Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.
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ABSTRACT: Background
We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.Materials and methods
From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R2 = 0.98, P < 0.001), neurodegeneration was defined by age-adjusted hippocampal volume. Multinomial regressions were used to test whether neuropsychological tests and regional brain volumes could distinguish ATN stages.Results
Age was 65 ± 7 years, with 58% females and 38% apolipoprotein E (APOE) ε4 carriers; 57.1% were A-T-N-, 32.5% were in the Alzheimer's disease (AD) continuum, and 10.4% suspected non-Alzheimer's pathology. Age and cerebrovascular burden progressed with biomarker positivity (P < 0.001). Cognitive dysfunction appeared with T+. Paradoxically higher regional gray matter volumes were observed in A+T-N- compared to A-T-N- (P < 0.001).Discussion
In non-demented individuals along the AD continuum, p-tau drives cognitive dysfunction. Memory and language domains are affected in the earliest stages.
SUBMITTER: Ingala S
PROVIDER: S-EPMC8359976 | biostudies-literature | 2021 Jul
REPOSITORIES: biostudies-literature
Publications
Application of the ATN classification scheme in a population without dementia: Findings from the EPAD cohort.
Ingala Silvia S De Boer Casper C Masselink Larissa A LA Vergari Ilaria I Lorenzini Luigi L Blennow Kaj K Chételat Gaël G Di Perri Carol C Ewers Michael M van der Flier Wiesje M WM Fox Nick C NC Gispert Juan Domingo JD Haller Sven S Molinuevo José Luís JL Muniz-Terrera Graciela G Mutsaerts Henri Jmm HJ Ritchie Craig W CW Ritchie Karen K Schmidt Mark M Schwarz Adam J AJ Vermunt Lisa L Waldman Adam D AD Wardlaw Joanna J Wink Alle Meije AM Wolz Robin R Wottschel Viktor V Scheltens Philip P Visser Pieter Jelle PJ Barkhof Frederik F
Alzheimer's & dementia : the journal of the Alzheimer's Association 20210403 7
<h4>Background</h4>We classified non-demented European Prevention of Alzheimer's Dementia (EPAD) participants through the amyloid/tau/neurodegeneration (ATN) scheme and assessed their neuropsychological and imaging profiles.<h4>Materials and methods</h4>From 1500 EPAD participants, 312 were excluded. Cerebrospinal fluid cut-offs of 1000 pg/mL for amyloid beta (Aß)1-42 and 27 pg/mL for p-tau181 were validated using Gaussian mixture models. Given strong correlation of p-tau and t-tau (R<sup>2</sup ...[more]
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Project description:IntroductionThe European Prevention of Alzheimer's Dementia (EPAD) project is funded initially by the Innovative Medicines Initiative and has been established to overcome the major hurdles hampering drug development for secondary prevention of Alzheimer's dementia, by conducting the EPAD Longitudinal Cohort Study (LCS) in alignment with the Bayesian adaptive designed EPAD Proof-of-Concept (PoC) trial.Methods and analysisEPAD LCS is an ongoing prospective, multicentre, pan-European longitudinal cohort study. Participants are recruited mainly from existing parent cohorts across Europe to form a 'probability-spectrum' population covering the entire continuum of anticipated probability for Alzheimer's dementia development. The primary objective of the EPAD LCS is to be a readiness cohort for the EPAD PoC trial though a second major objective is to generate a comprehensive and large data set for disease modelling of preclinical and prodromal Alzheimer's disease. This characterisation of cognitive, biomarker and risk factor (genetic and environmental) status of research participants over time will provide the necessary well-phenotyped population for developing accurate longitudinal models for Alzheimer's disease covering the entire disease course and concurrently create a pool of highly characterised individuals for the EPAD PoC trial.Ethics and disseminationThe study has received the relevant approvals from numerous Institutional Review Boards across Europe. Findings will be disseminated to several target audiences, including the scientific community, research participants, patient community, general public, industry, regulatory authorities and policy-makers. Regular and coordinated releases of EPAD LCS data will be made available for analysis to help researchers improve their understanding of early Alzheimer's disease stages and facilitate collaborations.Trial registration numberNCT02804789.
