{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:25:25Z","timestamp":1787318725073,"version":"build-2736575974"},"reference-count":33,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Young Investigators Award by the Association of Physicians of Great Britain and Ireland (2018)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diagnostics"],"abstract":"<jats:p>Objective: In this study, we evaluate small and large nerve fibre pathology in relation to diabetic foot ulceration (DFU) and incident cardiovascular and cerebrovascular events in type 1 diabetes (T1D). Methods: A prospective observational study was conducted on people with T1D without diabetic peripheral neuropathy (DPN) (n = 25), T1D with DPN (n = 28), T1D with DFU (n = 25) and 32 healthy volunteers. ROC analysis of parameters was conducted to diagnose DPN and DFU, and multivariate Cox regression analysis was performed to evaluate the predictive ability of corneal nerves for cardiac and cerebrovascular events over 3 years. Results: Corneal nerve fibre length (CNFL), fibre density (CNFD) and branch density (CNBD) were lower in T1D-DPN and T1D-DFU vs. T1D (all p &lt; 0.001). In ROC analysis, CNFD (sensitivity 88%, specificity 87%; AUC 0.93; p &lt; 0.001; optimal cut-off 7.35 no\/mm2) and CNFL (sensitivity 76%, specificity 77%; AUC 0.90; p &lt; 0.001; optimal cut-off 7.01 mm\/mm2) had good ability to differentiate T1D with and without DFU. Incident cardiovascular events (p &lt; 0.001) and cerebrovascular events (p &lt; 0.001) were significantly higher in T1D-DPN and T1D-DFU. Corneal nerve loss, specifically CNFD predicted incident cardiovascular (HR 1.67, 95% CI 1.12 to 2.50, p = 0.01) and cerebrovascular (HR 1.55, 95% CI 1.06 to 2.26, p = 0.02) events. Conclusions: Our study provides threshold values for corneal nerve fibre metrics for neuropathic foot at risk of DFU and further demonstrates that lower CNFD predicts incident cardiovascular and cerebrovascular events in T1D.<\/jats:p>","DOI":"10.3390\/diagnostics13172793","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:35:05Z","timestamp":1693298105000},"page":"2793","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Corneal Confocal Microscopy Predicts Cardiovascular and Cerebrovascular Events and Demonstrates Greater Peripheral Neuropathy in Patients with Type 1 Diabetes and Foot Ulcers"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3682-8910","authenticated-orcid":false,"given":"Jonathan Z. M.","family":"Lim","sequence":"first","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Diabetes, Endocrinology, and Metabolism Centre, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"},{"name":"Department of Medicine, Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7165-6918","authenticated-orcid":false,"given":"Jamie","family":"Burgess","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Department of Medicine, Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheong","family":"Ooi","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Department of Medicine, Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maryam","family":"Ferdousi","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR\/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shazli","family":"Azmi","sequence":"additional","affiliation":[{"name":"Diabetes, Endocrinology, and Metabolism Centre, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK"},{"name":"Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR\/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alise","family":"Kalteniece","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences, Cardiac Centre, Faculty of Medical and Human Sciences, University of Manchester and NIHR\/Wellcome Trust Clinical Research Facility, Manchester M13 9WL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Anson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Department of Medicine, Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6128-0822","authenticated-orcid":false,"given":"Daniel J.","family":"Cuthbertson","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Department of Medicine, Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK"},{"name":"Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool University NHS Foundation Trust, Liverpool L69 3BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ioannis N.","family":"Petropoulos","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7188-8903","authenticated-orcid":false,"given":"Rayaz A.","family":"Malik","sequence":"additional","affiliation":[{"name":"Department of Medicine, Weill Cornell Medicine-Qatar, Doha P.O. Box 24144, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John P. H.","family":"Wilding","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Department of Medicine, Clinical Sciences Centre, Aintree University Hospital, Longmoor Lane, Liverpool L9 7AL, UK"},{"name":"Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool University NHS Foundation Trust, Liverpool L69 