CN112788988A - 血管磁共振成像对痴呆的诊断 - Google Patents
血管磁共振成像对痴呆的诊断 Download PDFInfo
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Abstract
提供了一种诊断受试者的阿尔茨海默病和相关痴呆(ADRD病)发作或进展的可能性的方法。该方法要求根据受试者大脑的定量脑血容量(qCBV)图确定大脑不同区域的血管化变化。qCBV是从一幅或多幅脑部定量超短回波时间对比增强(QUTE‑CE)MRI图像中获得的。提供了一种治疗ADRD病患者的方法。还提供了阿尔茨海默病发作和进展的诊断标志物。
Description
相关申请的交叉引用
本申请要求2018年7月27日提交的美国临时申请第62/711,251号的优先权(根据《美国法典》第35篇第119(e)节),该临时申请题为“血管磁共振成像对痴呆的诊断”,其公开内容通过引用的方式并入本文中。
关于联邦资助的研究或开发的声明
本发明是在政府的支持下,由美国国立卫生研究院授予的编号为EB013180的资助下完成的。政府对这项发明有一定的权利。
背景技术
与年龄相关的痴呆症是一个全球性健康问题,影响到全球5000多万人,估计费用超过8180亿美元(WHO Fact Sheet,Dementia,2017)。仅在美国,痴呆症就影响了800多万老年人,总费用为2770亿美元(Alzheimer's Disease Facts and Figures,2018)。随着年龄的增长,阿尔茨海默病(AD)的风险也随之而来,阿尔茨海默病是一种退化性脑部疾病,被评为痴呆症的第一大病因(Wilson,R.S.等人,2012年;Barker,W.W.等人,2002年)。衰老还带来脑血管疾病的风险,传统上认为脑血管疾病是痴呆症的第二大病因(Banerjee,G等人,2015年;Roman,G.C.等人,2004年)。然而,有越来越多的证据表明脑血管疾病在AD的神经退化和痴呆症中起着关键作用(Schneider,J.A.等人,2007年;Wharton,S.B.等人,2011年),并且可能是老年人痴呆症最常见的形式(Gorelick,P.B.等人,2011年;Roman,G.C.等人,2001年)。这种区别很重要,因为脑血管疾病可能是AD病理生理学的一个关键因素(Kalaria,R.N.和Ballard,C.,1999年)。因此,早期发现和治疗脑血管疾病可以降低老年阿尔茨海默病的风险。从2025年到2050年,痴呆症和阿尔茨海默病的早期生物标志物每年可以为当前美国人口节省高达127.2亿至925.6亿美元(Alzheimer's Disease Facts andFigures,2018)。
支持AD的确切生化机制尚未明确。因此,迫切需要开发定量和可靠的生理生物标志物,以用于AD和相关形式的痴呆症的诊断、预后和治疗。
概要
本文提供了一种诊断阿尔茨海默病及相关痴呆症(ADRD)发作或进展可能性的方法。该方法采用测量技术,使用磁共振成像(MRI)超短回波时间(UTE)脉冲序列和血管内造影剂来量化整个大脑的血管分布。该技术允许测量大脑解剖区域每单位体积的血容量。这反过来允许确定大脑的给定解剖区域是富血管化还是乏血管化。根据本文所述技术的一个方面,相对于乏血管化区域,更多数量的富血管化区域表明ADRD病发作的可能性增加。相对于富血管化区域,大量的乏血管化区域表明ADRD进展的可能性增加。在所述技术的另一方面,大脑的富血管化区域的体积大于乏血管化区域的体积表明ADRD病发作的可能性增加,而乏血管化区域的体积大于富血管化区域的体积表明ADRD病进展的可能性增加。在其他方面,富血管化区域与乏血管化区域的比率增加表明ADRD病发作的可能性增加,而该比率的降低表明ADRD病进展的可能性增加。类似地,在所述技术的其他方面,与正常受试者相比富血管化的增加表明ADRD发作的可能性增加,而与正常受试者相比乏血管化的增加表明ADRD进展的可能性增加。此外,使用该技术进行动态测量可以通过利用较短的时标来观察生理血容量调节中的正常振荡以达到确定脑区域的连通性的目的,或者通过提供在神经功能调节(例如缺氧)之后的血容量测量,从而获得血管储备以评估脑血管反应性(CVR)。本文还提供了用于ADRD病的发作和进展的诊断标志物。
使用这种测量技术,在患有ADRD的APOE4临床前大鼠模型(7个月龄)发作前观察到富血管化趋势。这一趋势主要与微血管有关,表明毛细血管或小血管密度的增加可能是痴呆症代谢功能障碍的一种应对机制。在患有ADRD的APOE4临床前大鼠模型中,无论是小血管(微血管或毛细血管密度)还是平均血管分布(计算中包括较大的血管),均观察到了乏血管化的趋势(2岁龄大鼠)。这些观察结果与人类MRI研究的证据一致,其中发现人类APOE4携带者在ADRD发作前有高灌注,而在ADRD发作后观察到低灌注(Kim,S.M.等人,2013)。
在呼吸模型中的CO2挑战中,用95%的空气和5%的CO2代替空气,患有AD的大鼠APOE4模型的反应比野生型(WT)显著得多(约95/174解剖区域比25/174区域具有显著变化,p<0.05)。
CO2挑战在患有ADRD病的APOE4转基因鼠模型中产生了持久的反应。WT大鼠几乎立即从CO2挑战中恢复,而APOE4+大鼠几乎完全没有恢复。此外,再次应用挑战后,APOE4+大鼠的应答被放大(现在~125/174区域显著不同,p<0.05),而WT应答仅~20/174区域。因此,在2岁龄的APOE4+大鼠中发现了过敏反应。在人类的前痴呆或痴呆的最新阶段,如果血管储备已经在休息时被利用,那么可以预期缺氧挑战可能不会导致血管扩张,例如在烟雾病中发现的,已知烟雾病包括高量的富血管化但低CVR,这是因为储备被持续利用。
