Corneal Nerve Imaging Research Articles

Non-contact confocal calcium imaging of in vivo murine corneal nerves

Abnormal corneal nerve function and associated disease is a significant public health concern. It is associated with prevalent ocular surface diseases, including dry eye disease. Corneal nerve dysfunction is also a common side effect of refractive surgeries, as well as a symptom of diseases that cause peripheral neuropathies. Here, we demonstrate in vivo calcium imaging of mouse corneal nerves expressing GCaMP6f, a genetically encoded calcium indicator. A custom fluorescence imaging and stereotactic system was designed, allowing for non-contact imaging of the mouse cornea with an air objective. Dynamic imaging of neuronal activity is demonstrated in the various layers of the cornea and in response to local anesthetic administration. This approach demonstrates a less invasive means of assessing corneal nerve function than has been previously used, and has significant potential for studying the effects of ocular diseases, refractive surgeries, and peripheral neuropathies on corneal nerve function, as well as the effectiveness of various therapies to treat corneal nerve dysfunction.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal β-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased β-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation.

Impact of Age on the Characteristics of Corneal Nerves and Corneal Epithelial Cells in Healthy Adults.

The aim of this study was to investigate age-related changes in corneal nerves and corneal epithelial cell parameters and to establish age-adjusted reference values. A total of 7025 corneal nerve images and 4215 corneal epithelial images obtained using in vivo confocal microscopy from 281 eyes of 143 healthy participants were included. Seven corneal nerve parameters and 3 corneal epithelial cell parameters were quantified using 2 automatic analytic software and analyzed across 6 age groups ranging from 21 to 80 years. There was a declining trend in all 7 nerve parameters with advancing age. In particular, corneal nerve fiber length and corneal nerve fiber density demonstrated a significant decrease in subjects aged 65 years or older compared with subjects younger than 65 years (10.8 ± 2.6 mm/mm 2 vs. 9.9 ± 2.0 mm/mm 2 , P = 0.011 in corneal nerve fiber length; 15.8 ± 5.2 fibers/mm 2 vs. 14.4 ± 4.3 fibers/mm 2 , P = 0.046 in corneal nerve fiber density), whereas corneal nerve fractal dimension demonstrated a borderline significant decrease ( P = 0.057). Similarly, there was a general declining trend in all epithelial cell parameters with advancing age. Corneal epithelial cell circularity was significantly lower in subjects aged 65 years and older as compared to subjects younger than 65 years (0.722 ± 0.021 μm 2 vs. 0.714 ± 0.021 μm 2 ; P = 0.011). Advancing age results in reduced corneal nerve metrics and alteration of corneal cell morphology. Aging effects should be considered when evaluating patients with corneal neuropathy.

The impact of dry eye disease on corneal nerve parameters: A systematic review and meta-analysis.

Dry eye disease (DED) is a growing global health problem with a significant impact on the quality of life of patients. While neurosensory abnormalities have been recognised as a contributor to DED pathophysiology, the potential role of in vivo corneal confocal microscopy in detecting nerve loss or damage remains unclear. This systematic review with meta-analysis (PROSPERO registered CRD42022381861) investigated whether DED has an impact on sub-basal corneal nerve parameters. PubMed, Embase and Web of Science Core Collection databases were searched from inception to 9 December 2022. Studies using laser scanning confocal microscopy to compare corneal nerve parameters of DED with healthy eyes were included. Study selection process and data extraction were performed by two independent members of the review team. Twenty-two studies with 916 participants with DED and 491 healthy controls were included, with 21 of these studies included in subsequent meta-analyses. There was a decrease in total corneal nerve length (-3.85 mm/mm2 ; 95% CI -5.16, -2.55), corneal main nerve trunk density (-4.81 number/mm2 ; 95% CI -7.94, -1.68) and corneal nerve branch density (-15.52 number/mm2 ; 95% CI -27.20, -3.84) in DED eyes compared with healthy eyes, with subgroup analysis demonstrating that these differences were more evident in studies using NeuronJ software, a semi-automated procedure. While this review found evidence of loss of corneal nerve parameters in eyes with DED compared with healthy controls, particularly with the use of a semi-automated image analysis method, it is evident that there is substantial heterogeneity between studies in terms of corneal nerve imaging methodology. Standardisation is required in terms of terminology and analysis, with more research needed to potentially improve the clinical applicability and practicality of corneal nerve imaging. Further investigation is also required to confirm the diagnostic accuracy of this imaging modality and its potential for monitoring DED treatment efficacy.

