Journal Article

White Matter Geometry Confounds Diffusion Tensor Imaging Along Perivascular Space (DTI‐ALPS) Measures

Nilsson, Markus, Schilling, Kurt G., Chamberland, Maxime, Anderson, Adam, Tax, Chantal, Descoteaux, Maxime, Newton, Allen, Landman, Bennett

2025

Overview

The perivascular space (PVS) is integral to glymphatic function, facilitating fluid exchange and waste clearance in the brain. Diffusion tensor imaging along the perivascular space (DTI‐ALPS) has been proposed as a noninvasive marker of perivascular diffusion, yet its specificity remains unclear. ALPS measures assume radial symmetry in white matter (characterized by equal transverse diffusion eigenvalues, λ2 = λ3) and interpret deviations (i.e., radial asymmetry, where λ2 > λ3) as reflecting PVS contributions. However, anatomical and microstructural confounds may influence these metrics. We systematically evaluated potential biases in ALPS‐derived measures using high‐resolution, multishell diffusion MRI from the Human Connectome Project (HCP) and high‐field imaging. Specifically, we examined (1) the prevalence of radial asymmetry across white matter, (2) the influence of crossing fibers on ALPS indices, (3) the impact of axonal undulations and dispersion, and (4) the spatial alignment of vasculature with white matter in ALPS‐associated regions. Radial asymmetry is widespread across white matter and persists even at high b‐values, suggesting a dominant contribution from axonal geometry rather than faster PVS‐specific diffusion. Crossing fibers significantly inflate ALPS indices, with greater radial asymmetry observed in regions with a greater prevalence of crossing fibers. Furthermore, anisotropic axonal dispersion and undulations introduce systematic asymmetry independent of perivascular diffusion. Finally, high‐resolution vascular imaging reveals substantial heterogeneity in medullary vein orientation, challenging the assumption that PVS consistently aligns with the left–right axis in ALPS regions. ALPS indices are significantly influenced by white matter microstructure, including fiber crossings, undulations, and dispersion. These findings suggest that ALPS‐derived metrics may not provide a direct measure of glymphatic function but rather reflect underlying axonal geometry. Interpretations of ALPS‐derived metrics as biomarkers of glymphatic function must consider these anatomical complexities, and future studies should integrate advanced modeling approaches to disentangle perivascular contributions from white matter structure. Our findings reveal that the DTI‐ALPS index, a proposed marker of glymphatic function, is strongly influenced by white matter geometry—including fiber crossings, dispersion, and undulations. These findings challenge the specificity of ALPS and highlight the need for careful interpretation in studies linking ALPS metrics to glymphatic function.

• Publisher: John Wiley & Sons, Inc
• Subject: Adult / ALPS / Anisotropy / Brain - diagnostic imaging / Clinical Medicine / Connectome - methods / crossing fibers / Diagnostic imaging / Diffusion Tensor Imaging - methods / Diffusion Tensor Imaging - standards / dispersion / DTI‐ALPS / Female / glymphatic system / Glymphatic System - anatomy & histology / Glymphatic System - diagnostic imaging / Humans / Klinisk medicin / Male / Medical and Health Sciences / Medicin och hälsovetenskap / Neurologi / Neurology / Radiologi och bildbehandling / Radiology and Medical Imaging / undulation / White Matter - anatomy & histology / White Matter - diagnostic imaging