Deconstructing pathological tau by biological process in early stages of Alzheimer disease: a method for quantifying tau spatial spread in neuroimaging

Abstract

Background: Neuroimaging studies often quantify tau burden in standardized brain regions to assess Alzheimer disease (AD) progression. However, this method ignores another key biological process in which tau spreads to additional brain regions. We have developed a metric for calculating the extent tau pathology has spread throughout the brain and evaluate the relationship between this metric and tau burden across early stages of AD.

Methods: 445 cross-sectional participants (aged ≥ 50) who had MRI, amyloid PET, tau PET, and clinical testing were separated into disease-stage groups based on amyloid positivity and cognitive status (older cognitively normal control, preclinical AD, and symptomatic AD). Tau burden and tau spatial spread were calculated for all participants.

Findings: We found both tau metrics significantly elevated across increasing disease stages (p < 0.0001) and as a function of increasing amyloid burden for participants with preclinical (p < 0.0001, p = 0.0056) and symptomatic (p = 0.010, p = 0.0021) AD. An interaction was found between tau burden and tau spatial spread when predicting amyloid burden (p = 0.00013). Analyses of slope between tau metrics demonstrated more spread than burden in preclinical AD (β = 0.59), but then tau burden elevated relative to spread (β = 0.42) once participants had symptomatic AD, when the tau metrics became highly correlated (R = 0.83).

Interpretation: Tau burden and tau spatial spread are both strong biomarkers for early AD but provide unique information, particularly at the preclinical stage. Tau spatial spread may demonstrate earlier changes than tau burden which could have broad impact in clinical trial design.

Funding: This research was supported by the Knight Alzheimer Disease Research Center (Knight ADRC, NIH grants P30AG066444, P01AG026276, P01AG003991), Dominantly Inherited Alzheimer Network (DIAN, NIH grants U01AG042791, U19AG03243808, R01AG052550-01A1, R01AG05255003), and the Barnes-Jewish Hospital Foundation Willman Scholar Fund.

Keywords: Alzheimer disease; Positron emission tomography; Tau propagation; Tau spread.

Fig. 1

Calculation ofTauSpatialSpread. Tau Spatial Spread (TSS) was calculated for older participants relative to younger controls (YC) using aligned tau PET scans with voxel-wise SUVRs. For each voxel (white square), the SUVR value is identified for the older participant. The SUVR values for the corresponding voxel are identified in all YC scans, which are then used to calculate mean and standard deviation. The older participant's voxel z-score is next calculated from participant SUVR and YC mean and standard deviation. Voxels are then classified as normal or abnormal with the threshold z > 1.96. Once all voxels have been classified, a region of interest (ROI) mask is applied including the cortex, hippocampus, and amygdala. TSS is calculated as the proportion of abnormal voxels within the ROI mask. All abnormal voxels can be displayed overlaying the participant's MRI.

Fig. 2

Surface projections for tau PET SUVRs and frequency of abnormality across disease stages. (Left) Voxel-wise tau PET SUVRs averaged across group. Color coded for SUVR (range 1–2). (Right) Voxel-wise group frequency of abnormality, determined by z-scoring against younger controls and thresholding for significance at +1.96. Color coded for the proportion of participants (range 0–1) in which the voxel is “abnormal”.

Fig. 3

TauIndex andTauSpatialSpread are elevated across disease stages. (a–b) Comparison of Tau Index (a) and Tau Spatial Spread (b) across disease-stage groups. Pairwise comparisons conducted using Dunn's test with Bonferroni p-value adjustment (c) Tau Index and Tau Spatial Spread plotted for each disease-stage group with ranged major axis regression and Spearman correlation reported with 95% confidence interval and p-value. Shaded area refers to 95% confidence interval of the regression slope.

Fig. 4

Relationship ofTauIndex andTauSpatialSpread relative to amyloid burden. Tau metrics assessed against Centiloid. Shaded area refers to 95% confidence band. (a–b) TI and TSS for participants relative to Centiloid split by disease-stage group. Pearson correlation reported with 95% confidence interval and p-value. (c) Z-Scored TI and TSS relative to Centiloid with local regression. (d) Divergence of TI and TSS calculated by difference between z-scored TSS and z-scored TI and split by disease-stage group with Pearson correlation.