Systemic brain-body metabolic coupling patterns in amyotrophic lateral sclerosis: a whole-body [18F] fluorodeoxyglucose PET/CT study across clinical phenotypes.

PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both central and peripheral systems. Its marked heterogeneity and variable prognosis suggest pathophysiology beyond motor neuron degeneration. This study aimed to map brain–body metabolic networks using whole-body [18F]FDG PET/CT, characterize systemic remodeling, and to identify clinically meaningful brain-organ coupling axes and peripheral prognostic markers (lung, small intestine, cervical cord, intrinsic spinal muscles), providing imaging candidates for phenotype-informed stratification and hypothesis generation for future multimodal studies.

METHODS

We enrolled 121 ALS patients and 83 controls who underwent whole-body [18F]FDG PET/CT. Standardized uptake value ratios (SUVr), mean Standardized uptake value (SUVmean), and maximum Standardized uptake value (SUVmax) were extracted from brain regions and 11 peripheral organs. Interregional metabolic correlation networks were constructed, and subgroup analyses were performed according to King's stage, progression rate, site of onset, genetic mutations, and non-motor symptoms (NMS). Associations between metabolic alterations and survival were examined using longitudinal follow-up.

RESULTS

Compared to controls, ALS patients exhibited hypometabolism in the frontal lobe and motor cortex, but hypermetabolism in the posterior cingulate and parahippocampal regions. Peripheral alterations included increased metabolism in the liver, spleen, thoracic spinal cord, and spinal muscles, as well as reduced metabolism in the lungs. Brain–body network analysis revealed that advanced King's stages were associated with strengthened brain–heart metabolic coupling. Rapid progression subtypes exhibited enhanced brain-spinal cord coupling and concomitant hypometabolism in the small intestine and thoracic spinal cord. Bulbar-onset ALS demonstrated increased cardiac metabolism but reduced brain–heart coupling. Patients with genetic mutations or NMS exhibited disrupted brain–body co-variation. In unadjusted analyses, survival analysis demonstrated that lung and intestinal hypometabolism and hypermetabolism in the intrinsic spinal muscles and cervical spinal cord were significantly associated with poor prognosis; after Benjamini–Hochberg false discovery rate correction, only intrinsic spinal muscle SUVr remained significant.

CONCLUSION

ALS is a systemic disorder characterized by widespread remodeling of brain–body metabolic networks. Whole-body [18F]FDG PET/CT enables the detection of multi-organ metabolic abnormalities and uncovers inter-system coupling mechanisms, offering biomarkers for stratification, prognosis prediction, and individualized management.