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. 2025 Nov 17;272(12):766.
doi: 10.1007/s00415-025-13501-6.

Role of 2-[18F]FDG-PET as a biomarker of upper motor neuron involvement in amyotrophic lateral sclerosis

Sara Cabras  1   2 , Umberto Manera  3   4 , Francesca Di Pede  3 , Grazia Zocco  3 , Rosario Vasta  3 , Andrea Novara  3 , Emilio Minerva  3 , Enrico Matteoni  3 , Filippo De Mattei  3 , Giorgio Pellegrino  3 , Maurizio Grassano  3 , Barbara Iazzolino  3 , Francesca Palumbo  3 , Stefano Callegaro  3 , Giulia Polverari  5 , Silvia Daniela Morbelli  6   7 , Matteo Pardini  8   9 , Agostino Chiaravalloti  10   11 , Orazio Schillaci  10 , Klaus Leonard Leenders  12   13 , Rosalie Vered Kogan  13 , Cristina Moglia  3   4 , Andrea Calvo  3   4   14 , Adriano Chiò  3   4   14   15 , Marco Pagani  15   16 , Antonio Canosa  3   4   14   15
Affiliations

Role of 2-[18F]FDG-PET as a biomarker of upper motor neuron involvement in amyotrophic lateral sclerosis

Sara Cabras et al. J Neurol. .

Abstract

Introduction: Amyotrophic Lateral Sclerosis (ALS) affects upper (UMN) and lower (LMN) motor neurons. ALS diagnosis is challenging, especially in predominant LMN phenotypes. Electromyography can disclose LMN damage, while UMN involvement is detectable by clinical examination, with possible support of magnetic resonance imaging (MRI) and transcranial magnetic stimulation. Our aim was to investigate the role of 2-[18F]FDG-PET as an UMN biomarker in ALS.

Methods: In our cross-sectional study, we created an UMN burden score. Performing a multiple regression analysis in SPM12, we evaluated the relationship between UMNBS and brain metabolism. We split ALS cohort based on the UMN burden score median value (group A-under median, group B-above median). We ran a full factorial analysis including group A and B and healthy controls, followed by group comparisons.

Results: We included 118 ALS patients (group A and B, N = 59), with a median UMN burden score of 9.50 and a left lateralization of UMN signs. We found a negative correlation between motor cortex metabolism and UMN burden score. Comparing each ALS group with healthy controls, we found relative hypometabolism in the left frontal lobe and relative bilateral, right-prevalent hypermetabolism of cerebellum and corticospinal tracts. The relative hypermetabolism in corticospinal tracts was more evident in the group with low UMN signs.

Conclusions: Motor cortex metabolism reflects UMN burden. Corticospinal tracts' metabolic changes could provide information about UMN involvement even in patients with predominant LMN phenotype, suggesting a possible role of brain 2-[18F]FDG-PET as an UMN biomarker in ALS patients.

Keywords: 2-[18F]FDG-PET; Amyotrophic lateral sclerosis; Motor neuron disease; Upper motor neuron.

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Conflict of interest statement

Declarations. Conflicts of interest: Adriano Chiò serves on Scientific Advisory Boards or Speakers Bureaus for Mitsubishi Tanabe, Biogen, Roche, Denali Pharma, Cytokinetics, Lilly, Ferrer, Zambon Biotech, PCT Therapeutics, and Amylyx Pharmaceuticals. He serves as a member of the Data and Safety Monitoring Committee for ABScience, Corcept, and Ely Lilly. He received a research grant from Biogen. Silvia Daniela Morbelli received speaking honoraria from GE Healthare and Eli-Lilly. Matteo Pardini received speaking honoraria from Nutricia, Eisai, and Eli-Lilly. Andrea Calvo received a research grant from Cytokinetics. Ethical Approval: The study was approved by the ethical committee ‘Comitato Etico Interaziendale Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino.’ The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Participants signed a written informed consent. They did not receive any remuneration for participation. Data were anonymised according to the European regulations for the protection of privacy.

Figures

Fig. 1
Fig. 1
Clusters resulting from the negative correlation between whole-brain metabolism and UMNBS in the ALS cohort are marked in blue and are reported on axial sections of a brain magnetic resonance imaging template and on the brain surface of a glass brain rendering (bottom right)
Fig. 2
Fig. 2
Comparison with HC. Clusters of relative hypometabolism of ALS patients (section A, N = 118), Group A (section B, N = 59), and Group B (section C, N = 59), respectively. Clusters are marked in red and are reported on the brain surface of a glass brain rendering
Fig. 3
Fig. 3
Comparison with HC. Clusters of relative hypermetabolism of ALS patients (section A, N = 118), group A (section B, N = 59), and group B (section C, N = 59). They are represented on a brain magnetic resonance imaging (MRI) template
See this image and copyright information in PMC

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