Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging
Assessing Synaptic Density in Alzheimer Disease With Synaptic Vesicle Glycoprotein 2A Positron Emission Tomographic Imaging
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DOI：
10.1001/jamaneurol.2018.1836
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发表时间：
2018-10-01
期刊：
影响因子：
29
通讯作者：
van Dyck, Christopher H.
中科院分区：
文献类型：
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作者：
Chen, Ming-Kai;Mecca, Adam P.;van Dyck, Christopher H.
突触丢失是阿尔茨海默病（AD）认知障碍的主要结构相关因素。在体内测量突触密度的能力可以加速AD的疾病改善治疗的发展。突触囊泡糖蛋白2A（Synaptic vesicle glycoprotein 2A，SV 2A）是一种重要的囊泡膜蛋白，在几乎所有的突触中都有表达，可以作为一个合适的突触density. ObjectiveTo比较海马突触囊泡糖蛋白2A（synaptic vesicle glycoprotein 2A，SV 2A）在AD患者和认知正常者中的结合情况。这项横断面研究招募了10名AD参与者和11名在2015年11月至2017年6月期间认知正常的参与者。基于内嗅皮质细胞投射到海马的早期退化（通过穿通路径）和在尸检研究中观察到的海马SV 2A减少，我们假设AD中海马SV 2A结合减少。参与者接受了SV 2A的高分辨率PET扫描（（R）-14（3-（11 C-甲基-11 C）吡啶-4-基）甲基）-4-（3，4，5-三氟苯基）吡咯烷-2-酮），一种通常称为C-11-UCB-J的化合物。他们还接受了碳11标记的匹兹堡化合物B的高分辨率PET扫描（C-11-PiB）β-淀粉样蛋白，磁共振成像，主要结局和指标：C-UCB-J特异性结合（结合潜力[BPND]）通过PET成像在AD参与者和认知正常的参与者的感兴趣的脑区域中进行。研究人员将11名参与者（5名男性和5名女性;平均[SD]年龄，72.7 [6.3]岁; 10名[100%] β-淀粉样蛋白阳性）与11名认知正常的参与者（5名男性和6名女性;平均[SD]年龄，72.9 [8.7]岁; 11名[100%] β-淀粉样蛋白阴性）进行了比较。AD参与者的疾病阶段从遗忘型轻度认知障碍（n = 5）到轻度痴呆（n = 5）。根据C-11-UCB-J-PET BPND评估，与认知正常受试者相比，AD受试者的海马SV 2A特异性结合显著降低（41%）（认知正常受试者：平均[SD] BPND，1.47 [0.37]; AD受试者：0.87 [0.50]; P = 0.005）。在校正萎缩后，这些降低仍然显著（即，部分容量校正;认知正常的参与者：平均值[SD]，2.71 [0.46]; AD参与者：2.15 [0.55]; P = 0.02）。海马SV 2A特异性结合BPND与整个样本中的复合情景记忆评分相关（R = 056; P = 0.01）。结论和相关性据我们所知，这是第一项使用C-11-UCB-J-PET成像研究AD体内突触密度的研究。这种方法可以提供突触密度的直接测量，因此它有望作为AD的体内生物标志物和作为疾病修饰疗法试验的结果测量，特别是那些靶向突触保存和恢复的治疗。
IMPORTANCE Synaptic loss is well established as the major structural correlate of cognitive impairment in Alzheimer disease (AD). The ability to measure synaptic density in vivo could accelerate the development of disease-modifying treatments for AD. Synaptic vesicle glycoprotein 2A is an essential vesicle membrane protein expressed in virtually all synapses and could serve as a suitable target for synaptic density.OBJECTIVE To compare hippocampal synaptic vesicle glycoprotein 2A (SV2A) binding in participants with AD and cognitively normal participants using positron emission tomographic (PET) imaging.DESIGN. SETTING, AND PARTICIPANTS This cross-sectional study recruited 10 participants with AD and 11 participants who were cognitively normal between November 2015 and June 2017. We hypothesized a reduction in hippocampal SV2A binding in AD, based on the early degeneration of entorhinal cortical cell projections to the hippocampus (via the perforant path) and hippocampal SV2A reductions that had been observed in postmortem studies. Participants underwent high-resolution PET scanning with ((R)-14(3-(11C-methyl-11C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one), a compound more commonly known as C-11-UCB-J, for SV2A. They also underwent high-resolution PET scanning with carbon 11-labeled Pittsburgh Compound B (C-11-PiB) for beta-amyloid, magnetic resonance imaging, and cognitive and neurologic evaluation.MAIN OUTCOMES AND MEASURES Outcomes were "C-UCB-J-specific binding (binding potential [BPND]) via PET imaging in brain regions of interest in participants with AD and participants who were cognitively normal.RESULTS Ten participants with AD (5 male and 5 female; mean [SD] age, 72.7 [6.3] years; 10 [100%) beta-amyloid positive) were compared with 11 participants who were cognitively normal (5 male and 6 female; mean [SD] age, 72.9 [8.7] years; 11 [100%] beta-amyloid negative). Participants with AD spanned the disease stages from amnestic mild cognitive impairment (n = 5) to mild dementia (n = 5). Participants with AD had significant reduction in hippocampal SV2A specific binding (41%) compared with cognitively normal participants, as assessed by C-11-UCB-J-PET BPND (cognitively normal participants: mean [SD] BPND, 1.47 [0.37]; participants with AD: 0.87 [0.50]; P = .005). These reductions remained significant after correction for atrophy (ie, partial volume correction; participants who were cognitively normal: mean [SD], 2.71 [0.46]; participants with AD: 2.15 [0.55]; P = .02). Hippocampal SV2A-specific binding BPND was correlated with a composite episodic memory score in the overall sample (R = 056; P = .01).CONCLUSIONS AND RELEVANCE To our knowledge, this is the first study to investigate synaptic density in vivo in AD using C-11-UCB-J-PET imaging. This approach may provide a direct measure of synaptic density, and it therefore holds promise as an in vivo biomarker for AD and as an outcome measure for trials of disease-modifying therapies, particularly those targeted at the preservation and restoration of synapses.