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Aim: To assess if latent autoimmune diabetes of adulthood (LADA) is associated with small fibre neuropathy. Methods: Participants with LADA (n=31), Type 2 diabetes (n=31) and healthy control participants without diabetes (n=31) underwent a detailed assessment of neurologic deficits, quantitative sensory testing, electrophysiology, skin biopsy and corneal confocal microscopy. Results: The groups were matched for age (healthy control without diabetes: 53.5±9.1 vs. Type 2 diabetes: 58.0±6.5 vs. LADA: 53.2±11.6 years), duration of diabetes (Type 2 diabetes: 10.0±8.3 vs. LADA: 11.0±9.1 years) and blood pressure. However, BMI (P=0.01) and triglycerides (P=0.0008) were lower and HbA1c (P=0.0005), total cholesterol (P=0.01) and HDL (P=0.002) were higher in participants with LADA compared with Type 2 diabetes. Peroneal motor nerve conduction velocity (P=0.04) and sural sensory nerve conduction velocity (P=0.008) were lower in participants with latent autoimmune diabetes in adults compared with Type 2 diabetes. Intra‐epidermal nerve fibre density (P=0.008), corneal nerve fibre density (P=0.003) and corneal nerve branch density (P=0.006) were significantly lower in participants with LADA compared with Type 2 diabetes. There were no significant differences in the other neuropathy parameters. Conclusions: Despite comparable age and duration of diabetes, participants with LADA demonstrate more severe neuropathy and particularly small fibre neuropathy, compared with participants with Type 2 diabetes. What's new?: Treatment inertia in latent autoimmune diabetes of adulthood (LADA) leads to a prolonged period of poor glycaemic control, which may lead to complications.We demonstrate an excess of small fibre neuropathy in a cohort of patients with LADA compared with age‐ and diabetes duration‐matched people with Type 2 diabetes.Small fibre neuropathy can be diagnosed comparably using corneal confocal microscopy or skin biopsy, further supporting the utility of corneal confocal microscopy as a valid method to screen for diabetic neuropathy in at risk populations. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy is the most common cause of vision loss in people with diabetes mellitus; however, other causes of visual impairment/loss include other retinal and non-retinal visual problems, including glaucoma, age-related macular degeneration, non-arteritic anterior ischaemic optic neuropathy and cataracts. Additionally, when a person with diabetes complains of visual disturbance despite a visual acuity of 6/6, abnormalities in refraction, contrast sensitivity, straylight and amplitude of accommodation should be considered. We review and highlight these visual problems for physicians who manage people with diabetes to ensure timely referral and treatment to limit visual disability, which can have a significant impact on daily living, especially for those participating in sports and driving. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether corneal nerve analysis can identify and differentiate patients with multiple sclerosis (MS) from those with epilepsy., Methods: Participants with MS (n = 83), participants with epilepsy (n = 50), and healthy controls (HCs) (n = 20) underwent corneal confocal microscopy (CCM) and quantification of automated corneal nerve fiber length (ACNFL), automated corneal nerve fractal dimension (ACNFrD), and ACNFrD/ACNFL ratio of the subbasal nerve plexus., Results: ACNFL (MS: P < 0.0001; epilepsy: P = 0.002) and ACNFrD (MS: P < 0.0001; epilepsy: P = 0.025) were significantly lower and the ACNFrD/ACNFL ratio (MS: P < 0.0001; epilepsy: P = 0.018) was significantly higher compared to HCs. ACNFL (P = 0.001), ACNFrD (P = 0.0003), and ACNFrD/ACNFL ratio (P = 0.006) were significantly lower in patients with MS compared to those with epilepsy. ACNFL had the highest diagnostic utility for identifying patients with MS (sensitivity/specificity 0.86/0.85, area under the curve [AUC] 0.90, P < 0.0001), and ACNFrD had the highest diagnostic utility for identifying patients with epilepsy (sensitivity/specificity 0.78/0.75, AUC 0.76, P = 0.0008). ACNFrD had the highest diagnostic utility for differentiating patients with MS from epilepsy (sensitivity/specificity 0.66/0.65, AUC 0.70, <0.0001)., Conclusions: Corneal neurodegeneration occurs in and is characterized by a distinct pattern that differentiates patients with MS and epilepsy., Translational Relevance: CCM identifies and differentiates patients with MS and epilepsy, albeit with moderate performance. Further validation, with a larger sample size, is needed.

Aim: Obesity is a major risk factor for diabetic peripheral neuropathy (DPN) in type 2 diabetes (T2D). This study investigated the effect of glucose lowering medication associated with weight change on DPN., Methods: Participants with T2D were grouped based on whether their glucose lowering medications were associated with weight gain (WG) or weight loss (WL). They underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function and corneal confocal microscopy (CCM) at baseline and follow-up between 4 and 7 years., Results: Of 76 participants, 69.7% were on glucose lowering medication associated with WG, and 30.3% were on glucose lowering medication associated with WL. At baseline, participants in the WG group had a significantly longer duration of diabetes (p < .01), higher douleur neuropathique en 4 (DN4) score (p < .0001) and VPT (p = .01) compared with those in the WL group. Over a 56-month period, participants in the WG group showed no significant change in body weight (p = .11), HbA1c (p = .18), triglycerides (p = .42), DN4 (p = .11), VPT (p = .15) or Sudoscan (p = .43), but showed a decline in corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) (p < .0001). Participants in the WL group showed a reduction in weight (p = .01) and triglycerides (p < .05), no change in DN4 (p = .30), VPT (p = .31) or Sudoscan (p = .17) and a decline in the corneal nerve branch density (p < .01)., Conclusions: Participants treated with glucose lowering medication associated with weight gain had worse neuropathy and greater loss of corneal nerves during follow-up, compared to patients treated with medication associated with weight loss., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Background/aim: Obesity and related metabolic abnormalities in adults are associated with peripheral neuropathy. Acanthosis nigricans (AN) is associated with insulin resistance, fatty liver, hyperlipidemia and glucose intolerance, all of which are risk factors for neuropathy. The aim of this study was to investigate if obese adolescents with AN have evidence of small nerve fiber damage., Material and Methods: Adolescents with obesity with and without AN underwent body composition analysis, assessment of vibration perception threshold (VPT), monofilament sensitivity and corneal confocal microscopy (CCM) to quantify corneal nerve fiber density (CNFD), branch density (CNBD), length (CNFL) and inferior whorl length (IWL)., Results: Forty-six participants with obesity with (n = 31) and without (n = 15) AN aged 15(14-17) years were compared to 20 healthy controls aged 13(12-14) years. There was no difference in VPT, monofilament sensitivity and CCM measures between adolescents with obesity and controls. However, adolescents with AN had a significantly higher weight (P = 0.022), fat% (P = 0.029) and fat-muscle ratio (P = 0.012) with a lower CNFD (P = 0.045) compared to those with obesity without AN., Conclusion: Adolescents with obesity and acanthosis nigricans have a higher fat mass and small nerve fibre loss, indicative of a sub-clinical neuropathy., Competing Interests: NO authors have competing interests., (Copyright: © 2024 Gad et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: This study was undertaken to investigate whether sustained rather than a single measure of corneal nerve loss was associated with the onset of diabetic peripheral neuropathy (DPN) and the progression of neuropathic symptoms and deficits in individuals with type 2 diabetes (T2D)., Methods: Participants underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function, and corneal confocal microscopy (CCM) at baseline, 1, 2, and 4-7 years. Sustained corneal nerve loss was defined as abnormal corneal nerve fiber density (CNFD, <24 fibers/mm 2 ), corneal nerve branch density (CNBD, <21 branches/mm 2 ), and corneal nerve fiber length (CNFL, <16 mm/mm 2 ) persisting for ≥50% of the study duration., Results: A total of 107 participants with a mean duration of T2D of 13.3 ± 7.3 years, aged 54.8 ± 8.5 years, underwent baseline and follow-up assessments over a median duration of 4 years, ranging from 1 to 7 years. The DPN prevalence at baseline was 18/107 (16.8%), and of the 89 participants without DPN at baseline, 13 (14.6%) developed DPN during follow-up. Approximately half of the cohort had sustained corneal nerve damage, and corneal nerve measures were significantly lower in this group than those without sustained damage ( p  < 0.0001). Sustained corneal nerve damage was associated with the development of DPN ( p  < 0.0001), a progressive loss of vibration perception ( p  ≤ 0.05), an increased incidence of burning pain, numbness, or a combination of both ( p  = 0.01-0.001), and a borderline association with progressive sudomotor dysfunction ( p  = 0.07). Sustained abnormal CNFL effectively distinguished between participants who developed DPN and those who did not (AUC: 76.3, 95% CI: 65.9-86.8%, p  < 0.0001), while baseline and other sustained measures did not predict DPN onset., Conclusion: Sustained abnormal CCM is associated with more severe corneal nerve damage, DPN development, and the progression of neuropathic symptoms and deficits. Regular CCM monitoring may enable the identification of those at greater risk of developing and worsening DPN who may benefit from more aggressive risk factor reduction., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ponirakis, Al-Janahi, Elgassim, Homssi, Petropoulos, Gad, Khan, Zaghloul, Ali, Siddique, Mohamed, Ahmed, Dakroury, El Shewehy, Saeid, Mahjoub, Al-Thani, Ahmed, Hussein, Mahmoud, Hadid, Al Obaidan, Salivon, Mahfoud, Zirie, Al-Ansari, Atkin and Malik.)

