Boen Rune, Villalón-Reina Julio E, Kushan Leila, O'Hora Kathleen P, Fung Hoki, Parker Nadine, Akkouh Ibrahim A, Alnæs Dag, O'Hara Ruth, Marzelli Matthew John, Foland-Ross Lara, Chick Christina French, Cotto Isabelle, Reiss Allan L, Hallmayer Joachim, Thompson Paul M, Andreassen Ole A, Sønderby Ida E, Bearden Carrie E
Semel Institute for Neuroscience and Human Behavior, University of California Los Angeles, Los Angeles, CA, USA.
Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, University of Southern California, Los Angeles, CA, USA.
bioRxiv. 2025 May 30:2025.05.29.656839. doi: 10.1101/2025.05.29.656839.
22q11.2 deletion (22qDel) and duplication (22qDup) carriers have an increased risk of neurodevelopmental disorders and exhibit altered brain structure, including white matter microstructure. However, the underlying cellular architecture and age-related changes contributing to these white matter alterations remain poorly understood. Neurite orientation dispersion and density imaging (NODDI) was used on mixed cross-sectional and longitudinal data to examine group differences and age-related trajectories in measures of axonal density (i.e., intracellular volume fraction; ICVF), axonal orientation (orientation dispersion index; ODI) and free water diffusion (isotropic volume fraction; ISO) in 50 22qDel (n scans = 69, mean age = 21.7, age range = 7.4-51.1, 65.2% female) and 24 22qDup (n scans = 34, mean age = 23.3, age range = 8.3-49.4, 55.0% female) carriers, and 890 controls (n scans = 901, mean age = 21.9, age range = 7.8-51.1, 54.5%). The results showed widespread gene dosage effects, with higher ICVF in 22qDel and lower ICVF in 22qDup compared to controls, and region-specific effects of the 22qDel and 22qDup on ODI and ISO measures. However, 22qDel and 22qDup carriers did not exhibit an altered age-related trajectory relative to controls. Observed differences in ICVF suggest higher white matter axonal density in 22qDel and lower axonal density in 22qDup compared to controls. Conversely, differences in ODI are highly localized, indicating region-specific effects on axonal dispersion in white matter. We do not find evidence for altered developmental trajectories of axonal density or dispersion among 22q11.2 CNV carriers, suggesting stable disruptions to neurodevelopmental events before childhood.
22q11.2缺失（22qDel）和重复（22qDup）携带者患神经发育障碍的风险增加，且脑结构存在改变，包括白质微观结构。然而，导致这些白质改变的潜在细胞结构和与年龄相关的变化仍知之甚少。本研究使用神经突方向离散度和密度成像（NODDI）对混合的横断面和纵向数据进行分析，以检查50名22qDel携带者（扫描次数n = 69，平均年龄 = 21.7岁，年龄范围 = 7.4 - 51.1岁，女性占65.2%）、24名22qDup携带者（扫描次数n = 34，平均年龄 = 23.3岁，年龄范围 = 8.3 - 49.4岁，女性占55.0%）以及890名对照者（扫描次数n = 901，平均年龄 = 21.9岁，年龄范围 = 7.8 - 51.1岁，女性占54.5%）在轴突密度（即细胞内体积分数；ICVF）、轴突方向（方向离散度指数；ODI）和自由水扩散（各向同性体积分数；ISO）测量方面的组间差异和与年龄相关的轨迹变化。结果显示存在广泛的基因剂量效应，与对照组相比，22qDel携带者的ICVF较高，22qDup携带者的ICVF较低，且22qDel和22qDup对ODI和ISO测量存在区域特异性影响。然而，与对照组相比，22qDel和22qDup携带者并未表现出与年龄相关的轨迹变化。观察到的ICVF差异表明，与对照组相比，22qDel携带者的白质轴突密度较高，22qDup携带者的轴突密度较低。相反，ODI的差异高度局限，表明对白质轴突离散度存在区域特异性影响。我们没有发现22q11.2拷贝数变异（CNV）携带者轴突密度或离散度的发育轨迹发生改变的证据，这表明在儿童期之前神经发育事件就受到了稳定的破坏。
