Unfolding the Brain: Reduced Cortical Gyrification in T1D
Jonadab dos Santos Silva, Richard G. IJzerman, Martin Klein, Frederik Barkhof, Annette C. Moll, Frank J. Snoek and Eelco van Duinkerken
Reduced cortical gyrification in type 1 diabetes is associated with white matter integrity loss and cognitive decline. Metab Brain Dis. 2026 Jul 8;41(1):160.
Adults with type 1 diabetes (T1D) experience a moderate but clinically relevant decline in cognitive functions including information processing speed, attention and executive functioning — a finding confirmed by 32 years of follow-up in the landmark DCCT/EDIC study. Yet conventional brain imaging measures such as cortical volume and thickness have repeatedly failed to explain these changes. A less studied property of the brain — cortical gyrification, the complexity of the folding pattern of the brain's surface — may provide the missing link. This study, conducted by researchers from Amsterdam UMC/Diabeter Center Amsterdam/Diabeter NL, Yale University, University College London and the Universidade Federal Fluminense, examined whether the local gyrification index (LGI) is altered in adults with T1D, how this relates to the integrity of connecting white matter tracts, and whether gyrification mediates the relationship between white matter damage and cognitive decline.
Fifty-one adults with T1D and microangiopathy (proliferative retinopathy as a marker of chronic microvascular end-organ damage), 53 without clinically manifest microangiopathy, and 49 healthy controls underwent 1.5T MRI.
Key findings:
- Cortical gyrification is broadly reduced in adults with T1D: Compared to healthy controls, adults with T1D showed lower LGI across widespread brain regions. These reductions did not follow the normal aging pattern, but instead showed a posterior predominance consistent with prior evidence of posterior cerebrovascular vulnerability in T1D.
- The effect is primarily driven by microangiopathy: LGI reductions were most pronounced and statistically significant in those with microangiopathy. Adults without microangiopathy showed intermediate LGI values between the microangiopathy group and controls, suggesting a graded relationship with cumulative microvascular damage rather than a categorical effect.
- Conventional cortical measures failed to distinguish groups after adjustment: While global LGI differed significantly between T1D and controls after covariate adjustment, cortical thickness and grey matter volume did not — underscoring LGI as a more sensitive marker of subtle cortical changes in T1D.
- Lower gyrification is associated with poorer white matter tract integrity, consistent with the theory that white matter axonal tension shapes and maintains cortical folding.
- Reduced LGI is linked to poorer cognition: Lower bilateral LGI was associated with impaired attention, and lower right-hemisphere LGI was associated with reduced general cognitive ability in adults with T1D, even after adjusting for age and sex.
- Gyrification mediates the pathway from white matter damage to cognitive decline: Cortical folding captures essential aspects of brain architecture that are non-redundant with diffusion metrics alone.
- The findings align with models of cerebral small vessel disease: The authors propose that in T1D, chronic hyperglycaemia and microvascular damage lead to diffuse axonal injury, weakening the mechanical forces that maintain cortical folding and thereby gradually smoothing the cortical surface. This structural reorganisation then impairs the cognitive functions dependent on those networks.
This study provides the first integrative model linking microvascular white matter damage, cortical gyrification and cognitive decline in T1D, and establishes LGI as a sensitive, mechanistically motivated neuroimaging marker that bridges these levels of neural organisation. The findings are cross-sectional and causal directionality awaits longitudinal confirmation.
Concluding, the authors state
"These insights provide a more comprehensive understanding of the neural mechanisms underlying cognitive impairments in type 1 diabetes and underscore the importance of addressing both neural and vascular health to mitigate potential future cognitive decline."
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