Corneal confocal microscopy (CCM) is an ophthalmic imaging technique that enables the identification of corneal nerve fibre degeneration and regeneration. To undertake a systematic review and meta-analysis of studies utilizing CCM to assess for corneal nerve regeneration after pharmacological and surgical interventions in patients with peripheral neuropathy. Databases (EMBASE [Ovid], PubMed, CENTRAL and Web of Science) were searched to summarize the evidence from randomized and non-randomized studies using CCM to detect corneal nerve regeneration after pharmacological and surgical interventions. Data synthesis was undertaken using RevMan web. Eighteen studies including 958 patients were included. CCM identified an early (1-8 months) and longer term (1-5 years) increase in corneal nerve measures in patients with peripheral neuropathy after pharmacological and surgical interventions. This meta-analysis confirms the utility of CCM to identify nerve regeneration following pharmacological and surgical interventions. It could be utilized to show a benefit in clinical trials of disease modifying therapies for peripheral neuropathy., (© 2024 The Author(s). Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Diabetes is recognized as a risk factor for cognitive decline, but the underlying mechanisms remain elusive. We aimed to identify the metabolic pathways altered in diabetes-associated cognitive decline (DACD) using untargeted metabolomics. We conducted liquid chromatography-mass spectrometry-based untargeted metabolomics to profile serum metabolite levels in 100 patients with type 2 diabetes (T2D) (54 without and 46 with DACD). Multivariate statistical tools were used to identify the differentially expressed metabolites (DEMs), and enrichment and pathways analyses were used to identify the signaling pathways associated with the DEMs. The receiver operating characteristic (ROC) analysis was employed to assess the diagnostic accuracy of a set of metabolites. We identified twenty DEMs, seven up- and thirteen downregulated in the DACD vs. DM group. Chemometric analysis revealed distinct clustering between the two groups. Metabolite set enrichment analysis found significant enrichment in various metabolite sets, including galactose metabolism, arginine and unsaturated fatty acid biosynthesis, citrate cycle, fructose and mannose, alanine, aspartate, and glutamate metabolism. Pathway analysis identified six significantly altered pathways, including arginine and unsaturated fatty acid biosynthesis, and the metabolism of the citrate cycle, alanine, aspartate, glutamate, a-linolenic acid, and glycerophospholipids. Classifier models with AUC-ROC > 90% were developed using individual metabolites or a combination of individual metabolites and metabolite ratios. Our study provides evidence of perturbations in multiple metabolic pathways in patients with DACD. The distinct DEMs identified in this study hold promise as diagnostic biomarkers for DACD patients.

Aims: To assess sensory neuropathy development after severe COVID-19., Methods: Patients with severe COVID-19 underwent assessment of neuropathic symptoms, tendon reflexes, and quantitative sensory testing to evaluate vibration (VPT), cold (CPT), warm (WPT) and heat perception thresholds (HPT) within 1-3 weeks of admission and after 1-year., Results: 32 participants with severe COVID-19 aged 68.6 ± 12.4 (18.8 % diabetes) were assessed. At baseline, numbness and neuropathic pain were present in 56.3 % and 43.8 % of participants, respectively. On the feet, VPT, WPT, and HPT were abnormal in 81.3 %, CPT was abnormal in 50.0 % and HPT on the face was abnormal in 12.5 % of patients. At 1-year follow-up, the prevalence of abnormal VPT (81.3 % vs 50.0 %, P < 0.01), WPT (81.3 % vs 43.8 %, P < 0.01), and HPT (81.3 % vs 50.0 %, P < 0.01) decreased, with no change in CPT (P = 0.21) on the feet or HPT on the face (P = 1.0). Only participants without diabetes recovered from an abnormal VPT, CPT, and WPT. Patients with long-COVID (37.5 %) had comparable baseline VPT, WPT and CPT with those without long-COVID (P = 0.07-0.69)., Conclusions: Severe COVID-19 is associated with abnormal vibration and thermal thresholds which are sustained for up to 1 year in patients with diabetes. Abnormal sensory thresholds have no association with long-COVID development., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Phi Med Europe S.L. provided the NerveCheck Master device and funded the study. M.N. Odriozola, S. Odriozola, M.B. Odriozola and A. Odriozola are the owners and inventors of the NerveCheck Master. We declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship and are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us., (Copyright © 2023. Published by Elsevier B.V.)

Background: Dementia is a debilitating neurological disease affecting millions of people worldwide. The exact mechanisms underlying the initiation and progression of the disease remain to be fully defined. There is an increasing body of evidence for the role of immune dysregulation in the pathogenesis of dementia, where blood-borne autoimmune antibodies have been studied as potential markers associated with pathological mechanisms of dementia., Methods: This study included plasma from 50 cognitively normal individuals, 55 subjects with MCI (mild cognitive impairment), and 22 subjects with dementia. Autoantibody profiling for more than 1,600 antigens was performed using a high throughput microarray platform to identify differentially expressed autoantibodies in MCI and dementia., Results: The differential expression analysis identified 33 significantly altered autoantibodies in the plasma of patients with dementia compared to cognitively normal subjects, and 38 significantly altered autoantibodies in the plasma of patients with dementia compared to subjects with MCI. And 20 proteins had significantly altered autoantibody responses in MCI compared to cognitively normal individuals. Five autoantibodies were commonly dysregulated in both dementia and MCI, including anti-CAMK2A, CKS1B, ETS2, MAP4, and NUDT2. Plasma levels of anti-ODF3, E6, S100P, and ARHGDIG correlated negatively with the cognitive performance scores (MoCA) ( r 2 -0.56 to -0.42, value of p < 0.001). Additionally, several proteins targeted by autoantibodies dysregulated in dementia were significantly enriched in the neurotrophin signaling pathway, axon guidance, cholinergic synapse, long-term potentiation, apoptosis, glycolysis and gluconeogenesis., Conclusion: We have shown multiple dysregulated autoantibodies in the plasma of subjects with MCI and dementia. The corresponding proteins for these autoantibodies are involved in neurodegenerative pathways, suggesting a potential impact of autoimmunity on the etiology of dementia and the possible benefit for future therapeutic approaches. Further investigations are warranted to validate our findings., Competing Interests: KL and JB were employed by Sengenics Corporation. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ehtewish, Mesleh, Ponirakis, Lennard, Al Hamad, Chandran, Parray, Abdesselem, Wijten, Decock, Alajez, Ramadan, Khan, Ayadathil, Own, Elsotouhy, Albagha, Arredouani, Blackburn, Malik and El-Agnaf.)

