Neurovascular Dysfunction Precedes Neural Dysfunction in the Retina of Patients with Type 1 Diabetes

Department of Clinical Pharmacology, Medical University of Vienna, Austria.
Investigative ophthalmology & visual science (Impact Factor: 3.4). 01/2013; 54(1). DOI: 10.1167/iovs.12-10873
Source: PubMed


A variety of studies have shown that flicker-induced vasodilatation is reduced in patients with diabetes. It is, however, unclear whether reduced neural activity or abnormal neurovascular coupling is the reason for this phenomenon. In the present study, we hypothesized that retinal neurovascular dysfunction precedes neural dysfunction in patients with early type 1 diabetes.

In the present study, 50 patients with type 1 diabetes without retinopathy and 50 healthy age- and sex-matched control subjects were included. The retinal vascular response to flicker stimulation was measured using the dynamic Retinal Vessel Analyzer. In addition, the response in retinal blood velocity to flicker stimulation as assessed with laser Doppler velocimetry was studied in a subgroup of patients. Pattern electroretinography (ERG) was used to measure neural retinal function.

The flicker responses of both retinal arteries and veins were significantly reduced in patients with diabetes (veins in the diabetic group: 3.5 ± 2.3% versus healthy control group: 4.6 ± 2.0%; P = 0.022 between groups, whereas arteries in the diabetic group: 2.0 ± 2.7% versus healthy control group: 3.8 ± 1.7%; P < 0.001 between groups). Likewise, the response of retinal blood velocity was reduced in patients with diabetes, although adequate readings could only be obtained in a subgroup of subjects (diabetic group [n = 22]: 19 ± 7%; healthy control group [n = 24]: 43 ± 19% P < 0.001 between groups). The parameters of pattern ERG were not different between the two groups.

The study confirms that flicker responses are reduced early in patients with type 1 diabetes. This is seen before alterations in pattern ERG indicating abnormal neurovascular coupling.

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    • "The increase in retinal blood flow is pronounced and values in the order of 45%–60% were reported using different methodologies (Garhofer et al., 2004a; Michelson et al., 2002). Interestingly, flicker-induced changes in retinal hemodynamics appear to be disturbed early in patients with diabetes (Bek et al., 2008; Garhofer et al., 2004c; Lasta et al., 2013; Lecleire-Collet et al., 2011; Nguyen et al., 2009a,b; Pemp et al., 2009a; Pemp et al., 2009b) as well as in patients with glaucomatous optic neuropathy (Garhofer et al., 2004b; Gugleta et al., 2012, 2013a,b; Mroczkowska et al., 2013; Riva et al., 2004). An increase in retinal vessel diameter, retinal blood velocity and retinal blood flow was also observed using DOCT during flicker stimulation (Leitgeb, 2007). "
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    ABSTRACT: Optical Coherence Tomography (OCT) has revolutionized ophthalmology. Since its introduction in the early 1990s it has continuously improved in terms of speed, resolution and sensitivity. The technique has also seen a variety of extensions aiming to assess functional aspects of the tissue in addition to morphology. One of these approaches is Doppler OCT (DOCT), which aims to visualize and quantify blood flow. Such extensions were already implemented in time domain systems, but have gained importance with the introduction of Fourier domain OCT. Nowadays phase-sensitive detection techniques are most widely used to extract blood velocity and blood flow from tissues. A common problem with the technique is that the Doppler angle is not known and several approaches have been realized to obtain absolute velocity and flow data from the retina. Additional studies are required to elucidate which of these techniques is most promising. In the recent years, however, several groups have shown that data can be obtained with high validity and reproducibility. In addition, several groups have published values for total retinal blood flow. Another promising application relates to non-invasive angiography. As compared to standard techniques such as fluorescein and indocyanine-green angiography the technique offers two major advantages: no dye is required and depth resolution is required is provided. As such Doppler OCT has the potential to improve our abilities to diagnose and monitor ocular vascular diseases.
    Progress in Retinal and Eye Research 07/2014; 41(100). DOI:10.1016/j.preteyeres.2014.03.004 · 8.73 Impact Factor
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    • "Retinal vascular dysregulation has been observed in a variety of ocular diseases such as diabetic retinopathy or glaucoma (Pemp & Schmetterer 2008; Pournaras et al. 2008; Venkataraman et al. 2010; Kur et al. 2012; Pournaras & Riva 2013). As such, it has been shown that flicker-induced vasodilation is reduced in early-and late-stage diabetic retinopathy (Garhofer et al. 2004a,b,c; Mandecka et al. 2007; Nguyen et al. 2009a,b; Pemp et al. 2009; Lasta et al. 2013), in patients with early-stage glaucoma (Garhofer et al. 2004a,b,c; Gugleta et al. 2012) and in patients with systemic hypertension (Nagel et al. 2004). However, whether vascular dysregulation is also present in the retinal circulation of patients with AMD is still a matter of controversy. "
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    ABSTRACT: PurposeThe complement factor H (CFH) tyrosine 402 histidine (Y402H, rs1061170) variant is known to be significantly associated with age-related macular degeneration (AMD). Whether this genetic variant may impact retinal blood flow regulation is largely unknown. This study investigated whether flicker-induced vasodilation, an indicator for the coupling between neural activity and blood flow, is altered in subjects carrying the rs1061170 risk allele.Methods One hundred healthy subjects (aged between 18 and 45 years) were included in this study. Retinal blood flow regulation was tested by assessing retinal vessel calibres in response to stimulation with diffuse flicker light. Retinal vascular flicker responses were determined with a Dynamic Vessel Analyzer (DVA). In addition, genotyping for rs1061170 was performed.ResultsEighteen subjects were homozygous for the risk allele C, 50 were homozygous for the ancestral allele T, and 31 subjects were heterozygous (CT). One subject had to be excluded from data evaluation, as no genetic analysis could be performed due to technical difficulties. Baseline diameters of retinal arteries (p = 0.39) and veins (p = 0.64) were comparable between the three groups. Flicker-induced vasodilation in both retinal arteries (p = 0.38) and retinal veins (p = 0.62) was also comparable between the three studied groups.Conclusions Our data indicate that homozygous healthy young carriers of the C risk allele at rs1061170 do not show abnormal flicker-induced vasodilation in the retina. This suggests that the high-risk genetic variant of CFH polymorphism does not impact neuro-vascular coupling in healthy subjects.
    Acta ophthalmologica 05/2014; 92(7). DOI:10.1111/aos.12433 · 2.84 Impact Factor
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    • "Defective GJIC or HC responses are expected to disable ICWs and neurovascular coupling, resulting in a relative oxygen and glucose shortage during neuronal activity that may lead to convulsions and, on a longer term, to neuronal cell death. Chronically disturbed neurovascular coupling may lead to neurodegeneration (Zlokovic, 2011; Lasta et al., 2013) and this may be a possible mechanism at the basis of the motor deficiencies observed in ODDD patients. "
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    Frontiers in Pharmacology 09/2013; 4:120. DOI:10.3389/fphar.2013.00120 · 3.80 Impact Factor
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