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In vivo noninvasive mitochondrial redox assessment of the optic nerve head to predict disease.

ABSTRACT: Eye diseases are diagnosed by visualizing often irreversible structural changes occurring late in disease progression, such as retinal ganglion cell loss in glaucoma. The retina and optic nerve head have high mitochondrial energy need. Early mitochondrial/energetics dysfunction may predict vulnerability to permanent structural changes. In the in vivo murine eye, we used light-based resonance Raman spectroscopy (RRS) to assess noninvasively the redox states of mitochondria and hemoglobin which reflect availability of electron donors (fuel) and acceptors (oxygen). As proof of principle, we demonstrated that the mitochondrial redox state at the optic nerve head correlates with later retinal ganglion loss after acute intraocular pressure (IOP) elevation. This technology can potentially map the metabolic health of eye tissue in vivo complementary to optical coherence tomography, defining structural changes. Early detection (and normalization) of mitochondrial dysfunction before irreversible damage could lead to prevention of permanent neural loss.

SUBMITTER: Cakir B

PROVIDER: S-EPMC10230116 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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In vivo noninvasive mitochondrial redox assessment of the optic nerve head to predict disease.

Cakir Bertan B Tomita Yohei Y Yagi Hitomi H Romfh Padraic P Allen William W Ko Minji M Chen Peili P Fu Zhongjie Z Vakhshoori Daryoosh D Smith Lois E H LEH

PNAS nexus 20230502 5

Eye diseases are diagnosed by visualizing often irreversible structural changes occurring late in disease progression, such as retinal ganglion cell loss in glaucoma. The retina and optic nerve head have high mitochondrial energy need. Early mitochondrial/energetics dysfunction may predict vulnerability to permanent structural changes. In the in vivo murine eye, we used light-based resonance Raman spectroscopy (RRS) to assess noninvasively the redox states of mitochondria and hemoglobin which re ...[more]

PMID: 37265545

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Project description:Intracranial pressure (ICP) has been proposed to play an important role in the sensitivity to intraocular pressure (IOP) and susceptibility to glaucoma. However, the in vivo effects of simultaneous, controlled, acute variations in ICP and IOP have not been directly measured. We quantified the deformations of the anterior lamina cribrosa (ALC) and scleral canal at Bruch's membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three adult monkeys were imaged in vivo with OCT under four pressure conditions: IOP and ICP either at baseline or elevated. The BMO and ALC were reconstructed from manual delineations. From these, we determined canal area at the BMO (BMO area), BMO aspect ratio and planarity, and ALC median depth relative to the BMO plane. To better account for the pressure effects on the imaging, we also measured ALC visibility as a percent of the BMO area. Further, ALC depths were analyzed only in regions where the ALC was visible in all pressure conditions. Bootstrap sampling was used to obtain mean estimates and confidence intervals, which were then used to test for significant effects of IOP and ICP, independently and in interaction. Response to pressure manipulation was highly individualized between eyes, with significant changes detected in a majority of the parameters. Significant interactions between ICP and IOP occurred in all measures, except ALC visibility. On average, ICP elevation expanded BMO area by 0.17 mm2 at baseline IOP, and contracted BMO area by 0.02 mm2 at high IOP. ICP elevation decreased ALC depth by 10 μm at baseline IOP, but increased depth by 7 μm at high IOP. ALC visibility decreased as ICP increased, both at baseline (-10%) and high IOP (-17%). IOP elevation expanded BMO area by 0.04 mm2 at baseline ICP, and contracted BMO area by 0.09 mm2 at high ICP. On average, IOP elevation caused the ALC to displace 3.3 μm anteriorly at baseline ICP, and 22 μm posteriorly at high ICP. ALC visibility improved as IOP increased, both at baseline (5%) and high ICP (8%). In summary, changing IOP or ICP significantly deformed both the scleral canal and the lamina of the monkey ONH, regardless of the other pressure level. There were significant interactions between the effects of IOP and those of ICP on LC depth, BMO area, aspect ratio and planarity. On most eyes, elevating both pressures by the same amount did not cancel out the effects. Altogether our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

Project description:ObjectiveTo develop a noninvasive technique to quantitatively assess the pulsatile deformation due to cardiac contractions of the optic nerve head (ONH).DesignEvaluation of a diagnostic test or technology.ParticipantsHealthy subjects with no history of refractive surgery, divided into 2 cohorts on the basis of their axial length (AL).MethodsWe present a noninvasive technique to quantitatively assess the pulsatile deformation of the ONH tissue by combining high-frequency OCT imaging and widely available image processing algorithms. We performed a thorough validation of the approach, numerically and experimentally, evaluating the sensitivity of the method to artificially induced deformation and its robustness to different noise levels. We performed deformation measurements in cohorts of healthy (n = 9) and myopic (n = 5) subjects in different physiological strain conditions by calculating the amplitude of tissue displacement in both the primary position and abduction. The head rotation was measured using a goniometer. During imaging in abduction, the head was rotated 40° ± 3°, and subjects were instructed to direct their gaze toward the OCT visual target.Main outcome measuresPulsatile tissue displacement maps.ResultsThe robustness of the method was assessed using artificial deformations and increasing noise levels. The results show acceptable absolute errors before the noise simulations grossly exaggerate image degradation. For the group of subjects with AL of < 25 mm (n = 9), the median pulsatile displacement of the ONH was 7.8 ± 1.3 μm in the primary position and 8.9 ± 1.2 μm in abduction. The Wilcoxon test showed a significant difference (P ≤ 0.005) between the 2 paired measures. Reproducibility was tested in 2 different sessions in 5 different subjects with the same intraocular pressure, and an intraclass correlation coefficient of 0.99 was obtained (P < 0.005).ConclusionsThe computational pipeline demonstrated good reproducibility and had the capacity to accurately map the pulsatile deformation of the optic nerve. In a clinical setting, we detected physiological changes in normal subjects supporting its translation potential as a novel biomarker for the diagnosis and progression of optic nerve diseases.

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In vivo noninvasive mitochondrial redox assessment of the optic nerve head to predict disease.

Publications

In vivo noninvasive mitochondrial redox assessment of the optic nerve head to predict disease.

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