Effects of Beta-amyloid on the Temporo-parietal Network across the Alzheimer’s Disease Continuum
Poster No:
186
Submission Type:
Abstract Submission
Authors:
Yanin Suksangkharn1,2, Björn Schott3,4,5,6, Peter Zeidman7, René Lattmann2, Renat Yakupov2, Holger Amthauer8, Arda Cetindag9, Nicoleta Cosma9, Dominik Diesing9, Marie Ehrlich9, Silka Freiesleben9, Manuel Fuentes9,10, Wenzel Glanz2, Dietmar Hauser9, Nicole Hujer9, Enise Incesoy9, Christian Kainz11, Catharina Lange9, Katja Lindner9, Herlind Megges9,10, Oliver Peters9,10, Lukas Preis9, Slawek Altenstein10,12, Andrea Lohse12, Christiana Franke12, Josef Priller10,12, Eike Spruth12, Klaus Fließbach13, Doreen Grieger-Klose2, Deike Hartmann2, Coraline Metzger2, Christin Ruß2, Franziska Schulze2, Oliver Speck2, Frank Jessen13,14, Anne Maass2, Emrah Düzel1,2, Gabriel Ziegler1,2
Institutions:
1Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg, Magdeburg, Germany, 2German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany, 3German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany, 4Leibniz Institute for Neurobiology (LIN), Magdeburg, Germany, 5Center for Behavioral Brain Sciences (CBBS), Magdeburg, Germany, 6Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany, 7Wellcome Centre for Human Neuroimaging, London, England, 8Charité – Universitätsmedizin Berlin - Department of Nuclear Medicine, Berlin, Germany, 9Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy, Berlin, Germany, 10German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany, 11Center for Cognitive Neuroscience Berlin (CCNB), Freie Universität Berlin, Berlin, Germany, 12Department of Psychiatry and Psychotherapy, Charité, Berlin, Germany, 13German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany, 14Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany
First Author:
Yanin Suksangkharn
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg|German Center for Neurodegenerative Diseases (DZNE)
Magdeburg, Germany|Magdeburg, Germany
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg|German Center for Neurodegenerative Diseases (DZNE)
Magdeburg, Germany|Magdeburg, Germany
Co-Author(s):
Björn Schott
German Center for Neurodegenerative Diseases (DZNE)|Leibniz Institute for Neurobiology (LIN)|Center for Behavioral Brain Sciences (CBBS)|Department of Psychiatry and Psychotherapy, University Medical Center Göttingen
Göttingen, Germany|Magdeburg, Germany|Magdeburg, Germany|Göttingen, Germany
German Center for Neurodegenerative Diseases (DZNE)|Leibniz Institute for Neurobiology (LIN)|Center for Behavioral Brain Sciences (CBBS)|Department of Psychiatry and Psychotherapy, University Medical Center Göttingen
Göttingen, Germany|Magdeburg, Germany|Magdeburg, Germany|Göttingen, Germany
Holger Amthauer
Charité – Universitätsmedizin Berlin - Department of Nuclear Medicine
Berlin, Germany
Charité – Universitätsmedizin Berlin - Department of Nuclear Medicine
Berlin, Germany
Arda Cetindag
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Nicoleta Cosma
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Dominik Diesing
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Marie Ehrlich
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Silka Freiesleben
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Manuel Fuentes
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy|German Center for Neurodegenerative Diseases (DZNE)
Berlin, Germany|Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy|German Center for Neurodegenerative Diseases (DZNE)
Berlin, Germany|Berlin, Germany
Dietmar Hauser
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Nicole Hujer
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Enise Incesoy
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Christian Kainz
Center for Cognitive Neuroscience Berlin (CCNB), Freie Universität Berlin
Berlin, Germany
Center for Cognitive Neuroscience Berlin (CCNB), Freie Universität Berlin
Berlin, Germany
Catharina Lange
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Katja Lindner
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Herlind Megges
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy|German Center for Neurodegenerative Diseases (DZNE)
Berlin, Germany|Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy|German Center for Neurodegenerative Diseases (DZNE)
