A comparison of measures incorporated into the HD-ISS—the Symbol Digit Modalities Test (SDMT, panel a), Total Motor Score (TMS, panel b), Total Functional Capacity (TFC, panel c) and Independence score (panel d), grouped by participant membership into the PIN score-approximated HD-ISS. Colored bars (a, b) indicate the proposed threshold range for each measure, which vary by age and, for SDMT, education level (Panel a: green = less than or equal to high school education; blue = greater than high school education). TFC scores are required to be <13, and Independence scores are required to be <100, for membership into Stage 3 (dotted line in c, d), with lower cut-offs required for older age groups (not shown). Comparisons conducted using Kruskal–Wallis test with Dunn’s post-hoc comparisons. Error bars represent median and interquartile range; ∗∗∗∗p < 0.0001, ∗∗∗p < 0.001, ∗∗p < 0.01, ∗p < 0.05. Sample sizes: Stage 0 (S0) = 50, Stage 1 (S1) = 64, Stage 2 (S2) = 63, Stage 3 (S3) = 64, Healthy Controls (HC) = 50.