国产化淀粉样蛋白显像剂[~（11）C]6-OH-BTA-1结合~（18）F-FDG PET在阿尔茨海默病中的应用研究
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摘要
第一部分淀粉样蛋白显像剂11C-PIB国产化及临床应用可行性分析
目的：在原有的化学合成模块基础上,研究淀粉样蛋白显像剂[N一甲基-11C]2-[4’-(甲氨基)苯基]-6-羟基苯并噻唑(11C-6-OH-BTA-1, 111C-PIB,即匹兹堡化合物)自动化制备,实现PIB前体及制备的完全国产化。并对制备的PIB质量控制,进行药物临床应用的可行性分析。方法：采用氢化锂铝/四氢呋喃(LAH/THF)还原法制得的“C-碘代甲烷(11CH3I)在线转换成活性更高的“C-三氟磺酸甲酯(11CH3OTf),通入锥形反应瓶内和PIB前体(6-OH-BTA-O,进口及自制前体)丁酮溶液在盐冰浴条件下反应,利用改进的HPLC方法纯化产品,并对最终产品进行质量控制；比较国产化和进口前体的PIB生物学特性及安全性；进行不同人群脑部PET显像,验证国产化PIB的可行性、图像质量及注射后病人的不良反应评估。结果：通过改进自动化制备工艺,最终得到可供注射的11C-PIB10%乙醇溶液,产品中完全不含乙腈；合成的1'C-PIB在物理学、化学、生物学方面的鉴定结果均符合SFDA颁布的《正电子放射性药物质量控制指导原则》。自制前体(6-8mg)的用量相对于进口前体(1mg)用量较大,但价格相对便宜；在合成成功率、放化产率、放化纯度、产率方面,自制前提分别为95.4%、(40±4)%、92%-93%、(27±5)%,进口前提分别为87.5%、(40±4)%、92%-93%、(25±5)%；二者相似。在注射后患者除出现不同程度的疼痛(含有少量的乙醇溶液),均无其他不良反应(如过敏反应、头痛、静脉炎等症状)。自制前体的PIB显像剂脑部显像图像质量清晰,各脑区的放射性分布情况在与文献报道一致,与进口前体制备无明显差异；国产化试剂及进口前体制备的PIB PET脑部显像的全脑放射性-时间曲线变化一致。结论：自制国产化前体的11C-PIB制备路线稳定；对人体显像安全可靠；证明自行研制PIB前体制备及PIB完全国产化的可行性。
第二部分aMCI及AD基于统计参数图的FDG PET研究
目的：利用氟-18标记的脱氧葡萄糖正电子发射断层成像(18F-FDG PET)研究阿尔茨海默病(Alzheimer's disease, AD)、遗忘型轻度认知障碍(amnestic-typemild cognitive impairement, aMCI)患者相对于正常老年人脑部葡萄糖代谢改变的特点。方法：运用PET对27例轻度AD患者、10例aMCI患者及21例年龄匹配人群进行脑葡萄糖代谢成像,基于Matlab平台上SPM8对扫描获得的脑葡萄糖代谢图像进行预处理,再对AD组、aMCI组和对照组的葡萄糖代谢水平进行基于体素的统计学分析。结果：与正常老年组比较,AD组大脑葡萄糖代谢减低的脑区包括后扣带回(BA23、31)及楔前叶(BAl9)、双侧顶叶(BA40)、双侧颞叶(BA20、21、22、37)、双侧额叶(BA6、9、10)等部位(p<0.001, uncorrected, K≥50 voxels)。AD组大脑葡萄糖代谢相对于aMCI组减低的脑区包括后扣带回(BA23、31)及楔前叶(BAl9)、颞顶叶(BA40、20、21、22、39)及额叶(BA6、8、9)等部位(p<0.001, uncorrected,K≥50体素)。AD组与aMCI组葡萄糖减低的体素数目要少于AD组与正常对照组的体素数目。aMCI组葡萄糖代谢相对于正常组仅右侧枕叶的舌回(BAl7)有局部减低(p<0.05, uncorrected)。结论：基于像素水平的分析研究能早期发现AD患者的葡萄糖代谢减低模式改变。对轻微的认知功能障碍人群的脑部葡萄糖代谢有所减低但不显著,与AD有一定的区别。
第三部分“C-PIB PET结合FDG在认知功能改变人群中的临床应用研究
目的：运用自主合成的PIB进行脑部PET显像,分析AD、aMCI、正常对照组及其他认知功能障碍的PIB显像的脑部分布特征,并结合FDG代谢的变化对AD的早期诊断提供参考价值。方法：运用PET对13例轻度AD患者、6例aMCI患者及6例正常老年人进行脑PIB及FDG代谢显像。视觉分析不同人群PIB的分布特点,比较FDG、PIB对AD、aMCI、正常人及其他认知功能障碍的鉴别价值。Listmode软件RO1分析不同人群的脑皮质区的时间一放射性曲线、脑皮质／小脑的SUVR的变化曲线；基于Matlab平台上SPM8对扫描获得的脑PIB图像进行预处理,比较轻度AD组、aMCI组和对照组PIB基于体素差异的统计学分析。结果：所有人群早期都呈现快速血流相分布,随后小脑区域PIB快速洗脱；40分钟后不同人群PIB分布出现差异。所有AD及4例MCI的额叶、外侧颞叶、后扣带回及楔前叶PIB滞留明显,而正常对照组的相关区域PIB滞留量较少。正常人群的皮质功能区与小脑比值SUVR曲线显示呈下降趋势,而AD患者与小脑的SUVR比值提示30min后曲线呈上升趋势。PIB对AD诊断的敏感度为100%,而FDG为84.6%；正常对照组PIB与FDG诊断的具有一致性。但对aMCI的判断上有较大的差异,6例aMCI的FDG无明显特异性的改变而不能判断,而PIB有4例呈类AD表现。其他3例因进行性核上性麻痹、额颞叶痴呆、血管性痴呆无淀粉样蛋白沉积呈阴性表现,FDG有不同程度的改变。与正常对照组比较,AD组的额叶、外侧颞叶、顶叶、前后扣带回、楔前叶、基底节区域的PIB滞留量增加,内侧颞叶无增加(p<0.001, uncorrected, K≥50像素)；aMCI组的额叶、外侧颞叶、后扣带回、楔前叶、前扣带回的PIB治疗增加。40分钟后SUVR表明,AD患者呈上升趋势而正常人群呈下降趋势。结论：40分钟后PIB在AD中滞留量多,与小脑的SUVR曲线呈上升趋势,并与正常人及其他认知功能障碍分布不同,PIB对AD诊断和鉴别诊断是可行的；FDG代谢未见改变的aMCI人群PIB PET分布模式“类AD”表现；PIB在早期AD诊断方面有可能成为常规影像诊断的可能。
ENGLISH ABSTRACT
PartⅠ
The research of Beta amyloid imaging with domestic 11C-PIB and evaluation the efficiency in clinical utilities