Berlin, Germany|Berlin, Germany
Oliver Peters
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy|German Center for Neurodegenerative Diseases (DZNE)
Berlin, Germany|Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy|German Center for Neurodegenerative Diseases (DZNE)
Berlin, Germany|Berlin, Germany
Lukas Preis
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Charité – Universitätsmedizin Berlin - Institute of Psychiatry and Psychotherapy
Berlin, Germany
Slawek Altenstein
German Center for Neurodegenerative Diseases (DZNE)|Department of Psychiatry and Psychotherapy, Charité
Berlin, Germany|Berlin, Germany
German Center for Neurodegenerative Diseases (DZNE)|Department of Psychiatry and Psychotherapy, Charité
Berlin, Germany|Berlin, Germany
Josef Priller
German Center for Neurodegenerative Diseases (DZNE)|Department of Psychiatry and Psychotherapy, Charité
Berlin, Germany|Berlin, Germany
German Center for Neurodegenerative Diseases (DZNE)|Department of Psychiatry and Psychotherapy, Charité
Berlin, Germany|Berlin, Germany
Frank Jessen
German Center for Neurodegenerative Diseases (DZNE)|Department of Psychiatry, University of Cologne, Medical Faculty
Bonn, Germany|Cologne, Germany
German Center for Neurodegenerative Diseases (DZNE)|Department of Psychiatry, University of Cologne, Medical Faculty
Bonn, Germany|Cologne, Germany
Emrah Düzel
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg|German Center for Neurodegenerative Diseases (DZNE)
Magdeburg, Germany|Magdeburg, Germany
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg|German Center for Neurodegenerative Diseases (DZNE)
Magdeburg, Germany|Magdeburg, Germany
Gabriel Ziegler
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg|German Center for Neurodegenerative Diseases (DZNE)
Magdeburg, Germany|Magdeburg, Germany
Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg|German Center for Neurodegenerative Diseases (DZNE)
Magdeburg, Germany|Magdeburg, Germany
Introduction:
Beta-amyloid aggregation in Alzheimer's disease (AD) and subsequent accumulation of Tau protein predominantly affect a temporo-parietal network crucial for the memory encoding process (Düzel et al., 2022; Pasquini et al., 2019). Current evidence indicates an inverted U-shape pattern in the activity of the precuneus and a declining pattern in the hippocampus as the disease progresses (Billette et al., 2022). However, the relationship between CSF biomarkers and connectivity remains insufficiently established, hindering insights into pathology within the circuitry. Hence, our investigation focuses on effective connectivity (EC) in the temporo-parietal network during an encoding process across the AD continuum.
Methods:
We investigated the three cohorts from different study sites in the DELCODE study (Jessen et al., 2018). The participants (n=158; 36, 38, and 84 in cohorts 1, 2, and 3, respectively) were over 65 years old and were categorized as cognitively normal (CN), subjective cognitive decline (SCD), or mild cognitive impairment with Alzheimer's disease (MCI/AD). The participants were also identified as amyloid positive (A+) or amyloid negative (A-) status based on beta-amyloid 42/40 level (<= 0.08 for A+ status) (Düzel et al., 2022). The task included the presentation of novel and pre-familiarized images during the fMRI session and the post-fMRI self-report confidence score whether the images were seen in the fMRI session. The score was regarded as successfulness of memory encoding.
We assessed the EC of the temporo-parietal memory network using dynamic causal modelling (DCM) (Zeidman et al., 2019a), using a previously described model (Schott et al., 2023). We focused on the following regions of interest (ROI): parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU). ROIs were defined by anatomical constraints using Automated Anatomical Labelling (AAL) as implemented in WFU PickAtlas (Tzourio-Mazoyer et al., 2002), and by functional constraints derived from previous literature and activation maps. The model assumed full connectivity between the ROIs, including self-inhibitory connections. The driving input to the DCM model was defined as novelty-related activation of the PPA. The interregional connectivity was assumed to be modulated by memory encoding success.
