Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland.
Developmental Imaging and Psychopathology Laboratory, University of Geneva School of Medicine, Geneva, Switzerland.
Psychoneuroendocrinology. 2020 Mar;113:104540. doi: 10.1016/j.psyneuen.2019.104540. Epub 2019 Dec 6.
22q11.2 Deletion Syndrome (22q11DS) confers strongly increased genetic risk for multiple psychiatric disorders. Similarly to the general population, rates of psychiatric comorbidity suggest that common disease mechanisms are shared across dimensions of psychopathology. Such pleiotropic disease mechanisms remain however currently unknown. We hypothesized that pituitary dysmaturation, indicative of HPA-axis dysregulation, could correlate to reduced tolerance to daily life stressors and reflect pleiotropic risk factor for psychopathology. Moreover HPA-axis dysregulation could affect atypical cortical and hippocampal development previously described in 22q11DS.
Pituitary volume, hippocampal volume and cortical thickness measures were obtained from T1-weighted MRI images in a large longitudinal cohort of youth with 22q11DS (115 subjects, 260 scans, age-range = 5.4-31.6) and healthy controls (151 subjects, 280 scans, age-range = 5.1-32.3). We explored effects of pituitary dysmaturation on tolerance to stress, psychopathology and neurodevelopment employing mixed-models linear regression. Associations of pituitary and cortical development were correlated with the expression pattern of glucocorticoid receptor gene NR3C1 obtained from the Allen-Human-Brain-Atlas.
We observed aberrant pituitary developmental trajectories in 22q11DS, with volumetric reductions emerging by young-adulthood (P = 0.0006). Longitudinal pituitary decline was associated with to reduced tolerance to stress (P = 0.04), higher overall psychopathology (P = 0.0003) and increased risk of psychiatric comorbidity (P = 0.02). Moreover, pituitary decline correlated with blunted growth of the right hippocampus (P = 0.03) and to increased cortical thinning of mostly temporal and orbitofrontal regions mediated by NR3C1 gene expression.
Atypical pituitary development could reflect progressive extinction of HPAA due to chronic hyper-activation, in agreement with existing biochemical evidence in 22q11DS. HPAA dysregulation could represent and endophenotype that confers pleiotropic vulnerability to psychopathology and atypical neurodevelopment in 22q11DS.
22q11.2 缺失综合征（22q11DS）极大地增加了多种精神疾病的遗传风险。与一般人群一样，精神共病的发生率表明，精神病理学的各个维度都存在共同的疾病机制。然而，这种多效性疾病机制目前尚不清楚。我们假设，垂体发育不成熟，表明 HPA 轴失调，可能与对日常生活压力源的耐受性降低有关，并反映出精神病理学的多效性风险因素。此外，HPA 轴失调可能会影响以前在 22q11DS 中描述的非典型皮质和海马体发育。
我们从 22q11DS 患者的大样本纵向队列（115 例，260 次扫描，年龄范围为 5.4-31.6 岁）和健康对照组（151 例，280 次扫描，年龄范围为 5.1-32.3 岁）的 T1 加权 MRI 图像中获得了垂体体积、海马体体积和皮质厚度的测量值。我们采用混合模型线性回归方法，研究了垂体发育不良对压力耐受、精神病理学和神经发育的影响。垂体和皮质发育的相关性与从 Allen-Human-Brain-Atlas 获得的糖皮质激素受体基因 NR3C1 的表达模式相关联。
我们观察到 22q11DS 中存在异常的垂体发育轨迹，到青少年期时出现体积减小（P=0.0006）。纵向垂体下降与压力耐受降低（P=0.04）、整体精神病理学升高（P=0.0003）和精神共病风险增加（P=0.02）有关。此外，垂体下降与右侧海马体生长迟缓有关（P=0.03），与皮质厚度变薄有关，主要是颞叶和眶额区域，这与 NR3C1 基因表达有关。
异常的垂体发育可能反映了慢性过度激活导致的 HPA 轴逐渐衰竭，这与 22q11DS 中现有的生化证据一致。HPA 轴失调可能是 22q11DS 中精神病理学和非典型神经发育的一种表型，具有多效性易感性。
