Laird Harrison

Micoaneurysm turnover in the early stages of diabetic retinopathy predicts how much the disease will progress, according to researchers.

Measuring turnover is more predictive than simply counting aneurysms, and it can be done with automated analysis of just two fundus images, reported Dr Rajeev K. R. Pappuru from the L.V. Prasad Eye Institute in Hyderabad, India, and colleagues. They published the findings in the 

Identifying which cases of diabetic retinopathy are most likely progress can help clinicians to prevent threats to their patients’ vision, they wrote. Systematic markers of diabetes have not proved useful for this purpose, they note. And even under similar metabolic control, some patients progress rapidly to macular oedema while others do not.

The researchers wanted to see whether the development of microaneurysms could provide a more useful biomarker for diabetic retinopathy progression, so they recruited 205 people with type 2 diabetes who were over 35 years of age in Coimbra, Portugal and Hyderabad, India. The patients had mild non-proliferative diabetic retinopathy defined as levels 20 to 35 according to the Early Treatment of Diabetic Retinopathy Study (ETDRS).

They had best-corrected visual acuity (BCVA) greater than 20/25 on the ETDRS chart and glycated haemoglobin (HbA1c) of 11% at most. Other criteria included no previous treatment with laser, anti-vascular endothelial growth factors or steroid intravitreal injections, and the absence of other retinal vascular disease, glaucoma, or inadequate ocular media and/or pupil dilation.

The researchers used an automated computer-aided diagnostic system, the RetmarkerDR (Retmarker), to detect microaneurysms automatically on field-two colour fundus images. Its software includes an algorithm that compares the same location in a retina between different visits. This allowed the researchers to calculate the number of microaneurysms that appeared or disappeared for each patient per time interval.

They sorted patients into three phenotypes of diabetic retinopathy progression:

• Phenotype A: low microaneurysm turnover and normal retinal thickness (MA turnover <6 and central subfield retinal thickness less than 260 µm for women or less than 275 µm for men)
	• Phenotype B: low microaneurysm turnover and increased retinal thickness (MA turnover <6 and central subfield retinal thickness at least 260 µm for women or at least 275 µm for men)
	• Phenotype C: high MA turnover (MA turnover ≥6) with or without increased retinal thickness.

Forty-seven patients dropped out of the study. Compared to those who stayed in the study, more of those who dropped out were Asian, and their low-density-lipoprotein cholesterol and diastolic blood pressure were higher on average.

Only 158 eyes reached central-involved macular oedema after 24 months, which was the last study visit. Twenty-seven (17.1%) progressed to more advanced ETDRS: six progressed to mild non-proliferative diabetic retinopathy (level 35), 15 to moderate non-prolific diabetic retinopathy and five to moderately severe non-proliferative diabetic retinopathy. One progressed to the high-risk proliferative form.

Of the patients in phenotype A, only 1.1% developed central-involved macular oedema, compared with 28.8% of those in phenotype B and 29.4% of those in phenotype C.

Likewise, 19.8% of phenotype A patients experienced worsening of diabetic retinopathy of at least one step. This compared with 21.7% in phenotype B and 93.3% in phenotype C.

The researchers conducted a multivariate analysis to adjust for the affects of phenotypes, metabolic control and cardiovascular risk variables. They found that eyes from phenotype C had a higher risk of developing central-involved macular oedema than eyes from phenotype A (odds ratio [OD] 44.8, 95% confidence interval [CI] 6.8 to 293.8; p<0.001).

Eyes from phenotype B showed a higher chance of developing central-involved macular oedema than eyes/patients from phenotype A (OR 31.4, 95% CI 5.4 to 183.3; p<0.001). A higher percentage of the patients in India were phenotype C.  And most of the eyes that progressed were from India.

