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A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings

Baumeister, Hannah LU ; Vogel, Jacob W LU ; Insel, Philip S LU ; Kleineidam, Luca ; Wolfsgruber, Steffen ; Stark, Melina ; Gellersen, Helena M ; Yakupov, Renat ; Schmid, Matthias C and Lüsebrink, Falk , et al. (2024) In Brain : a journal of neurology 147(7). p.2400-2413
Abstract

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or... (More)

Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.

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organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
disease heterogeneity, Alzeimer's disease, Structural MRI, executive function, episodic memory
in
Brain : a journal of neurology
volume
147
issue
7
pages
14 pages
publisher
Oxford University Press
external identifiers
  • pmid:38654513
ISSN
1460-2156
DOI
10.1093/brain/awae118
language
English
LU publication?
yes
additional info
© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.
id
1364b7bb-4325-4125-b650-c0b242a2e27d
date added to LUP
2024-07-05 10:07:48
date last changed
2024-07-05 15:09:51
@article{1364b7bb-4325-4125-b650-c0b242a2e27d,
  abstract     = {{<p>Memory clinic patients are a heterogeneous population representing various aetiologies of pathological aging. It is unknown if divergent spatiotemporal progression patterns of brain atrophy, as previously described in Alzheimer's disease (AD) patients, are prevalent and clinically meaningful in this group of older adults. To uncover distinct atrophy subtypes, we applied the Subtype and Stage Inference (SuStaIn) algorithm to baseline structural MRI data from 813 participants enrolled in the DELCODE cohort (mean ± SD age = 70.67 ± 6.07 years, 52% females). Participants were cognitively unimpaired (CU; n = 285) or fulfilled diagnostic criteria for subjective cognitive decline (SCD; n = 342), mild cognitive impairment (MCI; n = 118), or dementia of the Alzheimer's type (n = 68). Atrophy subtypes were compared in baseline demographics, fluid AD biomarker levels, the Preclinical Alzheimer Cognitive Composite (PACC-5), as well as episodic memory and executive functioning. PACC-5 trajectories over up to 240 weeks were examined. To test if baseline atrophy subtype and stage predicted clinical trajectories before manifest cognitive impairment, we analysed PACC-5 trajectories and MCI conversion rates of CU and SCD participants. Limbic-predominant and hippocampal-sparing atrophy subtypes were identified. Limbic-predominant atrophy first affected the medial temporal lobes, followed by further temporal and, finally, the remaining cortical regions. At baseline, this subtype was related to older age, more pathological AD biomarker levels, APOE ε4 carriership, and an amnestic cognitive impairment. Hippocampal-sparing atrophy initially occurred outside the temporal lobe with the medial temporal lobe spared up to advanced atrophy stages. This atrophy pattern also affected individuals with positive AD biomarkers and was associated with more generalised cognitive impairment. Limbic-predominant atrophy, in all and in only unimpaired participants, was linked to more negative longitudinal PACC-5 slopes than observed in participants without or with hippocampal-sparing atrophy and increased the risk of MCI conversion. SuStaIn modelling was repeated in a sample from the Swedish BioFINDER-2 cohort. Highly similar atrophy progression patterns and associated cognitive profiles were identified. Cross-cohort model generalizability, both on the subject and group level, were excellent, indicating reliable performance in previously unseen data. The proposed model is a promising tool for capturing heterogeneity among older adults at early at-risk states for AD in applied settings. The implementation of atrophy subtype- and stage-specific end-points may increase the statistical power of pharmacological trials targeting early AD.</p>}},
  author       = {{Baumeister, Hannah and Vogel, Jacob W and Insel, Philip S and Kleineidam, Luca and Wolfsgruber, Steffen and Stark, Melina and Gellersen, Helena M and Yakupov, Renat and Schmid, Matthias C and Lüsebrink, Falk and Brosseron, Frederic and Ziegler, Gabriel and Freiesleben, Silka D and Preis, Lukas and Schneider, Luisa-Sophie and Spruth, Eike J and Altenstein, Slawek and Lohse, Andrea and Fliessbach, Klaus and Vogt, Ina R and Bartels, Claudia and Schott, Björn H and Rostamzadeh, Ayda and Glanz, Wenzel and Incesoy, Enise I and Butryn, Michaela and Janowitz, Daniel and Rauchmann, Boris-Stephan and Kilimann, Ingo and Goerss, Doreen and Munk, Matthias H and Hetzer, Stefan and Dechent, Peter and Ewers, Michael and Scheffler, Klaus and Wuestefeld, Anika and Strandberg, Olof and van Westen, Danielle and Mattsson-Carlgren, Niklas and Janelidze, Shorena and Stomrud, Erik and Palmqvist, Sebastian and Spottke, Annika and Laske, Christoph and Teipel, Stefan and Perneczky, Robert and Buerger, Katharina and Schneider, Anja and Priller, Josef and Peters, Oliver and Ramirez, Alfredo and Wiltfang, Jens and Heneka, Michael T and Wagner, Michael and Düzel, Emrah and Jessen, Frank and Hansson, Oskar and Berron, David}},
  issn         = {{1460-2156}},
  keywords     = {{disease heterogeneity; Alzeimer's disease; Structural MRI; executive function; episodic memory}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{7}},
  pages        = {{2400--2413}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{A generalizable data-driven model of atrophy heterogeneity and progression in memory clinic settings}},
  url          = {{http://dx.doi.org/10.1093/brain/awae118}},
  doi          = {{10.1093/brain/awae118}},
  volume       = {{147}},
  year         = {{2024}},
}