DTI-ALPS Primarily Reflects White Matter Diffusion Dispersion and Microstructural Heterogeneity in Neurodegeneration:...

The glymphatic system facilitates clearance of metabolic waste and pathological proteins from the brain, and its dysfunction has been implicated in neurodegenerative disease. The diffusion tensor imaging-analysis along the perivascular space (DTI-ALPS) has been proposed as a non-invasive MRI marker of glymphatic flow, although its biological specificity remains uncertain. This study aimed to identify the determinants of DTI-ALPS and evaluate whether it primarily reflects white-matter (WM) microstructure rather than glymphatic flow in the context of neurodegeneration. We examined 100 individuals referred to the Memory Clinic of the Policlinico Hospital in Milan for suspected dementia. All participants underwent a 3T-MRI protocol including 3D-T1-weighted and 3D-FLAIR imaging, double-shell diffusion-weighted imaging (b = 1000/2000 s/mm²), and multi-echo gradient-echo sequences for quantitative susceptibility mapping. Within standard DTI-ALPS ROIs, we extracted DTI-ALPS values together with fractional anisotropy (FA), mean diffusivity (MD), and mode of anisotropy (MA) at both b-values, as well as neurite orientation and density imaging (NODDI) metrics, particularly the orientation dispersion index (ODI). WM microstructure was further characterized using the T1/FLAIR ratio and diamagnetic component of susceptibility (DCS). DTI-ALPS correlated inversely with MA (r = -0.84 at b = 1000; r = -0.86 at b = 2000) and positively with ODI (r = 0.73). Moderate correlations with the T1/FLAIR ratio and DCS supported sensitivity to WM alterations. Factor analysis indicated that DTI-ALPS clustered with MA and ODI rather than forming a distinct factor, suggesting that DTI-ALPS primarily reflects WM diffusion dispersion and heterogeneity rather than glymphatic flow in the context of neurodegeneration.