Thanh T. Nguyen

Retinal Vascular changes in pre-diabetes and prehypertension : New findings and their research and clinical implications

The retinal vasculature can be viewed directly and noninvasively, offering a unique and easily accessible “window” to study the health and disease of the human microcirculation in vivo. In the last decade, advances in digital retinal photography and imaging techniques have allowed precise characterization of subtle retinal vascular changes in large populations. These retinal changes can be broadly divided into four groups: 1 ) classic retinal vascular changes in diabetes and hypertension (i.e., diabetic and hypertensive retinopathy), 2 ) isolated retinopathy signs in individuals with diabetes or hypertension (e.g., microaneurysm, retinal hemorrhage, or cotton wool spot), 3 ) changes in retinal vascular caliber, and 4 ) changes in retinal vascular architecture (e.g., retinal tortuosity). New studies in large populations now show that retinal vascular changes are common in the general population and may precede the subsequent development of overt diabetes and hypertension. A consistent pattern of associations is also emerging, showing that specific retinal vascular changes may be related differently to hyperglycemia and blood pressure. In this review, we summarize recent studies on the retinal vascular changes seen in diabetes and hypertension and speculate on potential research and clinical implications. ### Diabetic retinopathy In individuals with diabetes, the classic primary retinal vascular complication—diabetic retinopathy—is well described (1). Diabetic retinopathy signs are broadly divided into nonproliferative and proliferative retinopathy. The prevalence of diabetic retinopathy increases with duration of diabetes. The Australian Diabetes, Obesity and Lifestyle Study (AusDiab) showed that the prevalence of diabetic retinopathy is less than 10% in those with diabetes duration of less than 5 years but more than 50% in those with 20 years or longer diabetes (2). The two major risk factors of diabetic retinopathy are hyperglycemia and hypertension, with hyperlipidemia as a possible third major risk factor. The importance of hyperglycemia has been confirmed in epidemiological studies (3), as well as two pivotal …

Retinal vascular manifestations of metabolic disorders

Metabolic diseases have profound effects on the structure and function of the retinal circulation. The recent development of retinal photography and digital imaging has enabled more precise documentation of diabetic retinopathy, as well as other retinal microvascular changes, such as retinal arteriolar narrowing, venular dilation and isolated retinopathy signs in nondiabetic individuals. These retinal microvascular signs have been shown to be associated with long-term risks of type 2 diabetes and hypertension, components of the metabolic syndrome (e.g. obesity, dyslipidemia), and a range of macro- and micro-vascular conditions (e.g. stroke, cardiovascular mortality). There is evidence that endothelial dysfunction and inflammation might be possible mechanisms involved in the development of various retinal microvascular changes in patients with diabetes, hypertension and other metabolic disorders. Further understanding of how these processes influence the retinal vasculature might help to elucidate the diverse vascular manifestations of metabolic diseases.

Relationship of Retinal Vascular Caliber With Diabetes and Retinopathy The Multi-Ethnic Study of Atherosclerosis (MESA)

OBJECTIVE—To examine the relationship of retinal vascular caliber with diabetes, glycemia, and diabetic retinopathy. RESEARCH DESIGN AND METHODS—Population-based study using data from the Multi-Ethnic Study of Atherosclerosis (MESA), comprising 5,976 individuals (whites, blacks, Hispanics, and Chinese) residing in six U.S. communities who were free of clinical cardiovascular disease at baseline. Retinal vascular caliber was measured from digital retinal photographs. RESULTS—There were 4,585 individuals with normal fasting glucose (NFG), 499 with impaired fasting glucose (IFG), 165 with diabetes with retinopathy signs, and 727 with diabetes without retinopathy signs. After multivariate analysis, retinal arteriolar caliber increased from 143.8 μm in subjects with NFG to 144.5 μm in IFG and 146.1 μm in diabetes (P < 0.001 for trend). Retinal venular caliber increased from 214.4 μm in NFG to 216.7 μm in IFG and 218.0 μm in diabetes (P < 0.001 for trend). Retinal venular caliber was significantly larger with increasing levels of fasting glucose and A1C. In a subgroup analysis by ethnicity, the association between wider arteriolar caliber and diabetes was evident in whites only, whereas wider venular caliber and diabetes was evident in Hispanics and Chinese only. In people with diabetes, eyes with retinopathy had larger retinal venular but not arteriolar caliber. CONCLUSIONS—Retinal arteriolar and venular calibers are larger in individuals with diabetes, but the pattern of associations appears to vary by ethnicity. Retinal venular caliber is additionally associated with retinopathy signs. These findings add further to the concept that variations in retinal vascular caliber may reflect early diabetic microvascular damage.

