Glaucoma: the retina and beyond

Abstract

Over 60 million people worldwide are diagnosed with glaucomatous optic neuropathy, which is estimated to be responsible for 8.4 million cases of irreversible blindness globally. Glaucoma is associated with characteristic damage to the optic nerve and patterns of visual field loss which principally involves the loss of retinal ganglion cells (RGCs). At present, intraocular pressure (IOP) presents the only modifiable risk factor for glaucoma, although RGC and vision loss can continue in patients despite well-controlled IOP. This, coupled with the present inability to diagnose glaucoma until relatively late in the disease process, has led to intense investigations towards the development of novel techniques for the early diagnosis of disease. This review outlines our current understanding of the potential mechanisms underlying RGC and axonal loss in glaucoma. Similarities between glaucoma and other neurodegenerative diseases of the central nervous system are drawn before an overview of recent developments in techniques for monitoring RGC health is provided, including recent progress towards the development of RGC specific contrast agents. The review concludes by discussing techniques to assess glaucomatous changes in the brain using MRI and the clinical relevance of glaucomatous-associated changes in the visual centres of the brain.

Keywords: Cell death; Glaucoma; Imaging; Neurodegeneration; Retina; Retinal ganglion cell.

Fig. 1

Overview of the human visual pathway. a Diagrammatic representation of the human visual pathway. b Overview of the structure of the lateral geniculate nucleus illustrating the organisation of magnocellular (M-cells), parvocellular (P-cell), and Koniocellular cells (K-cells)

Fig. 2

Overview of the DARC technology for the detection of apoptotic retinal cells. a Fluorescently labelled annexin A5 (AnxV) preferentially interacts with phosphatidylserine (purple) in a calcium-dependent manner. Phosphatidylserine is predominantly localised to the inner leaflet of the plasma membrane of healthy retinal cells via the action of ATP dependent flippases. In apoptotic cells, phosphatidylserine is translocated to the outer membrane leaflet via the downregulation of flippase activity and activation of scramblases, which result in a net increase in phosphatidylserine externalisation. The binding of fluorescently labelled AnxV to this externalised phosphatidylserine permits the visualisation of apoptotic cells at a cellular resolution in vivo. b In vivo cSLO retinal image of a Dark Agouti rat with ocular hypertension (Morrison’s model) captured using a 55° lens 2 h after intravitreal administration of fluorescently labelled AnxV (DARC). Apoptotic retinal cells can be clearly visualised as white spots

Fig. 3

Anatomical depiction of retrograde and anterograde trans-synaptic degeneration in the visual pathway. a Diagrammatic representation of the organisation of the anterior (retina, optic nerve, chiasm, optic tracts and LGN) and posterior (optic radiations and visual cortex) visual pathway. b Retrograde trans-synaptic degeneration describes the process through which damage to the posterior visual pathway (black) results in subsequent retinal degeneration. c Anterograde trans-synaptic degeneration describes a process where retinal degeneration leads to a subsequent degeneration of the posterior visual pathway