Imaging of corneal nerves with in vivo confocal microscopy (IVCM)

AbstractThe subbasal corneal nerve plexus may serve as an important biomarker in ocular surface disease and ocular as well as systemic neuropathies. Changes in number and density of nerves, “beadings” and or tortuosity correlate to clinical signs of Dry Eye Disease. The same is true for atopic keratoconjunctivitis where – in addition – the number of perineural inflammatory cells was significantly increased. In patients with type 1 diabetes mellitus, the corneal subbasal nerve plexus was abnormal in 50% although classified as “normal” by the clinical and electrophysiological based tests for peripheral neuropathies. Although in vivo confocal microscopy is a wonderful tool to assess corneal nerves as reliable biomarkers, it is not generally available, the quality of different equipment may vary, and the analysis of nerves is still time‐consuming.

Artificial Intelligence and Corneal Confocal Microscopy: The Start of a Beautiful Relationship.

Corneal confocal microscopy (CCM) is a rapid non-invasive in vivo ophthalmic imaging technique that images the cornea. Historically, it was utilised in the diagnosis and clinical management of corneal epithelial and stromal disorders. However, over the past 20 years, CCM has been increasingly used to image sub-basal small nerve fibres in a variety of peripheral neuropathies and central neurodegenerative diseases. CCM has been used to identify subclinical nerve damage and to predict the development of diabetic peripheral neuropathy (DPN). The complex structure of the corneal sub-basal nerve plexus can be readily analysed through nerve segmentation with manual or automated quantification of parameters such as corneal nerve fibre length (CNFL), nerve fibre density (CNFD), and nerve branch density (CNBD). Large quantities of 2D corneal nerve images lend themselves to the application of artificial intelligence (AI)-based deep learning algorithms (DLA). Indeed, DLA have demonstrated performance comparable to manual but superior to automated quantification of corneal nerve morphology. Recently, our end-to-end classification with a 3 class AI model demonstrated high sensitivity and specificity in differentiating healthy volunteers from people with and without peripheral neuropathy. We believe there is significant scope and need to apply AI to help differentiate between peripheral neuropathies and also central neurodegenerative disorders. AI has significant potential to enhance the diagnostic and prognostic utility of CCM in the management of both peripheral and central neurodegenerative diseases.

Clinically Based Automated Tracing and Tortuosity Estimation of Corneal Nerve Fibers From Confocal Microscopy Images

The purpose of this study was the development of an algorithm able to automatically trace corneal nerves and to estimate a nerve tortuosity index that is useful in clinical practice. In vivo confocal microscopy is an imaging technique that allows the clinical assessment of corneal and systemic diseases. Many studies have demonstrated a correlation between the tortuosity level of nerve fibers in the subbasal plexus layer and some pathologies. We developed an algorithm that provides fully automatic tracing of nerve fibers. It also includes a new way of dealing with bifurcations, separating the main paths from the secondary ones. Based on this automated tracing, the tortuosity was estimated as the absolute curvature, tortuosity density, and fractal dimension. These metrics were considered first individually and then as a linear combination of 2 or 3 of them. We investigated the capability of the estimated tortuosity to emulate the clinical classification into low, mid, and high tortuosity levels. Furthermore, we investigated its ability to distinguish healthy subjects from pathological subjects. Excellent agreement between manual and automated grouping of tortuosity (96.6% accuracy) was obtained. Moreover, the proposed algorithm could differentiate between healthy and pathological subjects with an accuracy of 77.1% by analyzing each image individually. The accuracy improved to 86.31% by considering 3 images of the same subject simultaneously. The proposed framework provides completely automated analysis of corneal nerve images. The results demonstrate the ability of our method to emulate the clinical classification of tortuosity levels and its potential for identifying healthy and pathological subjects.

In vivo confocal microscopy of sub-basal corneal nerves and corneal densitometry after three kinds of refractive procedures for high myopia.

