Tau covariance patterns in Alzheimer's disease patients match intrinsic connectivity networks in the healthy brain

Abstract

According to the network model of neurodegeneration, the spread of pathogenic proteins occurs selectively along connected brain regions. We tested in vivo whether the distribution of filamentous tau (measured with [¹⁸F]flortaucipir-PET), fibrillar amyloid-β ([¹¹C]PIB-PET) and glucose hypometabolism ([¹⁸F]FDG-PET) follows the intrinsic functional organization of the healthy brain. We included 63 patients with Alzheimer's disease (AD; 30 male, 63 ± 8 years) who underwent [¹⁸F]flortaucipir, [¹¹C]PIB and [¹⁸F]FDG PET, and 1000 young adults (427 male, 21 ± 3 years) who underwent task-free fMRI. We selected six predefined disease epicenters as seeds for whole-brain voxelwise covariance analyses to compare correlated patterns of tracer uptake across AD patients against fMRI intrinsic connectivity patterns in young adults. We found a striking convergence between [¹⁸F]flortaucipir covariance patterns and intrinsic connectivity maps (range Spearman rho's: 0.32-0.78, p < .001), which corresponded with expected functional networks (range goodness-of-fit: 3.8-8.2). The topography of amyloid-β covariance patterns was more diffuse and less network-specific, while glucose hypometabolic patterns were more spatially restricted than tau but overlapped with functional networks. These findings suggest that the spatial patterns of tau and glucose hypometabolism observed in AD resemble the functional organization of the healthy brain, supporting the notion that tau pathology spreads through circumscribed brain networks and drives neurodegeneration.

Keywords: Alzheimer's disease; Amyloid; Flortaucipir; Functional connectivity; PET; Tau.

Fig. 1

Stepwise methods of the covariance approach. First, six seed regions were selected based on the peak atrophy voxels in a previous study comparing AD variants against controls (step 1). The left panel figure shows brain templates with significant regions identified in the respective studies, and the actual coordinates of the seeds used in the current study are provided in the methods section. Next, these seed regions were used to generate voxelwise covariance maps for both [¹⁸F]flortaucipir PET in 63 AD patients and task-free fMRI in 1000 young adults (step 2). Goodness-of-fit between the resulting [¹⁸F]flortaucipir covariance and functional connectivity maps were then i) visually compared, and ii) more formally assessed in eight predefined intrinsic connectivity templates (step 3). Similar procedures were followed for [¹⁸F]FDG and [¹¹C]PIB, instead of [¹⁸F]flortaucipir, for secondary analyses.

Fig. 2

[¹⁸F]flortaucipir/[¹⁸F]FDG/[¹¹C]PIB covariance in AD vs functional connectivity in young adults. [¹⁸F]Flortaucipir, [¹⁸F]FDG and [¹¹C]PIB covariance (AD patients) and functional connectivity (young adults) maps are superimposed on a standard ICBM152 smoothed surface with BrainNet Viewer (Xia et al., 2013), thresholded at p < .05 family-wise error corrected ([¹⁸F]Flortaucipir, [¹⁸F]FDG and [¹¹C]PIB) and at the default Neurosynth setting, i.e. Pearson r ≥ 0.2 (fMRI). Color scales were set with maximum values at SPM-t = 20 and Pearson r = 0.7 for visualization purposes. Legend: PIB = Pittsburgh Compound-B, FDG = Fluoro-deoxy glucose, FTP = [¹⁸F]Flortaucipir, FC = Functional Connectivity (maps), MFG = Middle Frontal Gyrus, MOG = Middle Occipital Gyrus, MTL = Medial Temporal Lobe, PCC = Posterior Cingulate Cortex, PoCG = Post-Central Gyrus, STG = Superior Temporal Gyrus.

Fig. 3

Associations between PET covariance in AD patients and functional connectivity in young adults. Hexed scatterplots showing the associations among PET covariance T-scores ([¹⁸F]FDG in red, [¹¹C]PIB in blue, and [¹⁸F]Flortaucipir in green) in AD patients and fMRI Pearson r in young adults, considering all voxels within cortical gray matter. For each plot, the Spearman correlation coefficient between PET covariance and fMRI is provided. The shape and density of the hexagonal heatmaps indicate the strength of the relationship between the two modalities. For example, [¹⁸F]Flortaucipir and [¹⁸F]FDG covariance patterns in MOG show strong relationships with functional connectivity of the middle occipital cortex, whereas [¹¹C]PIB shows a weaker association. The plots were generated with R software (r-project.org) and the ggplot2 package. Legend: PIB = Pittsburgh Compound-B, FDG = Fluoro-deoxy glucose, FTP = [¹⁸F]Flortaucipir, FC = Functional Connectivity (maps), MFG = Middle Frontal Gyrus, MOG = Middle Occipital Gyrus, MTL = Medial Temporal Lobe, PCC = Posterior Cingulate Cortex, PCG = Post-Central Gyrus, STG = Superior Temporal Gyrus.

Fig. 4

Accounting for the effects of auto-correlation: Associations between PET covariance SPM-t scores and distance metrics. Hexed scatterplots showing the associations among PET covariance T-scores ([¹⁸F]FDG in red, [¹¹C]PIB in blue, and [¹⁸F]Flortaucipir in green) in AD patients and Euclidean distance (millimeters) from the respective seed (see Materials and Methods for detailed information), considering all voxels within the cortical gray matter. For each model the percentage of allo-correlated voxels (i.e., distant voxels showing significant covariance with the seed) out of all significant voxels is shown (see also Table 4). Vertical dotted lines show the critical T-scores for the P_FWE < 0.05 SPM analysis for each model, while the horizontal dashed lines show the critical distance to define auto- vs. allo-correlation (i.e. 26.37 mm, see text for details on its derivation). For example, [¹⁸F]FDG covariance in the MTL shows null allo-correlation (0%), whereas [¹¹C]PIB covariance in the MFG shows almost complete allo-correlation (96.5%). The orange shaded area highlights the auto-correlation quadrant (significant voxels close to the seed). The plots were generated with R software (r-project.org) and the ggplot2 package. Legend: PIB = Pittsburgh Compound-B, FDG = Fluoro-deoxy glucose, FTP = [¹⁸F]Flortaucipir, FC = Functional Connectivity (maps), MFG = Middle Frontal Gyrus, MOG = Middle Occipital Gyrus, MTL = Medial Temporal Lobe, PCC = Posterior Cingulate Cortex, PCG = Post-Central Gyrus, STG = Superior Temporal Gyrus.

Supplemental Fig. 1

Tau PET covariance patterns when excluding age (but still including sex and GM volume as covariates) are more extended compared to the models including age.

Supplemental Fig. 2

Tau PET covariance maps excluding the subgroup from which the seed location was originally derived (Note that this was done in an independent sample). Hence, PCA patients were excluded from analysis with the right MOG seed, lvPPA patients from left STF analysis and EOAD patients from right MFG analysis.

Supplemental Fig. 3

Tau PET covariance analyses using 4 seeds in the medial parietal cortex selected from a report by Margulies et al. (PNAS, 2009) who identified distinct brain networks in both humans and monkeys: 1) limbic, 2) cognitive, 3) visual and 4) sensorimotor. We used the same seeds to extract intrinsic functional connectivity networks based on fMRI in young adults (Neurosynth) as well as tau PET covariance maps.