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Distributed abnormalities of brain white matter architecture in patients with dominant optic atrophy and OPA1 mutations

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Abstract

Using advanced MRI techniques, we investigated the presence and topographical distribution of brain grey matter (GM) and white matter (WM) alterations in dominant optic atrophy (DOA) patients with genetically proven OPA1 mutation as well as their correlation with clinical and neuro-ophthalmologic findings. Nineteen DOA patients underwent neurological, neuro-ophthalmologic and brainstem auditory evoked potentials (BAEP) evaluations. Voxel-wise methods were applied to assess regional GM and WM abnormalities in patients compared to 20 healthy controls. Visual acuity was reduced in 16 patients. Six DOA patients (4 with missense mutations) had an abnormal I peripheral component (auditory nerve) at BAEP. Compared to controls, DOA patients had significant atrophy of the optic nerves (p < 0.0001). Voxel-based morphometry (VBM) analysis showed that, compared to controls, DOA patients had significant WM atrophy of the chiasm and optic tracts; whereas no areas of GM atrophy were found. Tract-based spatial statistics (TBSS) analysis showed that compared to controls, DOA patients had significantly lower mean diffusivity, axial and radial diffusivity in the WM of the cerebellum, brainstem, thalamus, fronto-occipital-temporal lobes, including the cingulum, corpus callosum, corticospinal tract and optic radiation bilaterally. No abnormalities of fractional anisotropy were detected. No correlations were found between volumetric and diffusivity abnormalities quantified with MRI and clinical and neuro-ophthalmologic measures of disease severity. Consistently with pathological studies, tissue loss in DOA patients is limited to anterior optic pathways reflecting retinal ganglion cell degeneration. Distributed abnormalities of diffusivity indexes might reflect abnormal intracellular mitochondrial morphology as well as alteration of protein levels due to OPA1 mutations.

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Acknowledgements

E.L. is supported by Pierfranco e Luisa Mariani Foundation, Italy. We thank Franco Carrara, Melissa Petrolini and Elisabetta Pagani for their contribution to the analysis of the data.

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standard

This study was performed in accordance with the ethical standards laid down in the 1965 Declaration of Helsinski and its later amendments.

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Authors and Affiliations

  1. Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina, 60, 20132, Milan, Italy

    Maria A. Rocca, Roberta Messina & Massimo Filippi

  2. Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    Maria A. Rocca, Roberta Messina, Letizia Leocani, Giancarlo Comi & Massimo Filippi

  3. Department of Ophthalmology, Neuro-ophthalmology Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy

    Stefania Bianchi-Marzoli & Gabriella Cammarata

  4. Department of Ophthalmology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    Maria Lucia Cascavilla, Jacopo Milesi & Francesco Bandello

  5. Unit of Molecular Neurogenetics, Foundation ‘‘C. Besta’’ Neurological Institute-IRCCS, Milan, Italy

    Massimo Zeviani, Costanza Lamperti & Eleonora Lamantea

  6. MRC Mitochondrial Biology Unit, Cambridge, UK

    Massimo Zeviani

  7. Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T), Ophthalmology Unit, University of Parma, Parma, Italy

    Arturo Carta

  8. Experimental Neurophysiology Unit, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    Letizia Leocani

  9. Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy

    Andrea Falini

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  1. Maria A. Rocca
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  2. Stefania Bianchi-Marzoli
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Correspondence to Massimo Filippi.

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Rocca, M.A., Bianchi-Marzoli, S., Messina, R. et al. Distributed abnormalities of brain white matter architecture in patients with dominant optic atrophy and OPA1 mutations. J Neurol 262, 1216–1227 (2015). https://doi.org/10.1007/s00415-015-7696-5

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