Flicker Light-Induced Retinal Vasodilation in Diabetes and Diabetic Retinopathy

OBJECTIVE Flicker light–induced retinal vasodilation may reflect endothelial function in the retinal circulation. We investigated flicker light–induced vasodilation in individuals with diabetes and diabetic retinopathy. RESEARCH DESIGN AND METHODS Participants consisted of 224 individuals with diabetes and 103 nondiabetic control subjects. Flicker light–induced retinal vasodilation (percentage increase over baseline diameter) was measured using the Dynamic Vessel Analyzer. Diabetic retinopathy was graded from retinal photographs. RESULTS Mean ± SD age was 56.5 ± 11.8 years for those with diabetes and 48.0 ± 16.3 years for control subjects. Mean arteriolar and venular dilation after flicker light stimulation were reduced in participants with diabetes compared with those in control subjects (1.43 ± 2.10 vs. 3.46 ± 2.36%, P < 0.001 for arteriolar and 2.83 ± 2.10 vs. 3.98 ± 1.84%, P < 0.001 for venular dilation). After adjustment for age, sex, diabetes duration, fasting glucose, cholesterol and triglyceride levels, current smoking status, systolic blood pressure, and use of antihypertensive and lipid-lowering medications, participants with reduced flicker light–induced vasodilation were more likely to have diabetes (odds ratio 19.7 [95% CI 6.5–59.1], P < 0.001 and 8.14 [3.1–21.4], P < 0.001, comparing lowest vs. highest tertile of arteriolar and venular dilation, respectively). Diabetic participants with reduced flicker light–induced vasodilation were more likely to have diabetic retinopathy (2.2 [1.2–4.0], P = 0.01 for arteriolar dilation and 2.5 [1.3–4.5], P = 0.004 for venular dilation). CONCLUSIONS Reduced retinal vasodilation after flicker light stimulation is independently associated with diabetes status and, in individuals with diabetes, with diabetic retinopathy. Our findings may therefore support endothelial dysfunction as a pathophysiological mechanism underlying diabetes and its microvascular manifestations.

Sodium selenate specifically activates PP2A phosphatase, dephosphorylates tau and reverses memory deficits in an Alzheimer's disease model.

Neurofibrillary tangles composed of abnormally hyperphosphorylated tau protein are a hallmark of Alzheimers disease (AD) and related tauopathies. Tau hyperphosphorylation is thought to promote aggregation with subsequent tangle formation. Reducing tau phosphorylation by boosting the activity of the key phosphatase/s that mediate dephosphorylation of tau could be a viable clinical strategy in AD. One of the key phosphatases implicated in regulating tau protein phosphorylation is the serine-threonine phosphatase PP2A. We have determined that sodium selenate can act as a specific agonist for PP2A, significantly boosting phosphatase activity. Acute treatment of either neuroblastoma cells or normal aged mice with sodium selenate rapidly reduced tau protein phosphorylation. Sodium selenate-treated transgenic TAU441 mice had significantly lower levels of phospho- and total tau levels in the hippocampus and amygdala compared with controls and exhibited significantly improved spatial learning and memory on the Morris Water Maze task. Sodium selenate is a specific activator of PP2A with excellent oral bioavailability, and favourable central nervous system penetrating properties. Clinical studies in patients with AD are envisaged in the near future.

Inflammatory, hemostatic, and other novel biomarkers for diabetic retinopathy: the multi-ethnic study of atherosclerosis

OBJECTIVE There are conflicting data regarding relationships of systemic biomarkers of inflammation, hemostasis, and homocysteine with diabetic retinopathy. We examined these relationships in the Multi-Ethnic Study of Atherosclerosis. RESEARCH DESIGN AND METHODS A total of 921 participants with diabetes were included. Diabetic retinopathy was graded from retinal photographs. We defined two outcomes: any diabetic retinopathy and vision-threatening diabetic retinopathy (severe nonproliferative diabetic retinopathy or worse). Systemic markers analyzed were C-reactive protein, homocysteine, fibrinogen, plasmin-α2-antiplasmin complex (PAP), interleukin-6, d-dimer, factor VIII, serum creatinine, and urinary albumin-to-creatinine (UAC) ratio. RESULTS Prevalence of diabetic retinopathy was 33.2% and vision-threatening diabetic retinopathy 7.1%. After adjusting for established risk factors (diabetes duration, A1C, systolic blood pressure, waist-to-hip ratio, and use of diabetes medications), fibrinogen (odds ratio 1.14 [95% CI 1.01–1.32], P = 0.05) and PAP (1.25 [1.05–1.50], P = 0.01) were associated with any diabetic retinopathy, while PAP (1.54 [1.13–2.11], P = 0.007) and homocysteine (1.57 [1.16–2.11], P = 0.003) were associated with vision-threatening diabetic retinopathy. Only PAP remained significant after additional adjustment for serum creatinine and UAC ratio. Area under receiver-operator characteristic curve (AUROC) for diabetic retinopathy was constructed for established and novel risk factors. Established risk factors accounted for a 39.2% increase of the AUROC, whereas novel markers (fibrinogen, PAP, homocysteine, serum creatinine, and UAC ratio) only accounted for an additional 2.2%. CONCLUSIONS There were few associations of novel markers of inflammation, hemostasis, and homocysteine with diabetic retinopathy after controlling for established risk factors. These data suggest that there is limited clinical use of these biomarkers for prediction of diabetic retinopathy.

