Regional associations of white matter hyperintensities and early cortical amyloid pathology

doi:10.1093/braincomms/fcac150

Published June 15, 2022 | Version v1

Journal article Open

Regional associations of white matter hyperintensities and early cortical amyloid pathology

1. Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam Neuroscience , Amsterdam , The Netherlands
2. Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam , The Netherlands
3. Centre for Medical Image Computing (CMIC), Departments of Medical Physics & Biomedical Engineering and Computer Science, University College London , UK MRC Unit for Lifelong Health and Ageing - University College London , UK School of Biomedical Engineering , King's College London UK
4. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation , Barcelona , Spain IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain
5. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation , Barcelona , Spain IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain Universitat Pompeu Fabra , Barcelona , Spain
6. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation , Barcelona , Spain IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES) , Madrid , Spain
7. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation , Barcelona , Spain IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain Centro de Investigación Biomédica en Red de Fragilidad Y Envejecimiento Saludable (CIBERFES) , Madrid , Spain Atlantic Fellow for Equity in Brain Health at the University of California San Francisco , SanFrancisco, California , USA
8. Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam Neuroscience , Amsterdam , The Netherlands Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam , The Netherlands
9. Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam , The Netherlands Department. of Biological Psychology, Vrije Universiteit Amsterdam, Neuroscience Amsterdam , Amsterdam , The Netherlands
10. Department of Neurology, Alzheimer Center Amsterdam, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC , Amsterdam , The Netherlands Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University , Maastricht , The Netherlands
11. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation , Barcelona , Spain IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain Universitat Pompeu Fabra , Barcelona , Spain Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales Y Nanomedicina , Madrid , Spain
12. Dept. of Radiology and Nuclear Medicine, Amsterdam University Medical Center, Amsterdam Neuroscience , Amsterdam , The Netherlands Queen Square Institute of Neurology and Centre for Medical Image Computing, University College London , London , UK

Abstract:

White matter hyperintensities (WMH) have a heterogeneous etiology, associated with both vascular risk factors and amyloidosis due to Alzheimer’s disease (AD). While spatial distribution of both amyloid and WM lesions carry important information for the underlying pathogenic mechanisms, the regional relationship between these two pathologies and their joint contribution to early cognitive deterioration remains largely unexplored.

We included 662 non-demented participants from three AMYPAD-affiliated cohorts: EPAD-LCS (N = 176), ALFA+ (N = 310), and EMIF-AD Twin60++ (N = 176). Using PET imaging, cortical amyloid burden was assessed regionally within early-accumulating regions (medial-orbitofrontal, precuneus, and cuneus) and globally, using the Centiloid method. Regional WMH volume was computed using Bayesian Model Selection (BaMoS). Global associations between WMH, amyloid, and cardiovascular risk-scores (Framingham and CAIDE) were assessed using linear models. Partial least square (PLS) regression was used to identify regional associations. Models were adjusted for age, sex, and APOE-e4 status. Individual PLS scores were then related to cognitive performance in 4 domains (attention, memory, executive functioning, and language).

While no significant global association was found, the PLS model yielded two components of interest. In the first PLS component, a fronto-parietal WMH pattern was associated with medial orbitofrontal-precuneal amyloid, vascular risk, and age. Component 2 showed a posterior WMH pattern associated with precuneus-cuneus amyloid, less related to age or vascular risk. Component 1 was associated with lower performance in all cognitive domains, while component 2 only with worse memory.

In a large pre-dementia population, we observed two distinct patterns of regional associations between WMH and amyloid burden, and demonstrated their joint influence on cognitive processes. These two components could reflect the existence of vascular-dependent and -independent manifestations of WMH-amyloid regional association that might be related to distinct primary pathophysiology.

Notes

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No. 115952. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. This communication reflects the views of the authors and neither IMI nor the European Union and EFPIA are liable for any use that may be made of the information contained herein.

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