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Brain metabolic connectivity in ALS due to C9ORF72 hexanucleotide expansion: a [18F]FDG-PET study
Antonio Canosa1,2,3,4, Stefano Callegaro5, Umberto Manera5,6
1ALS Centre, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Via Cherasco 15, Turin, 10126, Italy. antonio.canosa@unito.it.
European Journal of Nuclear Medicine and Molecular Imaging
|December 11, 2025
Summary
Amyotrophic lateral sclerosis (ALS) patients with the C9ORF72 gene expansion (C9-ALS) show distinct brain metabolism patterns compared to other ALS patients. C9-ALS exhibits altered connectivity in brain networks, particularly the salience network, suggesting potential cognitive involvement.
Area of Science:
- Neuroscience
- Genetics
- Metabolic Imaging
Background:
- Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease.
- The C9ORF72 gene expansion is a common genetic cause of ALS.
- Understanding brain metabolic alterations in C9-ALS is crucial for disease characterization.
Purpose of the Study:
- To investigate brain metabolic connectivity in ALS patients with the C9ORF72 expansion (C9-ALS).
- To compare metabolic patterns between C9-ALS and ALS patients without major ALS-related gene mutations (ctrl-ALS).
- To assess interregional metabolic correlations to understand network connectivity.
Main Methods:
- Utilized [18F]FDG-PET imaging to assess brain metabolism.
- Employed two-sample t-tests (SPM12) to compare metabolic differences between C9-ALS and ctrl-ALS groups.
- Conducted interregional correlation analysis (IRCA) using significant metabolic clusters as seed regions.
Main Results:
- C9-ALS patients exhibited hypometabolism in the thalamus and sensorimotor cortex compared to ctrl-ALS.
- C9-ALS showed hypermetabolism in the cerebellum and brainstem relative to ctrl-ALS.
- Connectivity analyses revealed broader thalamic-cingulate cortex correlation in C9-ALS and more extensive negative correlations between thalamus and sensorimotor cortex.
Conclusions:
- C9-ALS is characterized by distinct patterns of brain metabolism and connectivity, with reduced thalamic and increased cerebellar/brainstem metabolism.
- Findings suggest predominant involvement of the salience network in C9-ALS, impacting cognitive and behavioral control.
- The cerebellum may play a compensatory role in managing cognitive impairments in C9-ALS.
