DETECTING CHANGES

As research continues to define the pathological characteristics of glaucoma, new diagnostic and prognostic indicators are being discovered which could help in the detection and monitoring of the disease, according to presenters speaking at the 11th Congress of the European Society of Glaucoma in Nice.
“Although at this point we don’t have one specific biomarker that is consistently measurable and helpful, there are a number of new potential biomarkers that are being studied and some of these are beginning to show some potential,” said M Roy Wilson MD, MS, Wayne State University, Detroit, US. 
Dr Wilson said that, although some authors use the term biomarkers in a much broader sense, he prefers to restrict the term to molecules that are involved with a function that influences the disease. 
Another important characteristic of biomarkers is that they should be highly specific. Therefore, for example, enhanced expression of neuronal thread protein is not a clinically important biomarker for glaucoma because it also occurs in Alzheimer’s disease and some other neurodegenerative disorders.
He noted that, in the case of primary open-angle glaucoma, various pathophysiological mechanisms have been suggested for the neurodegeneration that defines the disease. They include ischaemia and hypoxia, as well as aberrant immunity, autoimmunity, inflammatory cytokines and effects on the lamina cribrosa that in turn result in a blockade of neurotrophins.
Among the cytokines, TGF β2, the major transforming growth factor in the eye, may have some potential not only as a biomarker but as a treatment target at well. The growth factor is elevated in the eyes of patients with glaucoma and has the effect of increasing the fibrosis material in the trabecular meshwork. 
“Theoretically, if one could minimise TGF β2 one could possibly delay the ageing process of the trabecular meshwork in glaucoma patients,” Dr Wilson said.
He added that there is now some evidence that auto-antibodies may increase the susceptibility of the optic nerve to damage by changing the properties of the vasculature in the lamina cribrosa, which also increases the intraocular pressure (IOP) as a by-product.
Research suggests that serum antibodies against neuron-specific enolase are present in 20 per cent of glaucoma patients, he said. Those glaucoma patients with the auto-antibody also appear to have lower maximum IOP than those without it, and its presence and its levels may provide an additional gauge of disease progression.
Auto-antibodies for the detoxification enzyme, glutathione s-transferase, are also increased in open-angle glaucoma patients and may represent a response to tissue damage, he continued. 
Another potential immunological biomarker is H pylori immunoglobulin, levels of which are increased in the aqueous humour in open-angle glaucoma patients. Higher titres of the protein appear to correlate with the severity of glaucomatous damage

Bio-Signatures
Neeru Gupta MD, PhD, MBA suggested that a broader grouping of risk factors and biomarkers and surrogate outcomes, which she termed “bio-signatures”, could be useful in clinical practice. 
“By bio-signatures, I mean something that you can use to distinguish suspects from disease, that will help us predict treatment outcomes, and the course of disease,” said Dr Gupta, Professor and Dorothy Pitts Chair of Ophthalmology and Vision Science, St Michael’s Hospital, University of Toronto, Canada.
The classic bio-signature of glaucoma is damage to the optic nerve head. However, the correlation between damage to the optic nerve, as currently measured, and visual field test results tends to be inconsistent.
The same is true of IOP, which has a complex and as yet not fully understood role in pathology, although 24-hour monitoring may help clarify its role, she said. 
“Our signatures aren't always as good as they can be and the problem is that if we use them to follow and monitor our patients clinically, it takes a really long time,” she added. 

Glaucoma and the brain
Meanwhile, there is accumulating evidence that glaucomatous neurodegeneration extends beyond the optic nerve, through thelateral geniculate nucleus, and all the way through to the optic nerve. Structural changes in these areas could prove to be useful prognostic indicators regarding disease progression and treatment response.
For example, Dr Gupta's team in collaboration with Dr Yeni Yucel has shown that in human glaucoma there is  significant neural degeneration in the pre-chiasmal optic nerve, the lateral geniculate nucleus and visual cortex (Gupta et al, Br J Ophthalmol. 2006;90:6 674-78).
In addition, other MRI studies she and her associates conducted in glaucoma patients have shown significant atrophy of the lateral geniculate nucleus in human disease (Gupta et al, Br J Ophthalmol. 2009;93(1): 56–60).
Moreover, glaucomatous neurodegeneration likeley extends to the non-retino-geniculo-cortical visual pathway. That includes changes in the superior colliculus that may cause detectable changes in the behaviour of a patient’s visual system. She noted that in a recent study she and her associates conducted, that saccadic eye movements were significantly delayed in patients with glaucoma (Kanjee et al, Eye and Brain. 2012;4:63-68).
“This raises the question of whether there are other vision tasks that we should be looking for that might help us clinically. We need to pay much more attention to what is changing for the patient from a visual point of view and how it affects their quality of life - other than the routinely used visual field,” Dr Gupta added.

M Roy Wilson: president@wayne.edu 
Neeru Gupta: guptan@smh.ca