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Background: MRI studies reported that ALS patients with bulbar and spinal onset showed focal cortical changes in corresponding regions of the motor homunculus. We evaluated the capability of brain 2-[ 18 F]FDG-PET to disclose the metabolic features characterizing patients with pure bulbar or spinal motor impairment., Methods: We classified as pure bulbar (PB) patients with bulbar onset and a normal score in the spinal items of the ALSFRS-R, and as pure spinal (PS) patients with spinal onset and a normal score in the bulbar items at the time of PET. Forty healthy controls (HC) were enrolled. We compared PB and PS, and each patient group with HC. Metabolic clusters showing a statistically significant difference between PB and PS were tested to evaluate their accuracy in discriminating the two groups. We performed a leave-one-out cross-validation (LOOCV) over the entire dataset. Four classifiers were considered: support vector machines (SVM), K-nearest neighbours, linear classifier, and decision tree. Then, we used a separate test set, including 10% of patients, with the remaining 90% composing the training set., Results: We included 63 PB, 271 PS, and 40 HC. PB showed a relative hypometabolism compared to PS in bilateral precentral gyrus in the regions of the motor cortex involved in the control of bulbar function. SVM showed the best performance, resulting in the lowest error rate in both LOOCV (4.19%) and test set (9.09 ± 2.02%)., Conclusions: Our data support the concept of the focality of ALS onset and the use of 2-[ 18 F]FDG-PET as a biomarker for precision medicine-oriented clinical trials., (© 2022. The Author(s).)