Cognitive Reserve in Amyotrophic Lateral Sclerosis: A 2‐[18F]FDG-PET Study on Sex‐Related Differences

Background: Cognitive reserve (CR) applies to ALS-related cognitive impairment and education is a CR proxy. The influence of sex on CR in ALS is unclear. Methods: We compared brain 2-[18F]FDG-PET metabolism of male (m-ALS, n = 95) and female (f-ALS, n = 95) patients, matched for age, education, onset, and King's stage, with no significant difference in ECAS scores. In each group, clusters showing a negative/positive correlation with education were used as seed regions in an interregional correlation analysis (IRCA) to evaluate connectivity. We identified the seed regions including age, onset, King's stage and ECAS as covariates. Results: M-ALS showed a relative hypometabolism compared to f-ALS in bilateral frontotemporal regions. In f-ALS brain metabolism positively correlated with education in the left fusiform gyrus, cerebellum and pons. The IRCA showed a positive correlation of the seed region with the cerebellum, pons, right fusiform gyrus and cuneus, and the left precuneus, and a negative correlation with the frontal lobes and caudate nuclei. In m-ALS brain metabolism negatively correlated with education in the left frontotemporal and insular cortices. The IRCA showed a positive correlation of the seed region with bilateral frontotemporal and cingulate cortices, and the right parietal cortex, and a negative correlation with bilateral cerebellum and motor cortex, and the left lingual gyrus. Conclusions: M-ALS showed relative frontotemporal hypometabolism compared to f-ALS, suggesting a male prevalence of CR. In m-ALS the negative correlation of education with left frontotemporal and insular metabolism supports the CR hypothesis. In f-ALS the positive correlation of cerebellar metabolism with education suggests compensatory mechanisms, also supported by the IRCA.