To observe corneal nerve fibers and densitometry after small incision lenticule extraction (SMILE), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) and laser-assisted subepithelial keratomileusis (LASEK) for high myopia. This is a prospective, cross-sectional research study. Patients with high myopia (equivalent spherical lens: -6.00 and -11.00D) who underwent laser corneal refractive surgery were divided into three groups: SMILE, FS-LASIK and LASEK. Scheimpflug imaging of corneal nerves in five areas was observed by confocal microscopy before and 6, 12months after surgery. Corneal densitometry was measured by Pentacam anterior segment analysis system. Overall, 59 patients were enrolled. The nerve density in the central area did not recover to the preoperative level in three groups until 12months. The density and length of corneal nerves in central and lower area were better in the SMILE group 6months postoperatively (p = 0.01), while nerve density did not differ significantly among three groups 12months postoperatively (p = 0.18). Nerve fibers in central and temporal region were wider in LASEK than that in other two groups at 6- and 12-month follow-up. Corneal densitometry in the central 6mm diameter was significantly higher in the LASEK group compared with other two groups 6months postoperatively (p = 0.04). Twelvemonths postoperatively, corneal densitometry in range of all zone was lower in SMILE than in FS-LASIK and LASEK (p = 0.01, 0.03, 0.04). Compared with FS-LASIK and LASEK, SMILE-treated eyes with high myopia had certain advantages in nerve density, length and nerve connection way and had better corneal transparency after operation.

Corneal and Epidermal Nerve Quantification in Chemotherapy Induced Peripheral Neuropathy.

Chemotherapy-induced neurotoxicity is an increasingly recognized clinical issue in oncology. in vivo confocal microscopy (IVCM) of corneal nerves has been successfully used to diagnose peripheral neuropathies, including diabetic neuropathy. The purpose of this study was to test if the combination of corneal nerve density and morphology assessed by IVCM is useful to monitor the neurotoxic effects of chemotherapy compared to epidermal nerve quantification. Overall, 95 adult patients with different cancer types were recruited from the oncology and hematology departments of the San Raffaele Hospital. Neurological examination, including clinical Total Neuropathy Score, and in vivo corneal confocal microscopy (IVCM), were performed before and after chemotherapy. In a group of 14 patients, skin biopsy was performed at the first and last visit. In the group of 14 patients who underwent both skin biopsy and corneal nerve imaging, clinical worsening (+69%, p = 0.0018) was paralleled by corneal nerve fiber (CNF) density reduction (−22%, p = 0.0457). Clinical Total neuropathy score significantly worsened from the first to the last visit (+62%, p < 0.0001). CNF length was not significantly reduced overall. However, CNF density/tortuosity ratio significantly decreased after therapy. Correlation analysis showed that the CNF density/tortuosity ratio was also correlated with the number of chemotherapy cycles (r = −0.04790, P = 0.0009). Our data confirm that in vivo corneal confocal microscopy is a helpful, non-invasive tool which shows promise for the diagnosis of chemotherapy-induced peripheral neuropathies. IVCM could allow a rapid, reproducible and non-invasive quantification of peripheral nerve pathology in chemotherapy-associated neuropathy.

Artificial intelligence utilising corneal confocal microscopy for the diagnosis of peripheral neuropathy in diabetes mellitus and prediabetes

Aims/hypothesisWe aimed to develop an artificial intelligence (AI)-based deep learning algorithm (DLA) applying attribution methods without image segmentation to corneal confocal microscopy images and to accurately classify peripheral neuropathy (or lack of).MethodsThe AI-based DLA utilised convolutional neural networks with data augmentation to increase the algorithm’s generalisability. The algorithm was trained using a high-end graphics processor for 300 epochs on 329 corneal nerve images and tested on 40 images (1 image/participant). Participants consisted of healthy volunteer (HV) participants (n = 90) and participants with type 1 diabetes (n = 88), type 2 diabetes (n = 141) and prediabetes (n = 50) (defined as impaired fasting glucose, impaired glucose tolerance or a combination of both), and were classified into HV, those without neuropathy (PN−) (n = 149) and those with neuropathy (PN+) (n = 130). For the AI-based DLA, a modified residual neural network called ResNet-50 was developed and used to extract features from images and perform classification. The algorithm was tested on 40 participants (15 HV, 13 PN−, 12 PN+). Attribution methods gradient-weighted class activation mapping (Grad-CAM), Guided Grad-CAM and occlusion sensitivity displayed the areas within the image that had the greatest impact on the decision of the algorithm.ResultsThe results were as follows: HV: recall of 1.0 (95% CI 1.0, 1.0), precision of 0.83 (95% CI 0.65, 1.0), F1-score of 0.91 (95% CI 0.79, 1.0); PN−: recall of 0.85 (95% CI 0.62, 1.0), precision of 0.92 (95% CI 0.73, 1.0), F1-score of 0.88 (95% CI 0.71, 1.0); PN+: recall of 0.83 (95% CI 0.58, 1.0), precision of 1.0 (95% CI 1.0, 1.0), F1-score of 0.91 (95% CI 0.74, 1.0). The features displayed by the attribution methods demonstrated more corneal nerves in HV, a reduction in corneal nerves for PN− and an absence of corneal nerves for PN+ images.Conclusions/interpretationWe demonstrate promising results in the rapid classification of peripheral neuropathy using a single corneal image. A large-scale multicentre validation study is required to assess the utility of AI-based DLA in screening and diagnostic programmes for diabetic neuropathy.Graphical abstract