Background: Corneal immune cells (ICs) are antigen-presenting cells that are known to increase ocular and systemic inflammatory conditions., Objective: We aimed to assess longitudinal changes in corneal IC in patients with multiple sclerosis (MS) and relation to disability and ongoing treatment., Design: Prospective observational study conducted between September 2016 and February 2020., Methods: Patients with relapsing-remitting MS (RRMS) ( n  = 45) or secondary progressive MS (SPMS) ( n  = 15) underwent corneal confocal microscopy (CCM) at baseline and 2-year follow-up for estimation of corneal IC density [dendritic cells with (DCF) (cells/mm 2 ) or without nerve fiber contact (DCP); and non-dendritic cells with (NCF) or without nerve fiber contact (NCP)]. Optical coherence tomography, neuroimaging, and disability assessments were additionally performed. Healthy controls ( n  = 20) were assessed at baseline., Results: In both RRMS and SPMS compared to controls, DCP ( p  < 0.001 and p  < 0.001, respectively) and DCF ( p  < 0.001 and p  = 0.005) were higher and NCF ( p  = 0.007 and p  = 0.02) was lower at baseline. DCP showed excellent performance in identifying patients with MS (sensitivity/specificity = 0.88/0.90) followed by DCF (0.80/0.75) and NCF (0.80/0.85). At follow-up compared to baseline, DCP ( p  = 0.01) was significantly reduced, and NCP ( p  = 0.004) and NCF ( p  = 0.04) were increased. Subgroup analysis showed that baseline NCP and NCF were significantly higher ( p  = 0.04-0.05) in patients who switched disease-modifying treatment, and baseline NCP ( p  = 0.05) was higher in patients on interferon., Conclusion: Baseline and change in corneal IC were related to axonal degeneration and treatment status. Evaluation of corneal IC using CCM may allow an assessment of ongoing inflammation, disease progression, and the effect of treatment in MS., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)

Autism spectrum disorder (ASD) is a developmental disorder characterized by difficulty in communication and interaction with others. Postmortem studies have shown cerebral neuronal loss and neuroimaging studies show neuronal loss in the amygdala, cerebellum and inter-hemispheric regions of the brain. Recent studies have shown altered tactile discrimination and allodynia on the face, mouth, hands and feet and intraepidermal nerve fiber loss in the legs of subjects with ASD. Fifteen children with ASD (age: 12.00 ± 3.55 years) and twenty age-matched healthy controls (age: 12.83 ± 1.91 years) underwent corneal confocal microscopy (CCM) and quantification of corneal nerve fiber morphology. Corneal nerve fibre density (fibers/mm2) (28.61 ± 5.74 vs. 40.42 ± 8.95, p = 0.000), corneal nerve fibre length (mm/mm2) (16.61 ± 3.26 vs. 21.44 ± 4.44, p = 0.001), corneal nerve branch density (branches/mm2) (43.68 ± 22.71 vs. 62.39 ± 21.58, p = 0.018) and corneal nerve fibre tortuosity (0.037 ± 0.023 vs. 0.074 ± 0.017, p = 0.000) were significantly lower and inferior whorl length (mm/mm2) (21.06 ± 6.12 vs. 23.43 ± 3.95, p = 0.255) was comparable in children with ASD compared to controls. CCM identifies central corneal nerve fiber loss in children with ASD. These findings, urge the need for larger longitudinal studies to determine the utility of CCM as an imaging biomarker for neuronal loss in different subtypes of ASD and in relation to disease progression., Competing Interests: NO authors have competing interests, (Copyright: © 2023 Khan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Having lived through a pandemic and witnessed how regulatory approval processes can evolve rapidly; it is lamentable how we continue to rely on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN., Areas Covered: Small (Aδ and C) fibers are key to the genesis of pain, regulate skin blood flow, and play an integral role in the development of diabetic foot ulceration but continue to be ignored. This article challenges the rationale for the FDA insisting on symptoms/signs and nerve conduction as primary endpoints for clinical trials in DPN., Expert Opinion: Quantitative sensory testing, intraepidermal nerve fiber density, and especially corneal confocal microscopy remain an after-thought, demoted at best to exploratory secondary endpoints in clinical trials of diabetic neuropathy. If pharma are to be given a fighting chance to secure approval for a new therapy for diabetic neuropathy, the FDA needs to reassess the evidence rather than rely on 'opinion' for the most suitable endpoint(s) in clinical trials of diabetic neuropathy.

Aim: Cardiac autonomic neuropathy (CAN) has been suggested to be associated with hypoglycemia and impaired hypoglycemia unawareness. We have assessed the relationship between CAN and extensive measures of glucose variability (GV) in patients with type 1 and type 2 diabetes., Methods: Participants with diabetes underwent continuous glucose monitoring (CGM) to obtain measures of GV and the extent of hyperglycemia and hypoglycemia and cardiovascular autonomic reflex testing., Results: Of the 40 participants (20 T1DM and 20 T2DM) (aged 40.70 ± 13.73 years, diabetes duration 14.43 ± 7.35 years, HbA1c 8.85 ± 1.70%), 23 (57.5%) had CAN. Despite a lower coefficient of variation (CV) (31.26 ± 11.87 vs. 40.33 ± 11.03, P = 0.018), they had a higher CONGA (8.42 ± 2.58 vs. 6.68 ± 1.88, P = 0.024) with a lower median LBGI (1.60 (range: 0.20-3.50) vs. 4.90 (range: 3.20-7.40), P = 0.010) and percentage median time spent in hypoglycemia (4 (range:4-13) vs. 1 (range:0-5), P = 0.008), compared to those without CAN. The percentage GRADE Euglycemia (3.30 ± 2.78 vs. 5.69 ± 3.09, P = 0.017) and GRADE Hypoglycemia (0.3 (range: 0 - 3.80) vs. 1.8 (range: 0.9-6.5), P = 0.036) were significantly lower, while the percentage median GRADE Hyperglycemia (95.45 (range:93-98) vs. 91.6 (82.8-95.1), P = 0.013) was significantly higher in participants with CAN compared to those without CAN., Conclusion: CAN was associated with increased glycemic variability with less time in euglycemia attributed to a greater time in hyperglycemia but not hypoglycemia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Dementia is a progressive and debilitating neurological disease that affects millions of people worldwide. Identifying the minimally invasive biomarkers associated with dementia that could provide insights into the disease pathogenesis, improve early diagnosis, and facilitate the development of effective treatments is pressing. Proteomic studies have emerged as a promising approach for identifying the protein biomarkers associated with dementia. This pilot study aimed to investigate the plasma proteome profile and identify a panel of various protein biomarkers for dementia. We used a high-throughput proximity extension immunoassay to quantify 1090 proteins in 122 participants (22 with dementia, 64 with mild cognitive impairment (MCI), and 36 controls with normal cognitive function). Limma-based differential expression analysis reported the dysregulation of 61 proteins in the plasma of those with dementia compared with controls, and machine learning algorithms identified 17 stable diagnostic biomarkers that differentiated individuals with AUC = 0.98 ± 0.02. There was also the dysregulation of 153 plasma proteins in individuals with dementia compared with those with MCI, and machine learning algorithms identified 8 biomarkers that classified dementia from MCI with an AUC of 0.87 ± 0.07. Moreover, multiple proteins selected in both diagnostic panels such as NEFL, IL17D, WNT9A, and PGF were negatively correlated with cognitive performance, with a correlation coefficient (r 2 ) ≤ -0.47. Gene Ontology (GO) and pathway analysis of dementia-associated proteins implicated immune response, vascular injury, and extracellular matrix organization pathways in dementia pathogenesis. In conclusion, the combination of high-throughput proteomics and machine learning enabled us to identify a blood-based protein signature capable of potentially differentiating dementia from MCI and cognitively normal controls. Further research is required to validate these biomarkers and investigate the potential underlying mechanisms for the development of dementia.

