## Results: 5

1.

Mean volumes for left, right, and pooled (left plus right) caudate volumes in the 3 diagnostic groups; error bars denote standard errors of the mean. Compared to normal, caudate volume is lower bilaterally in MCI and still lower in AD. Also, right caudate volume is greater than left in the whole sample (

*p*< 0.001), MCI (*p*= 0.005), and controls (*p*< 0.001), but the asymmetry is not detected in AD. Between groups, the right caudate was smaller in AD (-300 mm^{3}, -8.47%,*p*= 0.001) and MCI (-163 mm^{3}, -4.43%,*p*= 0.002) than in controls.2.

After image preprocessing, our Adaboost algorithm automatically segments the caudate nucleus bilaterally. A central curve (

*top right*) was calculated through the longitudinal axis of each caudate and the radial distance to each point in a 3D surface mesh was used as a highly localized measure of atrophy (*middle right*).*P*-values are calculated at each surface point (*bottom right*) showing the significance of differences in radial distances between diagnostic groups or their associations with clinical scores. These maps visualized the profile of local shape differences or their clinical correlates at a point-wise level.3.

3D maps show areas of significant associations between local volumetric atrophy in the caudate nucleus and several additional clinical variables. Significant associations were found for age (Left:

*p*= 0.039, corrected; Right:*p*= 0.001, corrected; N=400) and sex (Left: p < 0.001, corrected; Right,*p*< 0.001, corrected; N=400), with smaller caudates in men than women (8.58% bilaterally). Significant associations were also found in the right caudate nucleus for Geriatric Depression scores (Right,*p*= 0.004, corrected; N=395) and for abnormal versus normal gait (Right,*p*= 0.027, corrected; N=395). BMI scores at time of scanning for all subjects and for AD subjects only. For BMI, significant associations were found in all subjects (Left:*p*< 0.001, corrected; Right:*p*= 0.0021, corrected; N=393) and in AD subjects only (Left*: p*= 0.015, corrected; Right:*p*= 0.005, corrected; N=96).4.

Maps of associations with MMSE scores at baseline and one year later, MCI-to-AD conversion, and CSF concentrations of Tau pathology. 3D maps show areas of significant associations between local volumetric atrophy in the caudate and MMSE scores at baseline and after a 1-year follow-up interval, with

*p*-values color-coded at each surface voxel. Associations were only detected in the right caudate nucleus for baseline MMSE scores (Right:*p*= 0.001, corrected). Change in MMSE score after a 1-year follow-up interval was bilaterally associated in the MCI group only (Left:*p*= 0.037; Right:*p*= 0.001, corrected; N=200). Those who converted from MCI to AD after one year and two years showed greater right caudate atrophy at baseline than those who did not (1-year conversion:*p*= 0.008, corrected; 2-year conversion:*p*= 0.035, corrected). For CSF levels of tau at time of scanning, associations were significant for the right but not left caudate for the tau CSF biomarker (*p*= 0.036, corrected, N=216)5.

3D maps show significant atrophy in AD and MCI versus controls, with

*p*-values color-coded at each surface point. Red indicates areas where reduced caudate nucleus volume is associated (p < 0.05) with the poorer clinical diagnosis; yellow to blue areas are weakly or not associated. The top set of significance maps are labeled to indicate the orientation of the average caudate nucleus shapes, which is consistent in all figures in this paper (anterior caudate head points upward in this figure, posterior tail points downward, the left pair of maps represents the superior surface, while the right pair represents the inferior surface of the caudate nucleus, as seen from below). Permutation tests showed that the group differences between AD and controls (Left:*p*= 0.022, corrected; Right:*p*= 0.001, corrected; N=200) and between MCI and controls (Left:*p*= 0.023, corrected; Right:*p*= 0.012, corrected; N=300) are significant bilaterally. Association maps are significant bilaterally for CDR-SB (Left:*p*= 0.002, corrected; Right:*p*< 0.001, corrected; N=400), CDR (Left:*p*= 0.029; Right:*p*= 0.022, corrected; N=400), and Delayed Logical Memory (Left:*p*= 0.015, corrected; Right:*p*= 0.003, corrected; N=395). Associations with Immediate Logical Memory (Right*: p*= 0.006, corrected; N=395) were detected only for the right caudate nucleus.