Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis

Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central in the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we perform a longitudinal analysis of glymphatic function in ALS and compare it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analyzed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate), and white matter hyperintensity (WMH) burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared to PLS and control participants across all three time points. There was no association with clinical factors, however the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.