Li Rihui, Foland-Ross Lara C, Jordan Tracy, Marzelli Matthew J, Ross Judith L, Reiss Allan L
Center for Cognitive and Brain Sciences, Institute of Collaborative Innovation, University of Macau, Taipa, Macao S.A.R., China.
Center for Interdisciplinary Brain Sciences Research, Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, 74305, USA.
Eur Child Adolesc Psychiatry. 2025 Feb;34(2):585-597. doi: 10.1007/s00787-024-02501-y. Epub 2024 Jun 21.
Klinefelter syndrome (KS), also referred to as XXY syndrome, is a significant but inadequately studied risk factor for neuropsychiatric disability. Whether alterations in functional brain connectivity or pubertal delays are associated with aberrant cognitive-behavioral outcomes in individuals with KS is largely unknown. In this observational study, we investigated KS-related alterations in the resting-state brain network, testosterone level, and cognitive-behavioral impairment in adolescents with Klinefelter syndrome.
We recruited 46 boys with KS, ages 8 to 17 years, and 51 age-matched typically developing (TD) boys. All participants underwent resting-state functional magnetic resonance imaging scans, pubertal, and cognitive-behavioral assessments. Resting-state functional connectivity and regional brain activity of the participants were assessed.
We found widespread alterations in global functional connectivity among the inferior frontal gyrus, temporal-parietal area, and hippocampus in boys with KS. Aberrant regional activities, including enhanced fALFF in the motor area and reduced ReHo in the caudate, were also found in the KS group compared to the TD children. Further, using machine learning methods, brain network alterations in these regions accurately differentiated boys with KS from TD controls. Finally, we showed that the alterations of brain network properties not only effectively predict cognitive-behavioral impairment in boys with KS, but also appear to mediate the association between total testosterone level and language ability, a cognitive domain at particular risk for dysfunction in this condition.
Our results offer an informatic neurobiological foundation for understanding cognitive-behavioral impairments in individuals with KS and contribute to our understanding of the interplay between pubertal status, brain function, and cognitive-behavioral outcome in this population.
克兰费尔特综合征（KS），也称为XXY综合征，是导致神经精神残疾的一个重要但研究不足的风险因素。KS患者大脑功能连接的改变或青春期延迟是否与异常的认知行为结果相关，目前很大程度上尚不清楚。在这项观察性研究中，我们调查了克兰费尔特综合征青少年静息态脑网络、睾酮水平和认知行为损伤与KS相关的改变。
我们招募了46名年龄在8至17岁的KS男孩和51名年龄匹配的发育正常（TD）男孩。所有参与者均接受了静息态功能磁共振成像扫描、青春期和认知行为评估。评估了参与者的静息态功能连接和脑区活动。
我们发现KS男孩的额下回、颞顶叶区域和海马之间的整体功能连接存在广泛改变。与TD儿童相比，KS组还发现了异常的区域活动，包括运动区fALFF增强和尾状核ReHo降低。此外，使用机器学习方法，这些区域的脑网络改变能够准确地区分KS男孩和TD对照组。最后，我们表明脑网络属性的改变不仅能有效预测KS男孩的认知行为损伤，而且似乎还介导了总睾酮水平与语言能力之间的关联，语言能力是这种情况下特别容易出现功能障碍的一个认知领域。
我们的结果为理解KS患者的认知行为损伤提供了信息神经生物学基础，并有助于我们理解该人群青春期状态、脑功能和认知行为结果之间的相互作用。