Objectives: This study compared the utility of corneal nerve measures with brain volumetry for predicting progression to dementia in individuals with mild cognitive impairment (MCI)., Methods: Participants with no cognitive impairment (NCI) and MCI underwent assessment of cognitive function, brain volumetry of thirteen brain structures, including the hippocampus and corneal confocal microscopy (CCM). Participants with MCI were followed up in the clinic to identify progression to dementia., Results: Of 107 participants with MCI aged 68.4 ± 7.7 years, 33 (30.8%) progressed to dementia over 2.6-years of follow-up. Compared to participants with NCI (n = 12), participants who remained with MCI (n = 74) or progressed to dementia had lower corneal nerve measures (p < 0.0001). Progressors had lower corneal nerve measures, hippocampal, and whole brain volume (all p < 0.0001). However, CCM had a higher prognostic accuracy (72%-75% vs 68%-69%) for identifying individuals who progressed to dementia compared to hippocampus and whole brain volume. The adjusted odds ratio for progression to dementia was 6.1 (95% CI: 1.6-23.8) and 4.1 (95% CI: 1.2-14.2) higher with abnormal CCM measures, but was not significant for abnormal brain volume., Interpretation: Abnormal CCM measures have a higher prognostic accuracy than brain volumetry for predicting progression from MCI to dementia. Further work is required to validate the predictive ability of CCM compared to other established biomarkers of dementia., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Resourceful endpoints of axonal loss are needed to predict the course of multiple sclerosis (MS). Corneal confocal microscopy (CCM) can detect axonal loss in patients with clinically isolated syndrome and established MS, which relates to neurological disability., Objective: To assess corneal axonal loss over time in relation to retinal atrophy, and neurological and radiological abnormalities in MS., Methods: Patients with relapsing-remitting (RRMS) ( n  = 68) or secondary progressive MS (SPMS) ( n  = 15) underwent CCM and optical coherence tomography. Corneal nerve fibre density (CNFD-fibres/mm 2 ), corneal nerve branch density (CNBD-branches/mm 2 ), corneal nerve fibre length (CNFL-mm/mm 2 ) and retinal nerve fibre layer (RNFL-μm) thickness were quantified along with neurological and radiological assessments at baseline and after 2 years of follow-up. Age-matched, healthy controls ( n  = 20) were also assessed., Results: In patients with RRMS compared with controls at baseline, CNFD ( p  = 0.004) and RNFL thickness ( p  < 0.001) were lower, and CNBD ( p  = 0.003) was higher. In patients with SPMS compared with controls, CNFD ( p  < 0.001), CNFL ( p  = 0.04) and RNFL thickness ( p  < 0.001) were lower. For identifying RRMS, CNBD had the highest area under the receiver operating characteristic (AUROC) curve (0.99); and for SPMS, CNFD had the highest AUROC (0.95). At follow-up, there was a further significant decrease in CNFD ( p  = 0.04), CNBD ( p  = 0.001), CNFL ( p  = 0.008) and RNFL ( p  = 0.002) in RRMS; in CNFD ( p  = 0.04) and CNBD ( p  = 0.002) in SPMS; and in CNBD ( p  = 0.01) in SPMS compared with RRMS. Follow-up corneal nerve loss was greater in patients with new enhancing lesions and optic neuritis history., Conclusion: Progressive corneal and retinal axonal loss was identified in patients with MS, especially those with more active disease. CCM may serve as an imaging biomarker of axonal loss in MS., Competing Interests: The authors declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: Drs Ioannis N. Petropoulos, Fatima Al-Shibani, Gulfidan Bitirgen, Georgios Ponirakis, Adnan Khan, Hoda Gad, Ziyad R. Mahfoud, Heba Altarawneh, Muhammad Hassan Rehman, Karen John, Dhabia Al-Merekhi, Pooja George, Ali Ulvi Uca, Ahmet Ozkagnici, Faiza Ibrahim, Reny Francis, Beatriz Canibano, Dirk Deleu, Ahmed El-Sotouhy, Surjith Vattoth, Ahmed Own, Ashfaq Shuaib, Naveed Akhtar and Saadat Kamran declare no conflict of interest. Dr. Rayaz A. Malik is a principal investigator on grants from Proctor and Gamble and Pfizer and has received consulting honoraria for serving on advisory boards for Novo Nordisk, Aventis Pharma, and Proctor and Gamble., (© The Author(s), 2023.)

Background/aims: Long COVID is characterised by a range of potentially debilitating symptoms which develop in at least 10% of people who have recovered from acute SARS-CoV-2 infection. This study has quantified corneal sub-basal nerve plexus morphology and dendritic cell (DC) density in patients with and without long COVID., Methods: Forty subjects who had recovered from COVID-19 and 30 control participants were included in this cross-sectional comparative study undertaken at a university hospital. All patients underwent assessment with the National Institute for Health and Care Excellence (NICE) long COVID, Douleur Neuropathique 4 (DN4) and Fibromyalgia questionnaires, and corneal confocal microscopy (CCM) to quantify corneal nerve fibre density (CNFD), corneal nerve branch density (CNBD), corneal nerve fibre length (CNFL), and total, mature and immature DC density., Results: The mean time after the diagnosis of COVID-19 was 3.7±1.5 months. Patients with neurological symptoms 4 weeks after acute COVID-19 had a lower CNFD (p=0.032), CNBD (p=0.020), and CNFL (p=0.012), and increased DC density (p=0.046) compared with controls, while patients without neurological symptoms had comparable corneal nerve parameters, but increased DC density (p=0.003). There were significant correlations between the total score on the NICE long COVID questionnaire at 4 and 12 weeks with CNFD (ρ=-0.436; p=0.005, ρ=-0.387; p=0.038, respectively) and CNFL (ρ=-0.404; p=0.010, ρ=-0.412; p=0.026, respectively)., Conclusion: Corneal confocal microscopy identifies corneal small nerve fibre loss and increased DCs in patients with long COVID, especially those with neurological symptoms. CCM could be used to objectively identify patients with long COVID., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Continuous glucose monitoring (CGM) has revealed that glycemic variability and low time in range are associated with albuminuria and retinopathy. We have investigated the relationship between glucose metrics derived from CGM and a highly sensitive measure of neuropathy using corneal confocal microscopy in participants with type 1 and type 2 diabetes., Methods: A total of 40 participants with diabetes and 28 healthy controls underwent quantification of corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL) and inferior whorl length (IWL) and those with diabetes underwent CGM for four consecutive days., Results: CNBD was significantly lower in patients with high glycemic variability (GV) compared to low GV (median (range) (25.0 (19.0-37.5) vs 38.6 (29.2-46.9); P = 0.007); in patients who spent >4% compared to <4% time in level 1 hypoglycemia (54-69 mg/dL) (25.0 (22.9-37.5) vs 37.5 (29.2-46.9); P = 0.045) and in patients who spent >1% compared to <1% time in level 2 hypoglycemia (<54 mg/dL) (25.0 (19.8-41.7) vs 35.4 (28.1-44.8); P = 0.04). Duration in level 1 hypoglycemia correlated with CNBD (r = -0.342, P = 0.031). Duration in level 1 (181-250 mg/dL) and level 2 (>250 mg/dL) hyperglycemia did not correlate with CNFD (P > 0.05), CNBD (P > 0.05), CNFL (P > 0.05) or IWL (P > 0.05)., Conclusions: Greater GV and duration in hypoglycemia, rather than hyperglycemia, are associated with nerve fiber loss in diabetes.

Celiac disease (CeD) is a common small bowel enteropathy characterized by an altered adaptive immune system and increased mucosal antigen presenting cells. This study aims to establish if quantification of corneal Langerhans cells (LCs) using corneal confocal microscopy (CCM) could act as a surrogate marker for antigen presenting cell status and hence disease activity in children with CeD. Twenty children with stable CeD and 20 age-matched controls underwent CCM and quantification of central corneal total, mature and immature LC density. There was no difference in age (11.78 ± 1.7 vs. 12.83 ± 1.91; P = 0.077) or height (1.38 ± 0.14 vs. 1.44 ± 0.13; P = 0.125). BMI (18.81 ± 3.90 vs. 22.26 ± 5.47; P = 0.031) and 25 OHD levels (43.50 ± 13.36 vs. 59.77 ± 22.45; P = 0.014) were significantly lower in children with CeD compared to controls. The total (33.33(16.67-59.37) vs. 51.56(30.21-85.42); P = 0.343), immature (33.33(16.67-52.08) vs. 44.79(29.17-82.29); P = 0.752) and mature (1.56(0-5) vs. 1.56(1.04-8.33); P = 0.752) LC density did not differ between the CeD and control groups. However, immature (r = 0.535, P = 0.015), mature (r = 0.464, P = 0.039), and total (r = 0.548, P = 0.012) LC density correlated with age. Immature (r = 0.602, P = 0.038) and total (r = 0.637, P = 0.026) LC density also correlated with tissue transglutaminase antibody (Anti-TtG) levels assessed in 12/20 subjects with CeD. There was no difference in corneal LC density between children with CeD and controls. However, the correlation between corneal LC density and anti-TtG levels suggests a relationship with disease activity in CeD and requires further study., (© 2022. The Author(s).)