Purpose:Based on the former chemical synthesis module, we investigated the automated synthesis of AD amyloid imaging agent [11C]6-OH-BTA-1 (11C-PIB), aimed at completely domestic produce of PIB and its precursor. In addition, we took quality control of PIB and verified the clinical efficacy of drugs by the clinical applications. Material and methods:Turn 11C-iodo methane (11CH3I) deoxidized from lithium aluminum hydride/THF (LAH/THF) ion into 11C-trifluoro-methanesulfonate (11CH3OTf) with higher activity, then introduced into conical reaction flask with PIB precursor (6-OH-BTA-O, imported and home-made precursors) inside. Reaction is on ice-salt conditions in butanone solution. Then employed the improved HPLC to purify the products, and took quality control finally. Biological characteristics and safety of the self-produced PIB precursors and the import ones were compared; Groups of subjects took brain PET imaging to verify the feasibility of self-produced PIB, image quality and adverse reactions after injection were assessed. Results:With the improved automatic produce process,11C-PIB in 10% ethanol solution available for injection was ultimately produced, which is completely free of acetonitrile. Physical, chemical, biological qualities of 11C-PIB were consistent with SFDA issued "positron radiopharmaceutical quality control guidelines". Relative to the produce amount of imported precursor (1mg), Self-produced precursor (6-8mg) needed a larger amount, but the price is relatively cheaper, while the success rate of synthesis, the radiochemical yield, radiochemical purity, production rate were similar. Except distinctive pain occur after injection (with a small amount of ethanol solution), no other adverse reactions observed. Brain PET imaging with agent self-produced PIB showed high quality and the distribution of radioactivity were consistent with former literature. No significant difference was noticed in the curve of time-global activity between self-produced and imported PIB. Conclusions:The self-produced precursors of 11C-PIB production route is stable and safe for human brain imaging, which support proof of feasibility of self production of PIB and its precursor. Key words:Positron emission tomography; quality control; [N-methyl-11C]2-[4'-(methylamino)phenyl]-6-hydroxyphenylbenzothiazole CLC number:R817.4
Part II
Research of FDG PET in Alzheimer's disease and mild cognitive impairment using Statistical Parametric Mapping
Purpose:Voxel-based analysis of the regional cerebral glucose metabolism in patients with mild Alzheimer's disease (AD), amnestic-type mild cognitive impairment (aMCI) compared to normal aging as control associated with characteristic and progressive reductions with Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET).
