Retinal Microvasculature Causally Affects the Brain Cortical Structure: A Mendelian Randomization Study.

Purpose: To reveal the causality between retinal vascular density (VD), fractal dimension (FD), and brain cortex structure using Mendelian randomization (MR).

Design: Cross-sectional study.

Participants: Genome-wide association studies of VD and FD involving 54 813 participants from the United Kingdom Biobank were used. The brain cortical features, including the cortical thickness (TH) and surface area (SA), were extracted from 51 665 patients across 60 cohorts. Surface area and TH were measured globally and in 34 functional regions using magnetic resonance imaging.

Methods: Bidirectional univariable MR (UVMR) was used to detect the causality between FD, VD, and brain cortex structure. Multivariable MR (MVMR) was used to adjust for confounding factors, including body mass index and blood pressure.

Main Outcome Measures: The global and regional measurements of brain cortical SA and TH.

Results: At the global level, higher VD is related to decreased TH ( = -0.0140 mm, 95% confidence interval: -0.0269 mm to -0.0011 mm,  = 0.0339). At the functional level, retinal FD is related to the TH of banks of the superior temporal sulcus and transverse temporal region without global weighted, as well as the SA of the posterior cingulate after adjustment. Vascular density is correlated with the SA of subregions of the frontal lobe and temporal lobe, in addition to the TH of the inferior temporal, entorhinal, and pars opercularis regions in both UVMR and MVMR. Bidirectional MR studies showed a causation between the SA of the parahippocampal and cauda middle frontal gyrus and retinal VD. No pleiotropy was detected.

Conclusions: Fractal dimension and VD causally influence the cortical structure and vice versa, indicating that the retinal microvasculature may serve as a biomarker for cortex structural changes. Our study provides insights into utilizing noninvasive fundus images to predict cortical structural deteriorations and neuropsychiatric disorders.

Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.