Purpose: To assess whether alterations in stromal keratocyte density are related to loss of corneal nerve fibres in children with type 1 diabetes mellitus (T1DM)., Methods: Twenty participants with T1DM and 20 age-matched healthy controls underwent corneal confocal microscopy. Corneal sub-basal nerve morphology and corneal keratocyte density (KD) were quantified., Results: Corneal nerve fibre density (CNFD) (p<0.001), corneal nerve branch density (p<0.001), corneal nerve fibre length (CNFL) (p<0.001) and inferior whorl length (IWL) (p<0.001) were lower in children with T1DM compared with healthy controls. Anterior (p<0.03) and mid (p=0.03) stromal KDs were lower with no difference in posterior KD (PKD) in children with T1DM compared with controls. Age, duration of diabetes, height, weight and body mass index did not correlate with anterior (AKD), mid (MKD) or PKD. Inverse correlations were found between glycated haemoglobin and PKD (r=-0.539, p=0.026), bilirubin with MKD (r=-0.540, p=0.025) and PKD (r=-0.531, p=0.028) and 25-hydroxycholecalciferol with MKD (r=-0.583, p=0.018). CNFD, CNFL and IWL did not correlate with AKD, MKD or PKD., Conclusion: This study demonstrates a reduction in corneal nerves and anterior and mid stromal KD in children with T1DM, but no correlation between corneal nerve and keratocyte cell loss., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/introduction: Limited studies have identified risk factors linked to the progression of diabetic peripheral neuropathy (DPN) in type 2 diabetes. This study examined the association of risk factors with change in neuropathy measures over 2 years., Materials and Methods: Participants with type 2 diabetes (n = 78) and controls (n = 26) underwent assessment of clinical and metabolic parameters and neuropathy using corneal confocal microscopy (CCM), vibration perception threshold (VPT), and the DN4 questionnaire at baseline and 2 year follow-up., Results: Participants with type 2 diabetes had a lower corneal nerve fiber density (CNFD), branch density (CNBD), and fiber length (CNFL) (P ≤ 0.0001) and a higher VPT (P ≤ 0.01) compared with controls. Over 2 years, despite a modest reduction in HbA1c (P ≤ 0.001), body weight (P ≤ 0.05), and LDL (P ≤ 0.05) the prevalence of DPN (P = 0.28) and painful DPN (P = 0.21) did not change, but there was a significant further reduction in CNBD (P ≤ 0.0001) and CNFL (P ≤ 0.05). CNFD, CNBD, and CNFL decreased significantly in physically inactive subjects (P < 0.05-0.0001), whilst there was no change in CNFD (P = 0.07) or CNFL (P = 0.85) in physically active subjects. Furthermore, there was no change in CNFD (P = 0.82), CNBD (P = 0.08), or CNFL (P = 0.66) in patients treated with glucose lowering medication associated with weight loss, whilst CNBD (P = 0.001) decreased in patients on glucose lowering medication associated with weight gain., Conclusions: In participants with type 2 diabetes, despite a modest improvement in HbA1c, body weight, and LDL there was a progressive loss of corneal nerve fibers; except in those who were physically active or on glucose lowering medication associated with weight loss., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: This study determined the prevalence and risk factors for diabetic peripheral neuropathy (DPN), painful DPN and diabetic foot ulceration (DFU) in patients with type 2 diabetes in secondary healthcare in Qatar, Kuwait and the Kingdom of Saudi Arabia., Materials and Methods: Adults aged 18-85 years with type 2 diabetes were randomly enrolled from secondary healthcare, and underwent clinical and metabolic assessment. DPN was evaluated using vibration perception threshold and neuropathic symptoms and painful Diabetic Peripheral Neuropathy was evaluated using the Douleur Neuropathique 4 questionnaire., Results: A total of 3,021 individuals were recruited between June 2017 and May 2019. The prevalence of DPN was 33.3%, of whom 52.2% were at risk of DFU and 53.6% were undiagnosed. The prevalence of painful DPN was 43.3%, of whom 54.3% were undiagnosed. DFU was present in 2.9%. The adjusted odds ratios for DPN and painful DPN were higher with increasing diabetes duration, obesity, poor glycemic control and hyperlipidemia, and lower with greater physical activity. The adjusted odds ratio for DFU was higher with the presence of DPN, severe loss of vibration perception, hypertension and vitamin D deficiency., Conclusions: This is the largest study to date from the Middle East showing a high prevalence of undiagnosed DPN, painful DPN and those at risk of DFU in patients with type 2 diabetes, and identifies their respective risk factors., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Hypertriglyceridemia has been identified as a risk factor for diabetic neuropathy., Objective: Patients with hypertriglyceridemia underwent assessment of neuropathy and corneal confocal microscopy., Methods: 24 patients with severe hypertriglyceridemia defined as a triglyceride level more than 5.5 mmol/L (485 mg/dL) with no history of diabetes and 19 age-matched controls underwent assessment of HbA1c, blood pressure, fasting lipid profile, neuropathy disability score (NDS) and corneal confocal microscopy (CCM)., Results: Patients with hypertriglyceridemia had a significantly higher NDS (P<0.001) and lower CNFD (no./mm 2 ) (27.1 [25.0-29.9] Vs 35.9 [31.2-40.6], p<0.001), CNBD (no./mm 2 ) (55.4±22.3 Vs 91.6±30.8, p<0.001), CNFL (mm/mm 2 ) (19.2±4.3 Vs 26.7±4.4, p<0.001) and IWL (mm/mm 2 ) (24.3±6.9 Vs 36.6±10.0, p<0.001) compared to control subjects. In subjects with hypertriglyceridemia serum triglyceride levels correlated with CNFD (rho= -0.473, p=0.002), CNBD (rho= -0.341, p=0.043), CNFL (rho= -0.446, p=0.006) and IWL (rho= -0.408, p=0.034), no correlation was found between triglycerides and CCM parameters in subjects without hypertriglyceridemia. Subjects with metabolic syndrome had a lower CNFD (32.3 [29.2-37.5] Vs 27.1 [20.8-30.2] no./mm 2 , p=0.003), CNBD (20.1±6.0 Vs 23.9±5.3 no./mm 2 , p=0.036), CNFL (57.7±26.9 Vs 79.2±32.6 mm/mm 2 , p=0.037) and IWL (25.4±7.1 Vs 32.9±11.2 mm/mm 2 , p=0.036) compared to subjects without metabolic syndrome., Conclusion: Hypertriglyceridemia and metabolic syndrome are associated with small nerve fibre damage and clinical neuropathy. Elevated serum triglycerides may be a potential therapeutic target for the treatment of peripheral neuropathy., Competing Interests: Disclosure Statement The authors have nothing to disclose in relation to this paper., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: Pial collateral blood flow is a major determinant of the outcomes of acute ischemic stroke. This study was undertaken to determine whether retinal vessel metrics can predict the pial collateral status and stroke outcomes in patients., Methods: Thirty-five patients with acute stroke secondary to middle cerebral artery (MCA) occlusion underwent grading of their pial collateral status from computed tomography angiography and retinal vessel analysis from retinal fundus images., Results: The NIHSS (14.7 ± 5.5 vs 10.1 ± 5.8, p = 0.026) and mRS (2.9 ± 1.6 vs 1.9 ± 1.3, p = 0.048) scores were higher at admission in patients with poor compared to good pial collaterals. Retinal vessel multifractals: D0 (1.673±0.028vs1.652±0.025, p = 0.028), D1 (1.609±0.027vs1.590±0.025, p = 0.044) and f(α)max (1.674±0.027vs1.652±0.024, p = 0.019) were higher in patients with poor compared to good pial collaterals. Furthermore, support vector machine learning achieved a fair sensitivity (0.743) and specificity (0.707) for differentiating patients with poor from good pial collaterals. Age (p = 0.702), BMI (p = 0.422), total cholesterol (p = 0.842), triglycerides (p = 0.673), LDL (p = 0.952), HDL (p = 0.366), systolic blood pressure (p = 0.727), HbA1c (p = 0.261) and standard retinal metrics including CRAE (p = 0.084), CRVE (p = 0.946), AVR (p = 0.148), tortuosity index (p = 0.790), monofractal Df (p = 0.576), lacunarity (p = 0.531), curve asymmetry (p = 0.679) and singularity length (p = 0.937) did not differ between patients with poor compared to good pial collaterals., Conclusions: This is the first translational study to show increased retinal vessel multifractal dimensions in patients with acute ischemic stroke and poor pial collaterals. A retinal vessel classifier was developed to differentiate between patients with poor and good pial collaterals and may allow rapid non-invasive identification of patients with poor pial collaterals., Competing Interests: The authors have declared that no competing interests exist.