Material and Methods:Twenty-seven patients with mild AD patients,10 aMCI patients and 21 age-matched normal aging were enrolled in this study. Glucose metabolism differences of brain were assessed by Statistical Parametric Mapping 8 (SPM8) based on the Matlab platform to compare the normal aging with the cognitive declined. Results:In comparison with the normal aging group, the AD group had significantly lower brain glucose metabolism in posterior cingulate (BA23,31), precuneus (BA19), bilateral parietal (BA40), bilateral temporal lobe (BA20,21,22,37) and bilateral frontal cortex (BA6,9,10) (p<0.001, uncorrected, K≥50 voxels). Compared with the aMCI group, the AD group had hypometabolism in posterior cingulate (BA23, 31), precuneus (BA19), temporal lobe (BA40,20,21,22,39) and frontal cortex (BA6,8,9) (p<0.001, uncorrected, K≥50 voxels). Decreased voxels of glucose metabolism between the AD group and the aMCI group were less than those between the AD group and the normal aging group. Brain glucose metabolism in aMCI group compared to the normal aging group decreased only in the right occipital cortex (BA17) (p<0.05, uncorrected). Conclusion: Voxel-wise comparison of glucose metabolism in whole brain between the patients and the normal aging can reveal widespread hypomeabolism in mild Alzheimer's disease. However aMCI had less metabolism reduction than the normal aging.
Part III
The research of 11C-PIB amyloid imaging combined with 18F-FDG PET in normal aging and cognitive declined
Objective:Beta amyloid plaques and impaired glucose metabolism are the most prevalent pathological characteristics of Alzheimer's disease (AD). The aim was to reveal the characteristics of positron emission tomography (PET) imaging using radiotracers (11)C-Pittsburgh compound B (PIB) in normal aging and the cognitive declined combined with fluoro-deoxyglucose (FDG) PET.
Material and Methods:Six normal aging,6 aMCI patients,13 mild AD patients and 3 other cognitive declined patients were enrolled in this study. The normal aging and the cognitive declined was compared by the distribution of PIB in the whole brain. It was assessed by visual analysis, regional of interest (ROI) analysis and Statistical Parametric Mapping 8 (SPM8) based on the Matlab platform. Results:The distribution of PIB showed rapid blood flow in early phase and then washed out quickly especially in cerebellum in all subjects. The type of distribution was different 40 minutes later after injection in AD and the normal aging. PIB retention was high in frontal, lateral temporal lobe, posterior cingulate and precuneus in the AD and four aMCI. Only little PIB was distributed in white matter and pons in the normal aging. The sensitivity of PIB was 100% while FDG was 84.6% in AD; PIB was negative in progressive supranuclear palsy, frontotemporal dementia and vascular dementia while FDG had changes. Compared with the normal aging, frontal, lateral temporal lobe, parietal lobe, cingulate, precuneus, and basal ganglia increased in AD and MCI(p<0.001, uncorrected, K≥50 pixels). No difference was found in medial temporal lobe. The curve of SUVR increased in AD while decreased in the normal aging from 40 to 60 minutes. Conclusions:The amount of PIB retention was different in AD other than the normal aging after 40 minutes post-injection which can diagnose and differentiate the different types of cognitive dysfunction. The SUV Ratio curve rase after 40 minutes which tested the feasibility of PIB in diagnosis of AD. The distribution of PIB was positive in all subjects. But 4 AD-like MCI patients were negative with glucose metabolism. Based on the above, we can conclude that PIB might be useful in the early stage of possible AD (aMCI).
