Reijner, Niels;
Frigerio, I;
Bouwman, MMA;
Boon, BDC;
Guizard, N;
Jubault, T;
Hoozemans, JJM;
... Jonkman, LE; + view all
(2025)
Clinical phenotypes of Alzheimer’s disease: investigating atrophy patterns and their pathological correlates.
Alzheimer’s Research & Therapy
, 17
, Article 93. 10.1186/s13195-025-01727-5.
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Abstract
Background: In Alzheimer’s disease (AD), MRI atrophy patterns can distinguish between amnestic (typical) and non-amnestic (atypical) clinical phenotypes and are increasingly used for diagnosis and outcome measures in clinical trials. However, understanding how protein accumulation and other key features of neurodegeneration influence these imaging measurements, are lacking. The current study aimed to assess regional MRI patterns of cortical atrophy across clinical AD phenotypes, and their association with amyloid-beta (Aβ), phosphorylated tau (pTau), neuro-axonal degeneration and microvascular deterioration. // Methods: Post-mortem in-situ 3DT1 3 T-MRI data was obtained from 33 AD (17 typical, 16 atypical) and 16 control brain donors. Additionally, ante-mortem 3DT1 3 T-MRI scans of brain donors were collected if available. Regional volumes were obtained from MRI scans using an atlas based parcellation software. Eight cortical brain regions were selected from formalin-fixed right hemispheres of brain donors and then immunostained for Aβ, pTau, neurofilament light, and collagen IV. Group comparisons and volume-pathology associations were analyzed using linear mixed models corrected for age, sex, post-mortem delay, and intracranial volume. // Results: Compared to controls, both typical and atypical AD showed volume loss in the temporo-occipital cortex, while typical AD showed additional volume loss in the parietal cortex. Posterior cingulate volume was lower in typical AD compared to atypical AD (- 6.9%, p = 0.043). In AD, a global positive association between MRI cortical volume and Aβ load (βs = 0.21, p = 0.010), and a global negative association with NfL load (βs = - 0.18, p = 0.018) were observed. Regionally, higher superior parietal gyrus volume was associated with higher Aβ load in typical AD (βs = 0.47, p = 0.004), lower middle frontal gyrus volume associated with higher NfL load in atypical AD (βs = - 0.50, p < 0.001), and lower hippocampal volume associated with higher COLIV load in typical AD (βs = - 1.69, p < 0.001). Comparing post-mortem with ante-mortem scans showed minimal volume differences at scan-intervals within 2 years, highlighting the translational aspect of this study. // Conclusion: For both clinical phenotypes, cortical volume is affected by Aβ and neuro-axonal damage, but in opposing directions. Differences in volume-pathology relationships between clinical phenotypes are region-specific. The findings of this study could improve the interpretation of MRI datasets in heterogenous AD cohorts, both in research and clinical settings.
| Type: | Article |
|---|---|
| Title: | Clinical phenotypes of Alzheimer’s disease: investigating atrophy patterns and their pathological correlates |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1186/s13195-025-01727-5 |
| Publisher version: | https://doi.org/10.1186/s13195-025-01727-5 |
| Language: | English |
| Additional information: | This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Alzheimer’s disease, Cortical volume, Clinical phenotypes, Pathological features, Post-mortem |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10208411 |
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