There is a need to accurately identify patients with diabetes at higher risk of developing and progressing diabetic peripheral neuropathy (DPN). Fifty subjects with Type 1 Diabetes Mellitus (T1DM) and sixteen age matched healthy controls underwent detailed neuropathy assessments including symptoms, signs, quantitative sensory testing (QST), nerve conduction studies (NCS), intra epidermal nerve fiber density (IENFD) and corneal confocal microscopy (CCM) at baseline and after 2 years of follow-up. Overall, people with type 1 diabetes mellitus showed no significant change in HbA1c, blood pressure, lipids or neuropathic symptoms, signs, QST, neurophysiology, IENFD and CCM over 2 years. However, a sub-group ( n = 11, 22%) referred to as progressors, demonstrated rapid corneal nerve fiber loss (RCNFL) with a reduction in corneal nerve fiber density (CNFD) ( p = 0.0006), branch density (CNBD) ( p = 0.0002), fiber length (CNFL) ( p = 0.0002) and sural ( p = 0.04) and peroneal ( p = 0.05) nerve conduction velocities, which was not related to a change in HbA1c or cardiovascular risk factors. The majority of people with T1DM and good risk factor control do not show worsening of neuropathy over 2 years. However, CCM identifies a sub-group of people with T1DM who show a more rapid decline in corneal nerve fibers and nerve conduction velocity.

Introduction: This study compared the capability of corneal confocal microscopy (CCM) with magnetic resonance imaging (MRI) brain volumetry for the diagnosis of mild cognitive impairment (MCI) and dementia., Methods: In this cross-sectional study, participants with no cognitive impairment (NCI), MCI, and dementia underwent assessment of Montreal Cognitive Assessment (MoCA), MRI brain volumetry, and CCM., Results: Two hundred eight participants with NCI (n = 42), MCI (n = 98), and dementia (n = 68) of comparable age and gender were studied. For MCI, the area under the curve (AUC) of CCM (76% to 81%), was higher than brain volumetry (52% to 70%). For dementia, the AUC of CCM (77% to 85%), was comparable to brain volumetry (69% to 93%). Corneal nerve fiber density, length, branch density, whole brain, hippocampus, cortical gray matter, thalamus, amygdala, and ventricle volumes were associated with cognitive impairment after adjustment for confounders (All P 's < .01)., Discussion: The diagnostic capability of CCM compared to brain volumetry is higher for identifying MCI and comparable for dementia, and abnormalities in both modalities are associated with cognitive impairment., Competing Interests: The authors confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship and are not listed. They also confirm that the order of authors listed in the manuscript has been approved by all authors. Dr. Surjith Vattoth has Elsevier book author royalty, received consulting fee as an Elsevier master author consultant in head and neck imaging, and received payment for ESNR ‐ ECHNR course faculty. None of the other authors have received or anticipate receiving income, goods, or benefit from a company that will influence the design, conduct, or reporting of the study., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

An alteration in circulating miRNAs may have important diagnostic and therapeutic relevance in diabetic neuropathy. Patients with type 2 diabetes mellitus (T2DM) underwent an assessment of neuropathic symptoms using Douleur Neuropathique 4 (DN4), the vibration perception threshold (VPT) using a Neurothesiometer, sudomotor function using the Sudoscan, corneal nerve morphology using corneal confocal microscopy (CCM) and circulating miRNAs using high-throughput miRNA expression profiling. Patients with T2DM, with (n = 9) and without (n = 7) significant corneal nerve loss were comparable in age, gender, diabetes duration, BMI, HbA1c, eGFR, blood pressure, and lipid profile. The VPT was significantly higher (p < 0.05), and electrochemical skin conductance (p < 0.05), corneal nerve fiber density (p = 0.001), corneal nerve branch density (p = 0.013), and corneal nerve fiber length (p < 0.001) were significantly lower in T2DM patients with corneal nerve loss compared to those without corneal nerve loss. Following a q-PCR-based analysis of total plasma microRNAs, we found that miR-92b-3p (p = 0.008) was significantly downregulated, while miR-22-3p (p = 0.0001) was significantly upregulated in T2DM patients with corneal nerve loss. A network analysis revealed that these miRNAs regulate axonal guidance and neuroinflammation genes. These data support the need for more extensive studies to better understand the role of dysregulated miRNAs’ in diabetic neuropathy.

Vascular and inflammatory mechanisms are implicated in the development of cerebrovascular disease and corneal nerve loss occurs in patients with transient ischemic attack (TIA) and acute ischemic stroke (AIS). We have assessed whether serum markers of inflammation and vascular integrity are associated with the severity of corneal nerve loss in patients with TIA and AIS. Corneal confocal microscopy (CCM) was performed to quantify corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) in 105 patients with TIA (n = 24) or AIS (n = 81) and age matched control subjects (n = 56). Circulating levels of IL-6, MMP-2, MMP-9, E-Selectin, P-Selectin and VEGF were quantified in patients within 48 h of presentation with a TIA or AIS. CNFL (P = 0.000, P = 0.000), CNFD (P = 0.122, P = 0.000) and CNBD (P = 0.002, P = 0.000) were reduced in patients with TIA and AIS compared to controls, respectively with no difference between patients with AIS and TIA. The NIHSS Score (P = 0.000), IL-6 (P = 0.011) and E-Selectin (P = 0.032) were higher in patients with AIS compared to TIA with no difference in MMP-2 (P = 0.636), MMP-9 (P = 0.098), P-Selectin (P = 0.395) and VEGF (P = 0.831). CNFL (r = 0.218, P = 0.026) and CNFD (r = 0.230, P = 0.019) correlated with IL-6 and multiple regression analysis showed a positive association of CNFL and CNFD with IL-6 (P = 0.041, P = 0.043). Patients with TIA and AIS have evidence of corneal nerve loss and elevated IL6 and E-selectin levels. Larger longitudinal studies are required to determine the association between inflammatory and vascular markers and corneal nerve fiber loss in patients with cerebrovascular disease., (© 2022. The Author(s).)

Neurodevelopmental and neurodegenerative pathology occur in Schizophrenia. This study compared the utility of corneal confocal microscopy (CCM), an ophthalmic imaging technique with MRI brain volumetry in quantifying neuronal pathology and its relationship to cognitive dysfunction and symptom severity in schizophrenia. Thirty-six subjects with schizophrenia and 26 controls underwent assessment of cognitive function, symptom severity, CCM and MRI brain volumetry. Subjects with schizophrenia had lower cognitive function (P ≤ 0.01), corneal nerve fiber density (CNFD), length (CNFL), branch density (CNBD), CNBD:CNFD ratio (P < 0.0001) and cingulate gyrus volume (P < 0.05) but comparable volume of whole brain (P = 0.61), cortical gray matter (P = 0.99), ventricle (P = 0.47), hippocampus (P = 0.10) and amygdala (P = 0.68). Corneal nerve measures and cingulate gyrus volume showed no association with symptom severity (P = 0.35-0.86 and P = 0.50) or cognitive function (P = 0.35-0.86 and P = 0.49). Corneal nerve measures were not associated with metabolic syndrome (P = 0.61-0.64) or diabetes (P = 0.057-0.54). The area under the ROC curve distinguishing subjects with schizophrenia from controls was 88% for CNFL, 84% for CNBD and CNBD:CNFD ratio, 79% for CNFD and 73% for the cingulate gyrus volume. This study has identified a reduction in corneal nerve fibers and cingulate gyrus volume in schizophrenia, but no association with symptom severity or cognitive dysfunction. Corneal nerve loss identified using CCM may act as a rapid non-invasive surrogate marker of neurodegeneration in patients with schizophrenia., (© 2022. The Author(s).)