目的：在原有的化学合成模块基础上,研究淀粉样蛋白显像剂[N一甲基-11C]2-[4’-(甲氨基)苯基]-6-羟基苯并噻唑(11C-6-OH-BTA-1, 111C-PIB,即匹兹堡化合物)自动化制备,实现PIB前体及制备的完全国产化。并对制备的PIB质量控制,进行药物临床应用的可行性分析。方法：采用氢化锂铝/四氢呋喃(LAH/THF)还原法制得的“C-碘代甲烷(11CH3I)在线转换成活性更高的“C-三氟磺酸甲酯(11CH3OTf),通入锥形反应瓶内和PIB前体(6-OH-BTA-O,进口及自制前体)丁酮溶液在盐冰浴条件下反应,利用改进的HPLC方法纯化产品,并对最终产品进行质量控制；比较国产化和进口前体的PIB生物学特性及安全性；进行不同人群脑部PET显像,验证国产化PIB的可行性、图像质量及注射后病人的不良反应评估。结果：通过改进自动化制备工艺,最终得到可供注射的11C-PIB10%乙醇溶液,产品中完全不含乙腈；合成的1'C-PIB在物理学、化学、生物学方面的鉴定结果均符合SFDA颁布的《正电子放射性药物质量控制指导原则》。自制前体(6-8mg)的用量相对于进口前体(1mg)用量较大,但价格相对便宜；在合成成功率、放化产率、放化纯度、产率方面,自制前提分别为95.4%、(40±4)%、92%-93%、(27±5)%,进口前提分别为87.5%、(40±4)%、92%-93%、(25±5)%；二者相似。在注射后患者除出现不同程度的疼痛(含有少量的乙醇溶液),均无其他不良反应(如过敏反应、头痛、静脉炎等症状)。自制前体的PIB显像剂脑部显像图像质量清晰,各脑区的放射性分布情况在与文献报道一致,与进口前体制备无明显差异；国产化试剂及进口前体制备的PIB PET脑部显像的全脑放射性-时间曲线变化一致。结论：自制国产化前体的11C-PIB制备路线稳定；对人体显像安全可靠；证明自行研制PIB前体制备及PIB完全国产化的可行性。
第二部分aMCI及AD基于统计参数图的FDG PET研究
目的：利用氟-18标记的脱氧葡萄糖正电子发射断层成像(18F-FDG PET)研究阿尔茨海默病(Alzheimer's disease, AD)、遗忘型轻度认知障碍(amnestic-typemild cognitive impairement, aMCI)患者相对于正常老年人脑部葡萄糖代谢改变的特点。方法：运用PET对27例轻度AD患者、10例aMCI患者及21例年龄匹配人群进行脑葡萄糖代谢成像,基于Matlab平台上SPM8对扫描获得的脑葡萄糖代谢图像进行预处理,再对AD组、aMCI组和对照组的葡萄糖代谢水平进行基于体素的统计学分析。结果：与正常老年组比较,AD组大脑葡萄糖代谢减低的脑区包括后扣带回(BA23、31)及楔前叶(BAl9)、双侧顶叶(BA40)、双侧颞叶(BA20、21、22、37)、双侧额叶(BA6、9、10)等部位(p<0.001, uncorrected, K≥50 voxels)。AD组大脑葡萄糖代谢相对于aMCI组减低的脑区包括后扣带回(BA23、31)及楔前叶(BAl9)、颞顶叶(BA40、20、21、22、39)及额叶(BA6、8、9)等部位(p<0.001, uncorrected,K≥50体素)。AD组与aMCI组葡萄糖减低的体素数目要少于AD组与正常对照组的体素数目。aMCI组葡萄糖代谢相对于正常组仅右侧枕叶的舌回(BAl7)有局部减低(p<0.05, uncorrected)。结论：基于像素水平的分析研究能早期发现AD患者的葡萄糖代谢减低模式改变。对轻微的认知功能障碍人群的脑部葡萄糖代谢有所减低但不显著,与AD有一定的区别。
第三部分“C-PIB PET结合FDG在认知功能改变人群中的临床应用研究
目的：运用自主合成的PIB进行脑部PET显像,分析AD、aMCI、正常对照组及其他认知功能障碍的PIB显像的脑部分布特征,并结合FDG代谢的变化对AD的早期诊断提供参考价值。方法：运用PET对13例轻度AD患者、6例aMCI患者及6例正常老年人进行脑PIB及FDG代谢显像。视觉分析不同人群PIB的分布特点,比较FDG、PIB对AD、aMCI、正常人及其他认知功能障碍的鉴别价值。Listmode软件RO1分析不同人群的脑皮质区的时间一放射性曲线、脑皮质／小脑的SUVR的变化曲线；基于Matlab平台上SPM8对扫描获得的脑PIB图像进行预处理,比较轻度AD组、aMCI组和对照组PIB基于体素差异的统计学分析。结果：所有人群早期都呈现快速血流相分布,随后小脑区域PIB快速洗脱；40分钟后不同人群PIB分布出现差异。所有AD及4例MCI的额叶、外侧颞叶、后扣带回及楔前叶PIB滞留明显,而正常对照组的相关区域PIB滞留量较少。正常人群的皮质功能区与小脑比值SUVR曲线显示呈下降趋势,而AD患者与小脑的SUVR比值提示30min后曲线呈上升趋势。PIB对AD诊断的敏感度为100%,而FDG为84.6%；正常对照组PIB与FDG诊断的具有一致性。但对aMCI的判断上有较大的差异,6例aMCI的FDG无明显特异性的改变而不能判断,而PIB有4例呈类AD表现。其他3例因进行性核上性麻痹、额颞叶痴呆、血管性痴呆无淀粉样蛋白沉积呈阴性表现,FDG有不同程度的改变。与正常对照组比较,AD组的额叶、外侧颞叶、顶叶、前后扣带回、楔前叶、基底节区域的PIB滞留量增加,内侧颞叶无增加(p<0.001, uncorrected, K≥50像素)；aMCI组的额叶、外侧颞叶、后扣带回、楔前叶、前扣带回的PIB治疗增加。40分钟后SUVR表明,AD患者呈上升趋势而正常人群呈下降趋势。结论：40分钟后PIB在AD中滞留量多,与小脑的SUVR曲线呈上升趋势,并与正常人及其他认知功能障碍分布不同,PIB对AD诊断和鉴别诊断是可行的；FDG代谢未见改变的aMCI人群PIB PET分布模式“类AD”表现；PIB在早期AD诊断方面有可能成为常规影像诊断的可能。
ENGLISH ABSTRACT
PartⅠ
The research of Beta amyloid imaging with domestic 11C-PIB and evaluation the efficiency in clinical utilities
