Brain metabolic connectivity in ALS due to C9ORF72 hexanucleotide expansion: a [18F]FDG-PET study.

European journal of nuclear medicine and molecular imaging 2026

Canosa A, Callegaro S, Manera U, Vasta R, Cabras S, Di Pede F, De Mattei F, Palumbo F, Iazzolino B, Dei Giudici A, Matteoni E, Zocco G, Minerva E, Maccabeo A, Pellegrino G, Pascariu D, Grassano M, Piombino P, Testa M, Polverari G, Fuda G, Merulla I, Casale F, Gallone S, Moglia C, Calvo A, Pagani M, Chiò A

Abstract

PURPOSE: Our aim was to investigate brain metabolic connectivity, as assessed via [18F]FDG-PET, in ALS patients carrying the C9ORF72 expansion (C9-ALS). METHODS: We compared brain metabolism of C9-ALS and patients without mutations of the main ALS-related genes (ctrl-ALS) through the two-sample t-test model of SPM12. Metabolic clusters showing a significant difference between the two groups were used as seed regions for an interregional correlation analysis (IRCA) in each group to evaluate metabolic connectivity. RESULTS: As compared to ctrl-ALS, C9-ALS showed a relative hypometabolism in bilateral thalamus and left precentral and postcentral gyri, and a relative hypermetabolism in bilateral cerebellum and brainstem. In the IRCA, a positive correlation was found between the thalamic seed region and the cingulate cortex, including its anterior part. This correlation was broader in C9-ALS than in Ctrl-ALS. A negative correlation between the thalamic seed region and the sensorimotor cortex was only found in C9-ALS. In the IRCA, based on the cerebellar/brainstem cluster, positive correlations with the seed region substantially represented autocorrelation in both groups. Negative correlation, which mainly included frontal cortices, was more extensive in C9-ALS than in Ctrl-ALS. CONCLUSION: In the comparison with ctrl-ALS, C9-ALS showed a relatively lower metabolism in the thalami and a relatively higher metabolism in the brainstem and the cerebellum. As compared to ctrl-ALS, C9-ALS showed a predominant involvement of the salience network, which is related to cognitive and behavioural control. The cerebellum might be recruited to cope with cognitive impairment to a greater extent in C9-ALS than in ctrl-ALS.

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