Introduction: Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that identifies corneal nerve fiber damage. Small studies suggest that CCM could be used to assess patients with diabetic peripheral neuropathy (DPN)., Aim: To undertake a systematic review and meta-analysis assessing the diagnostic utility of CCM for sub-clinical DPN (DPN - ) and established DPN (DPN + )., Data Sources: Databases (PubMed, Embase, Central, ProQuest) were searched for studies using CCM in patients with diabetes up to April 2020., Study Selection: Studies were included if they reported on at least one CCM parameter in patients with diabetes., Data Extraction: Corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), corneal nerve fiber length (CNFL), and inferior whorl length (IWL) were compared between patients with diabetes with and without DPN and controls. Meta-analysis was undertaken using RevMan V.5.3., Data Synthesis: Thirty-eight studies including ~4,000 participants were included in this meta-analysis. There were significant reductions in CNFD, CNBD, CNFL, and IWL in DPN - vs controls (P < 0.00001), DPN + vs controls (P < 0.00001), and DPN + vs DPN - (P < 0.00001)., Conclusion: This systematic review and meta-analysis shows that CCM detects small nerve fiber loss in subclinical and clinical DPN and concludes that CCM has good diagnostic utility in DPN., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Purpose: The purpose of this study was to evaluate the utility of corneal confocal microscopy (CCM) in identifying small nerve fiber damage and immune cell activation in patients with systemic lupus erythematosus (SLE)., Methods: This cross-sectional comparative study included 39 consecutive patients with SLE and 30 healthy control participants. Central corneal sensitivity was assessed using a Cochet-Bonnet contact corneal esthesiometer and a laser scanning CCM (Heidelberg, Germany) was used to quantify corneal nerve fiber density (CNFD), nerve branch density (CNBD), nerve fiber length (CNFL), and Langerhans cell (LC) density., Results: Age was comparable among patients with SLE (33.7 ± 12.7) and controls (35.0 ± 13.7 years, P = 0.670) and the median duration of disease was 3.0 years (2.0-10.0 years). CNBD (P = 0.003) and CNFL (P = 0.019) were lower and mature LC density (P = 0.002) was higher, but corneal sensitivity (P = 0.178) and CNFD (P = 0.198) were comparable in patients with SLE compared with controls. The SELENA-SLEDAI score correlated with CNFD (ρ = -0.319, P = 0.048) and CNFL (ρ = -0.373, P = 0.019), and the total and immature LC densities correlated with CNBD (ρ = -0.319. P = 0.048, and ρ = -0.328, P = 0.041, respectively). Immature LC density was higher (P = 0.025), but corneal sensitivity and nerve fiber parameters were comparable between patients with (33%) and without neuropsychiatric symptoms and SLE., Conclusions: Corneal confocal microscopy identifies distal corneal nerve fiber loss and increased immune cell density in patients with SLE and corneal nerve loss was associated with disease activity., Translational Relevance: Corneal confocal microscopy may enable the detection of subclinical corneal nerve loss and immune cell activation in SLE.

Axonal loss is the main determinant of disease progression in multiple sclerosis (MS). This study aimed to assess the utility of corneal confocal microscopy (CCM) in detecting corneal axonal loss in different courses of MS. The results were confirmed by two independent segmentation methods. 72 subjects (144 eyes) [(clinically isolated syndrome (n = 9); relapsing-remitting MS (n = 20); secondary-progressive MS (n = 22); and age-matched, healthy controls (n = 21)] underwent CCM and assessment of their disability status. Two independent algorithms (ACCMetrics; and Voxeleron deepNerve) were used to quantify corneal nerve fiber density (CNFD) (ACCMetrics only), corneal nerve fiber length (CNFL) and corneal nerve fractal dimension (CNFrD). Data are expressed as mean ± standard deviation with 95% confidence interval (CI). Compared to controls, patients with MS had significantly lower CNFD (34.76 ± 5.57 vs. 19.85 ± 6.75 fibers/mm 2 , 95% CI - 18.24 to - 11.59, P < .0001), CNFL [for ACCMetrics: 19.75 ± 2.39 vs. 12.40 ± 3.30 mm/mm 2 , 95% CI - 8.94 to - 5.77, P < .0001; for deepNerve: 21.98 ± 2.76 vs. 14.40 ± 4.17 mm/mm 2 , 95% CI - 9.55 to - 5.6, P < .0001] and CNFrD [for ACCMetrics: 1.52 ± 0.02 vs. 1.45 ± 0.04, 95% CI - 0.09 to - 0.05, P < .0001; for deepNerve: 1.29 ± 0.03 vs. 1.19 ± 0.07, 95% - 0.13 to - 0.07, P < .0001]. Corneal nerve parameters were comparably reduced in different courses of MS. There was excellent reproducibility between the algorithms. Significant corneal axonal loss is detected in different courses of MS including patients with clinically isolated syndrome., (© 2021. The Author(s).)

Aims/introduction: This study aimed to investigate whether insulin resistance (IR) in individuals with type 2 diabetes undergoing intensive glycemic control determines the extent of improvement in neuropathy., Materials and Methods: This was an exploratory substudy of an open-label, randomized controlled trial of individuals with poorly controlled type 2 diabetes treated with exenatide and pioglitazone or insulin to achieve a glycated hemoglobin <7.0% (<53 mmol/mol). Baseline IR was defined using homeostasis model assessment of IR, and change in neuropathy was assessed using corneal confocal microscopy., Results: A total of 38 individuals with type 2 diabetes aged 50.2 ± 8.5 years with (n = 25, 66%) and without (n = 13, 34%) IR were studied. There was a significant decrease in glycated hemoglobin (P < 0.0001), diastolic blood pressure (P < 0.0001), total cholesterol (P < 0.01) and low-density lipoprotein (P = 0.05), and an increase in bodyweight (P < 0.0001) with treatment. Individuals with homeostasis model assessment of IR <1.9 showed a significant increase in corneal nerve fiber density (P ≤ 0.01), length (P ≤ 0.01) and branch density (P ≤ 0.01), whereas individuals with homeostasis model assessment of IR ≥1.9 showed no change. IR was negatively associated with change in corneal nerve fiber density after adjusting for change in bodyweight (P < 0.05)., Conclusions: Nerve regeneration might be limited in individuals with type 2 diabetes and IR undergoing treatment with pioglitazone plus exenatide or insulin to improve glycemic control., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

In patients with acute ischemic stroke, pial collaterals play a key role in limiting neurological disability by maintaining blood flow to ischemic penumbra. We hypothesized that patient with poor pial collaterals will have greater corneal nerve and endothelial cell abnormalities. In a cross-sectional study, 35 patients with acute ischemic stroke secondary to middle cerebral artery (MCA) occlusion with poor (n = 12) and moderate-good (n = 23) pial collaterals and 35 healthy controls underwent corneal confocal microscopy and quantification of corneal nerve and endothelial cell morphology. In patients with MCA stroke, corneal nerve fibre length (CNFL) (P < 0.001), corneal nerve fibre density (CNFD) (P = 0.025) and corneal nerve branch density (CNBD) (P = 0.002) were lower compared to controls. Age, BMI, cholesterol, triglycerides, HDL, LDL, systolic blood pressure, NIHSS and endothelial cell parameters did not differ but mRS was higher (p = 0.023) and CNFL (p = 0.026) and CNBD (p = 0.044) were lower in patients with poor compared to moderate-good collaterals. CNFL and CNBD distinguished subjects with poor from moderate-good pial collaterals with an AUC of 72% (95% CI 53-92%) and 71% (95% CI 53-90%), respectively. Corneal nerve loss is greater in patients with poor compared to moderate-good pial collaterals and may act as a surrogate marker for pial collateral status in patients with ischemic stroke., (© 2021. The Author(s).)

