Diffusion tensor image analysis along the perivascular space (DTI-ALPS): redefining its interpretation and role

Diffusion tensor image analysis along the perivascular space (DTI-ALPS) was originally developed and defined as a noninvasive diffusion MRI method intended to evaluate glymphatic function and is now widely used in neuroimaging research. However, accumulating evidence suggests that the biological meaning of the ALPS index is more complex than initially assumed as a simple marker of glymphatic function. The ALPS index does not directly measure whole-brain fluid transport but rather reflects localized directional diffusivity based on the Brownian motion of water molecules. Its value is strongly influenced by white matter microstructure, including fiber orientation, crossing fibers, extracellular geometry, and age-related diffusivity changes. In addition, because the ALPS index is a ratio-based measure derived from directional diffusivity components, its alterations may arise from different combinations of numerator and denominator diffusivity changes, indicating that similar ALPS index reductions may reflect distinct underlying microstructural mechanisms. White matter microstructure may represent not merely a confounding factor, but a structural substrate guiding interstitial fluid transport itself. White matter hydraulic permeability exhibits strong anisotropy, and brain fluid transport may occur preferentially along white matter tracts. Thus, the structure dependence of the ALPS index may reflect physiologically relevant interactions between white matter architecture and interstitial fluid dynamics rather than simple measurement bias. In this review, we propose redefining the ALPS index not as a direct marker of glymphatic function, but as a "spatially fixed-point biomarker" evaluating directional diffusivity within anatomically defined regions. Within this framework, the ALPS index can be understood as a composite biomarker reflecting interactions among white matter microstructure, extracellular environment, vascular geometry, and neurofluid-related tissue environment. Because the ALPS index has been associated with aging, sleep, and various diseases, it may function less as a disease-specific marker and more as an adjunctive imaging marker relevant to brain health assessment and the brain tissue environment.