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Project description:IntroductionThe Amyloid/Tau/Neurodegeneration (ATN) framework was proposed to identify the preclinical biological state of Alzheimer's disease (AD). We investigated whether ATN phenotype can be predicted using routinely collected research cohort data.Methods927 EPAD LCS cohort participants free of dementia or Mild Cognitive Impairment were separated into 5 ATN categories. We used machine learning (ML) methods to identify a set of significant features separating each neurodegeneration-related group from controls (A-T-(N)-). Random Forest and linear-kernel SVM with stratified 5-fold cross validations were used to optimize model whose performance was then tested in the ADNI database.ResultsOur optimal results outperformed ATN cross-validated logistic regression models by between 2.2% and 8.3%. The optimal feature sets were not consistent across the 4 models with the AD pathologic change vs controls set differing the most from the rest. Because of that we have identified a subset of 10 features that yield results very close or identical to the optimal.DiscussionOur study demonstrates the gains offered by ML in generating ATN risk prediction over logistic regression models among pre-dementia individuals.
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Project description:BackgroundThe relationship between subtle cognitive decline and Alzheimer's disease (AD) pathology as measured by biomarkers in settings outside of specialty memory clinics is not well characterized.ObjectiveTo investigate how subtle longitudinal cognitive decline relates to neuroimaging biomarkers in individuals drawn from a population-based study in an economically depressed, small-town area in southwestern Pennsylvania, USA.MethodsA subset of participants without dementia (N = 115, age 76.53 years ± 6.25) from the Monongahela Youghiogheny Healthy Aging Team (MYHAT) study completed neuroimaging including magnetic resonance imaging (MRI) measures of AD-signature region cortical thickness and white matter hyperintensities (WMH), Pittsburgh compound B (PiB)-positron emission tomography (PET) for amyloid-β (Aβ) deposition, and [18F]AV-1451-PET for tau deposition. Neuropsychological evaluations were completed at multiple timepoints up to 11 years prior to neuroimaging. Aβ positivity was determined using a regional approach. We used linear mixed models to examine neuroimaging biomarker associations with retrospective cognitive slopes in five domains and a global cognitive composite.ResultsAmong Aβ(+) participants (38%), there were associations between (i) tau Braak III/IV and language decline (p < 0.05), (ii) cortical thickness and both memory decline (p < 0.001) and global cognitive decline (p < 0.01), and (iii) WMH and decline in executive function (p < 0.05) and global cognition (p < 0.05). Among Aβ(-) participants, there was an association between tau Braak III/IV and decline on tests of attention/psychomotor speed (p < 0.05).ConclusionsThese findings confirm an Aβ-dependent early AD biomarker pathway, and suggest a possible Aβ-independent, non-AD process underlying subtle cognitive decline in a population-based sample of older adults without dementia.
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Project description:The European Prevention of Alzheimer Dementia (EPAD) is a multi-center study that aims to characterize the preclinical and prodromal stages of Alzheimer's Disease. The EPAD imaging dataset includes core (3D T1w, 3D FLAIR) and advanced (ASL, diffusion MRI, and resting-state fMRI) MRI sequences. Here, we give an overview of the semi-automatic multimodal and multisite pipeline that we developed to curate, preprocess, quality control (QC), and compute image-derived phenotypes (IDPs) from the EPAD MRI dataset. This pipeline harmonizes DICOM data structure across sites and performs standardized MRI preprocessing steps. A semi-automated MRI QC procedure was implemented to visualize and flag MRI images next to site-specific distributions of QC features - i.e. metrics that represent image quality. The value of each of these QC features was evaluated through comparison with visual assessment and step-wise parameter selection based on logistic regression. IDPs were computed from 5 different MRI modalities and their sanity and potential clinical relevance were ascertained by assessing their relationship with biological markers of aging and dementia. The EPAD v1500.0 data release encompassed core structural scans from 1356 participants 842 fMRI, 831 dMRI, and 858 ASL scans. From 1356 3D T1w images, we identified 17 images with poor quality and 61 with moderate quality. Five QC features - Signal to Noise Ratio (SNR), Contrast to Noise Ratio (CNR), Coefficient of Joint Variation (CJV), Foreground-Background energy Ratio (FBER), and Image Quality Rate (IQR) - were selected as the most informative on image quality by comparison with visual assessment. The multimodal IDPs showed greater impairment in associations with age and dementia biomarkers, demonstrating the potential of the dataset for future clinical analyses.
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