Advances in Imaging of Subbasal Corneal Nerves With Micro-Optical Coherence Tomography.

PurposeTo investigate the most peripheral corneal nerve plexus using high-resolution micro–optical coherence tomography (µOCT) imaging and to assess µOCT's clinical potential as a screening tool for corneal and systemic diseases.MethodsAn experimental high-resolution (1.5 × 1.5 × 1 µm) µOCT setup was applied for three-dimensional imaging of the subbasal nerve plexus in nonhuman primates (NHPs) and swine within 3 hours postmortem. Morphologic features of subbasal nerves in µOCT were compared to β3 tubulin-stained fluorescence confocal microscopy (FCM). Parameters such as nerve density, nerve distribution, and imaging repeatability were evaluated, using semiautomatic image analysis in form of a custom corneal surface segmentation algorithm and NeuronJ.ResultsSwine and NHP corneas showed the species-specific nerve morphology in both imaging modalities. Most fibers showed a linear course, forming a highly parallel pattern, converging in a vortex with overall nerve densities varying between 9.51 and 24.24 mm/mm2. The repeatability of nerve density quantification of the µOCT scans as approximately 88% in multiple image recordings of the same cornea.ConclusionsCompared to the current gold standard of FCM, µOCT's larger field of view of currently 1 × 1 mm increases the conclusiveness of density measurements, which, coupled with µOCT's feature of not requiring direct contact, shows promise for future clinical application. The nerve density quantification may be relevant for screening for systemic disease (e.g., peripheral neuropathy).Translational RelevanceTechnological advances in OCT technology may enable a quick assessment of corneal nerve density, which could be valuable evaluating ophthalmic and systemic peripheral innervation.

Early corneal and optic nerve changes in a paediatric population affected by obstructive sleep apnea syndrome.

The relation between OSAS and eye diseases is well known in adults, while very few and contradictory data can be found regarding paediatric ages. The aim of this study is to explore the early corneal, macular and optic nerve changes in paediatric patients with OSAS. Prospective study that enrolled children aged ≥ 4years referred to the Paediatric Pneumology Clinic in Verona for suspected obstructive sleep apnoea syndrome (OSAS) and investigated with the overnight respiratory polygraphy. Patients with apnoea-hypopnea index (AHI) > 1 were classified as OSAS, while those with AHI < 1 were classified non-OSAS. All patients underwent comprehensive eye examination including slit lamp, refraction, intraocular pression (Goldman applanation tonometry), corneal tomography (corneal astigmatism, corneal keratometry at the apex, surface asymmetry index, central corneal thickness and thinnest corneal thickness) and optical coherence tomography (central macular thickness, macular volume and retinal nerve fibre layer). Seventy-two children were enrolled in the study. The overall prevalence of OSAS was 48.6%. Statistically significant differences were found between OSAS and non-OSAS group for corneal asymmetry (0.9 ± 0.5 and 0.6 ± 0.3, respectively; p = 0.02), thinnest corneal thickness (551.8 ± 33.9 and 563.7 ± 32.5; p = 0.04), average retinal nerve fibre layer (102.8 ± 10.5µm and 98.1 ± 12.3µm; p = 0.012) and in nasal quadrant (76.2 ± 15.4µm and 66.5 ± 12.6µm; p = 0.0002). A comprehensive eye examination with corneal and optic nerve imaging showed early corneal and optic nerve changes in children newly diagnosed with OSAS. These could be prelude of the known ocular manifestations associated with OSAS in adult patients.

Quantification of Increased Corneal Subbasal Nerve Tortuosity in Dry Eye Disease and Its Correlation With Clinical Parameters.

