Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degen- eration of upper and lower motor neurons. However, the neurobiological basis of disease heterogeneity and its prognostic relevance remain incompletely understood. Methods In this prospective study, 127 patients with ALS and 128 age- and sex-matched healthy controls underwent brain fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Clinical assessments included standardized evaluations of motor function, cognition, anxiety, and depression. Associations between regional cerebral metabolism and clinical variables were examined using linear regression, whereas survival outcomes were evaluated with Cox proportional hazards models. Whole-exome sequencing was performed to assess genetic mutation sta- tus and mutation burden, and a neuroimaging-transcriptomic association analysis was conducted to link regional metabolic alterations with spatial gene expression patterns. Results Compared with the healthy controls, patients with ALS exhibited a distinctive cerebral metabolic pattern character- ized by coexisting hypometabolism and hypermetabolism within the fronto-striatal-limbic network. Significant hypome- tabolism was observed in the visual pathways, temporal lobes, and cerebellum (all p<0.05). Hypermetabolism within the fronto-striatal-limbic circuit was associated with better motor and cognitive performance, and lower levels of anxiety and depression (all p < 0.05). Multivariate Cox regression identified hypermetabolism in the right inferior frontal gyrus (opercu- lar part), cognitive impairment, and disease progression rate as independent predictors of survival (all p < 0.05). In addition, genetic mutation status and mutation burden were significantly associated with region-specific metabolic alterations, and neuroimaging-transcriptomic analysis revealed distinct transcriptional signatures underlying hypermetabolic and hypometa- bolic brain regions. Conclusion Cerebral metabolic abnormalities in patients with ALS reflected a complex interplay between compensatory and degenerative processes, which were closely linked to clinical symptoms and prognosis. Integrating FDG-PET metabolic profiles with genetic and transcriptional information may improve understanding of disease heterogeneity and support per- sonalized prognostic assessment for patients with ALS.
Cerebral metabolic patterns on 18F-FDG PET are associated with clinical heterogeneity and prognosis in amyotrophic lateral sclerosis: a genetic and transcriptomic perspective
Grecucci, Alessandro;
2026-01-01
Abstract
Background Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive degen- eration of upper and lower motor neurons. However, the neurobiological basis of disease heterogeneity and its prognostic relevance remain incompletely understood. Methods In this prospective study, 127 patients with ALS and 128 age- and sex-matched healthy controls underwent brain fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). Clinical assessments included standardized evaluations of motor function, cognition, anxiety, and depression. Associations between regional cerebral metabolism and clinical variables were examined using linear regression, whereas survival outcomes were evaluated with Cox proportional hazards models. Whole-exome sequencing was performed to assess genetic mutation sta- tus and mutation burden, and a neuroimaging-transcriptomic association analysis was conducted to link regional metabolic alterations with spatial gene expression patterns. Results Compared with the healthy controls, patients with ALS exhibited a distinctive cerebral metabolic pattern character- ized by coexisting hypometabolism and hypermetabolism within the fronto-striatal-limbic network. Significant hypome- tabolism was observed in the visual pathways, temporal lobes, and cerebellum (all p<0.05). Hypermetabolism within the fronto-striatal-limbic circuit was associated with better motor and cognitive performance, and lower levels of anxiety and depression (all p < 0.05). Multivariate Cox regression identified hypermetabolism in the right inferior frontal gyrus (opercu- lar part), cognitive impairment, and disease progression rate as independent predictors of survival (all p < 0.05). In addition, genetic mutation status and mutation burden were significantly associated with region-specific metabolic alterations, and neuroimaging-transcriptomic analysis revealed distinct transcriptional signatures underlying hypermetabolic and hypometa- bolic brain regions. Conclusion Cerebral metabolic abnormalities in patients with ALS reflected a complex interplay between compensatory and degenerative processes, which were closely linked to clinical symptoms and prognosis. Integrating FDG-PET metabolic profiles with genetic and transcriptional information may improve understanding of disease heterogeneity and support per- sonalized prognostic assessment for patients with ALS.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