Aims/introduction: Painful diabetic peripheral neuropathy (pDPN) is associated with small nerve fiber degeneration and regeneration. This study investigated whether the presence of pDPN might influence nerve regeneration in patients with type 2 diabetes undergoing intensive glycemic control., Materials and Methods: This exploratory substudy of an open-label randomized controlled trial undertook the Douleur Neuropathique en 4 questionnaire and assessment of electrochemical skin conductance, vibration perception threshold and corneal nerve morphology using corneal confocal microscopy in participants with and without pDPN treated with exenatide and pioglitazone or basal-bolus insulin at baseline and 1-year follow up, and 18 controls at baseline only., Results: Participants with type 2 diabetes, with (n = 13) and without (n = 28) pDPN had comparable corneal nerve fiber measures, electrochemical skin conductance and vibration perception threshold at baseline, and pDPN was not associated with the severity of DPN. There was a significant glycated hemoglobin reduction (P < 0.0001) and weight gain (P < 0.005), irrespective of therapy. Participants with pDPN showed a significant increase in corneal nerve fiber density (P < 0.05), length (P < 0.0001) and branch density (P < 0.005), and a decrease in the Douleur Neuropathique en 4 score (P < 0.01), but no change in electrochemical skin conductance or vibration perception threshold. Participants without pDPN showed a significant increase in corneal nerve branch density (P < 0.01) and no change in any other neuropathy measures. A change in the severity of painful symptoms was not associated with corneal nerve regeneration and medication for pain., Conclusions: This study showed that intensive glycemic control is associated with greater corneal nerve regeneration and an improvement in the severity of pain in patients with painful diabetic neuropathy., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Purpose: Diagnosing early diabetic peripheral neuropathy remains a challenge due to deficiencies in currently advocated end points. The cornea is densely innervated with small sensory fibers, which are structurally and functionally comparable to intraepidermal nerve fibers. Corneal confocal microscopy is a method for rapid, noninvasive scanning of the living cornea with high resolution and magnification., Methods: This narrative review presents the framework for the development of biomarkers and the literature on the use and adoption of corneal confocal microscopy as an objective, diagnostic biomarker in experimental and clinical studies of diabetic peripheral neuropathy. A search was performed on PubMed and Google Scholar based on the terms "corneal confocal microscopy," "diabetic neuropathy," "corneal sensitivity," and "clinical trials.", Findings: A substantial body of evidence underpins the thesis that corneal nerve loss predicts incident neuropathy and progresses with the severity of diabetic peripheral neuropathy. Corneal confocal microscopy also identifies early corneal nerve regeneration, strongly arguing for its inclusion as a surrogate end point in clinical trials of disease-modifying therapies., Implications: There are sufficient diagnostic and prospective validation studies to fulfill the US Food and Drug Administration criteria for a biomarker to support the inclusion of corneal confocal microscopy as a primary end point in clinical trials of disease-modifying therapies in diabetic neuropathy., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

To assess the impact of renal transplantation on peripheral nerve damage in patients with chronic kidney disease (CKD). Fifteen patients with CKD (eGFR <15 mL/min/1.73 m 2 ) underwent longitudinal assessment after renal transplantation (age: 56.88 ± 2.53 years, eGFR: 46.82 ± 4.86) and were compared with 15 age-matched controls (age: 58.25 ± 2.18 years, eGFR: 86.0 ± 2.0). The neuropathy symptom profile (NSP), neuropathy disability score (NDS), vibration perception threshold (VPT), cold and warm sensation threshold (CST and WST), cold and heat induced pain (CIP and HIP), deep breathing heart rate variability (DB-HRV), nerve conduction studies and corneal confocal microscopy (CCM) to quantify small nerve fibre pathology, were undertaken within 1-month of renal transplantation (baseline) and at 6, 12 and 24 months of follow up. There was no significant difference in NSP (P = .1), NDS (P = .3), VPT (P = .6), CST (P = .2), CIP (P = .08), HIP (P = .1), DB-HRV (P = .9) and sural (P = .4) and peroneal (P = .1) nerve amplitude between patients with CKD and controls at baseline. However, sural (P = .04), peroneal (P = .002) and tibial (P = .007) nerve conduction velocity and tibial nerve amplitude (P = .03) were significantly lower, WST (P = .02) was significantly higher and corneal nerve fibre density (P = .004) was significantly lower in patients with CKD compared with controls. There was no significant change in NSP, NDS, quantitative sensory testing, DB-HRV, nerve conduction or CCM parameters 24 months after renal transplantation. There is evidence of small and large fibre neuropathy in patients with CKD, but no change up to 24 months after successful renal transplantation., (© 2021 Peripheral Nerve Society.)

Background: Diabetic microvascular complications are a major cause of morbidity and are related to glycaemic control and cardiovascular risk factors., Aims: We sought to determine the association of microvascular complications in relation to control of glycemia, blood pressure and lipids in T2DM patients attending secondary care in Qatar., Methods: This is a cross-sectional study undertaken in patients with T2DM attending Qatar's National Diabetes Centres. Patients underwent assessment of glycemia, blood pressure and lipids and prevalence of diabetic peripheral neuropathy (DPN), retinopathy and microalbuminuria., Results: We included 1114 subjects aged 52.1 ± 11.3 years with a duration of diabetes 10.0 ± 7.6 years and had a prevalence of 25.8% for DPN, 34.3% for painful DPN, 36.8% for microalbuminuria and 25.1% for retinopathy. Patients who achieved an HbA1c ≤ 7.0% compared to >7% had a significantly lower prevalence of DPN (P < 0.01), painful DPN (P < 0.01), retinopathy (P < 0.01) and microalbuminuria (P < 0.007). Patients who achieved a systolic BP ≤ 140 mmHg compared to >140 mmHg had a significantly lower prevalence of DPN (P < 0.001), painful DPN (P < 0.001), retinopathy (P < 0.001) and microalbuminuria (P < 0.001). Patients who achieved an LDL ≤2.6 mmol/l compared to >2.6 mmol/l had a significantly higher prevalence of DPN (P < 0.03), but no difference in other outcomes. There was no difference in microvascular complications between those who achieved a HDL-C ≥ 1.02 mmol/l, and among those who achieved triglycerides ≤1.7 mmol/l., Conclusions: Optimal control of glycemia and blood pressure, but not lipids is associated with a lower prevalence of diabetic microvascular complications., Competing Interests: Declaration of competing interest The authors report no conflict of interest in relation to this manuscript., (Copyright © 2021 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Neuropathic pain has multiple etiologies, but a major feature is small fiber dysfunction or damage. Corneal confocal microscopy (CCM) is a rapid non-invasive ophthalmic imaging technique that can image small nerve fibers in the cornea and has been utilized to show small nerve fiber loss in patients with diabetic and other neuropathies. CCM has comparable diagnostic utility to intraepidermal nerve fiber density for diabetic neuropathy, fibromyalgia and amyloid neuropathy and predicts the development of diabetic neuropathy. Moreover, in clinical intervention trials of patients with diabetic and sarcoid neuropathy, corneal nerve regeneration occurs early and precedes an improvement in symptoms and neurophysiology. Corneal nerve fiber loss also occurs and is associated with disease progression in multiple sclerosis, Parkinson's disease and dementia. We conclude that corneal confocal microscopy has good diagnostic and prognostic capability and fulfills the FDA criteria as a surrogate end point for clinical trials in peripheral and central neurodegenerative diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. There is no conflict of interest related to this work for any of the authors., (Copyright © 2021 Petropoulos, Bitirgen, Ferdousi, Kalteniece, Azmi, D'Onofrio, Lim, Ponirakis, Khan, Gad, Mohammed, Mohammadi, Malik, Gosal, Kobylecki, Silverdale, Soran, Alam and Malik.)