ArticleFrontiers in neurology2026
Gray matter atrophy mediates the association between cerebral hypometabolism and cognitive impairment in Alzheimer's disease.
Article in Frontiers in neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Objective: Alzheimer's disease (AD) is characterized by amyloid deposition, brain hypometabolism, gray matter atrophy and cognitive decline, yet their causal interactions are poorly defined. This multimodal PET/MRI study explored regional gray matter volume (GMV) loss and glucose hypometabolism in AD patients, and clarified their correlations with distinct cognitive deficits alongside mediating pathways. Methods: 134 probable dementia patients were split into AD and non-AD dementia cohorts based on Results: AD patients exhibited prominent regional GMV shrinkage and FDG hypometabolism in vulnerable brain regions relative to non-AD dementia subjects. Covariate-adjusted analyses linked both imaging biomarkers to domain-specific cognitive performance. Primary mediation analyses showed that regional GMV significantly mediated the associations between FDG metabolism and visuospatial, executive, and language function, accounting for 40.36, 35.60, and 49.99% of the total effects, respectively. Reverse mediation models identified only a weak indirect effect of right superior temporal gyrus metabolism on the association between right inferior parietal lobule GMV and visuospatial ability, accounting for 13.26% of the total effect. Moreover, after multiple-imputation sensitivity analyses, most indirect effects became unstable or nonsignificant, suggesting that the FDG metabolism-cognition association is predominantly direct, with limited evidence for GMV mediation. Conclusion: Integrated PET/MRI revealed AD-related patterns of regional atrophy and hypometabolism. Overall, the association between cerebral metabolic dysfunction and cognitive impairment appeared to be predominantly direct, with limited evidence supporting a mediating role of regional GMV.
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