An Early Imaging Marker of Emphysema

项目概要/摘要 慢性阻塞性肺疾病（COPD）是美国第三大死亡原因， 全球确诊病例达100万例。肺气肿和小气道疾病（SAD）是肺气肿的两个主要组成部分。 慢性阻塞性肺病与严重COPD相关的肺气肿导致肺泡破坏，并且是COPD的主要原因。 这一人群的死亡率。在组织水平上被认为是一种终末期疾病， 一旦确诊，因此，存在明确的未满足的临床需要来鉴定预测早期肿瘤的标记物。 肺气肿发作。小气道疾病是COPD的一种可治疗成分， 肺气肿的潜在前兆。尽管前景看好，但临床技术无法测量 SAD阻碍了其作为标记的使用。我们开发了一种3D分析软件， 这就是所谓的参数响应映射（PRM）。当应用于计算机断层摄影（CT）扫描时， PRM可识别非气肿性空气滞留，这是SAD的一种间接测量方法，即使存在以下情况， 肺气肿事实上，我们已经证明，PRM衍生的功能性SAD的相对肺体积 （%PRMfSAD）预测COPD患者的肺功能下降，突出了其作为COPD指标的潜力 进展然而，%PRMfSAD仅提供了全肺评估，限制了其在检测 肺气肿的发作和局部进展。为了充分认识到PRMfSAD作为肺气肿的预测因子，我们 先进的PRM技术应用拓扑方法，基于闵可夫斯基泛函，我们的3D PRM分类图。被称为拓扑PRM（tPRM），该方法在科学报告中报告 从3D PRMfSAD中提取并量化特征，从而产生相对密度（V;类似于 %PRMfSAD）、表面积（S）、平均宽度（B）和Euler-Poincaré统计量（χ）。我们的初步结果显示 显示tPRMfSAD比%PRMfSAD更好地与临床测量相关。基于这些发现，我们 假设我们的方法将提高PRM对疾病进展的敏感性，同时提供空间 检测肺气肿发作所需的信息。我们设定了三个目标来检验我们的假设。在 目标1，我们将评估我们的tPRM方法对与扫描仪类型相关的CT信号变化的灵敏度， CT采集和重建内核，以及证实tPRM与各种临床指标的相关性 如前所述。在目标2中，我们将确定tPRM对肺气肿和SAD的贡献的区别 如从获得自肺移植受者的冷冻肺芯的microCT分析所测量的， 慢性阻塞性肺病晚期最后，在目标3中，我们将把tPRM在5年时间间隔内的纵向变化与临床- 有关措施.这些目标将通过NIH赞助的临床试验的支持来实现 COPDGene和持续的多中心和多学科合作。相关性：我们预计， 这一努力的成功结果将通过实现以下目标来提高CT成像的诊断能力： 这是肺气肿发病的早期标志，通过精准医疗改善了患者护理。

PROJECT SUMMARY/ ABSTRACT Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death in the US, with nearly 60 million confirmed cases world-wide. Emphysema and small airways disease (SAD) are two main components of COPD. Emphysema, associated with severe COPD, results in alveolar destruction and is a leading cause of mortality in this population. Considered at the tissue level an end-stage disease, there are limited treatment options once diagnosed. As such, there is a clear unmet clinical need to identify markers that predict the early onset of emphysema. Small airways disease, a treatable component of COPD, has been identified in recent studies as a potential precursor of emphysema. Although promising, clinical techniques were unable to measure SAD hindering its use as a marker. This limitation was overcome through our development of a 3D analytical technique called Parametric Response Mapping (PRM). When applied to computed tomography (CT) scans, PRM identifies non-emphysematous air trapping, an indirect measure of SAD, even in the presence of emphysema. In fact, we have demonstrated that the relative lung volume of PRM-derived functional SAD (%PRMfSAD) predicted spirometric decline in COPD patients, highlighting its potential as an indicator of COPD progression. Nevertheless, %PRMfSAD provides only a whole-lung assessment, limiting its potential at detecting the onset and local progression of emphysema. To fully realize PRMfSAD as a predictor of emphysema, we have advanced our PRM technique by applying topological methods, based on the Minkowski Functionals, to our 3D PRM classification maps. Referred to as topological PRM (tPRM), this method reported in Scientific Reports extracts and quantifies features from 3D PRMfSAD resulting in 3D maps of relative density (V; analogous to %PRMfSAD), surface area (S), mean breadth (B) and Euler-Poincaré statistic (χ). Our preliminary results have shown that tPRMfSAD correlated better to clinical measures than the %PRMfSAD. Based on these findings, we hypothesize that our approach will improve PRM sensitivity to disease progression while providing the spatial information needed to detect the onset of emphysema. We have set out three aims to test our hypothesis. In Aim 1, we will evaluate the sensitivity of our tPRM method to CT signal variability associated with scanner type, CT acquisition and reconstruction kernel, as well as corroborate correlations in tPRM to various clinical measures as previously reported. In Aim 2, we will determine distinctions in tPRM to contributions of emphysema and SAD as measured from microCT analysis of frozen explanted lung cores obtained from lung transplant recipients with end-stage COPD. Finally, in Aim 3, we will correlate longitudinal changes over a 5-yr interval in tPRM to clinically- relevant measures. These aims will be accomplished through support from the NIH-sponsored clinical trial COPDGene and continued multi-center and multi-disciplinary collaborations. Relevance: We anticipate that the successful outcome of this effort will improve the diagnostic capability of CT imaging through the realization of an early marker for the onset of emphysema, leading to improved patient care through precision medicine.