RetVIC Australian Projects

Early retinal vessel changes in diabetes and the metabolic syndrome
(The AusDiab Study)

Investigators: Prof Tien Wong, A/ Prof Jonathan Shaw, Prof Paul Mitchell Prof Hugh Taylor, Prof Paul Zimmet, Dr Alex Harper, Dr Richard Simpson.
Timeline: 1 January 2005 - 31 December 2007
Study Population: The AusDiab Study is a population-based study of 11,247 people aged 25 years and older selected from urban and rural areas.

Abstract:

The proposed study will measure and characterize early retinal vessel changes in persons with diabetes and persons at high risk of diabetes (impaired fasting glucose [IFG], impaired glucose tolerance [IGT], and the metabolic syndrome) in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab), a population-based study of risk factors and complications of diabetes.

Specific Aims of the study are:

• To determine the relationship of retinal vessel diameter changes (generalized arteriolar narrowing, venular dilation, focal arteriolar narrowing, and arterio-venous nicking) to prevalent diabetes and glucose intolerance (IFG and IGT);
• To examine the relationship of retinal vessel diameter changes to the metabolic syndrome (obesity, dyslipidaemia, hypertension and insulin resistance);
• To quantify the relationship of retinal vessel diameter changes to macrovascular (cardiovascular disease [CVD], peripheral arterial disease [PVD]) and microvascular (nephropathy, neuropathy) complications in persons with diabetes, glucose intolerance; and
• To determine if retinal vessel diameter changes predict the 5-year incidence of overt diabetes, independent of known risk factors (e.g., glucose tolerance, obesity).

In the proposed study, we will measure retinal vessel diameters and other changes from the digital retinal photographs taken of a sample (n=2,177) of the AusDiab population. This will include a (1) new computer-based quantitative measurement of retinal vessel diameter, and a (2) qualitative assessment of the presence of discrete retinal arteriolar wall signs (focal arteriolar narrowing, arteriolar wall opacification, and AV nicking). We will then examine the relationship of these retinal vessel changes to diabetes and pre-diabetes status, to the metabolic syndrome, and to various diabetic complications (finally, we will determine if these retinal vessel changes at baseline are related prospectively to the five-year incidence of overt diabetes among participants who return for the follow-up AusDiab examination).

Multi-Retinal Stroke Study
(Sydney, Melbourne, Singapore)

Investigators: Prof Tien Wong, Prof R. Lindley, Dr Jie Jin Wang, Prof Paul Mitchell, Prof Stephen Davis, Dr Peter Hand, Professor Geoffrey Donnan, Dr Helen Dewey.
Timeline: 1 January 2005 - 31 December 2007
Study Population: 2000 patients with acute stroke from three hospital stroke units

• The Royal Melbourne Hospital, Melbourne
• The Westmead Hospital, Sydney
• The Singapore General Hospital, Singapore

Abstract:

Stroke is a major cause of disability, morbidity and mortality in Singapore. Retinal microvascular signs, as assessed from photography, have recently been shown to predict incident stroke and mortality, and may be useful as a marker of subclinical cerebrovascular diseases.

This proposal describes a prospective observational clinical study to determine the relationship of retinal microvascular signs to stroke subtypes (ischaemic, hemorrhagic, lacunar) and to stroke prognosis (recurrent stroke, other vascular events, disability and death) in patients with acute stroke at the Singapore General Hospital (SGH). This study will be part of a multi-centre collaborative study with the Royal Melbourne Hospital (Melbourne) and the Westmead Hospital (Sydney).

In the proposed study, we will recruit 2,000 patients with acute stroke at these three hospitals. Participants will undergo a standardized stroke assessment, including CT and MR imaging if needed, and retinal photography of both eyes. Retinal photographs will be graded for retinal microvascular signs, including generalized and focal arteriolar narrowing, arteriolar emboli and retinopathy at a central retinal reading centre. Participants will be followed-up over a six-month interval. We will examine the relationship of retinal signs with stroke subtypes; and with stroke outcomes at six months.

The study will extend our recent epidemiological research in predominantly healthy populations that demonstrate a strong association between retinal microvascular signs and risk of incident stroke. The current project will determine the clinical diagnostic and prognostic utility of a photographic assessment of retinal signs in an acute hospital setting.

Data from this study will provide important insights into the microvascular contribution to stroke. Retinal photography may ultimately complement cerebral CT and MR imaging in diagnosis, classification and risk stratification of acute stroke.