Only three of the 92 eyes (3.3%) from Portugal progressed to mild non-proliferative diabetic retinopathy. Of the 57 eyes from India, 24 (42.1%) progressed to more advanced ETDRS: three to mild, 15 to moderate and five to moderately severe (level 43) non-proliferative diabetic retinopathy. One progressed to high-risk proliferative diabetic retinopathy.

The researchers noted that previous studies have showed a genetic susceptibility to diabetic retinopathy, which could explain this difference in populations. However, in general, they wrote that the study results confirmed that microaneurysm turnover rates can help identify those patients most at risk of worsening diabetic retinpathy.

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Microaneurysm turnover predicts diabetic retinopathy progression

People with Alzheimer’s disease are more likely to have drusen in their peripheral retinas, as well as unusual vascular characteristics, researchers believe.

The finding could help prognose the disease and identify people at risk for it, potentially creating a new role for optometrists and ophthalmologists

“We have opened a window to identify high-risk groups who may benefit from specific prevention advice,” said Prof. Craig Ritchie, professor of psychiatry of ageing at the University of Edinburgh, UK, in a university press release.

He and his colleagues reported the finding in 

Previous research dating back to 1986 has linked other changes in the retina to Alzheimer’s disease, including deposition of amyloid plaque, thinning of the retinal fibre layer, signs of impaired vision or abnormal papillary reaction, and tortuoisity of blood vessels.

And such changes have shown up not only in Alzheimer’s but also Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Huntington’s disease and frontotemporal dementia.

However, exact correlations have remained elusive. One reason may be that researchers focused their attention on the macula, Prof. Ritchie and his colleagues say. Based on laboratory observations, the team hypothesised that changes in the peripheral retina could be more important.

So they used an ultra-wide field scanning laser ophthalmoscope (Optos P200C AF) to study this anatomy. They found a high incidence of drusen in 14 out of 55 people with Alzheimer's, compared to two out of 48 people without Alzheimer’s.

Drusen are small deposits of fat, proteins and minerals, including calcium and phosphate deposits that form in a layer underneath the retina. Their incidence increases with age and they are associated with macular degeneration.

They contain amyloid beta, the substance that forms damaging plaques in Alzheimer’s disease, and the process by which drusen and amyloid beta plaques form is similar, according to co-author Dr Imre Lengyel, senior lecturer at the School of Medicine Dentistry and Biomedical Sciences at Queen’s University, Belfast, UK.

The researchers noted potential association between Alzheimer’s disease and age-related macular degeneration in their study, but said their sample size was too small for this to reach statistical significance.

They also noted changes in peripheral retinal blood circulation in the patients with Alzheimer’s. These included wider blood vessels close to the optic nerve that thin faster than in control subjects towards the retinal periphery. Both of these are likely to slow blood flow and impair nutrient and oxygen flow in the peripheral retina, they said.

They speculated that decreased oxygenation could be related to the increased drusen accumulation.

While peripheral retinal imaging is not a diagnostic measure for Alzheimer’s disease, the simple, quick and inexpensive monitoring of changes in the eye could serve as a tool for disease progression in the brain, the researchers said.

“These exciting research results suggests that our original hypothesis was right and wide field eye imaging could indeed help monitoring disease progression in patients with [Alzheimer's],” Dr Lengyel said in the press release. “Eye imaging is quick, simple, well tolerated and costs a fraction to that of brain scans so there are tremendous benefits to both the professional and the patient.”

Catching signs of Alzheimer’s early in the disease will not necessarily confer an advantage in treatment because there are currently no good treatments for the disease, according to researchers. But understanding how rapidly the condition is progressing could help patients and their families plan for future disability.

In addition, it could help researchers monitor the effects of experimental treatments. “Changes in the eye are very easy to measure relative to other measures of brain health,” said Prof. Ritchie.

To extend these observations, the research team plans to follow patients with very early stage Alzheimer’s to see how the disease progression is reflected in their eyes.

Author | Laird Harrison

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Microaneurysm turnover predicts diabetic retinopathy progression

Peripheral retinal drusen more common in Alzheimer’s