Serum Apolipoprotein AI and B Are Stronger Biomarkers of Diabetic Retinopathy Than Traditional Lipids

OBJECTIVE To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. RESEARCH DESIGN AND METHODS This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non–HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. RESULTS Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16–0.94], highest versus lowest quartile; Ptrend = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59–0.98]), whereas apoB (per SD increase, 1.31 [1.02–1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13–1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. CONCLUSIONS ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures.

Ophthalmological manifestations of Fabry disease: a survey of patients at the Royal Melbourne Fabry Disease Treatment Centre

Background: Fabry disease is a rare X‐linked inborn error of glycosphingolipid metabolism. The aim of this study was to document the ophthalmological manifestations of patients attending the Royal Melbourne Hospital Fabry disease treatment centre.

Quantitative retinal vascular calibre changes in diabetes and retinopathy: the Singapore Malay eye study.

PurposeTo describe the relationship of retinal vascular calibre with diabetes and diabetic retinopathy in an Asian population.MethodsA total of 3280 (78.7% response) subjects, aged 40–80 years, of Malay ethnicity residing in Singapore participated in this population-based, cross-sectional study. Retinal vascular calibre was measured and summarized using a validated computer programme from digital retinal photographs. Diabetic retinopathy signs were graded from photographs using the modified Airlie House classification.ResultsOf the 3004 subjects with data for this analysis, 682 (22.7%) had diabetes, of whom 194 (28.4%) had retinopathy. After multivariable adjustment, retinal arteriolar calibre was significantly wider in persons with diabetes (141 vs139 μm, P<0.001); venular calibre was not associated with diabetes (P=0.93). Among participants with diabetes, venular calibre increased from 218.7 μm in those without retinopathy to 231.1 μm in those with moderate and 231.4 μm in those with severe retinopathy (Pfor trend=<0.001); arteriolar calibre was not associated with diabetic retinopathy.ConclusionsThis study shows wider retinal arterioles in diabetes and wider venules in those with diabetic retinopathy in an Asian population. These findings confirm earlier data on white population, supporting the concept that a quantitative assessment of retinal vasculature may provide further insights into early diabetic microvascular damage.

Retinal Vascular Caliber and Brachial Flow-Mediated Dilation The Multi-Ethnic Study of Atherosclerosis

Background and Purpose— Retinal vascular caliber changes have been shown to predict stroke, but the underlying mechanism of this association is unknown. We examined the relationship between retinal vascular caliber with brachial flow-mediated dilation (FMD), a measure of systemic endothelial function. Methods— The Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based study of persons 45 to 84 years of age residing in 6 US communities free of clinical cardiovascular disease at baseline. Brachial FMD data were collected at baseline (July 2000 to June 2002), and retinal vascular caliber was measured from digital retinal photographs at the second examination, immediately after the first (August 2002 to January 2004). Data were available for 2851 participants for analysis. Results— The mean brachial FMD was 4.39±2.79%. After adjusting for age and gender, brachial FMD was reduced in persons with wider retinal venular caliber (changes in FMD −0.25, 95% CI, −0.36, − 0.13; P<0.001, per SD increase in venular caliber). This relationship persists after adjusting for systolic blood pressure, serum total cholesterol, use of lipid-lowering and antihypertensive medication, body mass index, current smoking status, and hemoglobinA1C (−0.18; 95% CI −0.30, − 0.06; P=0.004, per SD increase in venular caliber). Brachial FMD was not associated with retinal arteriolar caliber. Conclusions— Persons with wider retinal venules have reduced brachial FMD, independent of other vascular risk factors. This suggests that retinal venular caliber, previously shown to predict stroke, may be a marker of underlying systemic endothelial dysfunction.