HAI Book 2025 - Flipbook - Page 171
Gallego-Rudolf, Jonathan
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Functional and structural connectivity patterns predict longitudinal
tau spreading in asymptomatic individuals expressing Aβ pathology
Jonathan Gallego-Rudolf1,2, Ting Qiu1, Mohammadali Javanray1, Alex Wiesman2, Frédéric StOnge1, Alfonso Fajardo-Valdez1, Sylvain Baillet2, Sylvia Villeneuve1
1
Douglas Research Centre, Montreal, QC, CA
Montreal Neurological Institute, Montreal, QC, CA
2
Alzheimer's disease (AD) is defined by the pathological accumulation of amyloid-beta (A´) and tau proteins in the
brain. Animal studies have demonstrated that tau can spread trans-synaptically, propagating from early
accumulating regions (epicenters) to the rest of the cortex. This process seems to be aggravated by the presence
of A´ pathology. Non-invasive human neuroimaging studies also suggest tau spreads across structural and
functional brain networks, but further longitudinal multimodal neuroimaging studies during the preclinical stage
of AD are needed to understand how brain connectivity shapes proteinopathy spreading, the synergistic influence
of A´ and its implications for clinical progression.
We estimated brain connectivity using task-free Magnetoencephalography (MEG), Diffusion Weighted Imaging
(DWI), and resting-state functional Magnetic Resonance Imaging (fMRI) and quantified A´ deposition and
longitudinal accumulation of tau using Positron Emission Tomography (PET) in a sample of 76 cognitively
unimpaired older adults with a family history of sporadic AD (Figure 1). We assessed whether functional (MEG,
fMRI) and structural (DWI) connectivity patterns of individual-specific tau epicenter regions predicted longitudinal
tau spreading across the cortex, the interactive effect of global neocortical A´ pathology on this association, and
whether tau accumulation within epicenter-connected regions predicted progression to mild cognitive
impairment (MCI).
Cortical regions showing stronger functional (MEG alpha-band, fMRI) and structural (DWI) connectivity with
individual-specific tau epicenters had higher longitudinal accumulation of tau in individuals expressing greater
levels of neocortical A´ deposition (Figure 2). Longitudinal tau accumulation within epicenter-connected regions
was associated with clinical progression to MCI (Figure 3).
We report consistent findings using three state-of-the-art imaging modalities for estimating brain connectivity,
showing that A´ pathology facilitates tau spreading across functional and structural brain networks, which in turn
relates to clinical progression to MCI. These findings advance our understanding of the neuropathological
mechanisms underlying early proteinopathy spread during the preclinical stage of AD.
HAI2025 - 171
