Developing Corneal Confocal Microscopy as a Screening Tool and Biomarker for Diabetic Neuropathy

开发角膜共聚焦显微镜作为糖尿病神经病变的筛查工具和生物标志物

• 批准号: 8832135
• 负责人: John Robinson Singleton
• 金额: $ 144.21万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-30 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8832135
• 关键词: Address; Affect; Age; Age-Years; American; Amputation; Axon; Biological Markers; Biopsy; Blindness; Clinical; Clinical Research; Clinical Trials; Complement; Confocal Microscopy; Consensus; Cornea; Data; Data Set; Defect; Development; Diabetes Mellitus; Diabetic Neuropathies; Diabetic Retinopathy; Diagnosis; Diagnostic; Diagnostic tests; Disease; Distal; Early Intervention; Early identification; Early treatment; Equilibrium; Evaluation; Eye; Eye diseases; Face; Failure; Fiber; Future; Goals; Guidelines; Health; Human; Image; Infection; Injury; Insulin-Dependent Diabetes Mellitus; Length; Life Style; Link; Location; Measurement; Measures; Meta-Analysis; Metabolic; Methodology; Methods; Metric; Modeling; Modification; Nerve; Nerve Fibers; Neural Conduction; Neurologic; Neuropathy; Outcome Measure; Pain; Participant; Patient Care; Patient Outcomes Assessments; Patient Schedules; Patients; Performance; Peripheral; Phase; Polyneuropathy; Pre-Clinical Model; Prevention; Preventive Intervention; Process; Prospective Studies; Protocols documentation; Public Health; Quality of life; Questionnaires; Receiver Operating Characteristics; Recording of previous events; Recruitment Activity; Regression Analysis; Relative (related person); Reporting; Retinal; Retinal Diseases; Risk; Risk Factors; Sensitivity and Specificity; Sex Distribution; Skin; Staging; Structure; Surface; Surrogate Endpoint; Symptoms; Techniques; Therapeutic Agents; Therapy Clinical Trials; Therapy Evaluation; Time; Treatment Efficacy; Ulcer; Unmyelinated Nerve Fibers; Utah; Walking; balance testing; base; clinically relevant; cohort; density; diabetes risk; diabetic; diabetic patient; disability; experience; fall risk; foot; functional outcomes; glycemic control; high risk; lifestyle intervention; nerve supply; novel; novel therapeutics; pre-clinical; prospective; protective effect; regenerative; screening; sex; tool

 DESCRIPTION (provided by applicant): Diabetes affects over 25 million Americans; 50% have distal symmetric polyneuropathy (DSP). DSP is a leading cause of disability and reduced quality of life. Once established, it is difficult to reverse. Early DSP progresses slowly and currently available surrogate endpoints do not change significantly. Early DSP is characterized by progressive loss of small unmyelinated nerve fibers. Skin biopsy with measurement of intraepidermal nerve fiber density (IENFD) is a reproducible tool to assess these fibers. Data from the Utah Diabetic Neuropathy Study indicate IENFD declines prior to DSP onset. Patients who experience progressive neuropathy have a significantly lower baseline IENFD. These findings suggest IENFD is a sensitive diagnostic measure that could be used to evaluate treatment efficacy. However, IENFD is invasive, technically demanding, expensive, and inconvenient. Corneal confocal microscopy (CCM) noninvasively and directly visualizes small unmyelinated axons on the cornea. CCM is well tolerated and rapid, and is a promising alternative to IENFD. Because reversible metabolic injury segues into irreversible axon loss, there is consensus that therapy should be initiated early. An ideal strategy is identification patients at high DSP risk using a screening strategy in order to facilitate prevention or early intervention. Annual screening for diabetic retinopathy has reduced the risk of diabetes related blindness and serves as a model. Availability of a similar screening method for DSP would enhance patient care and the ability to evaluate novel therapeutics. The proposed studies will evaluate CCM as a diagnostic and screening tool, and surrogate progression measure. There are a number of critical issues that must be resolved before CCM can be routinely used as a diagnostic test or surrogate measure, including demonstration of its clinical meaning and responsiveness to change. Because DSP is a length dependent process, the observation of abnormal corneal innervation is unexpected. Rigorous prospective evaluation is therefore necessary to establish utility. Preliminary data indicate CCM estimation of nerve fiber length (NFL) is highly reproducible, well tolerated and efficient and that NFL and other measures are reduced diabetic patients, more so in those with DSP. Specific aims include development of age and sex stratified normal data, determination of CCM's diagnostic utility and its responsiveness to DSP progression. The clinical meaning of CCM will be assessed by correlation with validated patient reported neuropathy questionnaires and functional measures of mobility and balance. These aims will be achieved by recruiting patients scheduled for their annual retinopathy screening. A major goal is to determine if CCM could be used as an effective screening strategy that would take place at the same time and location as yearly retinal screening. Early identification of patient with DSP would allow clinicians to begin treatment (e.g. lifestyle or ris modification strategies) while DSP is potentially reversible. Development of simple predictive tools for DSP risk would facilitate practically achievable prevention studies, something impossible using current methodologies.

 描述（由申请人提供）：糖尿病影响超过 2500 万美国人；50% 患有远端对称性多发性神经病 (DSP)，一旦形成，就很难逆转。目前可用的替代终点没有显着变化。早期 DSP 的特点是通过测量表皮内神经纤维密度进行皮肤活检。 (IENFD) 是评估这些纤维的可重复工具。来自犹他州糖尿病神经病变研究的数据表明，经历进行性神经病变的患者的 IENFD 基线显着降低。这些结果表明，IENFD 是一种敏感的诊断措施。然而，IENFD 具有侵入性、技术要求高、价格昂贵且不方便，并且可以非侵入性地直接观察微小的情况。角膜上的无髓鞘轴突具有良好的耐受性和快速性，是 IENFD 的一种有希望的替代方案，因为可逆的代谢损伤会导致不可逆的轴突损失，因此应尽早开始治疗，理想的策略是识别高 DSP 的患者。使用筛查策略以促进预防或早期干预的糖尿病视网膜病变的年度筛查降低了糖尿病相关失明的风险，并可作为 DSP 类似筛查方法的可用性。将增强患者护理和评估治疗小说的能力。拟议的研究将评估 CCM 作为诊断和筛查工具以及替代进展衡量标准，然后才能将 CCM 常规用作诊断工具。测试或替代测量，包括证明其临床意义和对变化的反应性，因为 DSP 是一个长度依赖的过程，因此需要进行严格的前瞻性评估来建立 CCM 估计的效用。神经纤维长度 (NFL) 具有高度可重复性、耐受性良好且高效，并且 NFL 和其他测量可减少糖尿病患者，尤其是对于 DSP 患者。具体目标包括开发年龄和性别分层正常数据、确定 CCM 的诊断效用和CCM 的临床意义将通过与经过验证的患者报告的神经病变问卷以及活动性和平衡功能测量的相关性来评估，这些目标将通过招募计划进行年度视网膜病变筛查的患者来实现。目的是确定 CCM 是否可以作为一种有效的筛查策略，与每年进行视网膜筛查的时间和地点同时进行，早期识别 DSP 患者将允许人群在 DSP 的同时开始治疗（例如生活方式或 ris 改变策略）。开发简单的 DSP 风险预测工具将有助于实际可行的预防研究，而使用当前的方法是不可能实现的。