Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET

Abstract

β-Amyloid plaques and tau-containing neurofibrillary tangles are the two neuropathological hallmarks of Alzheimer's disease (AD) and are thought to play crucial roles in a neurodegenerative cascade leading to dementia. Both lesions can now be visualized in vivo using positron emission tomography (PET) radiotracers, opening new opportunities to study disease mechanisms and improve patients' diagnostic and prognostic evaluation. In a group of 32 patients at early symptomatic AD stages, we tested whether β-amyloid and tau-PET could predict subsequent brain atrophy measured using longitudinal magnetic resonance imaging acquired at the time of PET and 15 months later. Quantitative analyses showed that the global intensity of tau-PET, but not β-amyloid-PET, signal predicted the rate of subsequent atrophy, independent of baseline cortical thickness. Additional investigations demonstrated that the specific distribution of tau-PET signal was a strong indicator of the topography of future atrophy at the single patient level and that the relationship between baseline tau-PET and subsequent atrophy was particularly strong in younger patients. These data support disease models in which tau pathology is a major driver of local neurodegeneration and highlight the relevance of tau-PET as a precision medicine tool to help predict individual patient's progression and design future clinical trials.

Figure 1.. Voxelwise patterns at the group level.

A. Group-average PET SUVR maps at baseline. B. Voxelwise pattern of longitudinal cortical atrophy. Left: average of 32 reversed GM-masked and smoothed reversed jacobian maps (higher value means higher rate of atrophy). Right: statistical map corresponding to a voxelwise one-sample t-test including the 32 individual maps, showing areas of significant atrophy (reversed jacobians > 0) based on three increasingly conservative thresholds (p_uncorrected < 0.001, Family-wise error (FWE) corrected p_FWE< 0.05 and p_FWE < 0.001 at the voxel level; all three with a p_FWE < 0.05 at the cluster level). All maps are available for visualization at https://neurovault.org/collections/WLDODMCY/

Figure 2.. Bivariate associations between baseline measures and subsequent atrophy across the 32 patients.

95% Confidence Intervals (95%CI) were computed using bootstrapping with 5,000 permutations. Details about the statistical analyses, including a multiple regression with all three baseline predictors are available in the result section and Table S1.

Figure 3.. Voxelwise spatial correlations between baseline PET patterns and the topography of subsequent atrophy.

A. Analyses conducted at the individual patient level to quantify the similarity between patterns of PET SUVR at baseline and maps of longitudinal atrophy (reversed jacobians). The images used for illustration correspond to a patient with close-to-average values. For each patient, correlations were assessed on all voxels of the cortex (see Figure S1 for details about specific image preprocessing steps). B. Group level analyses. Resulting correlation coefficients were z-transformed to be analyzed at the group level. Gray lines show individual patients while colored bars indicate average z-transformed coefficients (with 95% confidence intervals). P value corresponds to two-tailed paired t-test. The top panel shows the histogram of the difference between z-transformed spatial correlation coefficients between PIB and atrophy and FTP and atrophy across all 32 patients, highlighting that the latter was higher than the former in all 32 cases.

Figure 4.. Relative contribution of baseline partial volume corrected FTP-PET and baseline thickness patterns to predict the topography of subsequent atrophy using FreeSurfer-defined cortical regions of interest.

A. Group average values in the 68 FreeSurfer cortical regions of interest (ROI). . The colorscale was adapted to the range of values of each modality to best illustrate regional variations. SUVR_PVC: Partial Volume-Corrected Standardized Uptake Value Ratio. B. Spatial associations between patterns of baseline FTP-SUVR_PVC, thickness, and longitudinal atrophy were conducted for each patient based on the 68 ROI, as illustrated in the left panel. The spaghetti plots on the right illustrate the 32 regression lines obtained at the patient level for each pair of variables. The statistical indices on top of each spaghetti plot are related indicate the results of linear mixed effect models (LMEMs) to predict reverse jacobians; separate models were run with each of the two baseline variables as a predictor. A full model included both predictors together are described in the result section and in Table S2.

Figure 5.. Association between baseline FTP-PET and cortical thickness at baseline and follow-up

A. Association between baseline global cortical partial volume-corrected (PVC) FTP-SUVR values and cortical thickness at baseline (yellow) and follow-up (orange) across patients. Cortical thickness measures were Z-scored based on normative data and reversed so higher values indicate more neurodegeneration. 95% confidence intervals are based on bootstrap with 5,000 permutations. B. Spatial similarity between FTP-SUVR_PVC and low cortical thickness at each time point was assessed at the single patient level using a correlation approach based on Freesurfer regions of interest (top panel). Cortical thickness was extracted from 68 FreeSurfer cortical ROIs, transformed into a Z-score using normative data, and reversed to higher values indicate more neurodegeneration; FTP-SUVR_PVC values were extracted from each ROIs. Correlations were Fisher z-transformed to be analyzed at the group level (bottom panel). Each gray line represents a single patient and color bars illustrate group averages with bootstrap 95% confidence intervals. P value corresponds to a paired t-test, showing that patterns of baseline FTP binding are more similar to patterns of low cortical thickness at follow up than baseline.

Figure 6.. Effect of patient age on baseline tau pathology and subsequent atrophy.

A. Association between patient age and global cortical FTP-SUVR at baseline and longitudinal atrophy; see Figure S5 for associations between age and other variables. Mediation analysis showed that baseline cortical FTP-SUVR mediated the effect of age on longitudinal atrophy; see Figure S6 for the (non-significant) mediation models conducted with baseline PIB and baseline thickness instead of baseline FTP. B. Voxelwise analyses showing the regional associations between increasing patient’s age and lower FTP-SUVr or atrophy rates (see Figure S7 for unthresholded maps and https://neurovault.org/collections/WLDODMCY/ to access the 3D maps) C. Association between patient’s age and the topographical similarity between patterns of baseline FTP-SUVR and subsequent atrophy measured using voxelwise spatial correlation (as described in Figure 3); see Figure S5 for similar plot with PIB.