GLAUCOMA AS A CENTRAL NEURODEGENERATIVE DISEASE

  

The major length of the axon of the retinal ganglion cells (RGC) is extra-ocular, with pre-chiasmal, chiasmal and post-chiasmal components. Furthermore, 90% of RGCs project to the lateral geniculate nucleus (LGN), the first major vision center located deep within the brain. Therefore, glaucoma, in which RGC and axonal damage is prominent, has to be studied in terms of central connections and damages in those structures.

Recent advances in our understanding of the post-laminar changes in glaucoma vis-à-vis the mechanical theory of glaucoma have shed light on central changes occurring in this disease. [1]

Gupta and Yucel were among the first to suggest that elevated IOP and destruction of the RGCs could trigger transsynaptic degeneration in the lateral geniculate bodies (LGB) and visual cortex. This has led to the development of the central mechanism of glaucomatous neurodegeneration. [2]

A fundamental process shared by neurodegenerative diseases is the loss of specific neuron populations. Vision loss and dysfunction in glaucoma result from RGC death, atrophy, and axon degeneration extending to central visual targets in the brain. Changes similar to other neurodegenerative diseases such as Alzheimer’s and Parkinsons have been reported in glaucoma patients. Amyloid β protein deposits, synuclein, and pTau have been identified in the retina of glaucoma patients. [3]

Neurodegenerative diseases typically show a progressive decline in function related to the loss of relevant neuron systems, as seen in glaucomatous visual dysfunction in proportion to the RGC demise. The mode of disease spread in neurodegenerative disorders is called transsynaptic degeneration. Disease is transmitted from sick neurons to healthy neurons through synaptic connections along anatomic and functional neural pathways. This spread of disease between communicating neurons is a well-known feature of Alzheimer’s disease and Amyotrophic lateral sclerosis (ALS), and has more recently been described in experimental and human glaucoma. The extension of the neurodegenerative damage from the retina to the central visual pathways has the potential to disrupt the processing of visual information from the eye to the brain. [2]

Neuroinflammatory reactions, especially at the level of the glial and microglial cells have been reported in glaucoma patients; changes similar to those reported in neurodegenerative diseases. Various biochemical mechanisms have been proposed which cause damage to these neural structures. [4]

Shrinkage and loss of neurons, reduced metabolic activity, and dysfunction in the expression patterns of several markers of synaptic plasticity in the LGB and visual cortex appear in glaucoma disease and experimental primate models, after a period of increased IOP.

MRI imaging has shown degeneration of central visual pathways after damage to RGC axons. Degeneration of the lateral geniculate nucleus, genicular-cortical projections, and cortical areas themselves, have been explored in patients with glaucoma. 

MRI CHANGES IN GLAUCOMA:

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Researchers have reported a complex network of connectivity between different cortical areas, called the functional connectome. Profound functional reorganization of the entire brain in glaucoma patients has been found. [3]

Network disruption and the appearance-disappearance of specific hubs compared to healthy controls and a different spatial distribution in the density of functional connectivity on long or short-term in glaucoma. Two hub regions are absent in glaucoma patients: the gyrus right angular, situated in the anterolateral region of the parietal lobe, with the role in processing concepts rather than percepts in the perception-recognition-action interface and the left lobule VIIB of the cerebellar hemisphere (with a role in fine motor coordination, in the inhibition of involuntary movement by inhibitory neurotransmitters). In contrast, three hubs were present only in glaucoma patients: the right inferior occipital cortex - the region is located in the occipital lobe, which contains the primary visual pathway, the right inferior temporal gyrus, located in the temporal lobe, a key area involved in the simple processing of the visual field] and the left lobule IX of the cerebellar hemisphere, an area considered essential for the visual guidance of movement. [3]

Central visual pathway degeneration in glaucoma is a process that may begin early in the disease. For example, in primate glaucoma, elevated IOP may not show measurable optic nerve fiber loss but is found to induce shrinkage of target LGN neurons. Chronic ocular hypertension also induces significant dendrite pathology in the LGB. Transsynaptic injury to LGN neurons may thus be induced following RGC injury in the absence of detectable RGC death. [2]

In a case of human glaucoma, postmortem analysis of the visual system correlated optic nerve damage and visual field deficits, and revealed neuropathology in the intracranial optic nerve, LGN and visual cortex in a retinotopic fashion. [2]

Marked central visual system degeneration may be a factor in patients who show progressive glaucomatous damage despite well controlled IOP.

REFERENCES:

1. Ahmad SS. The mechanical theory of glaucoma in terms of prelaminar, laminar, and postlaminar factors. Taiwan J Ophthalmol. 2023 Dec 21;14(3):376-386. doi: 10.4103/tjo.TJO-D-23-00103. PMID: 39430347; PMCID: PMC11488796.
2. Gupta N, Yücel YH. Glaucoma as a neurodegenerative disease. Curr Opin Ophthalmol. 2007 Mar;18(2):110-4. doi: 10.1097/ICU.0b013e3280895aea. PMID: 17301611.
3. Neacșu AM, Ferechide D. Glaucoma - a neurodegenerative disease with cerebral neuroconnectivity elements. Rom J Ophthalmol. 2022 Jul-Sep;66(3):219-224. doi:
   10.22336/rjo.2022.43. PMID: 36349168; PMCID: PMC9585488.
4. Shoeb Ahmad S, Abdul Ghani S, Hemalata Rajagopal T. Current Concepts in the Biochemical Mechanisms of Glaucomatous Neurodegeneration. J Curr Glaucoma Pract. 2013 May-Aug;7(2):49-53. doi: 10.5005/jp-journals-10008-1137. Epub 2013 May 9. PMID: 26997782; PMCID: PMC4741173.