微血管模式和平均血管分布测量,如每个解剖区域,可用于识别正常老化的统计差异。血管进展可以用定量的方式对大脑的每个解剖区域进行评估。因此,可以评估特定大脑区域的血管病理生理学及其在ADRD中的作用。区域量化还可进行网络级分析。平均血管分布被简单地计算为感兴趣区(ROI)的平均值,每个ROI的分布模式可用作微血管分布的替代。
从疾病发作到进展的由富血管至乏血管趋势以前没有得到证实。本文从富血管至乏血管趋势的论证部分是利用上述测量技术实现的。目前对痴呆的血管发病机制尚不清楚,本文描述的趋势为早期检测ADRD病(占痴呆的60-70%)或早期检测一般意义上的痴呆提供了新的生物标志物。
现有的检测痴呆发作前发生的脑改变的方法需要大量的受试者进行相关统计,因此不适于早期检测。这些方法通常使用功能性MRI(fMRI)、淀粉样蛋白位置发射断层扫描(PET)或tau PET成像。相反,在本文所述的方法中,通过单次测量就可以进行检测。
因此,在本技术的某些方面,提供了检测受试者阿尔茨海默病或ADRD病发作或进展的概率增加的方法。在某些方面,该方法包括(a)获得受试者大脑的一幅或多幅定量超短回波时间对比增强(QUTE-CE)MRI图像,由此通常获得对比前和对比后图像;(b)获得B1+和B1-场测量值,用于获得更准确的结果;(c)从结合B1测量的图像中产生受试者大脑的定量脑血容量(qCBV)图;(d)基于将步骤(c)中获得的qCBV图与代表健康受试者大脑的预定qCBV图进行比较,确定受试者大脑的富血管化区域和乏血管化区域;以及(e)基于对富血管化和乏血管化模式的分析,诊断受试者发生ADRD、ADRD发作或ADRD进展的可能性。
富血管化区域是指与处于相似生理状态的相似年龄的正常大脑的相同区域相比,血管内血容量增加的区域。乏血管化区域是指与处于相似生理状态的相似年龄的正常大脑的相同区域相比,血管内血容量减少的区域。区域的边界可以随意选择,也可以通过标准的解剖学定义来定义。
在其他方面,该方法包括:(a)获取受试者大脑的一幅或多幅定量超短回波时间增强(QUTE-CE)MRI图像,包括对比前后的图像;(b)从该图像产生受试者大脑的定量脑血容量(qCBV)图;(c)基于将在步骤(b)中获得的qCBV图与代表健康受试者大脑的预定qCBV图进行比较,确定受试者大脑的富血管化区域和乏血管化区域;和(d)基于对富血管化和乏血管化区域的分析,诊断受试者患阿尔茨海默病、阿尔茨海默病发作或阿尔茨海默病进展的可能性。
在另一方面,提供了用于受试者的ADRD发作的诊断标志物或一组诊断标志物。合适的诊断标志物包括受试者大脑的一个或多个区域的富血管化,所述区域选自由腹侧被盖区、中缝线状核、网状被盖核、中缝隐核、缰核、中缝正中核、背内侧被盖区、背中缝核、脑桥核、中缝大核、腹侧海马下托、运动三叉神经核、锥体连接管、脑桥网状核尾侧、脑桥网状核口、斜方体、背侧下托、结合臂旁核、中脑网状核、尾椎压后皮质、脑桥被盖部、红核、蓝斑下核、PCRt、下丘脑、面神经核、第九小脑小叶、巨细胞网状核、三叉神经感觉主核、内嗅皮质、三叉神经根、初级视觉皮层、第十小脑小叶、前边缘皮层、前楔形核、边缘下区、上丘、孤束核、丘脑中央导水管周围灰质及其组合组成的组。例如,可以通过比较使用受试者大脑的一幅或多幅QUTE-CE MRI图像获得的受试者的大脑的一幅或多幅图像产生的受试者大脑的qCBV图,并且将qCBV图与代表健康受试者大脑的qCBV图进行比较来确定富血管化,所述健康受试者的大脑优选具有相似的年龄和生理状态,并且优选是预先确定的。
在其他方面,提供了用于受试者的ADRD进展的诊断标志物或一组诊断标志物。所述诊断标志物包括受试者大脑的一个或多个区域的乏血管化,所述区域选自由腹侧被盖区、中缝线状核、网状被盖核、中缝隐核、缰核、中缝正中核、背内侧被盖区、背中缝核、脑桥核、中缝大核、腹侧海马下托、运动三叉神经核、锥体连接管、脑桥网状核尾侧、脑桥网状核口、斜方体、背侧下托、结合臂旁核、中脑网状核、尾椎压后皮质、脑桥被盖部、红核、蓝斑下核、PCRt、下丘脑、面神经核、第九小脑小叶、巨细胞网状核、三叉神经感觉主核、内嗅皮质、三叉神经根、一级视觉皮层、第十小脑小叶、前边缘皮层、前楔形核、边缘下区、上丘、孤束核和丘脑中央导水管周围灰质组成的组,其中,通过比较使用受试者大脑的一幅或多幅QUTE-CE MRI图像获得的受试者大脑的一幅或多幅图像产生的受试者大脑的qCBV图,并将qCBV图与代表健康受试者大脑的qCBV图进行比较来确定乏血管化,所述健康受试者的大脑优选具有相似的年龄和生理状态,并且优选是预先确定的。
在其他方面,提供了一种用于受试者的诊断标志物发作的诊断标志物。所述诊断标志物包括受试者大脑的一个或多个区域的富血管化,所述区域选自由室旁核、腹侧海马下托、背中缝核、二级视觉皮层、背内侧被盖区、下丘脑、运动三叉神经核、初级躯体感觉皮层、三角隔核、腹内侧纹状体、视前外侧区组成的组,其中所述富血管化是通过使用所述受试者大脑的一幅或多幅QUTE-CE MRI图像比较受试者大脑的一幅或多幅图像产生的受试者大脑的qCBV图,以及比较所述qCBV图与代表健康受试者大脑的预先确定的qCBV图来确定的。
在进一步方面,提供了用于受试者的诊断标志物进展的诊断标记或一组诊断标志物。合适的诊断标志物包括受试者大脑的一个或多个区域的富血管化,所述区域选自由室旁核、腹侧海马下托、背中缝核、二级视觉皮层、背内侧被盖区、下丘脑、运动三叉神经核、初级躯体感觉皮层、三角隔核、腹内侧纹状体、视前外侧区组成的组,其中,通过使用受试者大脑的一幅或多幅QUTE-CE MRI图像比较受试者的脑的一幅或多幅图像产生的受试者的脑的qCBV图,并且将所述qCBV图与代表相似年龄和生理状态的健康受试者大脑的qCBV图进行比较,并且优选是预先确定的,来确定乏血管化。
