CN104081416A - 用于客观地表征医学图像的方法和组合物 - Google Patents

用于客观地表征医学图像的方法和组合物 Download PDF

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CN104081416A
CN104081416A CN201380003593.0A CN201380003593A CN104081416A CN 104081416 A CN104081416 A CN 104081416A CN 201380003593 A CN201380003593 A CN 201380003593A CN 104081416 A CN104081416 A CN 104081416A
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CN104081416B (zh
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Z·斯特罗索斯基
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Abstract

本发明提供了用于客观地表征患者的病理性病变的方法和组合物。所述方法包括：向所述患者体内引入造影增强剂；对所述患者进行磁共振成像和计算机断层扫描中的至少一项以获得图像；以及对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。所述方法还可以包括比较所述至少一个三维自相关谱与所述病理性病变所特有的预先存在的三维自相关谱。在一个实例中，所述方法和组合物可用于鉴别和客观地表征阿尔茨海默氏病所特有的淀粉样斑块沉积。

Description

用于客观地表征医学图像的方法和组合物
相关申请的交叉引用
本申请要求2012年1月20日提交的美国临时专利申请No.61/589,165的优先权，所述美国临时专利申请以全文引用的方式并入本文中。
发明背景
在筛检、诊断和治疗许多疾病时经常要获取医学图像。存在多种成像技术，包括例如磁共振成像（MRI）、X射线、计算机断层扫描（CT）、超声波成像以及核医学。确切地说，MRI、X射线和CT产生解剖结构图像，如病理性病变。
现有成像技术的一个局限性在于很少有方法能在不需要人工解释的情况下客观地表征所成像的结构（在病理性病变的情况下）。用于客观性图像分析的一种尝试性方法为二维（2-D）自相关函数。然而，由于多种原因，二维自相关函数在三维（3-D）图像的情形下实际上毫无意义。
需要使用能客观地表征图像的形态指数（即，某些医学图像的形态的一个量度）的系统和方法。因而，本文中提供使用三维自相关函数来客观地表征医学图像的系统和方法。
发明概述
在一个实施方案中，提供了一种用于表征患者的病理性病变的方法，所述方法包括：向所述患者体内引入造影增强剂；对所述患者进行MRI和CT中的至少一项以获得图像；以及对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。所述方法还可以包括比较所述至少一个三维自相关谱与所述病理性病变所特有的预先存在的三维自相关谱。
在另一个实施方案中，提供了一种用于检测患者脑部的淀粉样斑块沉积的方法，所述方法包括：向所述患者体内引入纳米粒子造影增强剂；对所述患者进行MRI和CT中的至少一项以获得图像；以及对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。所述方法还可以包括比较所述至少一个三维自相关谱与脑部淀粉样斑块沉积所特有的预先存在的三维自相关谱。