EC was compared as a function of amyloid status (A+ vs. A-), separately for each diagnostic group (CN, SCD, and MCI/AD). The group-level inference was performed using parametric empirical Bayes (PEB) framework (Zeidman et al., 2019b). The design matrix included regressors representing the effect of group and A+ status on each parameter. We then calculated the posterior probability of each parameter at group-level using Bayesian model reduction. Parameters were considered relevant when exceeded a posterior probability (Pp) >= 0.95 in at least two cohorts, with no contradictory results. Inferece statistics were performed to identify changes in EC between diagnostic groups in A+ and A- status.
We assessed the EC of the temporo-parietal memory network using dynamic causal modelling (DCM) (Zeidman et al., 2019a), using a previously described model (Schott et al., 2023). We focused on the following regions of interest (ROI): parahippocampal place area (PPA), hippocampus (HC), and precuneus (PCU). ROIs were defined by anatomical constraints using Automated Anatomical Labelling (AAL) as implemented in WFU PickAtlas (Tzourio-Mazoyer et al., 2002), and by functional constraints derived from previous literature and activation maps. The model assumed full connectivity between the ROIs, including self-inhibitory connections. The driving input to the DCM model was defined as novelty-related activation of the PPA. The interregional connectivity was assumed to be modulated by memory encoding success.
EC was compared as a function of amyloid status (A+ vs. A-), separately for each diagnostic group (CN, SCD, and MCI/AD). The group-level inference was performed using parametric empirical Bayes (PEB) framework (Zeidman et al., 2019b). The design matrix included regressors representing the effect of group and A+ status on each parameter. We then calculated the posterior probability of each parameter at group-level using Bayesian model reduction. Parameters were considered relevant when exceeded a posterior probability (Pp) >= 0.95 in at least two cohorts, with no contradictory results. Inferece statistics were performed to identify changes in EC between diagnostic groups in A+ and A- status.
Results:
While no significant effect of A+ status on connectivity parameters was observed in CN (Figure 1), A+ status was associated with a stronger excitatory input from PCU to PPA in individuals with SCD and with MCI/AD. Individuals with MCI/AD additionally showed an association of A+ status with a weaker self-inhibitory connection of the HC. A significant increase in connection strength from PCU to PPA was observed across the trajectory from CN to SCD in the A+ group (p = 0.03), whereas a decrease from CN to SCD was found in the A- group (p = 0.05) (Figure 2). A nominal decrease was from SCD to MCI/AD in the A+ group did not reach significance (p = 0.13).
Conclusions:
Collectively, our results suggest an inverted U-shaped progression of parieto-temporal connectivity across diagnostic groups. Particularly the connection from PCU to PPA appears to be susceptible to beta-amyloid as its increase in connection strength is dependent on A+ versus A- status in individuals with SCD and MCI/AD.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Bayesian Modeling
Connectivity (eg. functional, effective, structural)
fMRI Connectivity and Network Modeling 2
Keywords:
Aging
Degenerative Disease
FUNCTIONAL MRI
Modeling
1|2Indicates the priority used for review
Provide references using author date format
Düzel, E. (2022), Amyloid pathology but not \textitAPOE ε4 status is permissive for tau-related hippocampal dysfunction. Brain, 145(4), 1473–1485. https://doi.org/10.1093/brain/awab405 AB42/AB40
Jessen, F. (2018), Design and first baseline data of the DZNE multicenter observational study on predementia Alzheimer’s disease (DELCODE). Alzheimer’s Research & Therapy, 10(1), 15. https://doi.org/10.1186/s13195-017-0314-2
Pasquini, L. (2019), Medial Temporal Lobe Disconnection and Hyperexcitability Across Alzheimer’s Disease Stages. Journal of Alzheimer’s Disease Reports, 3(1), 103–112. https://doi.org/10.3233/adr-190121
Schott, B. H. (2023), Inhibitory temporo-parietal effective connectivity is associated with explicit memory performance in older adults. iScience, 26(10), 107765. https://doi.org/10.1016/j.isci.2023.107765
Tzourio-Mazoyer, N. (2002), Automated Anatomical Labeling of Activations in SPM Using a Macroscopic Anatomical Parcellation of the MNI MRI Single-Subject Brain. NeuroImage, 15(1), 273–289. https://doi.org/10.1006/nimg.2001.0978
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