Retinal Vessel Changes & Risk of Diabetic Microvascular Complications in Type 1 Diabetes

Investigators: Prof Tien Wong, A/Prof Alicia Jenkins, A/Prof Kim Donaghue.
Timeline: 1 Jan 2006 - 31 Dec 2008
Study Population: 823 children/adolescents aged 12 to 20 years with type 1 diabetes The Diabetes Complications Assessment Service, Children’s Hospital at Westmead.

Abstract:

This proposal describes a study in a cohort of children / adolescents with type-1 diabetes designed to measure retinal vascular changes, to determine their relationship to incident microvascular complications (diabetic retinopathy, nephropathy and neuropathy) and to early vascular dysfunction/glycation (e.g., small artery elasticity, 24-hour blood pressure variation, plantar fascia thickness). The study population includes approximately 823 children / adolescents aged 12 to 20 years with type-1 diabetes managed at the Children’s Hospital at Westmead, Sydney, Australia, between 1990 and 2002.

Specific aims of the study are:

• To characterize early retinal microvascular changes (retinal arteriolar and venular caliber, and presence of focal arteriolar narrowing and arterio-venous nicking) from baseline photographs in a cohort of children/adolescents with type-1 diabetes, and to examine the relationship of these retinal changes to glycemic control, blood pressure, body mass index and other risk factors
• To determine the relationship of these retinal changes at baseline to incident microvascular complications,

  (a) Retinopathy, as defined from 7-field fundus photographs;

  (b) Nephropathy, as defined by the albumin excretion ratio (AER)

  (c) Neuropathy, as defined by standardized measurements of autonomic and peripheral nerve function.

• To determine, in a sample of patients (n=300) returning for follow-up at 2006 and 2007, the cross-sectional relationship of retinal changes to new measures of vascular function and glycation, including

  (a) Small artery elasticity, as defined from pulse wave analysis;

  (b) Blood pressure and heart rate variation, as defined from 24-hour ambulatory blood pressure monitoring;

  (c) Plantar fascia thickness, as defined from ultrasonic measurement.

In the current study, we will measure retinal microvascular signs from photographs of these 823 individuals (Specific Aim 1 and 2), which will include a computer-based quantitative measurement of retinal vascular caliber, and a standardized assessment of discrete signs (e.g., focal arteriolar narrowing and arterio-venous nicking). We will determine their relationship to various risk factors for microvascular disease (glycemic control, blood pressure etc) and to the incidence of microvascular events (retinopathy, nephropathy and neuropathy).

For 300 patients attending follow-up examinations in 2006 and 2007 (Specific Aim 3), we will perform additional retinal photography and new clinical assessments of vascular function (pulse wave analysis and 24-hour blood pressure monitoring) and a surrogate measure of glycation (plantar fascia thickness from ultrasound). For these patients, we will evaluate the cross-sectional relationship between retinal microvascular signs and these novel measures of vascular function/glycation. This study will provide novel insights into the relationship of subclinical microvascular disease, evident in the retinal circulation, to subsequent development of overt complications and markers of vascular function/glycation in children with type-1 diabetes, ultimately offering new approaches to screening, prevention and treatment of these major debilitating conditions.

The Epidemiology, Causes and Patterns of CNV

Investigators: Prof Tien Wong, Dr. Gabriella Tikellis, Dr. Salmaan Qureshi, Dr. Quresh Mohamed, A/ Prof Mark Gillies, Dr Alex Harper.
Timeline: 1 June 2005 - July 2007
Study Population: Newly diagnosed CNV cases collected over a period of 12 months from 11 sites in Asia Pacific region. It is anticipated that each centre will contribute approximately 100-150 consecutive newly-diagnosed cases of CNV over this period. Centres include:

• Save Sight Institute - Sydney
• Eye and Vision Research Institute, Sydney
• Lions Eye Institute, Perth
• Retina Specialists, Auckland
• Singapura Eye Clinic & SNEC - Singapore
• The Aga Khan University Hospital, Karachi - Pakistan
• Rajvithi Hospital, Bangkok - Thailand
• Ramathibodi Hospital, Bangkok - Thailand
• Peking Union Medical College Hospital, Beijing, China
• Yamagata University - Japan
• Kyushu University - Japan

Abstract:

Macular degeneration (MD) is a term used for a number of different disorders effecting the central area of the retina known as the ‘macula’, which results in the decline and loss of central vision. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss but there are other causes such as short sightedness, infections and trauma.

Information from numerous centres in Australia and Asia regarding the number of people diagnosed with each MD type, their ages, gender, and ethnicity will be collected. These findings will lead to a clearer understanding of the causes of MD.