在另一个实施方案中，提供了一种用于诊断患者的阿尔茨海默氏病的方法，所述方法包括：向所述患者体内引入纳米粒子造影增强剂，所述纳米粒子造影增强剂包含：脂质体，所述脂质体包含：1,2-二棕榈酰-sn-甘油基-3-磷酸胆碱（DPPC）、Gd-DTPA双(硬脂酰胺)（Gd-DTPA-BSA）、胆固醇以及1,2-二硬脂酰-sn-甘油基-3-磷酸乙醇胺-N-[甲氧基(-聚(乙二醇))-2000]（mPEG2000-DSPE）；对所述患者进行MRI以获得图像；以及对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。所述方法还可以包括比较所述至少一个三维自相关谱与阿尔茨海默氏病所特有的预先存在的三维自相关谱。
附图简述
在附图中，给出实验数据，所述实验数据与下文所提供的详细描述一起描述所要求的发明的示例性实施方案。
图1说明在C57BL/6小鼠中进行的大脑磁共振血管造影术。
图2说明图1的大脑磁共振血管造影术中所示的脑部脉管系统的一个子域的二维视图。
图3a说明图2中所述子域的多重分形性和缺项性分析结果，其中所述子域已经过数字处理以便引入模拟淀粉样斑块的合成“孔”。
图3b说明图2中所述子域的二维自相关分析结果，其中所述子域已经过数字处理以便引入模拟淀粉样斑块的合成“孔”。
图4说明淀粉样蛋白阳性小鼠（A到C）和淀粉样蛋白阴性小鼠（D到F）的纵向弛豫时间（Tl）脉管系统图的三维自相关函数。
图5说明颅部脉管系统图像的三维自相关分析，其中所述图像已经过随机数字处理以便引入模拟淀粉样斑块的合成“孔”。
图6说明颅部脉管系统图像的三维自相关分析，其中所述图像已经过数字处理以便沿所述组织中的脉管系统结构引入模拟淀粉样斑块的合成“孔”。
详细描述
提供了用于客观地表征患者的病理性病变的方法和组合物。在一个实施方案中，所述方法包括向所述患者体内引入造影增强剂；对所述患者进行MRI和CT中的至少一项以获得图像；以及对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。所述方法还可以包括比较所述至少一个三维自相关谱与所述病理性病变所特有的预先存在的三维自相关谱。
较高维度下的自相关是如下定义：
A ( τ x , τ y , τ z ) = Σ x Σ y Σ z S ( x , y , z ) S ( x - τ x , y - τ y , z - τ z ) Σ x Σ y Σ z ( S ( x , y , z ) ) 2 .
这个量是函数S在域中任何位置的值相对于其在相距一定距离τ处的值的直接量度。作为一种分析时间的方法，从其原点开始，空间位移τ也称为“延迟”坐标。然而，这个形式上明确的表达式在数值上非常密集，其中每次函数求值的操作数的尺度为η2，其中η是欲使用的延迟间隔数。因而，一维数据的计算相对简单，但二维数据的尺度为η4，且三维数据为η6，从而造成了繁重的计算需要。对于更高阶的自相关函数，维纳-辛钦定理（Wiener-Khinchin theorem）就变得非常有必要，该定理显示自相关性等于原函数功率谱的傅里叶变换（Fourier transform）。使用快速傅里叶变换算法，计算负荷尺度为2ηlogη，这种情形就实际多了。
自相关函数的物理解释直接了当。它在本质上衡量函数在与域中任何起点相距一定距离处的特性。因而，在零延迟坐标处，自相关总是1，因为函数在任何点处都等于它本身。纯随机函数显示{A:Aτ=0=1；Aτ≠0=0}。函数的固有衰减和周期性在自相关中被放大，并且自动按比例放大到范围{0,1}。
在所述方法的一个示范性实施方案中，可以检测患者脑部的淀粉样斑块沉积。因而，向所述患者引入纳米粒子造影增强剂；并且对所述患者进行MRI和CT中的至少一项以获得图像。