PurposeThis study quantified corneal subbasal nerve tortuosity in dry eye disease (DED) and investigated its correlation with clinical parameters by proposing an aggregated measure of tortuosity (Tagg).MethodsThe sample consisted of 26 eyes of patients with DED and 23 eyes of healthy volunteers, which represented separately the dry eye group and the control group. Clinical evaluation of DED and in vivo confocal microscopy analysis of the central cornea were performed. Tagg incorporated six metrics of tortuosity. Corneal subbasal nerve images of subjects and a validation data set were analyzed using Tagg. Spearman's rank correlation was performed on Tagg and clinical parameters.ResultsTagg was validated using 1501 corneal nerve images. Tagg was higher in patients with DED than in healthy volunteers (P < 0.001). Tagg was positively correlated with the ocular surface disease index (r = 0.418, P = 0.003) and negatively correlated with tear breakup time (r = −0.398, P = 0.007). There was no correlation between Tagg and visual analog scale scores, corneal fluorescein staining scores, or the Schirmer I test.ConclusionsTagg was validated for quantification of corneal subbasal nerve tortuosity and was higher in patients with DED than in healthy volunteers. A higher Tagg may be linked to ocular discomfort, visual function disturbance, and tear film instability.Translational RelevanceCorneal subbasal nerve tortuosity is a potential biomarker for corneal neurobiology in DED.

Diabetic Corneal Neuropathy.

Diabetic keratopathy (DK) is a common, but underdiagnosed, ocular complication of diabetes mellitus (DM) that has a significant economic burden. It is characterised by progressive damage of corneal nerves, due to DM-induced chronic hyperglycaemia and its associated metabolic changes. With advances in corneal nerve imaging and quantitative analytic tools, studies have shown that the severity of diabetic corneal neuropathy correlates with the status of diabetic peripheral neuropathy. The corneal nerve plexus is, therefore, considered as an important surrogate marker of diabetic peripheral neuropathy and helps in the evaluation of interventional efficacy in the management of DM. The clinical manifestations of DK depend on the disease severity and vary from decreased corneal sensitivity to sight-threatening corneal infections and neurotrophic ulcers. The severity of diabetic corneal neuropathy and resultant DK determines its management plan, and a step-wise approach is generally suggested. Future work would focus on the exploration of biomarkers for diabetic corneal neuropathy, the development of new treatment for corneal nerve protection, and the improvement in the clinical assessment, as well as current imaging technique and analysis, to help clinicians detect diabetic corneal neuropathy earlier and monitor the sub-clinical progression more reliably.

Curved-field optical coherence tomography: large-field imaging of human corneal cells and nerves

Cell-resolution optical imaging methods, such as confocal microscopy and full-field optical coherence tomography, capture flat optical sections of the sample. If the sample is curved, the optical field sections through several sample layers, and the view of each layer is reduced. Here we present curved-field optical coherence tomography, capable of capturing optical sections of arbitrary curvature. We test the device on a challenging task of imaging the human cornea in vivo and achieve a 10 × larger viewing area comparing to the clinical state-of-the-art. This enables more precise cell and nerve counts, opening a path to improved monitoring of corneal and general health conditions (e.g., diabetes). The method is non-contact, compact, and works in a single fast shot (3.5 ms), making it readily available for use in optical research and clinical practice.

Automatic Tortuosity Estimation of Nerve Fibers and Retinal Vessels in Ophthalmic Images

The tortuosity changes of curvilinear anatomical organs such as nerve fibers or vessels have a close relationship with a number of diseases. Therefore, the automatic estimation and representation of the tortuosity is desired in medical image for such organs. In this paper, an automated framework for tortuosity estimation is proposed for corneal nerve and retinal vessel images. First, the weighted local phase tensor-based enhancement method is employed and the curvilinear structure is extracted from raw image. For each curvilinear structure with a different position and orientation, the curvature is measured by the exponential curvature estimation in the 3D space. Then, the tortuosity of an image is calculated as the weighted average of all the curvilinear structures. Our proposed framework has been evaluated on two corneal nerve fiber datasets and one retinal vessel dataset. Experiments on three curvilinear organ datasets demonstrate that our proposed tortuosity estimation method achieves a promising performance compared with other state-of-the-art methods in terms of accuracy and generality. In our nerve fiber dataset, the method achieved overall accuray of 0.820, and 0.734, 0.881 for sensitivity and specificity, respectively. The proposed method also achieved Spearman correlation scores 0.945 and 0.868 correlated with tortuosity grading ground truth for arteries and veins in the retinal vessel dataset. Furthermore, the manual labeled 403 corneal nerve fiber images with different levels of tortuosity, and all of them are also released for public access for further research.

