Brain insulin signaling and neurodegeneration: IRS‐1 isolated from neuronal enriched extracellular vesicles associates with frontal lobe gray matter volume in cognitively unimpaired adults

Abstract

AbstractBackgroundBrain insulin signaling, as measured by insulin signaling proteins in neuronal enriched extracellular vesicles (nEVs), has previously been associated with gray matter (GM) volume in the temporal lobe of nondemented older adults and in multiple brain regions in those with Alzheimer’s clinical syndrome (Walker et al, 2021; Mullins et al, 2017). We sought to extend these findings by performing a voxel‐wise analysis to test the relationship between whole‐brain GM volume and nEV tyrosine phosphorylated IRS‐1 (pY‐IRS‐1) in a cognitively unimpaired sample enriched for AD risk.MethodCognitively‐unimpaired adults (n=47) from the Wisconsin Registry for Alzheimer’s Prevention underwent MRI and blood collection (Table 1). nEVs were isolated from plasma samples by immunoprecipitation targeting neuronal marker L1CAM. pY‐IRS‐1 was measured in nEVs using an electrochemiluminescence assay (Meso Scale Discovery, Rockville, Maryland) (Mustapic et al, 2017). T1‐weighted images were analyzed using the FMRIB Software Library (FSL), where images were first normalized to MNI space and segmented into WM, GM, and CSF using FSL’s FLIRT, FNIRT, and FAST tools and resulting GM maps were smoothed with a Gaussian kernel (sigma = 3.5mm). General linear models and non‐parametric testing (FSL randomise) were used to assess voxelwise associations between nEV pY‐IRS‐1 concentration and GM volume, while controlling for sex and age effects. Significant associations between GM volume and nEV pY‐IRS‐1 were defined as p < 0.01, uncorrected.ResultWe observed lateralized positive associations between nEV pY‐IRS‐1 and GM volume in the right frontal lobe (Figures 1 and 2). After correcting for multiple comparisons, we observed no significant relationships between nEV pY‐IRS‐1 concentration and GM volume.ConclusionPrevious studies indicate that lower nEV pY‐IRS‐1 is associated with lower GM volume in regions such as the temporal and parietal lobes. Here, we determined that lower nEV pIRS‐1 concentrations were associated with lower GM volume laterally in the right frontal lobe of healthy middle‐aged and older adults. Future studies are needed to determine the mechanism by which disrupted insulin signaling in the brain may cause GM loss in these regions.