Purpose:Based on the former chemical synthesis module, we investigated the automated synthesis of AD amyloid imaging agent [11C]6-OH-BTA-1 (11C-PIB), aimed at completely domestic produce of PIB and its precursor. In addition, we took quality control of PIB and verified the clinical efficacy of drugs by the clinical applications. Material and methods:Turn 11C-iodo methane (11CH3I) deoxidized from lithium aluminum hydride/THF (LAH/THF) ion into 11C-trifluoro-methanesulfonate (11CH3OTf) with higher activity, then introduced into conical reaction flask with PIB precursor (6-OH-BTA-O, imported and home-made precursors) inside. Reaction is on ice-salt conditions in butanone solution. Then employed the improved HPLC to purify the products, and took quality control finally. Biological characteristics and safety of the self-produced PIB precursors and the import ones were compared; Groups of subjects took brain PET imaging to verify the feasibility of self-produced PIB, image quality and adverse reactions after injection were assessed. Results:With the improved automatic produce process,11C-PIB in 10% ethanol solution available for injection was ultimately produced, which is completely free of acetonitrile. Physical, chemical, biological qualities of 11C-PIB were consistent with SFDA issued "positron radiopharmaceutical quality control guidelines". Relative to the produce amount of imported precursor (1mg), Self-produced precursor (6-8mg) needed a larger amount, but the price is relatively cheaper, while the success rate of synthesis, the radiochemical yield, radiochemical purity, production rate were similar. Except distinctive pain occur after injection (with a small amount of ethanol solution), no other adverse reactions observed. Brain PET imaging with agent self-produced PIB showed high quality and the distribution of radioactivity were consistent with former literature. No significant difference was noticed in the curve of time-global activity between self-produced and imported PIB. Conclusions:The self-produced precursors of 11C-PIB production route is stable and safe for human brain imaging, which support proof of feasibility of self production of PIB and its precursor. Key words:Positron emission tomography; quality control; [N-methyl-11C]2-[4'-(methylamino)phenyl]-6-hydroxyphenylbenzothiazole CLC number:R817.4
Part II
Research of FDG PET in Alzheimer's disease and mild cognitive impairment using Statistical Parametric Mapping
Purpose:Voxel-based analysis of the regional cerebral glucose metabolism in patients with mild Alzheimer's disease (AD), amnestic-type mild cognitive impairment (aMCI) compared to normal aging as control associated with characteristic and progressive reductions with Fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET).
