Unchanged Early Diffusion Tensor Imaging Along Perivascular Space Index After Amyloid-Targeting Disease-Modifying Therapy in Alzheimer's Disease: A Preliminary Study

No longitudinal imaging biomarkers have been validated to capture early glymphatic changes during disease-modifying therapy (DMT) for Alzheimer's disease (AD). This study investigated whether the diffusion tensor imaging along the perivascular space (DTI-ALPS) index can detect early treatment-related changes in participants with AD who initiate amyloid-targeting DMT. Thirteen participants with AD (mean age, 72 years; 8 women) who initiated lecanemab therapy prospectively underwent DTI at baseline and three months. Projection and association fiber regions of interest, predefined in the HCP-1065 atlas, were inversely warped to the native space with vector-aware linear and non-linear registration, enabling a fully automated DTI-ALPS index calculation. Within-participant variances were obtained from 23 healthy volunteers in the OASIS dataset and used to set an equivalence margin of ±0.05 and determine a required sample size of 13. The primary end-point was equivalence of pre- and post-treatment DTI-ALPS indices (a two one-sided test; one-sided α = 0.05). Second, a paired t -test was used to assess the changes. The intraclass correlation coefficients (ICCs) of the DTI-ALPS indices were also evaluated in identical machine environments and between different environments. Baseline and three-month DTI-ALPS indices were 1.515 and 1.513, respectively. The mean change was 0.002 (90% confidence interval: -0.049, +0.045), entirely within the pre-specified margin; both one-sided p -values were < 0.05, confirming statistical equivalence. A paired t -test showed no significant difference ( p = 0.94). Automated processing yielded perfect within-platform reproducibility (ICC = 1.00) and excellent cross-platform reliability (ICC = 0.99). The DTI-ALPS index, an imaging metric associated with glymphatic activity, did not change during the first three months of lecanemab therapy. Although this finding suggests that glymphatic alterations may not be detectable early after treatment initiation, larger cohorts and longer follow-up periods are required to clarify the temporal relationship between DTI-ALPS index dynamics and therapeutic effects.