如果所选择的成像技术是MRI，则造影增强剂可以包含MR有效纳米粒子造影增强剂，如具有较长循环性质的钆络合物，如Ghaghada,K.B.等,“New dual mode gadolinium nanoparticle contrastagent for magnetic resonance imaging”.PloS One,4(10),e7628.Doi:10.1371/journal.pone.0007628中所描述的双钆脂质体剂，所述文献以全文引用的方式并入本文中。在一个实施方案中，双钆脂质体剂的平均直径小于约200nm。在一个实施方案中，双钆脂质体剂的平均直径小于约175nm。在一个实施方案中，双钆脂质体剂的平均直径小于约150nm。在一个实施方案中，双钆脂质体剂的平均直径为约100nm。另一种合适的MR有效药剂可以包括（钆磷维塞三钠）（由位于美国马萨诸塞州北比尔里卡的Lantheus MedicalImaging,Inc.制造），这是一种具有二苯基环己基磷酸酯基的稳定二亚乙基三胺五乙酸钆（GdDTPA）螯合衍生物。另一种合适的MR有效药剂可以包括包含脂质体的药剂，所述脂质体包含：磷脂（例如DPPC）；用聚合物衍生化的磷脂（例如聚乙二醇化磷脂，如mPEG2000-DSPE）；以及胆固醇，其中所述脂质体囊封、螯合或囊封并螯合呈各种形式的钆。
如果所选择的成像技术是CT，则造影增强剂可以包含CT有效纳米粒子造影增强剂，如包含脂质体的脂质体剂，所述脂质体囊封非放射性造影增强剂，例如碘化非放射性造影增强剂，如碘海醇或碘克沙醇。举例来说，纳米粒子造影增强剂可以包含：脂质体，所述脂质体包含：磷脂（例如DPPC）；用聚合物衍生化的磷脂（例如聚乙二醇化磷脂，如mPEG2000-DSPE）；以及胆固醇，其中所述脂质体囊封非放射性碘化造影增强剂（例如碘海醇和/或碘克沙醇）。在一个实施方案中，纳米粒子造影增强剂的平均直径小于约200nm。在一个实施方案中，纳米粒子造影增强剂的平均直径小于约175nm。在一个实施方案中，纳米粒子造影增强剂的平均直径小于约150nm。在一个实施方案中，纳米粒子造影增强剂的平均直径为约100nm。
在获得图像后，可以将三维自相关函数应用于所述图像中的所关注子域以获得至少一个三维自相关谱。换句话说，在一个实施方案中，三维自相关函数可以在局部意义上应用于谨慎选择的子域，且计算因此具有局限性，而不是计算整个图像的自相关函数。
所述方法还可以包括比较所述至少一个三维自相关谱与脑部淀粉样斑块沉积所特有的预先存在的三维自相关谱。
淀粉样斑块沉积是阿尔茨海默氏病的主要神经病理学标志，并且在可辨别临床症状之前很久就有所显现。因而，在一个实施方案中，所述方法可用于诊断活患者的阿尔茨海默氏病。
在一个实施方案中，可向患者投予纳米粒子造影增强剂，并后续进行MRI/CT和三维自相关分析，以便建立患者的正常图像和光谱的基线谱。在一个实施方案中，在建立基线谱时，患者是健康的。因而，后续给药可以然后例如用于确定相对于基线谱的偏差，所述偏差指示疾病状态。在另一个实施方案中，患者可能已经被诊断为患有已知或疑似改变患者光谱的疾病。在那种情况下，后续给药可以例如用于计量疾病进展程度或确定治疗效果。在又一个实施方案中，基线谱可以反映除研究中患者以外的健康或患病患者的取样。因而，向患者给药可以例如用于确定相对于基线谱或者指示疾病状态或不存在疾病状态的光谱的偏差或相似性。
实施例
下文以实施例形式描述了某些实施方案。不可能描述本发明的每一种可能应用。因而，尽管相当详细地描述了这些实施方案，但不打算使所附权利要求书的范围局限于或以任何方式受限于所述细节或任何特定的实施方案。
实施例1-制备双Gd脂质体
将包含摩尔比为30:25:40:5的DPPC、Gd-DTPA-BSA、胆固醇和mPEG2000-DSPE的脂质混合物溶解在三氯甲烷:甲醇（1:1v/v）混合物中。在真空下将溶剂混合物蒸发到干燥，并且用钆贝葡胺（Gd-BOPTA，500mM Gd）溶液来水合脂质内容物以实现40mM的脂质浓度。在60℃下将溶液搅拌90分钟，然后依次通过400nm核微孔膜挤出五遍、通过200nm核微孔膜挤出七遍且通过100nm核微孔膜挤出十遍。使用具有500kDa分子量截止值的组件（Spectrum Laboratories，CA）渗滤所得溶液以去除未囊封且未螯合的Gd螯合物分子。脂质体的粒径分析指示粒子的直径为约100nm。各种制剂的低多分散性指数指示狭窄粒径分布。超过95%的脂质体的直径小于150nm。
