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Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia

Visual impairments, such as difficulties in reading and finding objects, perceiving depth and structure from motion, and impaired stereopsis, have been reported in tauopathy disorders, such as frontotemporal dementia (FTD). These impairments however have been previously attributed to cortical pathol...

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Autores principales: Harrison, Ian F., Whitaker, Rozalind, Bertelli, Pietro Maria, O’Callaghan, James M., Csincsik, Lajos, Bocchetta, Martina, Ma, Da, Fisher, Alice, Ahmed, Zeshan, Murray, Tracey K., O’Neill, Michael J., Rohrer, Jonathan D., Lythgoe, Mark F., Lengyel, Imre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322294/
https://www.ncbi.nlm.nih.gov/pubmed/30616676
http://dx.doi.org/10.1186/s40478-018-0654-6
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author Harrison, Ian F.
Whitaker, Rozalind
Bertelli, Pietro Maria
O’Callaghan, James M.
Csincsik, Lajos
Bocchetta, Martina
Ma, Da
Fisher, Alice
Ahmed, Zeshan
Murray, Tracey K.
O’Neill, Michael J.
Rohrer, Jonathan D.
Lythgoe, Mark F.
Lengyel, Imre
author_facet Harrison, Ian F.
Whitaker, Rozalind
Bertelli, Pietro Maria
O’Callaghan, James M.
Csincsik, Lajos
Bocchetta, Martina
Ma, Da
Fisher, Alice
Ahmed, Zeshan
Murray, Tracey K.
O’Neill, Michael J.
Rohrer, Jonathan D.
Lythgoe, Mark F.
Lengyel, Imre
author_sort Harrison, Ian F.
collection PubMed
description Visual impairments, such as difficulties in reading and finding objects, perceiving depth and structure from motion, and impaired stereopsis, have been reported in tauopathy disorders, such as frontotemporal dementia (FTD). These impairments however have been previously attributed to cortical pathologies rather than changes in the neurosensory retina or the optic nerve. Here, we examined tau pathology in the neurosensory retina of the rTg(tauP301L)4510 mouse model of FTD. Optic nerve pathology in mice was also assessed using MRI, and corresponding measurements taken in a cohort of five FTD sufferers and five healthy controls. rTg(tauP301L)4510 mice were imaged (T2-weighted MRI) prior to being terminally anesthetized and eyes and brains removed for immunohistochemical and histological analysis. Central and peripheral retinal labelling of tau and phosphorylated tau (pTau) was quantified and retinal layer thicknesses and cell numbers assessed. MR volumetric changes of specific brain regions and the optic nerve were compared to tau accumulation and cell loss in the visual pathway. In addition, the optic nerves of a cohort of healthy controls and behavioural variant FTD patients, were segmented from T1- and T2-weighted images for volumetric study. Accumulation of tau and pTau were observed in both the central and peripheral retinal ganglion cell (RGC), inner plexiform and inner nuclear layers of the neurosensory retina of rTg(tauP301L)4510 mice. This pathology was associated with reduced nuclear density (− 24.9 ± 3.4%) of the central RGC layer, and a reduced volume (− 19.3 ± 4.6%) and elevated T2 signal (+ 27.1 ± 1.8%) in the optic nerve of the transgenic mice. Significant atrophy of the cortex (containing the visual cortex) was observed but not in other area associated with visual processing, e.g. the lateral geniculate nucleus or superior colliculus. Atrophic changes in optic nerve volume were similarly observed in FTD patients (− 36.6 ± 2.6%). The association between tau-induced changes in the neurosensory retina and reduced optic nerve volume in mice, combined with the observation of optic nerve atrophy in clinical FTD suggests that ophthalmic tau pathology may also exist in the eyes of FTD patients. If tau pathology and neurodegeneration in the retina were to reflect the degree of cortical tau burden, then cost-effective and non-invasive imaging of the neurosensory retina could provide valuable biomarkers in tauopathy. Further work should aim to validate whether these observations are fully translatable to a clinical scenario, which would recommend follow-up retinal and optic nerve examination in FTD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0654-6) contains supplementary material, which is available to authorized users.