在临床实践中可以对例如二氧化碳的挑战做出动态测量。因此,血管储备的测量也可以作为诊断标志物。疾病状态下的代谢功能障碍可包括对例如缺氧挑战的持久反应,这可能会改善疾病的表征或检测的敏感性。
本文所述的血管诊断标志物可用于早期诊断、预后、护理患者的费用预测,并可作为药物开发的生物标志物。许多ADRD药物临床试验失败是因为缺乏终点表征和治疗开始得太晚(发病后)。通过早期检测有助于预防性护理和规划。
本技术还进一步具有以下方面。
1.一种诊断受试者阿尔茨海默病或相关痴呆(ADRD)的发作或进展的方法,所述方法包括以下步骤:
(a)获得受试者大脑的一幅或多幅定量超短回波时间对比增强(QUTE-CE)MRI图像;
(b)从所述图像产生受试者大脑的定量脑血容量(qCBV)图;
(c)基于将在步骤(b)中获得的qCBV图与代表正常大脑的预定qCBV图进行比较,确定受试者大脑中的富血管化区域和乏血管化区域;和
(d)基于对富血管化和乏血管化区域的分析来诊断所述受试者的ADRD发作或ADRD进展的可能性。
2.所述方法的第I方面,其中在步骤(d)中,相对于乏血管化区域,更大数量的富血管化区域表明受试者已经发生了ADRD的发作。
3.所述方法的第1或2方面,其中在步骤(d)中,相对于富血管化区域,更大数量的乏血管化区域表明受试者已经发生了ADRD的进展。
4.所述方法的1-3中任一方面,进一步包括在后期重复该方法,其中在后期发现步骤(d)中乏血管化区域的数量或程度的减少指示受试者ADRD病的进展。
5.所述方法的1-4中任一方面,进一步包括在后期重复该方法,其中在后期发现步骤(d)中富血管化区域的数量或范围的增加指示受试者ADRD的进展。
6.所述方法的1-5中任一方面,其中基于对微血管、毛细血管密度或平均血管分布的测量来确定乏血管化和/或富血管化。
7.所述方法的1-6中任一方面,其中指示所述受试者的ADRD的进展,并且其中乏血管化和/或富血管化的程度指示受试者ADRD进展的程度。
8.所述方法的1-7中任一方面,其中所述富血管化在受试者大脑的一个或多个区域中,所述区域选自由腹侧被盖区、中缝线状核、网状被盖核、中缝隐核、缰核、中缝正中核、背内侧被盖区、背中缝核、脑桥核、中缝大核、腹侧海马下托、运动三叉神经核、锥体连接管、脑桥网状核尾侧、脑桥网状核口、斜方体、背侧下托、结合臂旁核、中脑网状核、尾椎压后皮质、脑桥被盖部、红核、蓝斑下核、PCRt、下丘脑、面神经核、第九小脑小叶、巨细胞网状核、三叉神经感觉主核、内嗅皮质、三叉神经根、初级视觉皮层、第十小脑小叶、前边缘皮层、前楔形核、边缘下区、上丘、孤束核和丘脑中央导水管周围灰质组成的组。
9.所述方法的1-8中任一方面,其中所述乏血管化在受试者大脑的一个或多个区域中,所述区域选自由腹侧被盖区、中缝线状核、网状被盖核、中缝隐核、缰核、中缝正中核、背内侧被盖区、背中缝核、脑桥核、中缝大核、腹侧海马下托、运动三叉神经核、锥体连接管、脑桥网状核尾侧、脑桥网状核口、斜方体、背侧下托、结合臂旁核、中脑网状核、尾椎压后皮质、脑桥被盖部、红核、蓝斑下核、PCRt、下丘脑、面神经核、第九小脑小叶、巨细胞网状核、三叉神经感觉主核、内嗅皮质、三叉神经根、初级视觉皮层、第十小脑小叶、前边缘皮层、前楔形核、边缘下区、上丘、孤束核和丘脑中央导水管周围灰质组成的组。
10.所述方法的1-9中任一方面,其中所述富血管化在受试者大脑的一个或多个区域中,所述区域选自由室旁核、腹侧海马下托、背中缝核、二级视觉皮层、背内侧被盖区、下丘脑、运动三叉神经核、初级躯体感觉皮层、三角隔核、腹内侧纹状体、视前外侧区组成的组。
11.所述方法的1-10中任一方面,其中所述乏血管化在受试者大脑的一个或多个区域中,所述一个或多个区域选自由室旁核、腹侧海马下托、背中缝核、二级视觉皮层、背内侧被盖区、下丘脑、运动三叉神经核、初级躯体感觉皮层、三角隔核、腹内侧纹状体、视前外侧区组成的组。
12.所述方法的1-11中任一方面,其中获得QUTE-CE MRI图像包括将顺磁性或超顺磁性造影剂引入受试者的大脑。
13.所述方法的第12方面,其中所述顺磁性或超顺磁性造影剂选自由氧化铁纳米颗粒、钆螯合物和钆化合物组成的组。
14.所述方法的第13方面,其中所述氧化铁纳米颗粒包含选自由Fe3O4(磁铁矿)、y-Fe2O3(磁赤铁矿)、a-Fe2O3(赤铁矿)、ferumoxytol、ferumoxides、铁羧葡胺和ferumoxtran组成的组的材料。
15.所述方法的第14方面,其中所述氧化铁纳米颗粒包含ferumoxytol。
16.一种治疗人类受试者ADRD的方法,该方法包括:
实施所述方法的1-15中任一方面以诊断人类受试者中ADRD发作或进展;和
治疗人类受试者的ADRD。
17.所述方法的第16方面,其中所述治疗步骤包括施用胆碱酯酶抑制剂,例如多奈哌齐、利伐斯的明、加兰他敏、美金刚;抗抑郁药例如西酞普兰、氟西汀、帕罗西汀、舍曲林或曲唑酮;抗焦虑药例如劳拉西泮或奥沙西泮;或者抗精神病药如阿立哌唑、氯氮平、氟哌啶醇、奥氮平、喹硫平、利培酮或齐拉西酮或其任意组合。
18.所述方法的第16或17方面,其中治疗人类受试者的步骤包括应用行为疗法;例如改变环境,重新引导注意力,避免对抗,提供休息或监测疼痛、饥饿、口渴、便秘、膀胱充盈、疲劳、感染、皮肤刺激和室温中的一种或多种;及其任意组合。
附图说明
图1A-1C显示了在3DSlicer中渲染的QUTE-CE MRI原始强度的代表性图像。图1A示出了造影前图像(在注射ferumoxytol造影剂之前),图1B示出了造影后图像(在注射ferumoxytol 14mg/kg之后)。渲染参数是等效的。图1C示出了来自图1B的分割的大脑。相关参数包括:3D径向UTE;FOV3×3×3cm3;矩阵网格大小200×200×200;TE 13μs;TR 3.5ms;以及θ=20°,扫描时间=8分22秒,2个平均值。