3BX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3190-1122","authenticated-orcid":false,"given":"Uazman","family":"Alam","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular & Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool L69 3BX, UK"},{"name":"Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool University NHS Foundation Trust, Liverpool L69 3BX, UK"},{"name":"Centre for Biomechanics and Rehabilitation Technologies, Staffordshire University, Stoke-on-Trent ST4 2DF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"109119","DOI":"10.1016\/j.diabres.2021.109119","article-title":"IDF Diabetes Atlas: Global, regional and country-level diabetes prevalence estimates for 2021 and projections for 2045","volume":"183","author":"Sun","year":"2022","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.jcot.2021.01.017","article-title":"The current burden of diabetic foot disease","volume":"17","author":"Edmonds","year":"2021","journal-title":"J. Clin. Orthop. Trauma"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2367","DOI":"10.1056\/NEJMra1615439","article-title":"Diabetic Foot Ulcers and Their Recurrence","volume":"376","author":"Armstrong","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Burgess, J., Frank, B., Marshall, A., Khalil, R.S., Ponirakis, G., Petropoulos, I.N., Cuthbertson, D.J., Malik, R.A., and Alam, U. (2021). Early Detection of Diabetic Peripheral Neuropathy: A Focus on Small Nerve Fibres. Diagnostics, 11.","DOI":"10.3390\/diagnostics11020165"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1111\/j.1742-481X.2012.01051.x","article-title":"Screening patients at risk for diabetic foot ulceration: A comparison between measurement of vibration perception threshold and 10-g monofilament test","volume":"11","author":"Richard","year":"2014","journal-title":"Int. Wound J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.2337\/dc14-2422","article-title":"Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: Comparing corneal confocal microscopy with intraepidermal nerve fiber density","volume":"38","author":"Chen","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Meng, Y., Preston, F.G., Ferdousi, M., Azmi, S., Petropoulos, I.N., Kaye, S., Malik, R.A., Alam, U., and Zheng, Y. (2023). Artificial Intelligence Based Analysis of Corneal Confocal Microscopy Images for Diagnosing Peripheral Neuropathy: A Binary Classification Model. J. Clin. Med., 12.","DOI":"10.3390\/jcm12041284"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/s00125-021-05617-x","article-title":"Artificial intelligence utilising corneal confocal microscopy for the diagnosis of peripheral neuropathy in diabetes mellitus and prediabetes","volume":"65","author":"Preston","year":"2022","journal-title":"Diabetologia"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/jdi.13643","article-title":"Corneal confocal microscopy for the diagnosis of diabetic peripheral neuropathy: A systematic review and meta-analysis","volume":"13","author":"Gad","year":"2022","journal-title":"J. Diabetes Investig."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Alam, U., Ponirakis, G., Asghar, O., Petropoulos, I.N., Azmi, S., Jeziorska, M., Marshall, A., Boulton, A.J.M., Efron, N., and Malik, R.A. (2022). Corneal Confocal Microscopy Identifies People with Type 1 Diabetes with More Rapid Corneal Nerve Fibre Loss and Progression of Neuropathy. J. Clin. Med., 11.","DOI":"10.3390\/jcm11082249"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1437","DOI":"10.1016\/j.jdiacomp.2016.07.004","article-title":"A rapid decline in corneal small fibers and occurrence of foot ulceration and Charcot foot","volume":"30","author":"Dehghani","year":"2016","journal-title":"J. Diabetes Its Complicat."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Diabetes Control and Complications Trial (DCCT)\/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group (2016). Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT\/EDIC Study 30-Year Follow-up. Diabetes Care, 39, 686\u2013693.","DOI":"10.2337\/dc15-1990"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2906","DOI":"10.1007\/s00125-012-2673-3","article-title":"The association of ulceration of the foot with cardiovascular and all-cause mortality in patients with diabetes: A meta-analysis","volume":"55","author":"Brownrigg","year":"2012","journal-title":"Diabetologia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.2337\/dc10-1303","article-title":"Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments","volume":"33","author":"Tesfaye","year":"2010","journal-title":"Diabetes Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17333","DOI":"10.1038\/s41598-018-35298-3","article-title":"Corneal Confocal Microscopy detects a Reduction in Corneal Endothelial Cells and Nerve Fibres in Patients with Acute Ischemic Stroke","volume":"8","author":"Khan","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.jcjd.2015.02.006","article-title":"In vivo corneal confocal microscopy and prediction of future-incident neuropathy in type 1 diabetes: