Matuskey David, Yang Yanghong, Naganawa Mika, Koohsari Sheida, Toyonaga Takuya, Gravel Paul, Pittman Brian, Torres Kristen, Pisani Lauren, Finn Caroline, Cramer-Benjamin Sophie, Herman Nicole, Rosenthal Lindsey H, Franke Cassandra J, Walicki Bridget M, Esterlis Irina, Skosnik Patrick, Radhakrishnan Rajiv, Wolf Julie M, Nabulsi Nabeel, Ropchan Jim, Huang Yiyun, Carson Richard E, Naples Adam J, McPartland James C
Department of Radiology and Biomedical Imaging, Yale University, New Haven, CT, USA.
Department of Psychiatry, Yale University, New Haven, CT, USA.
Mol Psychiatry. 2025 Apr;30(4):1610-1616. doi: 10.1038/s41380-024-02776-2. Epub 2024 Oct 4.
The neural bases of autism are poorly understood at the molecular level, but evidence from animal models, genetics, post-mortem studies, and single-gene disorders implicate synaptopathology. Here, we use positron emission tomography (PET) to assess the density of synapses with synaptic vesicle glycoprotein 2A (SV2A) in autistic adults using C-UCB-J. Twelve autistic (mean (SD) age 25 (4) years; six males), and twenty demographically matched non-autistic individuals (26 (3) years; eleven males) participated in a C-UCB-J PET scan. Binding potential, BP, was the primary outcome measure and computed with the centrum semiovale as the reference region. Partial volume correction with Iterative Yang was applied to control for possible volumetric differences. Mixed-model statistics were calculated for between-group differences. Relationships to clinical characteristics were evaluated based on clinician ratings of autistic features. Whole cortex synaptic density was 17% lower in the autism group (p = 0.01). All brain regions in autism had lower C-UCB-J BP compared to non-autistic participants. This effect was evident in all brain regions implicated in autism. Significant differences were observed across multiple individual regions, including the prefrontal cortex (-15%, p = 0.02), with differences most pronounced in gray matter (p < 0.0001). Synaptic density was significantly associated with clinical measures across the whole cortex (r = 0.67, p = 0.02) and multiple regions (rs = -0.58 to -0.82, ps = 0.05 to <0.01). The first in vivo investigation of synaptic density in autism with PET reveals pervasive and large-scale lower density in the cortex and across multiple brain areas. Synaptic density also correlated with clinical features, such that a greater number of autistic features were associated with lower synaptic density. These results indicate that brain-wide synaptic density may represent an as-yet-undiscovered molecular basis for the clinical phenotype of autism and associated pervasive alterations across a diversity of neural processes.
在分子水平上，人们对自闭症的神经基础了解甚少，但来自动物模型、遗传学、尸检研究和单基因疾病的证据表明其与突触病理学有关。在此，我们使用正电子发射断层扫描（PET），通过C-UCB-J评估自闭症成年人中与突触囊泡糖蛋白2A（SV2A）相关的突触密度。12名自闭症患者（平均（标准差）年龄25（4）岁；6名男性）和20名人口统计学匹配的非自闭症个体（26（3）岁；11名男性）参与了C-UCB-J PET扫描。结合潜能（BP）是主要的结局指标，并以半卵圆中心作为参考区域进行计算。应用迭代杨法进行部分容积校正，以控制可能的体积差异。计算混合模型统计量以分析组间差异。基于临床医生对自闭症特征的评分，评估其与临床特征的关系。自闭症组的全皮质突触密度降低了17%（p = 0.01）。与非自闭症参与者相比，自闭症患者所有脑区的C-UCB-J BP均较低。这种效应在所有与自闭症相关的脑区都很明显。在多个个体脑区观察到显著差异，包括前额叶皮质（-15%，p = 0.02），灰质中的差异最为显著（p < 0.0001）。全皮质的突触密度与临床指标显著相关（r = 0.67，p = 0.02），在多个脑区也有显著相关性（rs = -0.58至-0.82，ps = 0.05至<0.01）。首次使用PET对自闭症患者的突触密度进行的体内研究显示，皮质和多个脑区普遍存在大规模的低密度。突触密度也与临床特征相关，自闭症特征越多，突触密度越低。这些结果表明，全脑突触密度可能代表了自闭症临床表型以及多种神经过程中相关普遍改变尚未被发现的分子基础。