图2示出了Sprague Dawley大鼠的QUTE-CE MRI图像分析管线和生物标志物测量。关于方法:在左上角的图像中:分别在ferumoxytol注射前和注射后获得零对比度和血管造影图像。请注意,最大强度投影(MIP)图像中的对比度几乎完全是由于7T处存在ferumoxytol造成的,血流效应仅限于外周。线圈灵敏度(B1)和翻转角度分布(B1+)的场校正与对比前和对比后图像之间的运动校正一起应用。在中间的左图中:通过去掉大脑并用定量强度值应用相应的公式计算qCBV。在左下方的图像中:区域的特征是通过使用EVA软件(Ekam Solutions,Boston,MA USA)进行共配准仿射变换,将大脑中的500,000个体素分布到173个区域的图谱中。中间图像:构建了雄性Sprague Dawley大鼠(9-10周龄,n=11)的血管图谱,并应用(右侧)CO2罐测量血管反应性。值得注意的是,在清醒但受机械约束的大鼠上进行成像,以模拟用于人脑临床成像实验的神经生理学条件。因此,还测定了大鼠异氟醚麻醉期间血管变化的方向和幅度(标记为“ISO”)。
图3A显示了野生型(WT)雌性大鼠与APOE4雌性大鼠在24个月大时的乏血管形成。图3B显示了野生型雌性大鼠与APOE4雌性大鼠在8个月和24个月大时的血管密度平均值。图3C显示了野生型雌性大鼠与APOE4雌性大鼠在8个月和24个月大时的毛细血管密度(或小血管)-模式。
图4A示出了在8个月检测到的APOE4和WT的平均血管异常的比较。图4B示出了在8个月按区域检测到的APOE4和WT的微血管异常的比较。
图5A是在8个月大和2岁时小血管和所有血管的血管异常图,显示2岁时出现乏血管趋势。图5B为在APOE4和WT中CO2通道显示代谢功能障碍的CO2挑战图。
图6为在8个月大时的结构差异平均值的结果表。
图7是图6结果的图解说明。
图8是在8个月大时的结构差异模式的结果表。
图9是图8结果的图解说明。
图10是在2岁时结构差异平均值的结果表。
图11是图10的结果的图解说明。
图12是2岁时结构差异模式的结果表。
图13是图12结果的图解说明。
图14是WT大鼠在2岁时的CO2挑战状态下的WT平均差异结果表。
图15是WT大鼠在2岁时的CO2挑战状态的下WT模式差异的结果表。
图16是APOE大鼠在2岁时的CO2挑战状态的下APOE平均差异的结果表。
图17是APOE大鼠在2岁时的CO2挑战状态的下APOE模式差异的结果表。
具体实施方式
本技术采用了一种称为定量超短回波时间对比增强(QUTE-CE)MRI的成像方式(Gharagouzloo等人;2017;Gharagouzloo等人,2015),该方法能够克服MRI信号的半定量性质。初步数据表明,QUTE-CE MRI可以提供从小血管到大血管的大脑“血管体”的高度准确的定量图,为评估微血管对脑功能和神经系统疾病的贡献提供坚实的基础。
本发明人已经利用成像方式QUTE-CE MRI来研究APOE-ε4敲入大鼠模型中的微血管和大血管异常。值得注意的是,APOE-ε4等位基因是AD唯一最重要的遗传风险因素。这项研究涉及表征在大脑173个区域的血管变化。虽然173区的特征显示富血管化和乏血管化,但微血管的变化在早期(大鼠在8个月时)几乎完全是高血供,在后期(24个月时)几乎是低血供。
分辨率和灵敏度使得QUTE-CE可以在500,000个小体积(或体素)中绘制整个大鼠大脑的生理CBV图,这些小体积可以分布在173个解剖学上不同的3D体积上,用于指示毛细血管密度、小血管反应性和血管储备的网络级分析。重要的是,QUTE-CE MRI可以立即进行翻译,并且正在进行一项人类临床试验,以绘制一小群人的健康脑血管分布图。在ApoE4人敲除转基因AD大鼠模型中的初步临床前数据显示,在认知能力下降之前的早期发育阶段,存在富血管化至乏血管化的趋势。
QUTE-CE MRI是一种利用3D UTE脉冲序列和血管内造影剂(CA)来渲染具有定量信号的高对比噪声比(CNR)血管图像的方法。(参见WO2017/019812,在此引入作为参考。)在这种超短TE下,对比度从超顺磁性氧化铁纳米粒子(SPIONs)获得的典型负对比度反转为纯TI-增强的正对比度。可以在整个大鼠大脑中绘制微血管和大血管的定量测量结果,还可以测量状态的功能变化(Gharagouzloo等人,2017)。绝对脑血容量(qCBV)是通过使用二室模型对来自血液和组织的信号进行简单的部分容量计算而计算得到的:
IM=fBIB+(1–fB)IT (1)
其中,IM为每个体素的测量信号强度,IT为组织强度,IB为血液强度以及fB为血液所占体素的比例。通过在导管注射ferumoxytol(Feraheme,AMAGPharmaceuticals,Waltham,Massachusetts,USA,7mg/kg)后,将造影后强度减去造影前强度,按体素计算qCBV。得到血容量分数,
在全脑中测量,每张图像血液参考信号强度取自上矢状窦(SSS)。然后将图像拟合到173解剖区域图谱,利用解剖扫描进行分段分析。报告每个区域的平均qCBV,并将该模式作为微血管密度的替代。
大鼠大脑的定量血管构图从ferumoxytol扫描前后的采集开始。利用了具有用于血液造影和定量的优化参数的3D UTE序列。线圈灵敏度(B1-)和翻转角度分布(B1+)的场校正以及对比前和对比后图像之间的运动校正同时应用。使用两体积的血液/组织模型,并从大血管中获悉血液强度的情况下,对定量CBV(qCBV)进行体素化计算,以生成qCBV图。见图1A-1C为图像对比度,见图2为图像处理管线。对于本文所述的大鼠模型,体素被分布到具有173个区域的解剖学分段图谱中,用于定量分析全脑,包括从模型的区域表征获得的平均血管分布和微血管密度。通过比较健康、正常的血管与转基因大鼠疾病模型发现具有统计学意义的异常。
