Introduction

Leber’s Hereditary Optic Neuropathy (LHON) is a mitochondrial disorder causing central vision loss due to retinal ganglion cell degeneration and optic nerve atrophy. While visual pathway abnormalities are well studied¹, less is known about the integrity of remaining white matter tracts^2,3. This study investigates structural connectivity differences in LHON patients versus healthy controls (HC) using structural connectomics.

Methods

We recruited 12 acute LHON patients (11M/1F,34.1±15.0yo) without atypical findings and sex-age matched HC group (11M/1F,34.0±3.8yo). The 3T-MRI protocol used T1-weighted 3D images and multishell diffusion-weighted acquisition: 8×b=0(AP/PA); 12×b=300(AP/PA); 30×b=1000(AP/PA); 64×b=2000(AP); voxel size 2×2×2mm.

After standardization, whole-brain tractography was performed using the iFOD2 algorithm (MRtrix3) and structural connectivity was estimated using the Human Brainnetome Atlas.

Group differences were assessed using BCTpy (v.0.6.1) with Network-Based Statistics (NBS, 5000 permutations, t-threshold=2.5). Connectivity matrices were correlated with neuro-ophthalmological measures: logMAR (Minimum Angle of Resolution) and GCL (Ganglion Cell Layer).

Results

NBS-analysis evinced significantly reduced connected components (p-value=0.009) in LHON versus HC within cortical areas (occipital 23%, temporal 20%) and subcortical nuclei. For both eyes, resulted negative correlations between connectivity matrices cortical edges and logMAR scale, particularly temporal (0.001<p-value<0.048) and occipital (0.002<p-value<0.045), parietal (0.002<p-value<0.049), limbic (0.002<p-value<0.046) and frontal (0.001<p-value <0.048) lobes. The average-GCL was positively correlated with subcortical nuclei edges.

Conclusions

The reduced structural connectivity in temporal and parietal lobes, where visual association areas are located, and frontal areas (involved in conscious perception), along with subcortical nuclei (perceptual decision making), suggest a possible spread pathological mechanism in LHON beyond classical visual pathway.

References

¹Manners, D. N., Gramegna, L. L., La Morgia, C., Sighinolfi, G., Fiscone, C., Carbonelli, M., Romagnoli, M., Carelli, V., Tonon, C., & Lodi, R. (2022). Multishell Diffusion MR Tractography Yields Morphological and Microstructural Information of the Anterior Optic Pathway: A Proof-of-Concept Study in Patients with Leber’s Hereditary Optic Neuropathy. International journal of environmental research and public health, 19(11), 6914.

²Zhang, J., Wang, L., Ding, H., Fan, K., Tian, Q., Liang, M., Sun, Z., Shi, D., & Qin, W. (2021). Abnormal large-scale structural rich club organization in Leber’s hereditary optic neuropathy. NeuroImage. Clinical, 30, 102619.

³Tian, Q., Wang, L., Zhang, Y., Fan, K., Liang, M., Shi, D., Qin, W., & Ding, H. (2022). Brain Gray Matter Atrophy and Functional Connectivity Remodeling in Patients With Chronic LHON. Frontiers in neuroscience, 16, 885770.