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

 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）。DSP是残疾和生活质量下降的主要原因。一旦建立，就很难逆转。早期DSP进展缓慢，目前可用的替代终点没有显著变化。早期DSP的特征在于小的无髓神经纤维的进行性损失。皮肤活检测量表皮内神经纤维密度（IENFD）是一种可重复的工具，以评估这些纤维。来自犹他州糖尿病神经病变研究的数据表明，IENFD在DSP发作前下降。发生进行性神经病变的患者的基线IENFD显著较低。这些发现表明IENFD是一种敏感的诊断措施，可用于评估治疗效果。然而，IENFD是侵入性的，技术要求高，昂贵，不方便。角膜共聚焦显微镜（CCM）非侵入性地直接观察角膜上的小无髓鞘轴突。CCM具有良好的耐受性和快速性，是IENFD的有希望的替代品。由于可逆的代谢损伤会导致不可逆的轴突损失，因此人们一致认为应尽早开始治疗。理想的策略是使用筛查策略识别DSP高风险患者，以促进预防或早期干预。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，并作为一个模型。DSP的类似筛选方法的可用性将增强患者护理和评估新疗法的能力。拟议的研究将评估CCM作为诊断和筛查工具以及替代进展指标。在CCM可以常规用作诊断测试或替代措施之前，必须解决许多关键问题，包括证明其临床意义和对变化的反应。由于DSP是长度依赖性过程，因此观察到异常角膜神经支配是出乎意料的。因此，为了确定效用，必须进行严格的前瞻性评价。初步数据表明，CCM对神经纤维长度（NFL）的估计具有高度可重复性，耐受性良好且有效，并且NFL和其他措施减少了糖尿病患者，尤其是DSP患者。具体目标包括年龄和性别分层的正常数据的发展，CCM的诊断效用和DSP进展的反应的确定。CCM的临床意义将通过与经验证的患者报告的神经病变问卷以及移动性和平衡功能测量的相关性进行评估。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。一个主要的目标是确定CCM是否可以作为一种有效的筛查策略，在每年的视网膜筛查的同时和地点进行。DSP患者的早期识别将允许临床医生开始治疗（例如生活方式或风险调整策略），而DSP可能是可逆的。DSP风险的简单预测工具的开发将促进实际可实现的预防研究，这是使用当前方法学不可能实现的。

 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.