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

Kurt G Schilling1,2, Allen Newton1,2, Chantal Tax3,4

  • 1Vanderbilt University Medical Center, Vanderbilt University Institute of Imaging Science, Nashville, Tennessee, USA.

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|July 7, 2025
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Summary

Diffusion tensor imaging along the perivascular space (DTI-ALPS) may not accurately reflect brain glymphatic function. Microstructural complexities in white matter, like fiber crossings, significantly bias ALPS measures, suggesting they reflect axonal geometry instead.

Keywords:
ALPSDTI‐ALPScrossing fibersdispersionglymphatic systemundulation

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Area of Science:

  • Neuroimaging
  • White Matter Microstructure
  • Glymphatic System Function

Background:

  • The perivascular space (PVS) is crucial for brain fluid exchange and waste clearance via the glymphatic system.
  • Diffusion tensor imaging along the perivascular space (DTI-ALPS) is a proposed noninvasive marker for PVS diffusion.
  • ALPS measures assume radial symmetry and interpret deviations as PVS contributions, but specificity is debated.

Purpose of the Study:

  • To systematically evaluate potential biases in ALPS-derived measures.
  • To investigate the influence of white matter microstructure on ALPS indices.
  • To assess the validity of ALPS as a specific marker of glymphatic function.

Main Methods:

  • Analysis of high-resolution, multishell diffusion MRI data from the Human Connectome Project (HCP).
  • Examination of radial asymmetry prevalence, crossing fiber effects, axonal geometry impacts, and vascular alignment.
  • Utilized high-field imaging and advanced diffusion modeling approaches.

Main Results:

  • Widespread radial asymmetry in white matter persists even at high b-values, indicating axonal geometry's dominant role.
  • Crossing fibers and axonal dispersion/undulations significantly inflate ALPS indices, introducing systematic asymmetry.
  • Heterogeneous medullary vein orientation challenges the assumption of consistent PVS-vasculature alignment in ALPS regions.

Conclusions:

  • ALPS indices are substantially influenced by white matter microstructure, not solely by PVS diffusion.
  • ALPS measures may primarily reflect axonal geometry rather than directly indicating glymphatic function.
  • Future interpretations of ALPS as a glymphatic biomarker require accounting for anatomical complexities and advanced modeling.