TMS and imaging correlates of spasticity in persons at‐risk for the A431E PSEN1 mutation

Abstract

AbstractBackgroundSpastic paraparesis (SP) occurs in approximately 45% of carriers of the A431E PSEN1 mutation (MCs), sometimes preceding cognitive decline. SP is typically caused by reduced cortical excitatory output to spinal motor neurons resulting from delayed cortical conduction time or increased inhibitory output from cortex. Previous studies have observed that people with spasticity have increased corticospinal inhibition at rest and altered interhemispheric inhibitory control (amount of inhibition and conduction time) during isometric contraction. Hence, in this study, we sought to identify transcranial magnetic stimulation (TMS) and diffusion MRI and flortaucipir PET imaging predictors of SP using these inhibitory measures captured using TMS.MethodWe included 19 persons known to be at‐risk for the A431E PSEN1 mutation (15 MCs, 3 NCs) and one person affected by the F388S PSEN1 mutation who participated in a comprehensive study of autosomal dominant AD including TMS, diffusion MRI, and flortaucipir PET. We measured cosrticospinal inhibition for lower limbs at rest by targeting tibialis anterior muscle representation at primary motor cortex. For inter‐hemispheric inhbition (extent of inhibition and transcallosal conduction time), we stimulated the hemisphere ipsilateral to the limb performing isometric contraction. We ran a non‐parametric regression model for prediction using the gsm function from the npreg package in R© because several variables were not normally distributed (Shapiro‐Wilk test, p<0.05).ResultSpasticity score (Ashworth scale) was positively associated with interhemispheric inhibition, transcallosal conduction time, and DTI measures of the corticospinal tract and pre‐post‐para central lobes of both hemispheres (Spearman rank correlation, p< 0.05). Among all inhibitory TMS measures and DTI variables, the transcallosal conduction time for the lower limbs (β = 2.87) and suvr_rh_paracentral (β = ‐25.92) independently predicted increased spasticity scores. The interaction effect between these measures was insignificant. The prediction model had an adjusted R2 value of 0.89.ConclusionWe show increased transcallosal conduction time and decreased white matter integrity around the right‐hemisphere paracentral lobule is associated with increased mean spasticity scores in people with A431E PSEN1 mutations. This is consistent with other studies showing altered interhemispheric control in SP. Delay in transcallosal conduction time in A431E PSEN1 MCs may compromise inter‐hemispheric control limiting smooth movement control.