In-vivo quantification analysis of activated microglia in the brain of dementia

作为PET早期诊断痴呆的标记物，我们开发了新的放射性配体[^<11>C] DAA 1106，其具有高的脑渗透性，对外周苯二氮卓受体（PBR）具有高亲和力和特异性。在体外和离体研究中，我们发现高密度的PBR定位于模型小鼠老年斑周围活化的小胶质细胞中。阿尔茨海默病脑内PBR的变化应反映与老年斑特异性神经元变性相关的小胶质细胞活性，我们在体内人体研究中使用[^ C] DAA 1106通过PET定量PBR来检查我们是否可以在早期诊断痴呆<11>。我们对<11>阿尔茨海默病患者组（n=10）和年龄匹配的对照组（n=11）进行了[^ C] DAA 1106 PET扫描。结果显示，与年龄匹配的对照组相比，阿尔茨海默病组的宽脑区域的PBR结合电位（BP）显著增加。此外，为了检查我们是否可以在痴呆症状出现之前的非常早期阶段诊断痴呆，我们对患有轻度认知障碍（MCI）但在PET扫描时不能诊断为痴呆的受试者（n=7）进行了扫描。我们发现，与对照组相比，在这个组中，在广泛的脑区域中的PBR-BP显著增加。总之，用[^<11>C] DAA 1106进行PET扫描可以显示PBR的增加，这可能与阿尔茨海默病的神经退行性过程有关。在大多数情况下，MCI可被视为痴呆的前期，甚至在痴呆症状明显出现之前，我们就可以检测到PBR-BP的异常。[^<11>C] DAA 1106 PET显像对痴呆及其他神经退行性疾病的早期诊断有重要意义。

As a maker for the early diagnosis of the dementia with PET, we developed the new radioactive ligand [^<11>C]DAA1106, which has high permeability to the brain and shows high affinity and specificity to the peripheral benzodiazepine receptor (PBR). In vitro and ex-vivo study using the model mouse of Alzheimer disease, we found the high density of PBR was localized in the activated microglia at surroundings of senile plaque of model mouse. The change of PBR in the brain of Alzheimer disease should reflect the activity of microglia related to the effect of senile plaque specific to neuronal degeneration in this disease.We examined whether we can diagnose the dementia in early stage by the quantification of the PBR with PET using [^<11>C]DAA1106 in in-vivo human study. We performed the PET scan with [^<11>C]DAA1106 on the group of patients of Alzheimer disease (n=10) and age-matched control group (n=11). Results showed significant increase of PBR-binding potential (BP) in the broad brain regions in the group of Alzheimer disease when compared to the age-matched control group. Further, to examine whether we can diagnose the dementia in very early stage before appearance of demented symptoms, we performed the scan on the subjects who had mild cognitive impairment (MCI), but cannot be diagnosed as the dementia at the time of PET scanning (n=7). We found the significant increase of PBR-BP in this group in broad brain regions when compared to the control group.In conclusion, it was shown that PET scan with [^<11>C]DAA1106 can show the increase of PBR which might be related to the neurodegenerative process in the Alzheimer disease. In most of the cases, MCI can be regarded as the pre-stage of dementia, and we can detect the abnormality of PBR-BP even before symptoms of dementia clearly appeared. PET scan with [^<11>C]DAA1106 should be useful method for the early diagnosis of the dementia and other neuronal degenerative diseases.