Association Between Gray Matter Microstructure and Glucose Metabolism in Older Adults With Cognitive Decline: A...

Cortical glucose hypometabolism is a well-established early marker of neurodegeneration in dementia, mainly reflecting neuronal and synaptic dysfunction. Its relationship with underlying microstructural alterations remains unclear. Here, we combined multi-shell diffusion microstructural and [¹⁸F]-FDG PET data to investigate the possible association between regional cerebral glucose metabolism and microstructural integrity in patients with cognitive decline. Subjects from two independent datasets, an in-house dataset of 65 cognitively impaired patients from a memory-clinic cohort and a cognitively impaired cohort retrieved from the ADNI database (advanced ADNI3 protocol), underwent [¹⁸F]-FDG PET and MRI scanning. Multiple linear regression models were used to evaluate regional associations between glucose metabolism and gray matter microstructure, as measured by NODDI-derived metrics, namely neurite density index (NDI) and orientation dispersion index (ODI). Global spatial associations between metabolic and microstructural-derived maps were investigated via spin tests. Regional analysis showed widespread significant positive associations between glucose consumption and ODI across the cortex and subcortex. In both datasets, the global spatial association between NODDI and metabolism showed the ODI being significantly correlated with glucose metabolism (ρ = 0.36, p_spin < 0.001 for the in-house dataset; ρ = 0.54, p_spin < 0.001 for the ADNI dataset). Our findings provide new evidence that regional glucose metabolism in cognitive decline is positively associated with alterations in microstructural organization, as reflected by decreased neurite complexity. The significant association suggests that microstructural alterations may parallel the metabolic deficits characteristic of neurodegenerative diseases, pointing to a link between microstructural properties and neuronal metabolic dysfunction.