Insulin resistance and gray matter volume in neurodegenerative disease

• Insulin resistance was increased in individuals with AD and PD compared to healthy elderly subjects.
• AD subjects exhibited more severe metabolic dysfunction than PD subjects.
• Within-group assessments showed a significant relationship between gray matter volume and insulin resistance.
• Both the brain region and directionality of the relationship between metabolism and brain volume was unique in each group.

The goal of this study was to compare insulin resistance in aging and aging-related neurodegenerative diseases, and to determine the relationship between insulin resistance and gray matter volume (GMV) in each cohort using an unbiased, voxel-based approach. Insulin resistance was estimated in apparently healthy elderly control (HC, n = 21) and neurodegenerative disease (Alzheimer’s disease (AD), n = 20; Parkinson’s disease (PD), n = 22) groups using Homeostasis Model Assessment of Insulin Resistance 2 (HOMA2) and intravenous glucose tolerance test (IVGTT). HOMA2 and GMV were assessed within groups through General Linear Model multiple regression. We found that HOMA2 was increased in both AD and PD compared to the HC group (HC vs. AD, p = 0.002, HC vs. PD, p = 0.003), although only AD subjects exhibited increased fasting glucose (p = 0.005). Furthermore, our voxel-based morphometry analysis revealed that HOMA2 was related to GMV in all cohorts in a region-specific manner (p < 0.001, uncorrected). Significant relationships were observed in the medial prefrontal cortex (HC), medial temporal regions (AD), and parietal regions (PD). Finally, the directionality of the relationship between HOMA2 and GMV was disease-specific. Both HC and AD subjects exhibited negative relationships between HOMA2 and brain volume (increased HOMA2 associated with decreased brain volume), while a positive relationship was observed in PD. This cross-sectional study suggests that insulin resistance is increased in neurodegenerative disease, and that individuals with AD appear to have more severe metabolic dysfunction than individuals with PD or PD dementia.