实施例2-小鼠脑部脉管系统的MRI
在使用实施例1的双Gd脂质体以200mg脂质/kg剂量经静脉内注射的C57BL/6小鼠中获取大脑血管造影图。使用快速扰相梯度（FastSpoilt Gradient，FSPGR）研究使用5123图像矩阵和以下参数进行成像：重复时间（TR）=20.0ms；回声时间（TE）=3ms；翻转角（FA）=30°；视场（FOV）=30mm×30mm×30mm；并且产生各向异性体素大小为60μ的图像。图1显示小鼠颅部脉管系统的MRI图像。在图1中，整个颅部脉管系统清楚可见，包括通过颈动脉的第4代分叉周围的韦利斯环（circle of Willis）和微血管。
实施例3-形态计量学分析
为了测试三种形态计量学技术（多重分形性、缺项性以及二维自相关性）的敏感度，在MATLAB中针对各技术实施算法。使用来自于图1的小鼠脑部脉管系统的二维切面，且示于图2中。将具有脂质体造影的T1加权图像窗口化以显示血管信号，但无软组织造影。所述切面相对于中线处于右侧喙状突起处，且包括丘脑和海马体部分中的脉管系统。为了测试形态计量学测量对血管畸形的存在的敏感度，对切面图像进行数字处理以引入低于阈值的“孔”。这些孔将会在淀粉样斑块沉积物使血管扭曲时产生。产生三种所述案例，其中一个案例在所述切面中产生约1mm×0.5mm的单个大孔；其中第二个案例产生约100μ×200μ的单个小孔；且其中第三个案例产生多个小孔。使用随机产生球团的算法来产生孔，这些孔的直径在平均值周围正态分布，类似于扩散受限聚集体，以便模拟淀粉样斑块。当聚集体叠加在血管图像的体素结构上时，它们导致总体和部分体素闭塞，且体素强度完全或部分降到基线。
结果示于图3a和图3b中，案例A（正常孔）、B（大孔）、C（小孔）以及D（若干个小孔）。在各案例中，进行三种形态计量学分析：多重分形谱、缺项性以及二维自相关性。图像清楚显示多重分形特性，这由光谱特有的倒U形所证明。尽管引入一个占据约2%面积的大孔引起在多重分形谱中产生显著变化，但在实际淀粉样沉积中期望这种大变化是不切实际的。在较小面积分数下，多重分形谱不敏感。缺项性的敏感性仍较弱，且仅对最大孔这一组显示差异。二维自相关谱也显示非常微小的变化。
实施例4-基于体积的形态计量术
选择来自于七只不同的小鼠的大脑血管图像。这些小鼠中有三只是年龄在14到21个月范围内且展现出显著认知缺陷和痴呆病征的APP/PSEN1小鼠。这些小鼠中有两只是在同一大体年龄范围内的非转基因同胞。这些小鼠中有两只是约十个月大的正常C57BL/6小鼠。这些小鼠各自的MR大脑血管造影图是使用实施例1的血池造影剂获取。获取顺序如实施例2中所描述。
选择代表如图2中所示的皮层和海马体的体积，且进行三维自相关研究。所述体积为C：52^3个体素。体积C为体积B的子集。体积C内的血管图的三维自相关函数示于图4中（图4显示Tl血管图的三维自相关函数）。上一排中的三个图像（A、B、C）对应于淀粉样蛋白阳性转基因小鼠，而下一行对应于两只年龄相仿的淀粉样蛋白阴性小鼠（非转基因同胞，D和E）和12个月大的对照C57BL/6（F）。
淀粉样蛋白阳性小鼠的特征结构明显，自相关函数中具有显著裂隙，具有C2旋转对称性。相比之下，正常和阴性对照小鼠展现出了特征均匀结构，也展现出了C2对称性。因而，区分两种类型的结构并不重要；还有，它们自身的血管结构在直观上不显著。
相关函数是域中任何两个点之间的相关程度的指示，其中间隔等于相关函数的自变量。因而，完全相关（总在零位移时获得）为1，而非相关事件展现零相关性。因此，图4中各图像的原点为白色，指示在零位移时，相关性为1。其它位置的灰度级指示相关性降低且黑色指示无相关性。因而，在下一行的正常小鼠（D、E、F）中，从原点开始在所有方向上都存在相关性轻微下降现象。暗示在脉管系统（相关函数所取样的域）中的任一点，都与它周围的点存在有限相关性，这将会在正常血管图中预料到。