The specific aims of this research proposal are to:

• Determine the causes of newly-diagnosed CNV (AMD, PCV, pathological myopia) in a multi-ethnic Caucasian and Asian population, and possible association of these causes of CNV with age, gender, race / ethnicity and laterality of disease.
• Determine from cases of CNV-AMD the proportion of each subtype (i.e. predominantly classic, minimally classic and occult), and the possible association of each subtype with age, gender and race/ethnicity.
• Provide information regarding successful treatment options given a specific CNV type, location and size that will assist in the development of new treatment protocols for treatment of CNV.

Clinical Trial of Intravitreal Triamcinolone and Laser (THUNDERBIRD)

Investigators: A/Prof Mark Gillies, Prof Tien Wong, A/Prof Ian McAllister, Prof Paul Mitchell, Dr Jenny Arnold, Dr Alex Harper.
Timeline: 1 Jan 2005 – 31 Dec 2009.
Study Population: Patients presenting to clinics of participating sites 18+ years of age with diabetic macular oedema in one or both eyes for which laser treatment is indicated in the opinion of the investigator.

Participating sites

• Save Sight Institute Sydney
• Centre for Eye Research Australia
• Marsden Eye Specialists
• Lions Eye Institute
• Westmead Hospital Eye Clinic.

Abstract:

Intravitreal administration of slow release steroids is emerging as a revolutionary new treatment for diabetic macular oedema. The purpose of this study is to conduct a prospective, multi-centre, randomised, double-masked, placebo-controlled, clinical trial of intravitreal triamcinolone (IVTA) plus laser treatment versus laser treatment alone for diabetic foveal edema. This builds upon our present randomised clinical trial presented at ARVO last year which is the first to prove that IVTA results in improved vision and, marked reduction of diabetic macular oedema within three months in eyes with impaired vision despite adequate laser treatment. The next question that needs to be addressed is whether intravitreal steroids will be beneficial if they are used earlier in the course of diabetic macular oedema in conjunction with standard laser treatment, the current gold standard. Since the beneficial effect of IVTA on macular oedema is already evident within four weeks of treatment, we propose that pretreatment with intravitreal triamcinolone of an eye with macular oedema will allow laser treatment to be applied more accurately and with lower power, resulting in greater reduction of oedema and better visual outcomes. Laser treatment after the instillation of the triamcinolone will also reduce the risk of the oedema recurring as the steroid wears off. Thus we hypothesize that the two treatments will act synergistically to improve the efficacy of both at the same time as reducing the risks of adverse events. The study proposed herein is designed to test this hypothesis.

This proposal describes a prospective, multicentre, randomised, double-masked, placebo-controlled, clinical trial of intravitreal triamcinolone (IVTA) plus laser treatment versus laser treatment alone for diabetic foveal edema.

Retinal Vessel Diameters, Inflammation and Endothelial Dysfunction (IDI Study)

Investigators: Prof Tien Wong, A/ Prof Jonathan Shaw, Prof Paul Zimmet, Dr. Richard Simpson, Dr. Carol Delaney
Timeline: June 2005 - July 2007.
Study Population: 100 consecutive patients with type-1 and type-2 diabetes attending the clinics of the International Diabetes Institute, Melbourne, Australia and the Eastern Clinical Research Unit (ECRU). The first 50 type-1 and type-2 diabetes patients who agree to participate will be recruited. For this study, type-1 diabetes is defined as diabetes onset before the age of 30 years, with continuous insulin treatment since diagnosis. Type-2 diabetes will be defined as diabetes onset after the age of 40 years and no insulin treatment.

Abstract:

The proposed study aims to examine the relationship of retinal vessel diameter changes with skin vascular endothelial function and biomarkers of endothelial activation and inflammation in patients with diabetes. This study extends new research that shows retinal vessel diameter changes (arteriolar narrowing, venular dilation and reduced arteriolar-venular ration) are related to various macro and micro vascular complications (nephropathy and retinopathy) in people with type-1 diabetes. There is currently no data on the pathophysiological basis for these associations, and the mechanisms causing retinal vessel caliber changes are unclear.

Our study will test the hypothesis that retinal vessel diameter changes are related to endothelial dysfunction in patients with diabetes. We will recruit 50 patients with type-1 diabetes and 50 with type-2 diabetes from the International Diabetes Institute, Australia and the Eastern Clinical Research Unit. Endothelial function will be measured via skin blood flow, comparing the effects of iontophorised acetylcholine (which causes vasodilation via the endothelium) with the effects of sodium nitroprusside (which causes vasodilation by direct action on smooth muscle). Fasting blood samples will be obtained for measuring fasting glucose, lipids, glycated haemoglobin and biomarkers of endothelial activation (PAI-1, ICAM-1, VCAM-1), general inflammation (hs-CRP, fibrinogen) and fat mass/activation (leptin and adiponectin). Retinal photographs of patients will be taken and analysed for retinal vessel diameter using a validated developed computer-based method. The relationship between retinal vessel diameters and measures of endothelial function and inflammation will be examined.

