Longitudinal structural changes in ALS: a three time-point imaging study of white and gray matter degeneration

Background: Cross-sectional imaging studies offer valuable pathological insights into the neurodegenerative changes of amyotrophic lateral sclerosis. However, clinical trials urgently require sensitive monitoring markers that can detect subtle progressive changes over relatively short periods of time. We have conducted a three time-point longitudinal study to explore anatomical patterns of disease spread and to determine whether MRI metrics capture longitudinal changes over four and eight-month intervals. Methods: Thirty-two ALS patients were enrolled into a multiparametric imaging study to evaluate progressive cortical thickness, grey matter density and white matter alterations. Whole-brain and region-of-interest analyses were conducted in the precentral gyrus, corticospinal tracts, corpus callosum and cerebellum. Additionally, pre-symptomatic changes were explored in patients with no bulbar or lower limb disability. Results: Our findings suggest that considerable white matter degeneration can be detected early in the course of the disease which shows limited progression over time, whereas grey matter pathology is relatively limited at baseline and exhibits relentless progression. Moreover, progressive presymptomatic structural changes can be identified in the bulbar and lower limb representations of the precentral gyrus. Conclusions: Our longitudinal imaging study confirms that MRI metrics readily capture progressive changes in ALS. Our data also indicate that white matter metrics are of potential use as diagnostic markers, and grey matter measures may be superior as monitoring biomarkers. One of the most interesting findings of our study is the gradually progressive cerebellar grey matter degeneration throughout the three time-points.