Retinal Microvascular Alterations Link Astroglial Activation to Neurodegeneration in Mild Cognitive Impairment

Purpose: To investigate the associations between retinal microvascular complexity and neurodegeneration, cerebral small vessel disease (SVD), plasma biomarkers, and cognition in mild cognitive impairment (MCI). Methods: This cross-sectional study included 77 individuals with MCI and 93 cognitively unimpaired (CU) older adults. Retinal microvascular complexity was quantified from color fundus photographs using the fractal dimension (FD). Neuroimaging measures included hippocampal volume, choroid plexus volume, and cerebral SVD burden. Plasma biomarkers included amyloid-β42, amyloid-β40, phosphorylated tau (p-tau181 and p-tau217), neurofilament light chain, and glial fibrillary acidic protein (GFAP). Results: The retinal FD was lower in MCI than CU participants (1.29 ± 0.08 vs. 1.44 ± 0.04; P < 0.001). Within MCI, a lower FD was associated with a smaller hippocampal volume (β = 0.552; 95% confidence interval [CI], 0.391-0.713), a larger choroid plexus volume (β = -0.320; 95% CI, -0.473 to -0.167), and a greater SVD burden (β = -0.291; 95% CI, -0.453 to -0.130; all P < 0.001). A lower FD was associated with higher p-tau181, p-tau217, p-tau217/Aβ42, and GFAP levels. The FD interacted with GFAP in association with the hippocampal volume (β = -0.364; 95% CI, -0.566 to -0.163; P < 0.001). The hippocampal volume and SVD burden partially mediated the association between the FD and cognitive performance. Conclusions: Retinal microvascular complexity is associated with neurodegenerative, cerebrovascular, and plasma biomarker abnormalities in MCI. Translational Relevance: A quantitative retinal microvascular assessment from color fundus photographs may provide a noninvasive approach for characterizing brain vascular and neurodegenerative abnormalities in early cognitive impairment.