Brain metabolic imaging with 18 F-PET-CT and machine-learning clustering analysis reveal divergent metabolic phenotypes in patients with amyotrophic lateral sclerosis.

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by significant clinicopathologic heterogeneity. This study aimed to identify distinct ALS phenotypes by integrating brain 18 F-fluorodeoxyglucose positron emission tomography-computed tomography (18 F-FDG PET-CT) metabolic imaging with consensus clustering data. METHODS This study prospectively enrolled 127 patients with ALS and 128 healthy controls. All participants underwent a brain 18 F-FDG-PET-CT metabolic imaging, psychological questionnaires, and functional screening. K-means consensus clustering was applied to define neuroimaging-based phenotypes. Survival analyses were also performed. Whole exome sequencing (WES) was utilized to detect ALS-related genetic mutations, followed by GO/KEGG pathway enrichment and imaging-transcriptome analysis based on the brain metabolic activity on the 18 F-FDG-PET-CT imaging. RESULTS Consensus clustering identified two metabolic phenotypes, i.e., the metabolic attenuation phenotype and the metabolic non-attenuation phenotype according to their glucose metabolic activity pattern. The metabolic attenuation phenotype was associated with worse survival (p = 0.022), poorer physical function (p = 0.005), more severe depression (p = 0.026) and greater anxiety level (p = 0.05). WES testing and neuroimaging-transcriptome analysis identified specific gene mutations and molecular pathways with each phenotype. CONCLUSIONS We identified two distinct ALS phenotypes with varying clinicopathologic features, indicating that the unsupervised machine learning applied to PET imaging may effectively classify metabolic subtypes of ALS. These findings contributed novel insights into the heterogeneous pathophysiology of ALS, which should inform personalized therapeutic strategies for patients with ALS.