Biomarkers

Poor glymphatic clearance is associated with various neurodegenerative disorders. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) has been suggested as a non-invasive technique to assess glymphatic function, with lower DTI-ALPS indices having been linked to reduced glymphatic function. We evaluated the relationships between the DTI-ALPS index, plasma circulating extracellular vesicles (EV), whole brain atrophy and executive function in mild cognitive impairment (MCI) and cognitively normal (CN) individuals.

Study participants (CN=35, MCI=33) were recruited from the Gait & Brain Cohort Study at Western University. DTI data was preprocessed using FSL Diffusion Toolbox commands, then FA and diffusivity maps were registered to a template. DTI-ALPS indices were calculated by extracting diffusion data from designated regions of interest. EV blood-based biomarkers were also collected: Total EV, TMEM119, pTau181, GFAP, GAL3, TMEM119/pTau181, TMEM119/GAL3, GFAP/GAL3. T-tests were used to compare CN vs. MCI and regression models were used to evaluate associations between DTI-ALPS, perivascular spaces (PVS), atrophy via the brain parenchymal fraction (BPF), and executive function (Trail-making-tests B-A). Age, sex, education, body mass index, white matter hyperintensities, and systolic blood pressure were included as covariates.

The mean and left DTI-ALPS indices were significantly lower in the MCI group compared to CN (left: p <0.02, mean p = 0.05). Regression models revealed that within the CN cohort, only age was negatively associated with BPF (β=0.704, p <0.001), however in the MCI cohort the mean DTI-ALPS index was strongly associated with BPF (β=0.786, p <0.001). In both CN and MCI, GFAP/GAL3 was associated with PVS (CN: β=-0.739, p = 0.013; MCI: β=1.089, p = 0.003). Furthermore, regression models revealed a negative association between Left DTI-ALPS index and executive function in both the CN (β=-0.395 p = 0.025) and MCI cohorts (β=-0.447, p = 0.02).

These preliminary results suggest that glymphatic dysfunction estimated by the DTI-ALPS index is associated with brain atrophy, where the left hemisphere DTI-ALPS is associated with executive dysfunction in both CN and MCI. Additionally, GFAP/GAL3 may be a potential useful astrocytic EV biomarker to indicate dysfunction of perivascular space clearance. Future work will examine mediation models with these imaging and EV biomarkers in neurodegenerative clinical populations.