在WO 2017/019182中详细描述了受试者的QUTE-CE MRI图像的产生过程,当施加到受试者的大脑时,磁场被施加到大脑,随后以选定的重复时间(TR)施加射频脉冲序列,并施加磁场梯度以提供选定的翻转角度(fa)来激发感兴趣区域中的质子。通常,重复时间小于约10ms,FA在约10°至约30°的范围内,在掺杂血液的Ernst角附近或在掺杂和未掺杂血液之间的最大对比度角处。在选定的回波时间(TE)测量质子弛豫期间的响应信号,并采集T1加权信号。回波时间是超短回波时间,设置为小于约300μs。通过这种方式,产生大脑的图像。接下来,通过将药剂注射到血管中以使顺磁性或超顺磁性CA引入受试者的脑中。获得的信号代表大脑中CA的浓度和该大脑区域中特定区域的血液量。
例如,可以将TE设置为小于180μs、160μs、140μs、120μs、100μs、90μs、80μs、70μs、60μs、50μs、40μs、30μs、20μs或10μs。另外,回波的时间可以设置为小于某个时间,在这个时间内,大脑感兴趣区域的血容量位移比体素尺寸小一个数量级左右。可以将TR设置为大约2到10ms左右的值。ROI图像的对比噪声比(CNR)至少为4、至少为5、至少为10、至少为15、至少为20、至少为30、至少为40、至少为50或至少为60。在对比后图像和对比前图像中表示的ROI之间确定CNR。例如,通过检查SSS中的ROI并取两个信噪比(SNR)之间的差值来找到CNR,SNR本身是由任何给定ROI的平均值除以相应图像中噪声的标准偏差来定义的。可以沿着k空间中的轨迹测量响应信号,其中总采集时间可以比TE长。磁场的强度范围为0.2T至14.0T。
应当注意的是感兴趣区域(ROI),例如大脑的特定区域,可以包括由血液占据的体积分数和由组织占据的体积分数。确定血液所占体积分数包括:在将CA引入到ROI之前,在选定的TR处施加射频脉冲序列以激发感兴趣区域中的质子,并且在所选TE处测量质子弛豫过程中的响应信号,以从ROI获取信号;并比较引入CA之前和引入造影剂之后ROI的信号强度。
任何在MRI中提供对比度的顺磁性制剂都可以作为QUTE-CE方法的CA。含有顺磁性氧化铁纳米粒子、含钆对比剂(GBCAs),例如分子螯合物或纳米颗粒,或锰纳米颗粒的化合物可用作CA。例如,如果CA是ferumoxytol,则会将CA以0.1至15mg/kg的浓度引入血液中。纳米颗粒可通过静脉推注或动脉内注射递送,也可重复进行。顺磁性和超顺磁性纳米颗粒可用作CA。顺磁性分子螯合物和超顺磁性纳米颗粒可以作为CA。例如顺磁性纳米颗粒可以是氧化铁、钆或锰纳米颗粒。氧化铁纳米颗粒可以是Fe3O4(磁铁矿),y-Fe2O3(磁赤铁矿),a-Fe2O3(赤铁矿),ferumoxytol、ferumoxides、铁羧葡胺或ferumoxtran。铁氧化物纳米颗粒可以用碳水化合物涂覆,并且通过动态光散射测量其直径,约为1nm至约999nm、或约2nm至约100nm、或约10nm至约100nm。纳米颗粒CAs可以有其他涂层,以使其在血液中循环。纳米颗粒CAs具有不同的尺寸,从而使其可以被肾脏或肝脏排泄。一些钆化合物包括钆磷维塞三钠、钆特酸葡胺、钆塞酸二钠盐、钆布醇、钆喷酸葡胺、钆贝葡胺、钆双胺、钆弗塞胺或钆特醇。
按照以下所述测定ROI中的血液体积分数。首先,施加磁场。接下来在选定的TR处和磁场梯度处施加射频脉冲序列,以提供选定的翻转角度来激发感兴趣区域中的质子。TR小于约10ms,翻转角度约为10°~30°。在选定TE处测量质子弛豫期间的响应信号,以从ROI获取T1加权信号。TE是超短回波时间。约小于300μs。第一图像是在没有CA的情况下使用3DUTE序列生成的。其次,在血液中引入顺磁性或超顺磁性CA。然后,生成ROI的第二图像。测定血液体积分数包括比较引入CA前和引入CA后感兴趣区域的信号强度。具体地,确定血液体积分数包括确定第一图像和第二图像之间的总信号强度的差以及确定第一图像和第二图像之间的血液信号强度的差,其中血液体积分数包括总信号强度差与血液信号强度差的比值。
QUTE-CE MRI是定量的,可直接测定CA浓度以定量MRI,与核成像一样,但无辐射毒性或与放射性药物相关的其他并发症。由于采集到的信号是定量的,该技术可用于采用两种容积法进行部分血容量测量。迄今为止,还没有报道过有可能对全脑的脑血容量(qCBV)进行绝对测量的技术。QUTE-CE MRI可以在单个体素和区域水平上使用解剖或功能图谱来鉴别富血管化或乏血管化、小血管密度和血管储备、血管对CO2挑战的反应性、灌注缺损和标准化摄取值或器官吸收剂量。因此,QUTE-CE MRI为评估功能和状态提供了一套有利的成像生物标志物或诊断标志物。
在某些方面,CA可以是ferumoxytol,一种带有葡聚糖涂层的超小型超顺磁性氧化铁纳米粒子(USPION)。由于其大小超过了肾小球滤过的界限值(~6nm),因此ferumoxytol不会被肾脏清除,而是一种出色的血池造影剂,具有~15h的长血管半衰期(Bremerich等人,2007年)。大量使用ferumoxytol的临床MRI研究已在儿童和成人中进行,未发现重大不良作用(Muehe等人,2016年);因此,QUTE-CE可以很容易地用于临床研究SVD。
与以往临床影像技术的比较。