淀粉样蛋白阳性小鼠的相关函数中的特征性裂隙对应于相关函数在该狭窄裂隙区域中的陡降。裂隙是旋转对称的（C2），表明血管域中存在各向异性点对称（D2n）。不存在这种下降的与裂隙平行的特定方向表明，血管域中存在某些保持相关性的方向。
F也是一只正常小鼠，显示在一定程度上不同的特性，其中在相关性方面具有较小局部化下降。局部化下降表明极具特定方向性的相关性损失，但可明显区别于淀粉样蛋白阳性案例的显著裂隙结构。
实施例5-血管裂隙的模拟
为了确定血管域中相关函数上的裂隙结构的含意，以正常血管图开始模拟裂隙（类似于实施例3中所描述的程序）。各向异性点对称（D2n）将与覆盖有斑块样致密物的血管一致。因而，在血管的轴向方向上，将不存在强度下降现象，而在其它角度下，将环绕参考中心具有点对称性。另一方面，如果斑块未覆盖在血管上，则此对称性将被破坏。
模拟两个案例。首先，合成斑块随机分布于体积中，从而打断了血管，在此情况下存在重叠。第二，合成斑块优选沿血管分布。在两种情况下，都假定斑块在MR图中展现强度损失且看起来与正常组织相似。
图5显示这些“模拟”斑块覆盖在所选组织域中否则将正常的脉管系统上的一个实例。显示了三个案例，其中平均“斑块”大小在半径100μ与300μ之间变化，并且占据组织域总体积的约5%。所选基础案例是17个月大的正常小鼠（非转基因）的血管图。显示血管图像在自相关函数的Z方向（XY平面）和Z横切面（XY平面）上的投影。所述自相关函数都显现出了相关性损失的旋转对称团块，但与淀粉样蛋白阳性小鼠的相关函数不共有任何特性。
另一方面，图6显示合成斑块优选沿脉管系统结构分布的案例。基础案例是17个月大的正常小鼠（非转基因）的血管图。用逐渐增加的图像强度显示斑块（在多个ΔΙ中，未改变的图像强度分布占99%宽度）。图6中还显示模拟斑块的三维透视图，即血管图在各案例的自相关函数的Z方向（XY平面）和Z横切面上的投影。相关图清楚地显现出了淀粉样蛋白阳性案例所特有的旋转对称裂隙结构。
因而，可以得出以下结论：（1）正常小鼠脑部脉管系统显示均匀自相关函数或在一些情况下由于血管信号中的噪音而在相关函数中显示岛状结构，伴随局部下降；以及（2）淀粉样蛋白小鼠脉管系统在自相关函数中显示可明显区别于所有其它形式的特征裂隙结构。
在术语“包括”用于本说明书或权利要求书中的意义上，打算以类似于术语“包含”的方式为包括性的，如同在权利要求中用作过渡性词语时对该术语的解释。此外，在采用术语“或”（例如A或B）的意义上，打算意指“A或B或两者”。当打算指“仅A或B而不是两者”时，则将采用术语“仅A或B而不是两者”。因而，本文中术语“或”的使用为包括性使用，而不是排他性使用。参见Bryan A.Garner,ADictionary of Modern Legal Usage624(1995第2版)。同样，在术语“在……中”或“到……中”用于本说明书或权利要求书中的意义上，打算另外意指“在……上”或“到……上”。最后，在术语“约”联合数字使用的情况下，打算包括所述数字的±10%。举例来说，“约10”可以意指9到11。
如上所述，尽管已经通过描述实施方案而说明了本申请，并且尽管已经相当详细地描述了实施方案，但不打算使所附权利要求书的范围局限于或以任何方式受限于所述细节。其它优势和修改对于本领域技术人员来说将为显而易见的。所以，本申请在其较广泛方面不限于所示出的具体细节和说明性实施例。可在不背离总体发明概念的精神或范围的情况下偏离所述细节和实施例。

Claims (22)

1.一种用于表征患者的病理性病变的方法，所述方法包括：
向所述患者体内引入造影增强剂；
对所述患者进行MRI和CT中的至少一项以获得图像；以及