Data from the proposed study will provide a greater understanding of early microvascular changes and how they relate to vascular complications in diabetes, and whether a quantitative assessment of retinal vascular caliber may be useful as a non-invasive predictor of diabetic complications.

Retinal arteriolar signs and cardiovascular disease in an Australian cohort - Melbourne Collaborative Cohort Study (MCCS)

Investigators: Prof Tien Wong, Prof Paul Mitchell, Prof Andrew Tonkin, Prof John McNeil, Dr Dianna Magliono
Timeline: 1 June 2003 – 31 Dec 2008
Study Population: The study population includes MCCS participants 50-80+ years of age who return for the 10-year examination. From the original 41,528 who participated at baseline, assuming a 10% non-participation rate to the follow-up examination (n=4,000), and a further 10% non-participation rate to retinal photography specifically (n=4,000), retinal photographic data will be available in approximately 32,000 people. Of these, assuming a prevalence of diabetes of 10% and hypertension of about 40%, the number of people with hypertension and diabetes is 2,000, hypertension only 10,400, diabetes only 1,200 and neither condition 18,400.

Abstract:

Diabetes and hypertension effect a significant proportion of adult Australians. Individuals with diabetes and hypertension are two to four times more likely to develop a Cardiovascular Disease (CVD) event, and to die from CVD, than persons without these conditions. A greater understanding of the pathogenic mechanisms for CVD in diabetes and hypertension is therefore important.

The aim of this study is to characterize retinal arteriolar signs and examine their relationship to cardiovascular disease (CVD) and CVD mortality, in persons with and without diabetes and hypertension in 40,000 participants 50+ years of age returning for the 10-year examination of the Melbourne Collaborative Cohort Study.

Specific aims of the study are:

• To examine the prevalence and risk factors of retinal arteriolar signs in persons with and without diabetes and hypertension
• To determine the relationship of these retinal signs to prevalent CVD and five-year cardiovascular mortality in persons with and without diabetes and hypertension

The current study will lead to a better understanding of the role and contribution of small vessel (microvascular) disease, as reflected by presence and severity of retinal arteriolar signs, to CVD risk in people with and without diabetes and hypertension. This information may eventually lead to novel treatment strategies specifically targeted at the microcirculation, and to new approaches in the prevention and early identification of CVD in Australians.

Retinopathy and high blood pressure in Non-diabetic participants of the Visual Impairment Project (VIP)

Investigators: Dr Gabriella Tikellis, Prof Hugh Taylor, Prof Tien Wong, Prof Paul Mitchell, Dr Alex Harper, Dr Jie Jin Wang.
Timeline: Ongoing
Study Population: The original 5147 VIP participants who had baseline examinations between 1992-1994 were aged 40 years and older. Of these 4144 (81%) non-diabetic participants with an average age of 58 years (range 40-96 years), were analysed for the presence of retinopathy and its association with high blood pressure.

The presence of microaneurysms and hemorrhages were assessed from masked grading of stereo macula photographs at the Blue Mountains Eye Study Grading Centre. High blood pressure and diabetes status was self-reported.

Abstract:

Micro-aneurysms, hemorrhages, cotton wool spots, hard exudates and changes to arteriolar caliber and appearance have traditionally been observed in people with diabetes and/or elevated blood pressure.

Recent population based studies such as the Blue Mountains, the Beaver Dam and the Cardiovascular Health Study have examined the prevalence of retinopathy (defined as the presence of microaneurysms and hemorrhages) in non-diabetic people and found it to occur in 7-10% of non-diabetic people. In fact, retinopathy lesions in non-diabetic people has been suggested to be associated with incident stroke, prevalent coronary heart disease and carotid artery thickening.

In our VIP cohort, the prevalence of retinopathy lesions was found to be 9.2%. The risk of having microaneurysms and hemorrhages in non-diabetic people was significantly increased risk in participants who reported having high blood pressure compared to normotensive non-diabetic participants.

The aims of our study are:

• To examine the association of numerous risk factors (including traditional CVD factors) with the prevalence of retinopathy lesions;
• To look at the five-year incidence of retinopathy lesions in non-diabetic participants;
• To examine whether non-specific retinopathy lesions in non-diabetic participants predict the development of diabetes after five years of follow up;
• To examine all of the above in association with changes in arteriolar caliber and appearance.