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Abstract：
BACKGROUND: Microglia are increasingly understood to play an important role in the pathogenesis of Alzheimer\'s disease. The rs75932628 (p.R47H) TREM2 variant is a well-established risk factor for Alzheimer\'s disease. TREM2 is a microglial cell surface receptor. In this multi-modal/multi-tracer PET/MRI study we investigated the effect of TREM2 p.R47H carrier status on microglial activation, tau and amyloid deposition, brain structure and cognitive profile.
METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype.
RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores.
CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer\'s disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer\'s disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer\'s disease should aim to enhance protective microglial actions.
METHODS: We compared TREM2 p.R47H carriers (n = 8; median age = 62.3) and participants with mild cognitive impairment (n = 8; median age = 70.7). Participants underwent two [18F]DPA-714 PET/MRI scans to assess TSPO signal, indicative of microglial activation, before and after receiving the seasonal influenza vaccination, which was used as an immune stimulant. Participants also underwent [18F]florbetapir and [18F]AV1451 PET scans to assess amyloid and tau burden, respectively. Regional tau and TSPO signal were calculated for regions of interest linked to Braak stage. An additional comparison imaging healthy control group (n = 8; median age = 45.5) had a single [18F]DPA-714 PET/MRI. An expanded group of participants underwent neuropsychological testing, to determine if TREM2 status influenced clinical phenotype.
RESULTS: Compared to participants with mild cognitive impairment, TREM2 carriers had lower TSPO signal in Braak II (P = 0.04) and Braak III (P = 0.046) regions, despite having a similar burden of tau and amyloid. There were trends to suggest reduced microglial activation following influenza vaccine in TREM2 carriers. Tau deposition in the Braak VI region was higher in TREM2 carriers (P = 0.04). Furthermore, compared to healthy controls TREM2 carriers had smaller caudate (P = 0.02), total brain (P = 0.049) and white matter volumes (P = 0.02); and neuropsychological assessment revealed worse ADAS-Cog13 (P = 0.03) and Delayed Matching to Sample (P = 0.007) scores.
CONCLUSIONS: TREM2 p.R47H carriers had reduced levels of microglial activation in brain regions affected early in the Alzheimer\'s disease course and differences in brain structure and cognition. Changes in microglial response may underlie the increased Alzheimer\'s disease risk in TREM2 p.R47H carriers. Future therapeutic agents in Alzheimer\'s disease should aim to enhance protective microglial actions.
摘要：
背景：小胶质细胞在阿尔茨海默病的发病机制中起着重要作用。rs75932628（p。R47H）TREM2变体是阿尔茨海默病的一个公认的危险因素。TREM2是小胶质细胞表面受体。在这项多模态/多示踪剂PET/MRI研究中，我们调查了TREM2p.R47H载体状态对小胶质细胞活化的影响，tau和淀粉样蛋白沉积,大脑结构和认知特征。
方法：我们比较了TREM2p.R47H携带者（n=8；中位年龄=62.3）和轻度认知障碍参与者（n=8；中位年龄=70.7）。参与者接受了两次[18F]DPA-714PET/MRI扫描以评估TSPO信号，指示小胶质细胞激活，在接受季节性流感疫苗接种之前和之后，用作免疫刺激剂。参与者还接受了[18F]florbetapir和[18F]AV1451PET扫描，以评估淀粉样蛋白和tau蛋白负担。分别。计算与Braak阶段相关的感兴趣区域的区域tau和TSPO信号。另一个比较成像健康对照组(n=8;中位年龄=45.5)具有单个[18F]DPA-714PET/MRI。一组扩大的参与者接受了神经心理学测试，以确定TREM2状态是否影响临床表型。
结果：与轻度认知障碍的参与者相比，TREM2携带者在BraakII（P=0.04）和BraakIII（P=0.046）区域的TSPO信号较低，尽管有类似的tau和淀粉样蛋白负担。有趋势表明TREM2携带者接种流感疫苗后小胶质细胞活化减少。在TREM2载体中，BraakVI区域的Tau沉积较高（P=0.04）。此外，与健康对照组相比，TREM2携带者的尾状较小（P=0.02），总脑(P=0.049)和白质体积(P=0.02);神经心理学评估显示ADAS-Cog13(P=0.03)和样本延迟匹配(P=0.007)评分较差.
结论：TREM2p.R47H携带者在阿尔茨海默病病程早期受影响的脑区小胶质细胞激活水平降低，脑结构和认知差异也降低。小胶质细胞反应的变化可能是TREM2p.R47H携带者阿尔茨海默病风险增加的基础。未来阿尔茨海默病的治疗剂应旨在增强保护性小胶质细胞作用。
方法：我们比较了TREM2p.R47H携带者（n=8；中位年龄=62.3）和轻度认知障碍参与者（n=8；中位年龄=70.7）。参与者接受了两次[18F]DPA-714PET/MRI扫描以评估TSPO信号，指示小胶质细胞激活，在接受季节性流感疫苗接种之前和之后，用作免疫刺激剂。参与者还接受了[18F]florbetapir和[18F]AV1451PET扫描，以评估淀粉样蛋白和tau蛋白负担。分别。计算与Braak阶段相关的感兴趣区域的区域tau和TSPO信号。另一个比较成像健康对照组(n=8;中位年龄=45.5)具有单个[18F]DPA-714PET/MRI。一组扩大的参与者接受了神经心理学测试，以确定TREM2状态是否影响临床表型。
结果：与轻度认知障碍的参与者相比，TREM2携带者在BraakII（P=0.04）和BraakIII（P=0.046）区域的TSPO信号较低，尽管有类似的tau和淀粉样蛋白负担。有趋势表明TREM2携带者接种流感疫苗后小胶质细胞活化减少。在TREM2载体中，BraakVI区域的Tau沉积较高（P=0.04）。此外，与健康对照组相比，TREM2携带者的尾状较小（P=0.02），总脑(P=0.049)和白质体积(P=0.02);神经心理学评估显示ADAS-Cog13(P=0.03)和样本延迟匹配(P=0.007)评分较差.
结论：TREM2p.R47H携带者在阿尔茨海默病病程早期受影响的脑区小胶质细胞激活水平降低，脑结构和认知差异也降低。小胶质细胞反应的变化可能是TREM2p.R47H携带者阿尔茨海默病风险增加的基础。未来阿尔茨海默病的治疗剂应旨在增强保护性小胶质细胞作用。
