Aberrant frontal lobe maturation in adolescents with fragile X syndrome is related to delayed cognitive maturation

Abstract

Background: Fragile X syndrome (FXS) is the most common known heritable cause of intellectual disability. Prior studies in FXS have observed a plateau in cognitive and adaptive behavioral development in early adolescence, suggesting that brain development in FXS may diverge from typical development during this period.

Methods: In this study, we examined adolescent brain development using structural magnetic resonance imaging data acquired from 59 individuals with FXS and 83 typically developing control subjects aged 9 to 22, a subset of whom were followed up longitudinally (1-5 years; typically developing: 17, FXS: 19). Regional volumes were modeled to obtain estimates of age-related change.

Results: We found that while structures such as the caudate showed consistent volume differences from control subjects across adolescence, prefrontal cortex (PFC) gyri showed significantly aberrant maturation. Furthermore, we found that PFC-related measures of cognitive functioning followed a similarly aberrant developmental trajectory in FXS.

Conclusions: Our findings suggest that aberrant maturation of the PFC during adolescence may contribute to persistent or increasing intellectual deficits in FXS.

Figure 1. Total grey and white matter volumes

A) Total grey matter volumes plotted against age, separately for typically developing (TD; left), and Fragile X syndrome (FXS; right). Regression lines estimated from linear mixed models (LMMs) are plotted; slopes were not significantly different between gender or diagnostic groups. B) Total white matter volumes plotted against age for TD (left), and FXS (right). Regression lines estimated from LMMs are plotted.

Figure 2. Development of PFC and caudate volumes

A) Bilateral MFG/SFG volumes plotted against age, separately for typically developing (TD; left), and Fragile X syndrome (FXS; right), volumes adjusted for total grey matter. Regression lines estimated from linear mixed models (LMMs) are plotted. The age x diagnosis (p<0.05/3) and age x gender x diagnosis interactions (p=0.006) are significant in this model, indicating a significant group difference in regional development. B) Bilateral caudate volumes plotted against age, typically developing (TD; left), and Fragile X syndrome (FXS; right), volumes adjusted for total grey matter. Regression lines estimated from LMMs are plotted. The interaction between age and diagnosis was not significant in the caudate.

Figure 3. Development of cognitive measures: Spatial Relations (SR) and Verbal Fluency (VF) scores

A) Spatial relations scores plotted against age, for typically developing (TD; left), and Fragile X syndrome (FXS; right). B) Verbal fluency scores plotted against age, separately for typically developing (TD; left), and Fragile X syndrome (FXS; right). Regression lines estimated from linear mixed models (LMMs) are plotted. For both measures, the age x diagnosis interaction is significant, indicating significantly aberrant development in FXS.