Objective:

To verify the presence of glymphatic function impairment, as shown by diffusion tensor imaging analysis along the perivascular space (DTI-ALPS), and to explore its clinical correlates in motor neuron disease (MND) phenotypes.

Background:

Converging evidence supports a key pathogenic role of the glymphatic system in the accumulation of pathological aggregates in several proteinopathies, including amyotrophic lateral sclerosis (ALS) and other MNDs.

Design/Methods:

Fifty-seven patients with MND phenotypes (including 41 ALS, 7 with pure lower motor neuron and 9 with pure upper motor neuron clinical presentations) and 32 age- and sex-matched healthy controls underwent a brain MRI protocol including DTI sequences on a 3 Tesla scanner.  We obtained DTI-ALPS index from each individual, evaluating its relationship with measures of motor and cognitive disability, site of symptom onset, cognitive status and fractional anisotropy (FA) values of the white matter tracts. Comparisons between groups were evaluated using ANCOVA models, age- and sex-adjusted. Partial correlations with clinical and cognitive measures were also tested.

Results:

Compared with healthy controls, MND patients showed significantly decreased DTI-ALPS index values (p<0.001). MND patients with a bulbar onset of symptoms showed greater reduction of DTI-ALPS index values, as compared with individuals with a spinal onset (p=0.005). Similar DTI-ALPS values were found across all MND phenotypes, with no effect of cognitive diagnosis or C9orf72 expansion status. Significant correlations were found between DTI-ALPS and disease duration (r=-0.30, p=0.03) and FA values of the anterior corona radiata (r=0.31, p=0.02) and body of the corpus callosum (r=0.37, p=0.049).

Conclusions:

In this study, we confirm the presence of altered glymphatic function across MND phenotypes, with greatest damage in patients with a bulbar symptom onset. Our findings support a pathogenic involvement of this system for the accumulation of TDP-43 proteinopathy in MND.