Mitigating Head Position Bias in Perivascular Fluid Imaging: LD-ALPS, a Novel Method for DTI-ALPS Calculation.

Background/objectives: The glymphatic system is a recently characterized glial-dependent waste clearance pathway in the brain, which makes use of perivascular spaces for cerebrospinal fluid exchange. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) offers a non-invasive method for estimating perivascular flow, but its biological specificity and susceptibility to methodological variation, particularly head position during MRI acquisition, remain as threats to the validity of this technique. This study aimed to assess the prevalence of current DTI-ALPS practices, evaluate the impact of head orientation on ALPS index calculation, and propose a novel computational approach to improve measurement validity.

Methods: We briefly reviewed DTI-ALPS literature to determine the use of head-orientation correction strategies. We then analyzed diffusion MRI data from 172 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) to quantify the influence of head orientation on ALPS indices computed using the conventional Unrotated-ALPS, a vecrec-corrected ALPS, and the new LD-ALPS method proposed within.

Results: A majority of studies employed Unrotated-ALPS, which does not correct for head orientation. In our sample, Unrotated-ALPS values were significantly associated with absolute head pitch (r₁₆₉ = -0.513, p < 0.001), indicating systematic bias. This relationship was eliminated using either vecreg or LD-ALPS. Additionally, LD-ALPS showed more sensitivity to cognitive status as measured by Mini-Mental State Examination scores.

Conclusions: Correcting for head orientation is essential in DTI-ALPS studies. The LD-ALPS method, while computationally more demanding, improves the reliability and sensitivity of perivascular fluid estimates, supporting its use in future research on aging and neurodegeneration.