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:
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:
- 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.
- 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.
- 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. - 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.
