PET Amyloid Predicts Longitudinal Atrophy in Non-Demented Individuals: Results from the AMYPAD PNHS
Poster No:
185
Submission Type:
Abstract Submission
Authors:
Leonard Pieperhoff1, Luigi Lorenzini1, Sophie Mastenbroek1, Mario Tranfa2, Mahnaz Shekari3, Alle Meije Wink1, Robin Wolz4, Sylke Grootoonk4, Isadora Lopes Alves1, Craig Ritchie5, Mercè Boada6, Marta Marquié6, Philip Scheltens1, Rik Vandenberghe7, Bernard Hanseeuw8, Pablo Martinez-Lage9, Pierre Payoux10, Pieter Jelle Visser1, Michael Schöll11, Giovanni B. Frisoni12, Andrew Stephens13, Christopher Buckley14, Gill Farrar14, Frank Jessen15, Oriol Grau-Rivera3, Juan Domingo Gispert3, David Vallez Garcia1, Lyduine Collij1, Frederik Barkhof1
Institutions:
1Amsterdam UMC, Amsterdam, Netherlands, 2University of Naples, Naples, Italy, 3Barcelonaβeta Brain Research Center, Barcelona, Spain, 4IXICO, London, United Kingdom, 5University of Edinburgh, Edinburgh, United Kingdom, 6Ace Alzheimer Center Barcelona, Barcelona, Spain, 7UZ Leuven, Leuven, Belgium, 8UCLouvain, Louvain, Belgium, 9Fundación CITA-alzhéimer, San Sebastián, Spain, 10Centre hospitalier universitaire de Toulouse, Toulouse, France, 11University of Gothenburg, Gothenburg, Sweden, 12Geneva University Hospital, Geneva, Switzerland, 13Life Molecular Imaging, Berlin, Germany, 14GE HealthCare, Chalfont St Giles, United Kingdom, 15German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
First Author:
Co-Author(s):
Introduction:
As the field of anti-amyloid therapy is shifting towards early intervention, there is a need to understand the effect of amyloid-beta (Aβ) accumulation on atrophy in preclinical stages of the disease. We investigated the cross-sectional and longitudinal association between cortical amyloid deposition and subsequent neurodegeneration in a large cohort of non-demented individuals.
Methods:
We included 1365 participants from the AMYPAD Prognostic & Natural History study (PNHS; v202306, doi:10.5281/zenodo.8017084) with available MRI and amyloid-PET. Among those, 708 had longitudinal MRI and PET, with a mean follow-up time of 3.74 years (SD=1.87). Grey matter thickness and volumes in 40 regions of interest (ROI) were measured using the FreeSurfer 7.1.1 longitudinal pipeline. Global cortical amyloid burden was determined using the Centiloid (CL) method from PET scans. MRI-derived atrophy measures were harmonised across sites with neuroCombat. All PET and MR variables were Z-scored to obtain standardised regression coefficients.
Linear mixed-effect models with subject-specific random intercept and slope were used to investigate the effect of amyloid burden at baseline and its interaction with time on longitudinal, regional volume and thickness measurements. Covariates included age, sex, and baseline CDR score. P-values were FDR-adjusted. For the subset of 708 participants, secondary, nested models including longitudinal amyloid PET were compared to the original model using ANOVA based on the Akaike Information Criterion (AIC). Finally, the modulating effect of sex and APOE-ε4 carriership on the interaction of amyloid and time was investigated by adding each covariate to the model in a three-way interaction term.
Linear mixed-effect models with subject-specific random intercept and slope were used to investigate the effect of amyloid burden at baseline and its interaction with time on longitudinal, regional volume and thickness measurements. Covariates included age, sex, and baseline CDR score. P-values were FDR-adjusted. For the subset of 708 participants, secondary, nested models including longitudinal amyloid PET were compared to the original model using ANOVA based on the Akaike Information Criterion (AIC). Finally, the modulating effect of sex and APOE-ε4 carriership on the interaction of amyloid and time was investigated by adding each covariate to the model in a three-way interaction term.
Results:
Cohort characteristics are shown in Figure 1. At baseline, higher amyloid burden was related to reduced volumes and thickness in multiple temporal and parietal ROIs, as well as hippocampal and amygdala volume. Over time, individuals with higher baseline amyloid burden experienced greater volume- and thickness loss primarily in temporal and parietal regions, as well as cingulate, amygdala and hippocampal volume (Figure 2A). Incorporating longitudinal amyloid PET improved the prediction especially in medial-parietal, cingulate and basal-frontal ROIs (Figure 2B). Sex differences in how predictive cortical amyloid burden was of longitudinal atrophy were only found for caudate volume, while differences between APOE ε4 carriers and non-carriers could be observed in thickness of the medial and lateral orbitofrontal cortex, as well as hippocampal and pallidum volume.
Conclusions:
In the largely asymptomatic AMYPAD PNHS cohort, we demonstrate that baseline amyloid burden is predictive of future neurodegeneration, particularly affecting parietal volume and thickness in addition to hippocampal volume, rather than lateral temporal regions. Prediction of future atrophy improved when changes in amyloid burden were included in the model, illustrating the potential of natural history studies to act as trial readiness cohorts for optimal patient selection.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
PET Modeling and Analysis
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping 2
Novel Imaging Acquisition Methods:
Anatomical MRI
PET
Keywords:
Aging
Degenerative Disease
MRI
Positron Emission Tomography (PET)
STRUCTURAL MRI
Other - Amyloid
1|2Indicates the priority used for review
Provide references using author date format
Desikan, R.S. (2006), 'An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest', NeuroImage, vol. 31, no. 3, pp. 968–980
Fortin, J.-P. (2018), 'Harmonization of cortical thickness measurements across scanners and sites', NeuroImage, vol. 167, pp. 104–120
Lopes Alves, I. (2020). 'Quantitative amyloid PET in Alzheimer’s disease: the AMYPAD prognostic and natural history study' Alzheimer’s & Dementia, vol. 16, no. 5, pp. 750–758
Pemberton, H.G. (2022), 'Quantification of amyloid PET for future clinical use: a state-of-the-art review', European Journal of Nuclear Medicine and Molecular Imaging, vol. 49, pp. 3508–3528