Morphological changes in the visual pathway induced by experimental glaucoma in Japanese monkeys.
ABSTRACT Glaucoma, an optic neuropathy, is the leading cause of world blindness. In this condition, the damage extends from the retina to the visual center in the brain, although the primary region of damage is thought to be the optic nerve head (ONH), with the lateral geniculate nucleus (LGN) being secondarily affected. We investigated time-dependent alterations in the ONH, the optic nerve (ON), and the LGN after intraocular pressure (IOP) elevation in Japanese monkeys (a species more similar to humans than other macaque species). Nine Japanese monkeys, each with an experimental glaucomatous left eye, and two naive monkeys were studied. Ocular-testing sessions (including IOP measurement and fundus photography) were held weekly. Eyes and brains were enucleated at 2-48 weeks after IOP elevation, and alterations in ONs and LGN were evaluated. The IOP of the treated eyes was monitored periodically and found to be elevated continuously throughout the observation period in each monkey. The ONH of the glaucomatous eyes exhibited time-dependent deep cupping and thinning of the rim area from 2 weeks after the IOP elevation. Loss of axons and a decrease in the area of ON were first observed at 4 and 28 weeks, respectively. Neuronal loss was first observed at 2 weeks in layers 1 and 2 of LGN [magnocellular (M)-layer] and at 12 weeks in layers 3-6 of LGN [parvocellular (P)-layer]. Neuronal shrinkage was first observed at 2 weeks in all layers in LGN. These findings indicate that in Japanese monkeys, damage to neurons in LGN can be detected in the early phase (first few weeks) after an IOP elevation, as can damage to ONH.
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ABSTRACT: Purpose: To analyze functional connectivity (FC) of the visual cortex using resting-state functional MRI in human primary open-angle glaucoma (POAG) patients. Materials and Methods: Twenty-two patients with known POAG and 22 age-matched controls were included in this IRB-approved study. Subjects were evaluated by 3 T MR using resting-state blood oxygenation level dependent and three-dimensional brain volume imaging (3D-BRAVO) MRI. Data processing was performed with standard software. FC maps were generated from Brodmann areas (BA) 17/18/19/7 in a voxel-wise fashion. Region of interest analysis was used to specifically examine FC among each pair of BA17/18/19/7. Results: Voxel-wise analyses demonstrated decreased FC in the POAG group between the primary visual cortex (BA17) and the right inferior temporal, left fusiform, left middle occipital, right superior occipital, left postcentral, right precentral gyri, and anterior lobe of the left cerebellum. Increased FC was found between BA17 and the left cerebellum, right middle cerebellar peduncle, right middle frontal gyrus, and extra-nuclear gyrus (P < 0.05). In terms of the higher visual cortices (BA18/19), positive FC was disappeared with the cerebellar vermis, right middle temporal, and right superior temporal gyri (P < 0.05). Negative FC was disappeared between BA18/19 and the right insular gyrus (P < 0.05). Region of interest analysis demonstrated no statistically significant differences in FC between the POAG patients relative to the controls (P > 0.05). Conclusion: Changes in FC of the visual cortex are found in patients with POAG. These include alterations in connectivity between the visual cortex and associative visual areas along with disrupted connectivity between the primary and higher visual areas. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.Human Brain Mapping 10/2013; 34(10). DOI:10.1002/hbm.22079 · 6.92 Impact Factor
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ABSTRACT: PURPOSE: To analyze the axonal architecture of the optic nerve in patients with normal-pressure glaucoma and determine whether these parameters correlate with the disease severity. Methods: Using magnetic resonance (MRI) imaging (1.5-Tesla unit) and diffusion tensor (DT) MRI, we measured the optic nerve diameter, optic chiasm height and lateral geniculate nucleus (LGN) volume in patients with normal-pressure glaucoma and an age-matched control group. The retinal nerve fibre layer thickness (RNFL) was determined by optical coherence tomography (OCT). Results: The study included 30 patients with normal-pressure glaucoma and 30 age-matched control subjects. Optic nerve diameter (p < 0.001), optic chiasm height (p < 0.001) and LGN volume (p = 0.02) were significantly smaller in the glaucoma group than in the control group and were significantly correlated with RNFL thickness and perimetric loss. In the control group, the parameters significantly (p < 0.05) decreased with age. The DT-MRI-derived fractional anisotropy for the optic nerve was significantly lower (p < 0.001), and the DT-MRI-derived mean diffusivity (p < 0.001), radial diffusivity (λ(⊥) ; p < 0.001) and axial diffusivity (λ(||) ; p = 0.009) for the optic nerve were significantly higher in the glaucoma group and significantly correlated with RNFL thickness and mean perimetric defect. Conclusions: Patients with normal-pressure glaucoma show an age-adjusted reduced optic nerve diameter, optic chiasm height and LGN volume as measured by MRI, correlating with a reduced RNFL thickness and increased perimetric loss. MRI may be applied to examine the optic nerve in patients with glaucoma with opaque optic media.Acta ophthalmologica 04/2012; 90(4):e295-302. DOI:10.1111/j.1755-3768.2011.02346.x · 2.51 Impact Factor
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ABSTRACT: We investigated whether endoplasmic reticulum (ER) stress was involved in the pathophysiological mechanisms underlying neuronal death of the lateral geniculate nucleus (LGN) after intraocular pressure (IOP) elevation. Five cynomolgus monkeys, four with a glaucomatous left eye after laser photocoagulation treatment and one normal monkey, were studied. At 4, 11, 15 and 24 weeks after the laser photocoagulation treatment, the numbers of LGN neurons and atrophy were immunohistochemically evaluated using anti-parvalbumin-antibody, which was used to specifically label relay neurons connecting to the visual cortex. In addition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells, polyubiquitin, and production of ER stress-related proteins, such as the phosphorylation of eukaryotic initiation factor 2α (p-eIF2α) and C/EBP-homologous protein (CHOP), were also measured using in situ hybridization and immunostaining. Loss of neurons and/or neuronal atrophy in layers 1, 4 and 6 of the LGN on the contralateral side were observed at 4-24 weeks after the laser photocoagulation treatment. Furthermore, the retinal input from the high IOP eye projected to layers 2 (magnocellular layer), 3 and 5 (parvocellular layer) on the ipsilateral side. Neuronal damage was also confirmed in these layers. In the LGN region, TUNEL-positive cells, polyubiquitin, p-eIF2α and CHOP were also detected at 11-24 weeks after the laser photocoagulation treatment. These findings indicate that ER stress may play a pivotal role in neuronal death of the LGN after IOP elevation.European Journal of Neuroscience 03/2011; 33(5):843-55. DOI:10.1111/j.1460-9568.2010.07578.x · 3.67 Impact Factor