Abstract
We assessed abnormalities within the principal brain resting state networks (RSNs) in patients with Leber's hereditary optic neuropathy (LHON) to define whether functional abnormalities in this disease are limited to the visual system or, conversely, tend to be more diffuse. We also defined the structural substrates of fMRI changes using a connectivity-based analysis of diffusion tensor (DT) MRI data. Neuro-ophthalmologic assessment, DT MRI and RS fMRI data were acquired from 13 LHON patients and 13 healthy controls. RS fMRI data were analyzed using independent component analysis and SPM5. A DT MRI connectivity-based parcellation analysis was performed using the primary visual and auditory cortices, bilaterally, as seed regions. Compared to controls, LHON patients had a significant increase of RS fluctuations in the primary visual and auditory cortices, bilaterally. They also showed decreased RS fluctuations in the right lateral occipital cortex and right temporal occipital fusiform cortex. Abnormalities of RS fluctuations were correlated significantly with retinal damage and disease duration. The DT MRI connectivity-based parcellation identified a higher number of clusters in the right auditory cortex in LHON vs. controls. Differences of cluster-centroid profiles were found between the two groups for all the four seeds analyzed. For three of these areas, a correspondence was found between abnormalities of functional and structural connectivities. These results suggest that functional and structural abnormalities extend beyond the visual network in LHON patients. Such abnormalities also involve the auditory network, thus corroborating the notion of a cross-modal plasticity between these sensory modalities in patients with severe visual deficits.
Highlights
Leber’s Hereditary Optic Neuropathy (LHON) is a maternally inherited genetic disease characterised by an acute or subacute bilateral loss of vision, which predominantly affects young men, with a clinical onset between 15 and 35 years [1,2,3]
LHON has been linked to three ‘‘primary’’ mitochondrial DNA point mutations, which affect oxidative phosphorylation in mitochondria [5,6]. It is still unclear whether central nervous system (CNS) involvement in patients with LHON is restricted to the optic nerve and visual pathways via chronic damage, as has been described in other ocular pathologies, including optic neuritis [7,8], chronic glaucoma [9], retinal degeneration [10], and albinism [11]
At the time of magnetic resonance imaging (MRI) assessment, all LHON patients had bilateral visual impairment and a variable degree of optic nerve pallor detectable at fundoscopy, which was evident in the temporal sector
Summary
Leber’s Hereditary Optic Neuropathy (LHON) is a maternally inherited genetic disease characterised by an acute or subacute bilateral loss of vision, which predominantly affects young men, with a clinical onset between 15 and 35 years [1,2,3]. LHON has been linked to three ‘‘primary’’ mitochondrial DNA (mtDNA) point mutations, which affect oxidative phosphorylation in mitochondria [5,6] At present, it is still unclear whether central nervous system (CNS) involvement in patients with LHON is restricted to the optic nerve and visual pathways via chronic damage (i.e., the lateral geniculate nucleus and the visual cortex may be involved by trans-synaptic degeneration phenomena), as has been described in other ocular pathologies, including optic neuritis [7,8], chronic glaucoma [9], retinal degeneration [10], and albinism [11]. MR spectroscopy (MRS) studies of LHON have shown an abnormal mitochondrial energy metabolism in the occipital lobe [14,15,16], and diffuse abnormalities in the normalappearing white matter have been detected using magnetization transfer MRI [17]
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