Brain Metabolic Changes Across King's Stages in Amyotrophic Lateral Sclerosis: a 18F-2-fluoro-2-deoxy-D-glucose-Positron Emission Tomography Study

Purpose. A corticofugal, regional ordered spreading model of neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) has been proposed. Being 18F-FDG-PET a marker of neurodegeneration, we used it to evaluate the metabolic correlates of ALS King's stages. Methods. 406 ALS cases underwent brain 18F-FDG-PET at diagnosis. King's stage at PET was derived from ALSFRS-R. We focused on stages 1, 2, and 3 (n=390), i.e. involvement of 1, 2, and 3 body regions respectively. King's stage was regressed out against whole brain metabolism in the whole sample. We used the full factorial design to test the hypothesis that differences among groups (King's 1, King's 2, King's 3, and 40 healthy controls - HC) exist overall. Then, comparisons among stage groups and between each group and HC were performed. We included age at PET and sex as covariates. Results. Brain metabolism was inversely correlated with King's stage in medial frontal gyrus bilaterally (BA 6), and right precentral (BA 4) and postcentral (BA 2) gyri. The full factorial design resulted in a significant main effect of groups. There was no significant difference between King's stages 1 and 2. Comparing King's stage 3 to King's stage 1+2, a significant relative hypometabolism was highlighted in the former in the left precentral and medial frontal gyri (BAs 4, 6), and in the right medial frontal, postcentral, precentral, and middle frontal gyri (BAs 4, 6, 3, 9, 8). The comparisons between each group and HC showed the extension of frontal metabolic changes from stage 1 to stage 3, with the larger metabolic gap between stage 2 and 3. Conclusions. Our findings support the hypothesis that in ALS the propagation of neurodegeneration follows a corticofugal, regional ordered pattern, extending from the motor cortex to posterior and anterior regions.