Exploring the ATN classification system using brain morphology

Abstract

Background: The NIA-AA proposed amyloid-tau-neurodegeneration (ATN) as a classification system for AD biomarkers. The amyloid cascade hypothesis (ACH) implies a sequence across ATN groups that patients might undergo during transition from healthy towards AD: A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+. Here we assess the evidence for monotonic brain volume decline for this particular (amyloid-conversion first, tau-conversion second, N-conversion last) and alternative progressions using voxel-based morphometry (VBM) in a large cross-sectional MRI cohort.

Methods: We used baseline data of the DELCODE cohort of 437 subjects (127 controls, 168 SCD, 87 MCI, 55 AD patients) which underwent lumbar puncture, MRI scanning, and neuropsychological assessment. ATN classification was performed using CSF-Aβ42/Aβ40 (A+/-), CSF phospho-tau (T+/-), and adjusted hippocampal volume or CSF total-tau (N+/-). We compared voxel-wise model evidence for monotonic decline of gray matter volume across various sequences over ATN groups using the Bayesian Information Criterion (including also ROIs of Braak stages). First, face validity of the ACH transition sequence A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was compared against biologically less plausible (permuted) sequences among AD continuum ATN groups. Second, we evaluated evidence for 6 monotonic brain volume progressions from A-T-N- towards A+T+N+ including also non-AD continuum ATN groups.

Results: The ACH-based progression A-T-N-➔A+T-N-➔A+T+N-➔A+T+N+ was consistent with cognitive decline and clinical diagnosis. Using hippocampal volume for operationalization of neurodegeneration (N), ACH was most evident in 9% of gray matter predominantly in the medial temporal lobe. Many cortical regions suggested alternative non-monotonic volume progressions over ACH progression groups, which is compatible with an early amyloid-related tissue expansion or sampling effects, e.g., due to brain reserve. Volume decline in 65% of gray matter was consistent with a progression where A status converts before T or N status (i.e., ACH/ANT) when compared to alternative sequences (TAN/TNA/NAT/NTA). Brain regions earlier affected by tau tangle deposition (Braak stage I-IV, MTL, limbic system) present stronger evidence for volume decline than late Braak stage ROIs (V/VI, cortical regions). Similar findings were observed when using CSF total-tau for N instead.

Conclusion: Using the ATN classification system, early amyloid status conversion (before tau and neurodegeneration) is associated with brain volume loss observed during AD progression. The ATN system and the ACH are compatible with monotonic progression of MTL atrophy.

Trial registration: DRKS00007966, 04/05/2015, retrospectively registered.

Keywords: ATN; Alzheimer’s disease; Amyloid; Biomarker; MRI; Memory; VBM; Voxel-based morphometry.

Fig. 1

Monotonic and non-monotonic volume decline using ATN. A An illustration of monotonic GM volume decline as hypothesized when following the ACH hypothesis using ATN groups. B A permutated order of the upper case that clearly not shows a monotonic volume decline. A temporary volume increase causes large residuals that cannot be explained by a monotonic model. Therefore, the pathway in A would be preferred over B (“higher evidence for monotonic decline in A”)

Fig. 2

Comparison between selected ATN groups. Boxplots of age, sex, cognition for selected ATN groups. *: p < .05 after Bonferroni correction, **: p < .001 after Bonferroni correction

Fig. 3

Distribution of ATN status and clinical diagnosis. Left: percentual distribution of selected ATN groups per clinical diagnosis; right: percentual distribution of clinical diagnosis per ATN groups

Fig. 4

Volume decline following the ACH sequence. Regions showing significant GM volume loss along the ACH sequence. Unmasked log p map with p < .05, FDR-corrected. A Neurodegeneration (N) defined by aHV. B Neurodegeneration (N) defined by CSF total tau

Fig. 5

Face validity of ACH using VBM. Voxel-based evidence for monotonic volume decline over 24 sequences gained by permutation of the ACH sequence (ACH, A−T−N−➔A+T−N−➔A+T+N−➔A+T+N+); AP 1: A+T−N−➔A+T+N−➔A−T−N−➔A+T+N+; AP 2: A+T−N−➔A−T−N−➔A+T+N−➔A+T+N+; A voxels where sequence shows highest evidence; B percentage of gray matter voxels where sequence has highest evidence

Fig. 6

Comparing progression sequences towards AD pathology using VBM. Regions with highest evidence for monotonic volume decline assuming 6 potential disease progressions from A−T−N− towards A+T+N+ (ACH, ANT, TAN, TNA, NAT, NTA). Sequences are denoted in the order of biomarker positivity along the pathway (e.g., ANT = amyloid-positivity first, neurodegeneration second, tau last). A Voxels where sequence shows highest evidence; Notably, regions of highest evidence for each progression are disjunct. B Percentage of gray matter voxels where sequence has highest evidence. N-first sequences (NAT, NTA) are not shown as only few voxels are supported