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

Schilling, Kurt G. ; Newton, Allen ; Tax, Chantal ; Nilsson, Markus LU ; Chamberland, Maxime ; Anderson, Adam ; Landman, Bennett and Descoteaux, Maxime (2025) In Human Brain Mapping 46(10).
Abstract

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... (More)

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.

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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ALPS, crossing fibers, dispersion, DTI-ALPS, glymphatic system, undulation
in
Human Brain Mapping
volume
46
issue
10
article number
e70282
publisher
Wiley-Liss Inc.
external identifiers
  • pmid:40622117
  • scopus:105009914577
ISSN
1065-9471
DOI
10.1002/hbm.70282
language
English
LU publication?
yes
additional info
Publisher Copyright: © 2025 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.
id
d35d6e25-0b2c-4531-8065-b3dad44d3f11
date added to LUP
2025-12-15 16:04:50
date last changed
2025-12-15 16:05:52
@article{d35d6e25-0b2c-4531-8065-b3dad44d3f11,
  abstract     = {{<p>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, λ<sub>2</sub> = λ<sub>3</sub>) and interpret deviations (i.e., radial asymmetry, where λ<sub>2</sub> &gt; λ<sub>3</sub>) 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.</p>}},
  author       = {{Schilling, Kurt G. and Newton, Allen and Tax, Chantal and Nilsson, Markus and Chamberland, Maxime and Anderson, Adam and Landman, Bennett and Descoteaux, Maxime}},
  issn         = {{1065-9471}},
  keywords     = {{ALPS; crossing fibers; dispersion; DTI-ALPS; glymphatic system; undulation}},
  language     = {{eng}},
  number       = {{10}},
  publisher    = {{Wiley-Liss Inc.}},
  series       = {{Human Brain Mapping}},
  title        = {{White Matter Geometry Confounds Diffusion Tensor Imaging Along Perivascular Space (DTI-ALPS) Measures}},
  url          = {{http://dx.doi.org/10.1002/hbm.70282}},
  doi          = {{10.1002/hbm.70282}},
  volume       = {{46}},
  year         = {{2025}},
}