In vivo imaging of corneal nerves and cellular structures in mice with Gabor-domain optical coherence microscopy.

Gabor-domain optical coherence microscopy (GDOCM) demonstrated in vivo corneal imaging with cellular resolution and differentiation in mice over a field of view of 1 mm2. Contact and non-contact imaging was conducted on six healthy and six hyperglycemic C57BL/6J mice. Cellular resolution in the 3D GDOCM images was achieved after motion correction. Corneal nerve fibers were traced and their lengths and branches calculated. Noncontact, label-free imaging of corneal nerves has clinical utility in health and disease, and in transplant evaluation. To the authors' knowledge, this is the first report of in vivo 3D corneal imaging in mice with the capability to resolve nerve fibers using a non-contact imaging modality.

Corneal Nerve and Brain Imaging in Mild Cognitive Impairment and Dementia.

Background:Visual rating of medial temporal lobe atrophy (MTA) is an accepted structural neuroimaging marker of Alzheimer’s disease. Corneal confocal microscopy (CCM) is a non-invasive ophthalmic technique that detects neuronal loss in peripheral and central neurodegenerative disorders.Objective:To determine the diagnostic accuracy of CCM for mild cognitive impairment (MCI) and dementia compared to medial temporal lobe atrophy (MTA) rating on MRI.Methods:Subjects aged 60–85 with no cognitive impairment (NCI), MCI, and dementia based on the ICD-10 criteria were recruited. Subjects underwent cognitive screening, CCM, and MTA rating on MRI.Results:182 subjects with NCI (n = 36), MCI (n = 80), and dementia (n = 66), including AD (n = 19, 28.8%), VaD (n = 13, 19.7%), and mixed AD (n = 34, 51.5%) were studied. CCM showed a progressive reduction in corneal nerve fiber density (CNFD, fibers/mm2) (32.0±7.5 versus 24.5±9.6 and 20.8±9.3, p < 0.0001), branch density (CNBD, branches/mm2) (90.9±46.5 versus 59.3±35.7 and 53.9±38.7, p < 0.0001), and fiber length (CNFL, mm/mm2) (22.9±6.1 versus 17.2±6.5 and 15.8±7.4, p < 0.0001) in subjects with MCI and dementia compared to NCI. The area under the ROC curve (95% CI) for the diagnostic accuracy of CNFD, CNBD, CNFL compared to MTA-right and MTA-left for MCI was 78% (67–90%), 82% (72–92%), 86% (77–95%) versus 53% (36–69%) and 40% (25–55%), respectively, and for dementia it was 85% (76–94%), 84% (75–93%), 85% (76–94%) versus 86% (76–96%) and 82% (72–92%), respectively.Conclusion:The diagnostic accuracy of CCM, a non-invasive ophthalmic biomarker of neurodegeneration, was high and comparable with MTA rating for dementia but was superior to MTA rating for MCI.

This issue of ACTA

This issue of ACTA

Select noxious stimuli induce changes on corneal nerve morphology.

The surface of the cornea contains the highest density of nociceptive nerves of any tissue in the body. These nerves are responsive to a variety of modalities of noxious stimuli and can signal pain even when activated by low threshold stimulation. Injury of corneal nerves can lead to altered nerve morphology, including neuropathic changes which can be associated with chronic pain. Emerging technologies that allow imaging of corneal nerves in vivo are spawning questions regarding the relationship between corneal nerve density, morphology, and function. We tested whether noxious stimulation of the corneal surface can alter nerve morphology and neurochemistry. We used concentrations of menthol, capsaicin, and hypertonic saline that evoked comparable levels of nocifensive eye wipe behaviors when applied to the ocular surface of an awake rat. Animals were sacrificed and corneal nerves were examined using immunocytochemistry and three-dimensional volumetric analyses. We found that menthol and capsaicin both caused a significant reduction in corneal nerve density as detected with β-tubulin immunoreactivity 2 hr after stimulation. Hypertonic saline did not reduce nerve density, but did cause qualitative changes in nerves including enlarged varicosities that were also seen following capsaicin and menthol stimulation. All three types of noxious stimuli caused a depletion of CGRP from corneal nerves, indicating that all modalities of noxious stimuli evoked peptide release. Our findings suggest that studies aimed at understanding the relationship between corneal nerve morphology and chronic disease may also need to consider the effects of acute stimulation on corneal nerve morphology.