P 1 Grey matter atrophy in Amyotrophic Lateral Sclerosis correlates with quantitative disease progression

Abstract

Background: There is a growing demand for the development and evaluation of biomarkers that allow the improvement of clinical disease management and trials in Amyotrophic Lateral Sclerosis (ALS). Ideal biomarkers should be able to represent individual disease covered, independent from disease aggressiveness. The D50 model provides distinct parameters of individual clinical disease progression and a framework within with to interpret any biomarker signal. Objectives: In this study we examined Magnetic Resonance Imaging (MRI)-derived measures of grey matter in correlation with D50 model parameters. Based on our previous work, we hypothesized that loss of cortical and subcortical structural integrity would correlate with disease covered, independent from disease aggressiveness (1,2). Methods: T1-MRI images of 72 healthy controls and 100 ALS patients from a 1.5 T scanner were analyzed using surface-based morphometry to obtain cortical thickness (CT) and region-of-interest based volumetric analyses of subcortical deep grey matter (DGM). Applying the D50 model, we conducted subgroup-analyses of patients, divided by a) Phase of disease covered at the time of MRI-scan and b) individual overall disease aggressiveness. Additionally, correlations between the grey matter measures and D50 model-derived parameters were examined in multiple regression analyses. Statistical significance was set at p < 0.001 for CT and p < 0.05 Holm-Bonferroni corrected for DGM. Results: Inter-group analyses revealed ALS-related cortical and subcortical grey matter atrophy compared to healthy controls. Comparison of patients in different Phases showed further decrease of grey matter along with disease progression. However, there were no differences of CT or DGM between patients with low and high disease aggressiveness. Regression analyses identified negative correlations between CT/DGM and individual disease covered. Discussion and Conclusions: We were able to reveal structural grey matter changes in ALS compared to healthy controls that worsen along with disease progression. Application of the D50 model identified robust correlations between the decrease of GM integrity and ALS-related functional disability, but not with disease aggressiveness. This indicates that CT and DGM analyses could be biomarkers representing individual disease covered independent from the overall speed of disease progression. Our findings demonstrate the applicability of structural MRI as a biomarker in ALS.