对所述图像中所关注的子域应用三维自相关函数，以获得至少一个三维自相关谱。
2.根据权利要求1所述的方法，其还包括比较所述至少一个三维自相关谱与所述病理性病变所特有的预先存在的三维自相关谱。
3.根据权利要求1所述的方法，其中所述进行包括对所述患者进行MRI。
4.根据权利要求3所述的方法，其中所述造影增强剂包含：
脂质体，所述脂质体包含：
磷脂；
用聚合物衍生化的磷脂；以及
胆固醇，
其中所述脂质体至少囊封或螯合钆化合物。
5.根据权利要求3所述的方法，其中所述造影增强剂包含：
脂质体，所述脂质体包含：
DPPC；
Gd-DTPA-BSA；
胆固醇；以及
mPEG2000-DSPE。
6.根据权利要求3所述的方法，其中所述造影增强剂包含具有二苯基环己基磷酸酯基的GdDTPA螯合衍生物。
7.根据权利要求1所述的方法，其中所述进行包括对所述患者进行CT。
8.根据权利要求7所述的方法，其中所述造影增强剂包含：
脂质体，所述脂质体包含：
磷脂；
用聚合物衍生化的磷脂；以及
胆固醇，
其中所述脂质体囊封非放射性碘化造影增强剂。
9.根据权利要求7所述的方法，其中所述造影增强剂包含：
脂质体，所述脂质体包含：
DPPC；
mPEG2000-DSPE；以及
胆固醇，
其中所述脂质体囊封碘海醇和碘克沙醇中的至少一种。
10.一种用于检测患者脑部的淀粉样斑块沉积的方法，所述方法包括：
向所述患者体内引入纳米粒子造影增强剂；
对所述患者进行MRI和CT中的至少一项以获得图像；以及
对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。
11.根据权利要求10所述的方法，其还包括比较所述至少一个三维自相关谱与脑部淀粉样斑块沉积所特有的预先存在的三维自相关谱。
12.根据权利要求10所述的方法，其中所述进行包括对所述患者进行MRI。
13.根据权利要求12所述的方法，其中所述纳米粒子造影增强剂包含：
脂质体，所述脂质体包含：
磷脂；
用聚合物衍生化的磷脂；以及
胆固醇，
其中所述脂质体至少囊封或螯合钆化合物。
14.根据权利要求12所述的方法，其中所述纳米粒子造影增强剂包含：
脂质体，所述脂质体包含：
DPPC；
Gd-DTPA-BSA；
胆固醇；以及
mPEG2000-DSPE。
15.根据权利要求12所述的方法，其中所述纳米粒子造影增强剂包含具有二苯基环己基磷酸酯基的GdDTPA螯合衍生物。
16.根据权利要求10所述的方法，其中所述进行包括对所述患者进行CT。
17.根据权利要求16所述的方法，其中所述纳米粒子造影增强剂包含：
脂质体，所述脂质体包含：
磷脂；
用聚合物衍生化的磷脂；以及
胆固醇，
其中所述脂质体囊封非放射性碘化造影增强剂。
18.根据权利要求16所述的方法，其中所述纳米粒子造影增强剂包含：
脂质体，所述脂质体包含：
DPPC；
mPEG2000-DSPE；以及
胆固醇，
其中所述脂质体囊封碘海醇和碘克沙醇中的至少一种。
19.一种用于诊断患者的阿尔茨海默氏病的方法，所述方法包括：
向所述患者体内引入纳米粒子造影增强剂，所述纳米粒子造影增强剂包含：
脂质体，所述脂质体包含：
DPPC；
Gd-DTPA-BSA；
胆固醇；以及
mPEG2000-DSPE；
对所述患者进行MRI以获得图像；以及
对所述图像中所关注的子域应用三维自相关函数以获得至少一个三维自相关谱。
20.根据权利要求19所述的方法，其还包括比较所述至少一个三维自相关谱与阿尔茨海默氏病所特有的预先存在的三维自相关谱。
21.根据权利要求19所述的方法，其中所述DPPC、所述Gd-DTPA-BSA、所述胆固醇以及所述mPEG2000-DSPE的摩尔比率为约30:25:40:5。
22.根据权利要求19所述的方法，其中所述脂质体的平均直径小于约150nm。
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