Optical coherence tomography angiography reveals insights into complementary vascular and neurodegenerative mechanisms in multiple sclerosis

Optical coherence tomography angiography quantifies retinal microvasculature biomarkers, offering insights into neurovascular mechanisms underlying brain damage in multiple sclerosis. This study evaluated these potential mechanisms of neurodegeneration by examining associations between optical coherence tomography and optical coherence tomography angiography metrics, brain volumes and clinical outcomes in people with multiple sclerosis. This cross-sectional study included multiple sclerosis patients from a prospective cohort. Participants underwent optical coherence tomography/optical coherence tomography angiography, vision and clinical assessments and brain MRI. Age- and sex-matched controls underwent optical coherence tomography/optical coherence tomography angiography. The OCTA Vascular Analyser toolbox was used to derive metrics that reflect superficial plexus retinal vessel density (vessel area density, vessel length density) and network complexity. Differences in optical coherence tomography angiography and optical coherence tomography (peripapillary retinal nerve fibre layer and macular ganglion cell-inner plexiform layer) metrics between controls and patient eyes and associations with brain volumes and visual outcomes were analysed using linear-mixed models, adjusted for age, sex, disease duration and optic neuritis. Vision outcome models were compared using Akaike Information Criterion. The study included 323 multiple sclerosis patients (603 eyes; 98 with prior optic neuritis) and 80 controls (147 eyes), with 267 patients undergoing brain MRI. Patients exhibited reduced vessel area density and vessel length density and thinner peripapillary retinal nerve fibre layer and macular ganglion cell-inner plexiform layer in non-optic neuritis eyes compared with controls. Optic neuritis eyes showed deviations compared with non-optic neuritis eyes. In patients, reductions in optical coherence tomography angiography and optical coherence tomography metrics were associated with smaller volumes of the primary visual cortex (calcarine cortex and occipital pole) and thalamus but reduced vessel area density/vessel length density correlated predominantly with smaller higher-order visual processing region volumes, such as the cuneus (vessel area density: β = 0.36, vessel length density: β = 0.070), inferior occipital (vessel area density: β = 0.28, vessel length density: β = 0.057) and occipital fusiform gyrus (vessel area density: β = 0.51, vessel length density: β = 0.094) (all P < 0.01). In contrast, peripapillary retinal nerve fibre layer thinning was associated with smaller white matter (β = 0.10, P = 0.008) and optic chiasm volumes (β = 293.30, P < 0.0001). Reduced vessel densities were more strongly associated with worse high-contrast visual acuity and colour vision than macular ganglion cell-inner plexiform layer and peripapillary retinal nerve fibre layer. Retinal microvasculature abnormalities were associated with regional grey matter atrophy in higher-order vision processing regions. We speculate that cerebral hypoperfusion—and by proxy, retinal hypoperfusion—may be mechanistically related to region-specific neurodegeneration. In contrast, peripapillary retinal nerve fibre layer thinning may reflect broader neurodegenerative processes, including Wallerian degeneration and disrupted white matter connectivity. Clinically, this manifests as impaired contrast sensitivity and colour vision. These findings underscore optical coherence tomography angiography’s potential as a complementary biomarker to optical coherence tomography in probing visual pathway integrity, highlighting its promise for assessing neurovascular pathology and progression in early multiple sclerosis.