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: 3.66). 01/2013; 54(1). DOI: 10.1167/iovs.12-10873
Source: PubMed

ABSTRACT PURPOSE: A variety of studies has shown that flicker-induced vasodilatation is reduced in patients with diabetes. It is, however, unclear whether reduced neural activity or abnormal neuro-vascular 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. METHODS: 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. RESULTS: The flicker response of both retinal arteries and veins was significantly reduced in patients with diabetes (veins: diabetic group: 3.5±2.3%, healthy control group: 4.6±2.0%; p=0.022 between groups; arteries: diabetic group: 2.0±2.7%, 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. CONCLUSIONS: 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.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To investigate the role of epoxyeicosatrienoic acids (EETs) and prostaglandins (PGs) in retinal blood vessel calibers and vasodilation during flicker light stimulation in humans. Methods: Twelve healthy non-smokers participated in a balanced crossover study. Oral fluconazole 400 mg and dispersible aspirin 600 mg were used to inhibit production of EETs and PGs, respectively. Retinal imaging was performed 1 h after drug ingestion with the Dynamic Vessel Analyzer. Resting calibers of selected vessel segments were recorded in measurement units (MU). Maximum percentage dilations during flicker stimulation were calculated from baseline calibers. We then studied six participants each after fluconazole and aspirin ingestions at 30 min intervals for 2 h. Within-subject differences were assessed by analysis of variance and Dunnett-adjusted pairwise comparisons with significance taken at P < 0.05. Results: In crossover study participants, mean (standard deviation [SD]) arteriole and venule dilations without drug administration were 4.4 (2.0)% and 4.6 (1.7)%, respectively. Neither drug affected vasodilation during flicker stimulation. Mean (SD) resting arteriole and venule calibers on no-drug visits were 119.6 (10.6) MU and 145.7 (17.0) MU, respectively. Fluconazole reduced mean (±95% C.I.) resting venule calibers by 5.1 (4.3) MU. In repeated measures participants, neither drug affected vasodilations, but fluconazole reduced resting venule calibers over 2 h (P < 0.001). Conclusions: EETs and PGs are unlikely to be primary mediators of flicker light-induced retinal vasodilation in humans. However, EETs may play a role in the regulation of retinal vascular tone and blood flow under resting physiological conditions.
    Investigative Ophthalmology &amp Visual Science 10/2014; 55(10). DOI:10.1167/iovs.14-14947 · 3.66 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A wide variety of ocular diseases are associated with abnormalities in ocular circulation. As such, there is considerable interest in techniques for quantifying retinal blood flow, among which Doppler optical coherence tomography (OCT) may be the most promising. We present an approach to measure retinal blood flow in the rat using a new optical system that combines the measurement of blood flow velocities via Doppler Fourier-domain optical coherence tomography and the measurement of vessel diameters using a fundus camera-based technique. Relying on fundus images for extraction of retinal vessel diameters instead of OCT images improves the reliability of the technique. The system was operated with an 841-nm superluminescent diode and a charge-coupled device camera that could be operated at a line rate of 20 kHz. We show that the system is capable of quantifying the response of 100% oxygen breathing on the retinal blood flow. In six rats, we observed a decrease in retinal vessel diameters of 13.2% and a decrease in retinal blood velocity of 42.6%, leading to a decrease in retinal blood flow of 56.7%. Furthermore, in four rats, the response of retinal blood flow during stimulation with diffuse flicker light was assessed. Retinal vessel diameter and blood velocity increased by 3.4% and 28.1%, respectively, leading to a relative increase in blood flow of 36.2%. The presented technique shows much promise to quantify early changes in retinal blood flow during provocation with various stimuli in rodent models of ocular diseases in rats. (C) The Authors. Published by SPIE under a Creative Commons Attribution 3.0 Unported License.
    Journal of Biomedical Optics 10/2014; 19(10):106008. DOI:10.1117/1.JBO.19.10.106008 · 2.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose:Oxygen extraction fraction (OEF), defined by the ratio of oxygen metabolism (MO2) to delivery (DO2) determines the level of compensation of MO2 by DO2. In the current study, we tested the hypothesis that inner retinal OEF remains unchanged during light flicker under systemic normoxia and hypoxia in rats due to the matching of MO2 and DO2. Methods:Retinal vascular oxygen tension (PO2) measurements were obtained in 10 rats by phosphorescence lifetime imaging. Inner retinal OEF was derived from vascular PO2 based on Fick's principle. Measurements were obtained before and during light flicker under systemic normoxia and hypoxia. The effects of light flicker and systemic oxygenation on retinal vascular PO2 and OEF were determined by analysis of variance. Results:During light flicker, retinal venous PO2 decreased (P < 0.01; N = 10), while inner retinal OEF increased (P = 0.02). Under hypoxia, both retinal arterial and venous PO2 decreased (P < 0.01), while OEF increased (P < 0.01). The interaction effect was not significant on OEF (P = 0.52), indicating the responses of OEF to light flicker were similar under normoxia and hypoxia. During light flicker, OEF increased from 0.46 ± 0.13 to 0.50 ± 0.11 under normoxia, while under hypoxia, OEF increased from 0.67 ± 0.16 to 0.74 ± 0.14. Conclusions:Inner retinal OEF increased during light flicker indicating the relative change in DO2 is less than that in MO2 in rats under both systemic normoxia and hypoxia. Inner retinal OEF is a potentially useful parameter for assessment of the relative changes of MO2 and DO2 under physiologic and pathologic conditions.
    Investigative Ophthalmology &amp Visual Science 09/2014; 55(9). DOI:10.1167/iovs.13-13811 · 3.66 Impact Factor