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spelling pubmed-63222942019-01-09 Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia Harrison, Ian F. Whitaker, Rozalind Bertelli, Pietro Maria O’Callaghan, James M. Csincsik, Lajos Bocchetta, Martina Ma, Da Fisher, Alice Ahmed, Zeshan Murray, Tracey K. O’Neill, Michael J. Rohrer, Jonathan D. Lythgoe, Mark F. Lengyel, Imre Acta Neuropathol Commun Research Visual impairments, such as difficulties in reading and finding objects, perceiving depth and structure from motion, and impaired stereopsis, have been reported in tauopathy disorders, such as frontotemporal dementia (FTD). These impairments however have been previously attributed to cortical pathologies rather than changes in the neurosensory retina or the optic nerve. Here, we examined tau pathology in the neurosensory retina of the rTg(tauP301L)4510 mouse model of FTD. Optic nerve pathology in mice was also assessed using MRI, and corresponding measurements taken in a cohort of five FTD sufferers and five healthy controls. rTg(tauP301L)4510 mice were imaged (T2-weighted MRI) prior to being terminally anesthetized and eyes and brains removed for immunohistochemical and histological analysis. Central and peripheral retinal labelling of tau and phosphorylated tau (pTau) was quantified and retinal layer thicknesses and cell numbers assessed. MR volumetric changes of specific brain regions and the optic nerve were compared to tau accumulation and cell loss in the visual pathway. In addition, the optic nerves of a cohort of healthy controls and behavioural variant FTD patients, were segmented from T1- and T2-weighted images for volumetric study. Accumulation of tau and pTau were observed in both the central and peripheral retinal ganglion cell (RGC), inner plexiform and inner nuclear layers of the neurosensory retina of rTg(tauP301L)4510 mice. This pathology was associated with reduced nuclear density (− 24.9 ± 3.4%) of the central RGC layer, and a reduced volume (− 19.3 ± 4.6%) and elevated T2 signal (+ 27.1 ± 1.8%) in the optic nerve of the transgenic mice. Significant atrophy of the cortex (containing the visual cortex) was observed but not in other area associated with visual processing, e.g. the lateral geniculate nucleus or superior colliculus. Atrophic changes in optic nerve volume were similarly observed in FTD patients (− 36.6 ± 2.6%). The association between tau-induced changes in the neurosensory retina and reduced optic nerve volume in mice, combined with the observation of optic nerve atrophy in clinical FTD suggests that ophthalmic tau pathology may also exist in the eyes of FTD patients. If tau pathology and neurodegeneration in the retina were to reflect the degree of cortical tau burden, then cost-effective and non-invasive imaging of the neurosensory retina could provide valuable biomarkers in tauopathy. Further work should aim to validate whether these observations are fully translatable to a clinical scenario, which would recommend follow-up retinal and optic nerve examination in FTD. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s40478-018-0654-6) contains supplementary material, which is available to authorized users. BioMed Central 2019-01-07 /pmc/articles/PMC6322294/ /pubmed/30616676 http://dx.doi.org/10.1186/s40478-018-0654-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Harrison, Ian F.
Whitaker, Rozalind
Bertelli, Pietro Maria
O’Callaghan, James M.
Csincsik, Lajos
Bocchetta, Martina
Ma, Da
Fisher, Alice
Ahmed, Zeshan
Murray, Tracey K.
O’Neill, Michael J.
Rohrer, Jonathan D.
Lythgoe, Mark F.
Lengyel, Imre
Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia
title Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia
title_full Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia
title_fullStr Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia
title_full_unstemmed Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia
title_short Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia
title_sort optic nerve thinning and neurosensory retinal degeneration in the rtg4510 mouse model of frontotemporal dementia
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6322294/
https://www.ncbi.nlm.nih.gov/pubmed/30616676
http://dx.doi.org/10.1186/s40478-018-0654-6
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