A preliminary longitudinal analysis","volume":"39","author":"Lovblom","year":"2015","journal-title":"Can. J. Diabetes"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2010","DOI":"10.2337\/diacare.25.11.2010","article-title":"Can motor nerve conduction velocity predict foot problems in diabetic subjects over a 6-year outcome period?","volume":"25","author":"Carrington","year":"2002","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2042018819826890","DOI":"10.1177\/2042018819826890","article-title":"Diagnosing and managing diabetic somatic and autonomic neuropathy","volume":"10","author":"Azmi","year":"2019","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"308","DOI":"10.3389\/fendo.2020.00308","article-title":"A Synoptic Overview of Neurovascular Interactions in the Foot","volume":"11","author":"Balasubramanian","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.mcna.2013.03.007","article-title":"The pathway to foot ulceration in diabetes","volume":"97","author":"Boulton","year":"2013","journal-title":"Med. Clin. N. Am."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/iwj.13861","article-title":"Risk factors for foot ulcer recurrence in patients with comorbid diabetic foot osteomyelitis and diabetic nephropathy: A 3-year follow-up study","volume":"20","author":"Zhang","year":"2023","journal-title":"Int. Wound J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"732753","DOI":"10.3389\/fbioe.2021.732753","article-title":"The Role of Cutaneous Microcirculatory Responses in Tissue Injury, Inflammation and Repair at the Foot in Diabetes","volume":"9","author":"Balasubramanian","year":"2021","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1007\/s11892-016-0727-5","article-title":"Inflammation as a Therapeutic Target for Diabetic Neuropathies","volume":"16","author":"Ang","year":"2016","journal-title":"Curr. Diabetes Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.trsl.2021.05.003","article-title":"Cutaneous innervation in impaired diabetic wound healing","volume":"236","author":"Nowak","year":"2021","journal-title":"Transl. Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e3255","DOI":"10.1002\/dmrr.3255","article-title":"Diabetic neuropathy: A focus on small fibres","volume":"36","author":"Malik","year":"2020","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Alam, U., Jeziorska, M., Petropoulos, I.N., Asghar, O., Fadavi, H., Ponirakis, G., Marshall, A., Tavakoli, M., Boulton, A.J.M., and Efron, N. (2017). Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0180175"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"671","DOI":"10.2337\/dc14-2114","article-title":"Corneal confocal microscopy predicts 4-year incident peripheral neuropathy in type 1 diabetes","volume":"38","author":"Pritchard","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.2337\/dc19-0951","article-title":"Rapid Corneal Nerve Fiber Loss: A Marker of Diabetic Neuropathy Onset and Progression","volume":"43","author":"Lewis","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1016\/j.clinthera.2022.09.002","article-title":"Cardiac Autonomic Neuropathy in Type 1 and 2 Diabetes: Epidemiology, Pathophysiology, and Management","volume":"44","author":"Williams","year":"2022","journal-title":"Clin. Ther."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Khan, A., Akhtar, N., Kamran, S., Almuhannadi, H., Ponirakis, G., Petropoulos, I.N., Babu, B., Jose, N.R., Ibrahim, R.G., and Gad, H. (2020). Corneal confocal microscopy identifies greater corneal nerve damage in patients with a recurrent compared to first ischemic stroke. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0231987"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2570","DOI":"10.2337\/dc18-1236","article-title":"Atherosclerosis and Microvascular Complications: Results from the Canadian Study of Longevity in Type 1 Diabetes","volume":"41","author":"Lovshin","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41586-022-04673-6","article-title":"Neuroimmune cardiovascular interfaces control atherosclerosis","volume":"605","author":"Mohanta","year":"2022","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"101694","DOI":"10.1016\/j.cpcardiol.2023.101694","article-title":"Machine learning predicts cardiovascular events in patients with diabetes: The Silesia Diabetes-Heart Project","volume":"48","author":"Nabrdalik","year":"2023","journal-title":"Curr. Probl. Cardiol."}],"container-title":["Diagnostics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/17\/2793\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:41:41Z","timestamp":1760128901000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4418\/13\/17\/2793"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,29]]},"references-count":33,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["diagnostics13172793"],"URL":"https:\/\/doi.org\/10.3390\/diagnostics13172793","relation":{},"ISSN":["2075-4418"],"issn-type":[{"value":"2075-4418","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,29]]}}}