DTI-ALPS as a marker of glymphatic function: Review of the literature findings, methodology, and interpretation

The glymphatic system (GS) describes how the brain clears toxins and metabolic waste. Accumulation of these elements can contribute to onset and severity of brain disorders, so the importance of measuring the GS is vital to understanding how neurological disease may occur and potentially lead to developing preventative treatments. A simple technique referred to as Diffusion Tensor Image Analysis ALong the Perivascular Space (DTI-ALPS) was developed as a non-invasive MRI marker of GS functioning. However, various aspects of its measurement and putative interpretation have led to critiques of the technique and discussion focused upon whether it is truly a measure of GS. We located 393 DTI-ALPS articles with an exponential growth during the past few years. The most studied conditions where this technique has been employed was neurodegenerative diseases, followed by many other conditions such as sleep disorders, epilepsy, stroke, and mood disturbances. While most studies found a significant association with DTI-ALPS and their cohorts, there has been significant discussion related to the interpretation of the DTI-ALPS index and the mechanisms underlying changes in this value. The majority of studies found significant associations between DTI-ALPS and disease severity, although issues related to differences in methodologies are important to consider. Finally, the methods employed to generate the DTI-ALPS measurements as well as the variation in these approaches are summarized. DTI-ALPS is mathematically governed by radial diffusivity asymmetry and axonal geometry, and it serves as a highly sensitive but non-specific marker of white matter microstructural damage and neuroinflammation. Retrospectively applicable and highly reproducible, DTI-ALPS offers substantial translational potential for low-cost, large-scale clinical screening and longitudinal trial stratification when paired with other biomarkers.