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

 描述(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)。数字信号处理器是导致残疾和生活质量下降的主要原因。一旦确立，就很难逆转。早期的DSP进展缓慢，当前可用的代理端点没有显著变化。早期DSP的特点是小的无髓神经纤维进行性丢失。皮肤活检和测量表皮内神经纤维密度(IENFD)是评估这些纤维的一种可重复的工具。犹他州糖尿病神经病变研究的数据表明，在DSP发作之前，IENFD下降。进行性神经病患者的基础IENFD显著降低。这些发现表明IENFD是一种敏感的诊断指标，可用于评估治疗效果。然而，IENFD是侵入性的、技术要求高、成本高且不方便。角膜共聚焦显微镜(CCM)非侵入性地直接观察到角膜上的小的无髓鞘轴突。CCM耐受性好，速度快，是IENFD的一种有前途的替代方案。由于可逆性代谢损伤会导致不可逆性轴突丢失，因此人们一致认为应该尽早开始治疗。理想的策略是使用筛查策略识别具有高DSP风险的患者，以便于预防或早期干预。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，并起到了示范作用。类似的DSP筛查方法的可获得性将增强患者护理和评估新疗法的能力。建议的研究将评估CCM作为一种诊断和筛查工具，以及替代进展测量。在CCM被常规用作诊断测试或替代措施之前，有许多关键问题必须解决，包括证明其临床意义和对变化的响应性。由于DSP是一个长度依赖的过程，观察到异常的角膜神经支配是意想不到的。因此，严格的前瞻性评估对于建立实用性是必要的。初步数据表明，CCM对神经纤维长度(NFL)的估计具有高度的重复性、良好的耐受性和高效，并且NFL和其他测量方法可以减少糖尿病患者，尤其是那些患有DSP的患者。具体目标包括发展年龄和性别分层的正常数据，确定CCM的诊断效用及其对DSP进展的响应。CCM的临床意义将通过与有效的患者报告的神经病变问卷和活动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。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，与每年一次的视网膜筛查在同一时间和同一地点进行。及早识别患有DSP的患者将允许临床医生开始治疗(例如，生活方式或RIS调整策略)，而DSP可能是可逆的。开发简单的数字信号处理器风险预测工具将促进实际可实现的预防研究，而使用当前的方法是不可能做到的。

 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.