Reader Response: Association of Sleep, Neuropsychological Performance, and Gray Matter Volume With Glymphatic Function in Community-Dwelling Older Adults

In this article, Siow et al.^1,2 used diffusion tensor imaging along the perivascular space (DTI-ALPS) as a marker of glymphatic function in community-dwelling older adults. We raise 4 notes of caution in interpreting the findings from studies using DTI-ALPS to measure human brain glymphatic function. First, the relationship between the DTI-ALPS index and gold standard contrast-based glymphatic imaging has not yet been rigorously defined. In addition, glymphatic exchange occurs throughout the brain volume and exhibits regional variability. The relationship between diffusion parameters at a single anatomical location and glymphatic function throughout the rest of the brain is currently unknown.

In addition, the resolution of DTI may not allow precise delineation of perivascular vs nonperivascular spaces. Because partial volume effects from free water compartments obscure DTI measurements,³ it is possible that any age-related correlations found may be because of cell rarefaction or edema. Last, the authors loosely interpret the methodology for measuring the DTI-ALPS index using 2 fiber bundles without ascertaining the location or orientation of the associated perivascular spaces, resulting in further ambiguity as to the relationship between this measure and glymphatic perivascular transport.

We recommend that until DTI-ALPS is substantially validated, studies using DTI-ALPS should avoid suggesting that its outcomes are synonymous with glymphatic function.