Material and Methods:Twenty-seven patients with mild AD patients,10 aMCI patients and 21 age-matched normal aging were enrolled in this study. Glucose metabolism differences of brain were assessed by Statistical Parametric Mapping 8 (SPM8) based on the Matlab platform to compare the normal aging with the cognitive declined. Results:In comparison with the normal aging group, the AD group had significantly lower brain glucose metabolism in posterior cingulate (BA23,31), precuneus (BA19), bilateral parietal (BA40), bilateral temporal lobe (BA20,21,22,37) and bilateral frontal cortex (BA6,9,10) (p<0.001, uncorrected, K≥50 voxels). Compared with the aMCI group, the AD group had hypometabolism in posterior cingulate (BA23, 31), precuneus (BA19), temporal lobe (BA40,20,21,22,39) and frontal cortex (BA6,8,9) (p<0.001, uncorrected, K≥50 voxels). Decreased voxels of glucose metabolism between the AD group and the aMCI group were less than those between the AD group and the normal aging group. Brain glucose metabolism in aMCI group compared to the normal aging group decreased only in the right occipital cortex (BA17) (p<0.05, uncorrected). Conclusion: Voxel-wise comparison of glucose metabolism in whole brain between the patients and the normal aging can reveal widespread hypomeabolism in mild Alzheimer's disease. However aMCI had less metabolism reduction than the normal aging.
Part III
The research of 11C-PIB amyloid imaging combined with 18F-FDG PET in normal aging and cognitive declined
Objective:Beta amyloid plaques and impaired glucose metabolism are the most prevalent pathological characteristics of Alzheimer's disease (AD). The aim was to reveal the characteristics of positron emission tomography (PET) imaging using radiotracers (11)C-Pittsburgh compound B (PIB) in normal aging and the cognitive declined combined with fluoro-deoxyglucose (FDG) PET.
Material and Methods:Six normal aging,6 aMCI patients,13 mild AD patients and 3 other cognitive declined patients were enrolled in this study. The normal aging and the cognitive declined was compared by the distribution of PIB in the whole brain. It was assessed by visual analysis, regional of interest (ROI) analysis and Statistical Parametric Mapping 8 (SPM8) based on the Matlab platform. Results:The distribution of PIB showed rapid blood flow in early phase and then washed out quickly especially in cerebellum in all subjects. The type of distribution was different 40 minutes later after injection in AD and the normal aging. PIB retention was high in frontal, lateral temporal lobe, posterior cingulate and precuneus in the AD and four aMCI. Only little PIB was distributed in white matter and pons in the normal aging. The sensitivity of PIB was 100% while FDG was 84.6% in AD; PIB was negative in progressive supranuclear palsy, frontotemporal dementia and vascular dementia while FDG had changes. Compared with the normal aging, frontal, lateral temporal lobe, parietal lobe, cingulate, precuneus, and basal ganglia increased in AD and MCI(p<0.001, uncorrected, K≥50 pixels). No difference was found in medial temporal lobe. The curve of SUVR increased in AD while decreased in the normal aging from 40 to 60 minutes. Conclusions:The amount of PIB retention was different in AD other than the normal aging after 40 minutes post-injection which can diagnose and differentiate the different types of cognitive dysfunction. The SUV Ratio curve rase after 40 minutes which tested the feasibility of PIB in diagnosis of AD. The distribution of PIB was positive in all subjects. But 4 AD-like MCI patients were negative with glucose metabolism. Based on the above, we can conclude that PIB might be useful in the early stage of possible AD (aMCI).
引文
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