer’s disease in patients with mild cognitive impairment: a follow-up study. Lancet Neurol 2006;5:228–34. 10.1016/S1474-4422(06)70355-6. - DOI - PubMed
    1. Blennow K, Shaw LM, Stomrud E, Mattsson N, Toledo JB, Buck K, et al. Predicting clinical decline and conversion to Alzheimer’s disease or dementia using novel Elecsys Aβ(1–42), pTau and tTau CSF immunoassays. Sci Rep 2019;9:1–11. 10.1038/s41598-019-54204-z. - DOI - PMC - PubMed
    1. Heneka MT, Carson MJ, Khoury J el, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol 2015;14:388–405. 10.1016/S1474-4422(15)70016-5. - DOI - PMC - PubMed
    1. Milà-Alomà M, Suárez-Calvet M, Molinuevo JL. Latest advances in cerebrospinal fluid and blood biomarkers of Alzheimer’s disease. Ther Adv Neurol Disord 2019;12. 10.1177/1756286419888819. - DOI - PMC - PubMed

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