目前,大脑SVD的临床影像学表现为间接性,多表现为后遗症,如缺血性(白质高信号(WMH)(Reijmer等人,2016)、腔隙性梗死)和出血性(脑内微出血(CMBs))病变(Shi等人,2016;Greenberg等人,2009年)。SVD的此类后果可在常规MRI序列的临床环境中检测到,包括T2/FLAIR(WMH,慢性梗死)、DWI(急性梗死)和敏感性加权成像(SWI)(CMB)(Wardlaw等人,2013)。然而,这些技术在评估微血管病变状态的总体定量负荷的特异性、准确性和可靠性方面存在局限性(Wey等人,2013;Brunser等人,2013年)。此外,目前的MRI技术没有提供关于大脑的小血管系统或血管体(郭等人,2012年)的整体网络的脑微架构的见解,这可能在理解潜在SVD病理和患者的疾病机制方面发挥关键作用,所述患者是中风患者以及明显健康的患有SVD老年人,SVD可能是沉默但持续进行的,并最终导致残疾。因此,迫切需要新的诊断方法来可靠地量化SVD的总范围,以解决SVD相关残疾日益加重的负担。
与用于测量CBV的其他现有技术方法的比较。
SPION成像的其他MRI方法利用了长程易感性诱导效应(Cunninham等人,2005;Stuber等人,2007年;Seppenwoolde等人,2003),而QUTE-CEMRI通过使用比标准模态短1000倍的TEs进行T1增强测量来避免这些问题。请注意,常规T1加权成像不是定量的,也不会使用QUTE-CE而导致获得详细的图像。动态磁敏感对比(DSC)或灌注加权MRI通常用于测量CBV值(Barbier等人,2001),但需要准确确定动脉输入函数(AIF)(Rempp等人,1994;Yankeelov等人,2009),或钆对比剂(GBCA)浓度-时间曲线,该曲线通常有15-30%不准确(Walker-Samuel等人,2007;Schabel等人,2008年)。其他测量CBV的技术,如稳态磁化率对比图(SSGRE)、稳态CBV(SS_CBV)和ΔR2(troprès等人,2001年;Christen等人,2012)都利用了T2和T2*效应,这些效应易受体细胞内和体细胞外去相、流动伪影以及脉管尺寸、密度和取向的影响(Kim等人,2012)。使用SPIONs的铁fMRI与QUTE-CE的不同之处在于它是T2*加权的,需要高CA剂量,并且对血管外间隙敏感(Stuber等人,2007;曼德维尔,2012年)。QUTE-CE是唯一一种能够实现正对比成像而不会引起易感性诱导信号丢失的MR成像技术。
因此,从QUTE-CE MRI获得的qCBV测量值可用作ADRD病的定量诊断标志物。
实施例
所有动物实验均按照IACUC认可的机构方案进行。对5只野生型(WT)和6只7个月大的APOE-ε4敲入雌性大鼠进行QUTE-CE测量,发现有轻度认知障碍体征。
数据表明,初始富血管化可能是一种应对机制,以补偿衰老和痴呆的代谢功能障碍。
方法
行为测试
在翻译神经成像中心(CTNI)上常规进行的认知行为测量是用于空间记忆的Barnes迷宫和用于物体记忆的新事物偏好(NOP)。Barnes和NOP都依赖于海马,但涉及不同的“学习”策略(McLay等人,1997;Assini等人,2009年;Larkin等人,2014年;Pardo等人,2016年)。虽然一次测试就足够了,但是优选进行至少两次测试,其招募相同的功能/区域(例如,记忆/海马)。关注海马依赖功能是可取的,因为它涉及精神疾病和跨物种的相似性(Squire等人,1992)。
动物实验
QUTE-CE MRI标志物
如图2所示为QUTE-CE MRI测量管线。QUTE-CE血管生物标志物:(1)基于体素的生理血分(qCBV)从0-1测量,其中1为动脉或静脉。区域(2)大血管和(3)微血管测量分别通过考虑区域分布的均值或模式获得。高分辨率、173-区域大鼠解剖图谱(Ekam Solutions,Boston,MA USA)详细描述了感兴趣区域体积(VOIs),该图谱使用仿射变换与大脑数字匹配。(4)通过考虑均值与模式之间的距离,可按血管异质性对区域进行分类。(5)动态功能测试,例如5%CO2的高碳酸血症挑战,可用于检查血管储备的反应性。
数据格式和分析的基本原理
在这些测量中,通过使用对比前和对比后的UTE图像计算qCBV。在整个大鼠大脑中,大约8分钟内获得150微米各向同性分辨率的约500,000个体素。然而,可以注意到,虽然产生了明显的血管图像,但是在体素水平的量化仍然具有高度的误差。考虑到基于体素的误差,并考虑到从一只动物到另一只动物的神经解剖结构略有变化,最好对这些小动物的局部血管测量值进行量化。为了实现这一目标,使用手动调整的仿射变换将每只大鼠的大脑拟合到具有173个区域的解剖图谱。在图谱中,大脑的左半部和右半部默认被集中到一个区域。因此,将500,000个体素分布到173个区域中,并计算每个区域的平均值和模式。
为了测试组间比较,将一组的平均值和模式列表与另一组的平均值或模式列表对所有173个区域进行比较。通过t检验两表之间的差异(P<0.05或P<0.01)具有统计学意义。
微血管或小血管的变化与模式有关;其根本原因是,可以预期大部分脑体积主要由较小的血管填充,并且这是一种从100%填充有血液的大血管去除影响的方式。
在8个月大和2岁大的雌性野生型(WT)和APOE4+Sprague Dawley(SD)大鼠上进行了QUTE-CE MRI测量。
8个月大时的实验(全部为雌性SDs)
结构QUTE-CE
第1组(n=5):WT
第2组(n=5):APOE4+
2岁大时的实验(全部为雌性SDs)
结构QUTE-CE
第1组(n=5):WT
第2组(n=5):APOE4+
2岁大时的动态CO2挑战(全部为雌性SDs)
动态QUTE-CE(多重CO2挑战)
第1组(n=5):WT
