Engler Henry, Forsberg Anton, Almkvist Ove, Blomquist Gunnar, Larsson Emma, Savitcheva Irina, Wall Anders, Ringheim Anna, Långström Bengt, Nordberg Agneta
Uppsala Imanet AB, Imanet, GE Healthcare Uppsala University, Uppsala.
Brain. 2006 Nov;129(Pt 11):2856-66. doi: 10.1093/brain/awl178. Epub 2006 Jul 19.
Beta amyloid is one of the major histopathological hallmarks of Alzheimer's disease. We recently reported in vivo imaging of amyloid in 16 Alzheimer patients, using the PET ligand N-methyl[11C]2-(4'-methylaminophenyl)-6-hydroxy-benzothiazole (PIB). In the present study we rescanned these 16 Alzheimer patients after 2.0 +/- 0.5 years and have described the interval change in amyloid deposition and regional cerebral metabolic rate for glucose (rCMRGlc) at follow-up. Sixteen patients with Alzheimer's disease were re-examined by means of PET, using PIB and 2-[18F]fluoro-2-deoxy-d-glucose (FDG) after 2.0 +/- 0.5 years. The patients were all on cholinesterase inhibitor treatment and five also on treatment with the N-methyl-d-aspartate (NMDA) antagonist memantine. In order to estimate the accuracy of the PET PIB measurements, four additional Alzheimer patients underwent repeated examinations with PIB within 20 days (test-retest). Relative PIB retention in cortical regions differed by 3-7% in the test-retest study. No significant difference in PIB retention was observed between baseline and follow-up while a significant (P < 0.01) 20% decrease in rCMRGlc was observed in cortical brain regions. A significant negative correlation between rCMRGlc and PIB retention was observed in the parietal cortex in the Alzheimer patients at follow-up (r = 0.67, P = 0.009). A non-significant decline in Mini-Mental State Examination (MMSE) score from 24.3 +/- 3.7 (mean +/- standard deviation) to 22.7 +/- 6.1 was measured at follow-up. Five of the Alzheimer patients showed a significant decline in MMSE score of >3 (21.4 +/- 3.5 to 15.6 +/- 3.9, P < 0.01) (AD-progressive) while the rest of the patients were cognitively more stable (MMSE score = 25.6 +/- 3.1 to 25.9 +/- 3.7) (AD-stable) compared with baseline. A positive correlation (P = 0.001) was observed in the parietal cortex between Rey Auditory Verbal Learning (RAVL) test score and rCMRGlc at follow-up while a negative correlation (P = 0.018) was observed between RAVL test and PIB retention in the parietal at follow-up. Relatively stable PIB retention after 2 years of follow-up in patients with mild Alzheimer's disease suggests that amyloid deposition in the brain reaches a plateau by the early clinical stages of Alzheimer's disease and therefore may precede a decline in rCMRGlc and cognition. It appears that anti-amyloid therapies will need to induce a significant decrease in amyloid load in order for PIB PET images to detect a drug effect in Alzheimer patients. FDG imaging may be able to detect a stabilization of cerebral metabolism caused by therapy administered to patients with a clinical diagnosis of Alzheimer's disease.
β淀粉样蛋白是阿尔茨海默病主要的组织病理学特征之一。我们最近报道了对16例阿尔茨海默病患者体内淀粉样蛋白的成像研究，使用正电子发射断层显像（PET）配体N-甲基[11C]2-(4'-甲氨基苯基)-6-羟基苯并噻唑（PIB）。在本研究中，我们在2.0±0.5年后对这16例阿尔茨海默病患者进行了再次扫描，并描述了随访时淀粉样蛋白沉积和局部脑葡萄糖代谢率（rCMRGlc）的间隔变化。16例阿尔茨海默病患者在2.0±0.5年后通过PET使用PIB和2-[18F]氟-2-脱氧-D-葡萄糖（FDG）进行了重新检查。所有患者均接受胆碱酯酶抑制剂治疗，5例还接受N-甲基-D-天冬氨酸（NMDA）拮抗剂美金刚治疗。为了评估PET PIB测量的准确性，另外4例阿尔茨海默病患者在20天内接受了PIB的重复检查（重测）。在重测研究中，皮质区域的相对PIB滞留率相差3-7%。在基线和随访之间未观察到PIB滞留率有显著差异，而在皮质脑区观察到rCMRGlc显著下降（P<0.01）20%。在随访时，阿尔茨海默病患者的顶叶皮质中观察到rCMRGlc与PIB滞留率之间存在显著负相关（r = 0.67，P = 0.009）。随访时测量的简易精神状态检查表（MMSE）评分从24.3±3.7（平均值±标准差）降至22.7±6.1，差异无统计学意义。5例阿尔茨海默病患者的MMSE评分显著下降>3（从21.4±3.5降至15.6±3.9，P<0.01）（AD进展型），而其余患者与基线相比认知更稳定（MMSE评分从25.6±3.1降至25.9±3.7）（AD稳定型）。随访时在顶叶皮质中观察到雷伊听觉词语学习（RAVL）测试评分与rCMRGlc之间存在正相关（P = 0.001），而在随访时RAVL测试与顶叶PIB滞留率之间存在负相关（P = 0.018）。轻度阿尔茨海默病患者随访2年后PIB滞留率相对稳定，这表明在阿尔茨海默病的临床早期，脑内淀粉样蛋白沉积达到平台期，因此可能先于rCMRGlc和认知功能下降。看来抗淀粉样蛋白疗法需要使淀粉样蛋白负荷显著降低，以便PIB PET图像能够检测到阿尔茨海默病患者的药物疗效。FDG成像可能能够检测到对临床诊断为阿尔茨海默病的患者进行治疗后引起的脑代谢稳定情况。
