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

基本信息

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
项目类别：
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

项目摘要

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（适用提供）：糖尿病影响超过2500万美国人； 50％具有不同的对称多神经病（DSP）。 DSP是残疾和生活质量降低的主要原因。建立后，很难逆转。早期DSP的进展缓慢，目前可用的替代端点不会发生显着变化。早期DSP的特征是逐渐丧失了小小的不髓神经纤维。皮肤活检，测量表皮内神经纤维密度（IENFD）是评估这些纤维的可重复性工具。来自犹他州糖尿病神经病研究的数据表明，IENFD在DSP发作之前下降。经历进行性神经病的患者的基线IENFD明显降低。这些发现表明，IENFD是一种敏感的诊断方法，可用于评估治疗效率。但是，IENFD具有侵入性，技术要求，昂贵和不便。角膜共聚焦显微镜（CCM）无创，并直接可视化角膜上的小型不髓鞘轴突。 CCM的耐受性良好和快速，是IENFD的承诺替代品。由于可逆的代谢损伤种子会损失不可逆的轴突损失，因此有共识，应尽早开始治疗。理想的策略是使用筛查策略识别高DSP风险的患者，以促进预防或早期干预。糖尿病性视网膜病的年度筛查降低了与糖尿病相关的失明的风险，并作为模型。 DSP的类似筛查方法的可用性将增强患者护理和评估新型治疗的能力。拟议的研究将评估CCM作为诊断和筛查工具，并替代进展度量。在CCM通常用作诊断测试或替代测量之前，必须解决许多关键问题，包括证明其临床含义和对变化的反应。由于DSP是一个依赖长度的过程，因此异常中央神经神经的观察是出乎意料的。因此，必须进行严格的前瞻性评估以建立效用。初步数据表明CCM的神经纤维长度（NFL）的估计值高度可重现，耐受性且有效，并且NFL和其他措施减少了糖尿病患者，在患有DSP的患者中更是如此。具体目的包括发展年龄和性别分层的正常数据，确定CCM的诊断效用以及其对DSP进展的反应。 CCM的临床含义将通过与经过验证的患者报告的神经病问卷以及活动性和平衡功能指标的相关性评估。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。一个主要目标是确定CCM是否可以用作有效的筛查策略，该策略将在年度视网膜筛查的同时和位置进行。 DSP的早期鉴定DSP患者可以开始治疗（例如生活方式或RIS修改策略），而DSP则可以可逆。开发用于DSP风险的简单预测工具将有助于实际实现的预防研究，这是使用当前方法不可能的。