第2组(n=5):APOE4+
结果
在APOE4敲入雌性大鼠的衰老过程中,使用QUTE-CE MRI纵向测量了血管系统的结构和功能变化。该方法使用了FDA批准的对比剂,并且与现有临床扫描仪兼容,表明该方法可用于人类CNS疾病的常规筛查。
在8个月大的ApoE4大鼠中发现了富血管化
小血管:173个区域中有44个区域改变(P<0.05),其中39个区域增加。参见图6-9。平均血管变化模式由11个增加区和25个减少区组成(p<0.01)。
2岁时出现乏血管化的趋势
在该模型中,雄性比雌性的AD进展速度更快,尽管雌性尚未表现出具有统计学意义的认知功能损害,但静态QUTE-CE MRI显示了存在年龄依赖性的富微血管至乏微血管重塑趋势(图5A、5B)。这种由APOE4基因引起的雄性/雌性损伤趋势已在啮齿动物中得到验证(www.NCBI.NLM.NIH.gov/PMC/articles/PMC 4687024/pdf/nihms 740272.pdf)。通过回波平面成像(EPI)测量,发现高微血管趋势与表现出高连通性的脑区高度相关。根据Barnes迷宫和新物体识别测试,发现雌性在2岁大时出现认知障碍(p<0.05)。
ApoE4大鼠:过敏性和迟滞性血管功能障碍
动态QUTE-CE MRI显示血管储备过度敏感募集。(图5B)观察到ApoE4大鼠对呼吸5%CO2气体具有非常显著的反应,并且与WT不同,它们在1分钟的休息期间没有恢复。这些数据可能表明,初始富血管化可能是补偿衰老和痴呆代谢功能障碍的一种应对机制。
在8个月大时的结构差异
图6-9中的表格列出了关于结构差异的结果,包括平均值(p<0.01,上图)和模式(p<0.05,下图)。显示了P值,且可获得两组中所有动物的平均qCBV和STD(参见方法,年龄在8个月大时的组的比较)。区域编号是在解剖图谱中指定的区域编号,并且已对行进行组织,以使最大qCBV(APOE4平均值或模式–WT平均值或模式)位于顶部(富血管化APOE4)。在比较模式的底部表格右侧,区域名称及其p值按从最高到最低的顺序列出。在173个区域中,省略了非重要区域。
在2岁大时的结构差异
图10-13中的表从平均值(p<0.01,左)和模式(p<0.05,右)两方面列出了关于结构差异的结果。提供了H值和P值,还提供了WT和APOE4的平均qCBV以及STD。计算两组之间的差异,并采用用于减去平均值的误差传播法计算差异的标准差。区域编号是解剖图谱中指定的区域编号,并且已对行进行组织,以使最大减少量位于顶部(乏血管化APOE4),依此类推。如果这些相同的区域在8个月大的大鼠中的变化也具有统计学意义,则这些区域已被着色为深灰色和较深灰色。如果它们富血管化,左侧代表8个月大的状态的颜色为深灰色(原始颜色为红色);如果乏血管化,则为深灰色(原始颜色为蓝色)。右侧的颜色对应于2岁大的状态下的乏血管化或富血管化。
就平均值而言,可以观察到,在2岁大时具有统计学意义的66个变化区域中,18个在8个月大时也具有统计学意义。其中13个区域乏血管化并保持乏血管化,3个区域富血管化并保持富血管化,2个区域富血管化并变为乏血管化,但均未从乏血管化变为富血管化。
对于该模式,可以观察到,在2岁大时具有统计学意义的32个变化区域中,6个在8个月大时也具有统计学意义。其中两个区域乏血管化且保持乏血管化,两个区域富血管化且保持富血管化,两个区域富血管化并变为乏血管化,但均未从乏血管化转变为富血管化。
2岁大时的动态CO2
图14-17中的表列出了在2岁大时测试的两组的结果。这些表列出了CO2挑战状态下的平均值和模式差异。这意味着M1及其STD代表了每只动物在每个地区的差异平均值。通过遵循动物内差异的平均值而不是绝对值,可以检验统计显著性而忽略动物间的比较。
将所有内容与计算qCBV的第一次对比后扫描(扫描1)进行比较。扫描2-4是在打开CO2(M1为平均差异),关闭CO2(M2为平均差异)和最后打开CO2(M3为平均差异)的情况下进行的。还提供了h和p值。注意,比较h1、p1对应于第一CO2状态;h2,p2是切换回CO2的时间;h3,p3是CO2重新打开CO2的时间。
如本文所用,“基本上由……组成”允许包括实质上不影响权利要求的基本和新颖特征的材料或步骤。本文对术语“包括”的任何叙述,特别是在组合物的组分的描述中或在装置的元件的描述中,都可以用“基本上由……组成”或“由……组成”来代替。
尽管已经结合某些优选实施例描述了本技术,但是本领域普通技术人员在阅读了前述说明书之后将能够对本文阐述的组成和方法进行各种改变,等同物的替换以及其他改变。
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Claims (18)
1.一种诊断受试者阿尔茨海默病或相关痴呆(ADRD)的发作或进展的方法,所述方法包括以下步骤:
(a)获得受试者大脑的一幅或多幅定量超短回波时间对比增强(QUTE-CE)MRI图像;
(b)从所述图像产生受试者大脑的定量脑血容量(qCBV)图;
(c)基于将在步骤(b)中获得的qCBV图与代表正常大脑的预定qCBV图进行比较,确定受试者大脑中的富血管化区域和乏血管化区域;和
(d)基于对富血管化和乏血管化区域的分析来诊断所述受试者的ADRD发作或ADRD进展的可能性。
2.如权利要求1所述的方法,其中在步骤(d)中,相对于乏血管化区域,更大数量的富血管化区域表明受试者已经发生了ADRD的发作。
3.如权利要求1所述的方法,其中在步骤(d)中,相对于富血管化区域,更大数量的乏血管化区域表明受试者已经发生了ADRD的进展。
4.如权利要求1所述的方法,进一步包括在后期重复该方法,其中在后期步骤(d)中发现乏血管化区域的数量或程度的减少指示受试者ADRD病的进展。
