Fig. 3: Annualized changes in biofluid markers longitudinally.
a–c, CSF NfL (a), CSF PENK (b) and CSF YKL-40 (c) are shown. For each biofluid biomarker, we present (i) comparison of standardized residuals (age- and sex-adjusted) for the annualized rate of change in HDGE (n = 48; red) and control (n = 30; gray) groups, (ii) comparison of standardized residuals for annualized rate of change within HDGE by HD-ISS stage 0 (orange) and stage 1 (green) and (iii) scatterplots of biofluid marker levels by CAP100 score, colored by HD-ISS stage within HDGE. Repeated visits per participant are connected by black lines, with baseline shown as squares and follow-up as circles. HD-ISS stages are represented as follows: stage 0 (orange), stage 1 (green) and stage 2 (blue). Negative standardized residuals denote a rate of change below the adjusted mean across groups. Each box plot displays the median (horizontal line), interquartile range (box) and whiskers extending to 1.5× IQR. Sample sizes (n) reflect biological replicates per group, with n = 48 for HDGE and n = 30 for controls; data represent longitudinal measures per participant. All statistical analyses were conducted using mixed-effect linear models with a participant-specific random effect, controlling for age, sex and their interaction. Natural log-transformed concentrations served as the outcomes in these models. Statistical two-sided group comparisons were adjusted for multiple comparisons using the FDR, with P values, degrees of freedom and confidence limits provided in Supplementary Table 17. Please note one prominent outlier in the control group with marked NfL elevation, as previously reported at baseline25. This outlier showed no additional cause on further investigation, with normal T1 MRI brain scan and normal CSF white and red cell counts. Additionally, this control participant did not deviate from other biofluid or cognitive parameters and was, therefore, not excluded from the analysis.
