Subject-Specific functional connectivity constraints on tau pathology in Alzheimer’s disease
Poster No:
197
Submission Type:
Abstract Submission
Authors:
Harry H. Behjat1, Jacob Vogel2, Olof Strandberg1, Nicola Spotorno1, Jonathan Rittmo2, Lyduine Collij1, Alexa Pichet Binette1, Xiao Yu2, Danielle van Westen3, Erik Stomrud4, Sebastian Palmqvist1, Niklas Mattsson-Carlgren1, Ruben Smith1, Dimitri Van De Ville5, Oskar Hansson1, Rik Ossenkoppele1
Institutions:
1Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden, 2Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden, 3Department of Diagnostic Radiology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden, 4Memory Clinic, Skåne University Hospital, Malmö, Sweden, Lund, Sweden, 5École polytechnique fédérale de Lausanne (EPFL), Geneva, Geneva
First Author:
Harry Behjat
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Co-Author(s):
Jacob Vogel
Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Olof Strandberg
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Nicola Spotorno
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Jonathan Rittmo
Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Lyduine Collij
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Alexa Pichet Binette
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Xiao Yu
Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Neurodegenerative Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Danielle van Westen
Department of Diagnostic Radiology, Department of Clinical Sciences Lund, Lund University
Lund, Sweden
Department of Diagnostic Radiology, Department of Clinical Sciences Lund, Lund University
Lund, Sweden
Sebastian Palmqvist
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Niklas Mattsson-Carlgren
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Ruben Smith
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Oskar Hansson
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Rik Ossenkoppele
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University
Lund, Sweden
Introduction:
In vitro findings suggest that tau pathology in Alzheimer's disease (AD) may spread 'prion-like' across neuronal connections in an activity-dependent manner (Evans et al., 2018). Supporting this notion, group-level fMRI networks show a spatial correspondence to tau deposition patterns (Vogel et al., 2020; Franzmeier et al., 2020). Nevertheless, tau spatial patterns entail notable heterogeneity across subjects. Furthermore, it remains unclear whether brain connectivity facilitates tau spread, and whether subject-specific idiosyncrasies in connectivity are linked to the observed heterogeneity in spatial patterns of tau. In this study, we investigate the role of individualized connectivity patterns in constraining the spatial patterns of tau above and beyond template, group-averaged connectivity.
Methods:
We used structural MRI, resting-state fMRI, tau-PET, and amyloid-β (Aβ)-PET data from 733 participants aged 50 and above from the BioFINDER-2 study, including 402 cognitively unimpaired (CU), 157 mild cognitive impairment (MCI), and 174 AD dementia. All MCI and AD participants included were Aβ+ as defined by cerebrospinal fluid testing, whereas the CU group included 89 Aβ+ and 313 Aβ- individuals. fMRI data were acquired on a 3T scanner, preprocessed and retained in subject-space using an in-house pipeline and subsequently surface parcellated using the Schaefer atlas (Schaefer et al., 2018). Functional connectivity (FC) was estimated via pairwise Pearson's correlation between resting-state activity of pairs of cortical regions. FC matrices were Fisher z-transformed and positive values were retained, without ad hoc thresholding. For each individual we combined template (group-average of CU Aβ- individuals) and subject-specific connectivity matrices into a 'hybrid FC' to reduce instability in subject-level estimations while retaining individual information. This was done by statistically estimating the contribution of each region's subject-specific vs template connectivity in explaining tau-PET and subsequently integrating the two connectivity profiles relative to their contribution.
Results:
Integrating subject-specific FC information into template FC patterns explained tau-PET patterns better than template FC alone (Fig 1A); explained variance increased as the spatial resolution of FC increased. Individual tau patterns were explained better by hybrid FC than by canonical tau-PET patterns at later stages of the disease (Fig 1B). In contrast to tau-PET patterns, individual Aβ-PET patterns–for which prion-like spread hypothesis was not assumed–were not better explained by hybrid FC than by canonical patterns (Fig 2A). Subject-specific and template connectivity showed a stark differential significance across the cortex in explaining individual tau patterns, across scales (Fig 2B). Compared to a null model of hybrid FC, hybrid FC showed substantially higher additional explained variance over template FC at the regional level (Fig 2C).
Conclusions:
Our results provide compelling implicit evidence in support for the hypothesis of tau spread via communicating neurons at the subject-level, corroborating prior group-level findings. Compared to canonical PET patterns, hybrid FC better explained individual tau-PET patterns, but not Aβ-PET patterns for which connectivity-based spread evidence is largely lacking and also not expected. For the limbic, default-mode network and associative cortices wherein tau largely accumulates, the dominant role of subject-specific connectivity over template connectivity in explaining global tau patterns suggests the intricate potential role of individual's FC in facilitating tau spread. The present work does not establish a causal role for connectivity to be the driver of tau spread since tau can also lead to connectivity change. Nevertheless, our findings provide substantial individualised evidence that warrants future work to decipher the direction of causality, or to potentially reveal that the two mechanisms are not mutually exclusive.
Disorders of the Nervous System:
Neurodegenerative/ Late Life (eg. Parkinson’s, Alzheimer’s) 1
Modeling and Analysis Methods:
Connectivity (eg. functional, effective, structural) 2
fMRI Connectivity and Network Modeling
PET Modeling and Analysis
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Cortical Anatomy and Brain Mapping
Keywords:
Cortex
Degenerative Disease
Design and Analysis
FUNCTIONAL MRI
MRI
Positron Emission Tomography (PET)
Statistical Methods
Other - tau pathology
1|2Indicates the priority used for review
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Provide references using APA citation style.
Franzmeier, N., Neitzel, J., Rubinski, A., Smith, R., Strandberg, O., Ossenkoppele, R., ... & Ewers, M. (2020). Functional brain architecture is associated with the rate of tau accumulation in Alzheimer’s disease. Nature communications, 11(1), 347.
Vogel, J. W., Iturria-Medina, Y., Strandberg, O. T., Smith, R., Levitis, E., Evans, A. C., & Hansson, O. (2020). Spread of pathological tau proteins through communicating neurons in human Alzheimer’s disease. Nature communications, 11(1), 2612.
Schaefer, A., Kong, R., Gordon, E. M., Laumann, T. O., Zuo, X. N., Holmes, A. J., ... & Yeo, B. T. (2018). Local-global parcellation of the human cerebral cortex from intrinsic functional connectivity MRI. Cerebral cortex, 28(9), 3095-3114.