5.如权利要求1所述的方法,进一步包括在后期重复该方法,其中在后期步骤(d)中发现富血管化区域的数量或范围的增加指示受试者ADRD的进展。
6.如权利要求1所述的方法,其中基于对微血管、毛细血管密度或平均血管分布的测量来确定乏血管化和/或富血管化。
7.如权利要求1所述的方法,其中指示所述受试者的ADRD的进展,并且乏血管化和/或富血管化的程度指示受试者ADRD进展的程度。
8.如权利要求1所述的方法,其中所述富血管化在受试者大脑的一个或多个区域中,所述区域选自由腹侧被盖区、中缝线状核、网状被盖核、中缝隐核、缰核、中缝正中核、背内侧被盖区、背中缝核、脑桥核、中缝大核、腹侧海马下托、运动三叉神经核、锥体连接管、脑桥网状核尾侧、脑桥网状核口、斜方体、背侧下托、结合臂旁核、中脑网状核、尾椎压后皮质、脑桥被盖部、红核、蓝斑下核、PCRt、下丘脑、面神经核、第九小脑小叶、巨细胞网状核、三叉神经感觉主核、内嗅皮质、三叉神经根、初级视觉皮层、第十小脑小叶、前边缘皮层、前楔形核、边缘下区、上丘、孤束核和丘脑中央导水管周围灰质组成的组。
9.如权利要求1所述的方法,其中所述乏血管化在受试者大脑的一个或多个区域中,所述区域选自由腹侧被盖区、中缝线状核、网状被盖核、中缝隐核、缰核、中缝正中核、背内侧被盖区、背中缝核、脑桥核、中缝大核、腹侧海马下托、运动三叉神经核、锥体连接管、脑桥网状核尾侧、脑桥网状核口、斜方体、背侧下托、结合臂旁核、中脑网状核、尾椎压后皮质、脑桥被盖部、红核、蓝斑下核、PCRt、下丘脑、面神经核、第九小脑小叶、巨细胞网状核、三叉神经感觉主核、内嗅皮质、三叉神经根、初级视觉皮层、第十小脑小叶、前边缘皮层、前楔形核、边缘下区、上丘、孤束核和丘脑中央导水管周围灰质组成的组。
10.如权利要求1所述的方法,其中所述富血管化在受试者大脑的一个或多个区域中,所述区域选自由室旁核、腹侧海马下托、背中缝核、二级视觉皮层、背内侧被盖区、下丘脑、运动三叉神经核、初级躯体感觉皮层、三角隔核、腹内侧纹状体、视前外侧区组成的组。
11.如权利要求1所述的方法,其中所述乏血管化在受试者大脑的一个或多个区域中,所述一个或多个区域选自由室旁核、腹侧海马下托、背中缝核、二级视觉皮层、背内侧被盖区、下丘脑、运动三叉神经核、初级躯体感觉皮层、三角隔核、腹内侧纹状体、视前外侧区组成的组。
12.如权利要求1-11任一项所述的方法,其中获得QUTE-CE MRI图像包括将顺磁性或超顺磁性造影剂引入受试者的大脑。
13.如权利要求12所述的方法,其中所述顺磁性或超顺磁性造影剂选自由氧化铁纳米颗粒、钆螯合物和钆化合物组成的组。
14.如权利要求13所述的方法,其中所述氧化铁纳米颗粒包含选自由Fe3O4(磁铁矿)、y-Fe2O3(磁赤铁矿)、a-Fe2O3(赤铁矿)、ferumoxytol、ferumoxides、铁羧葡胺和ferumoxtran组成的组的材料。
15.如权利要求14所述的方法,其中所述氧化铁纳米颗粒包含ferumoxytol。
16.一种治疗人类受试者ADRD病的方法,所述方法包括:
实施如权利要求1所述的方法以诊断人类受试者中ADRD发作或进展;和
治疗人类受试者的ADRD。
17.如权利要求16所述的方法,其中所述治疗步骤包括施用胆碱酯酶抑制剂,例如多奈哌齐、利伐斯的明、加兰他敏、美金刚;抗抑郁药例如西酞普兰、氟西汀、帕罗西汀、舍曲林或曲唑酮;抗焦虑药例如劳拉西泮或奥沙西泮;或者抗精神病药如阿立哌唑、氯氮平、氟哌啶醇、奥氮平、喹硫平、利培酮或齐拉西酮或其任意组合。
18.如权利要求16所述的方法,其中治疗人类受试者的步骤包括应用行为疗法;例如改变环境,重新引导注意力,避免对抗,提供休息或监测疼痛、饥饿、口渴、便秘、膀胱充盈、疲劳、感染、皮肤刺激和室温中的一种或多种;及其任意组合。
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US20160000945A1 (en) * | 2013-02-21 | 2016-01-07 | University Of Rochester | Methods for evaluating brain-wide paravascular pathway for waste clearance function and methods for treating neurodegenerative disorders based thereon |
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US20160000945A1 (en) * | 2013-02-21 | 2016-01-07 | University Of Rochester | Methods for evaluating brain-wide paravascular pathway for waste clearance function and methods for treating neurodegenerative disorders based thereon |
WO2018094076A1 (en) * | 2016-11-16 | 2018-05-24 | Sanford Burnham Prebys Medical Discovery Institute | Peptides and antibodies for detecting changes in alzheimer's disease brain and methods of use thereof |
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