Morphological changes in the visual pathway induced by experimental glaucoma in Japanese monkeys

Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, Gifu 502-8585, Japan.
Experimental Eye Research (Impact Factor: 2.71). 04/2009; 89(2):246-55. DOI: 10.1016/j.exer.2009.03.013
Source: PubMed


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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    • "The role of these connections may relate to the integration of visual information and generation of conscious perception. Associated pathological changes of primary open-angle glaucoma (POAG) include dendritic neuronal degeneration, pyknosis, and death of neuronal soma, as well progressive loss of cells throughout the visual pathway, and atrophy of the lateral geniculate body and visual cortex [Gupta and Yucel, 2007; Ito et al., 2009; Yucel et al., 2003]. These structural changes in the visual cortices of glaucoma patients are likely to be caused by anterograde cross-synaptic degeneration, thus raising the question of what, if any, functional changes also occur. "
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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.
    Full-text · Article · Oct 2013 · Human Brain Mapping
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    • "Glaucoma model animals were evaluated in detail for histological changes in microglial cells, astrocytes, and neurons in the lateral geniculate nucleus, and the results were published elsewhere [50]. Visual field defects and pathological features of this animal model are also described in detail in our previous studies [19,20,54]. Before being enrolled into these experiments, all animals were confirmed by ophthalmoscopy to have no abnormalities in their ocular fundus. "
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    ABSTRACT: Background Neurodegenerative diseases including Parkinson’s and Alzheimer’s diseases progress slowly and steadily over years or decades. They show significant between-subject variation in progress and clinical symptoms, which makes it difficult to predict the course of long-term disease progression with or without treatments. Recent technical advances in biomarkers have facilitated earlier, preclinical diagnoses of neurodegeneration by measuring or imaging molecules linked to pathogenesis. However, there is no established “biomarker model” by which one can quantitatively predict the progress of neurodegeneration. Here, we show predictability of a model with risk-based kinetics of neurodegeneration, whereby neurodegeneration proceeds as probabilistic events depending on the risk. Results We used five experimental glaucomatous animals, known for causality between the increased intraocular pressure (IOP) and neurodegeneration of visual pathways, and repeatedly measured IOP as well as white matter integrity by diffusion tensor imaging (DTI) as a biomarker of axonal degeneration. The IOP in the glaucomatous eye was significantly increased than in normal and was varied across time and animals; thus we tested whether this measurement is useful to predict kinetics of the integrity. Among four kinds of models of neurodegeneration, constant-rate, constant-risk, variable-risk and heterogeneity models, goodness of fit of the model and F-test for model selection showed that the time course of optic nerve integrity was best explained by the variable-risk model, wherein neurodegeneration kinetics is expressed in an exponential function across cumulative risk based on measured IOP. The heterogeneity model with stretched exponential decay function also fit well to the data, but without statistical superiority to the variable-risk model. The variable-risk model also predicted the number of viable axons in the optic nerve, as assessed by immunohistochemistry, which was also confirmed to be correlated with the pre-mortem integrity of the optic nerve. In addition, the variable-risk model identified the disintegrity in the higher-order visual pathways, known to underlie the transsynaptic degeneration in this disease. Conclusions These findings indicate that the variable-risk model, using a risk-related biomarker, could predict the spatiotemporal progression of neurodegeneration. This model, virtually equivalent to survival analysis, may allow us to estimate possible effect of neuroprotection in delaying progress of neurodegeneration.
    Full-text · Article · Jan 2013 · Molecular Neurodegeneration
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    • "Consequently, in patients with advanced glaucomatous visual field loss, the optic chiasm was markedly atrophic (Iwata et al. 1997). In a similar manner, experimental investigations on monkeys with induced glaucoma have shown glaucomarelated changes of the lateral geniculate nucleus (LGN) and visual cortex (Weber et al. 2000; Yu¨cel et al. 2001; Gupta et al. 2007; Ito et al. 2009). In a clinicopathological report of a patient with glaucoma, Gupta et al. (2006)were the first to demonstrate in patient glaucoma-related degenerative changes of the brain involving the intracranial optic nerves, the LGN and the visual cortex. "
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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.
    Preview · Article · Apr 2012 · Acta ophthalmologica
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