Behavioral features in child and adolescent huntingtin gene-mutation carriers

Abstract

Introduction: We compared neuropsychiatric symptoms between child and adolescent huntingtin gene-mutation carriers and noncarriers. Given previous evidence of atypical striatal development in carriers, we also assessed the relationship between neuropsychiatric traits and striatal development.

Methods: Participants between 6 and 18 years old were recruited from families affected by Huntington's disease and tested for the huntingtin gene expansion. Neuropsychiatric traits were assessed using the Pediatric Behavior Scale and the Behavior Rating Inventory of Executive Function. Striatal volumes were extracted from 3T neuro-anatomical images. Multivariable linear regression models were conducted to evaluate the impact of group (i.e., gene nonexpanded [GNE] or gene expanded [GE]), age, and trajectory of striatal growth on neuropsychiatric symptoms.

Results: There were no group differences in any behavioral measure with the exception of depression/anxiety score, which was higher in the GNE group compared to the GE group (estimate = 4.58, t(129) = 2.52, FDR = 0.051). The growth trajectory of striatal volume predicted depression scores (estimate = 0.429, 95% CI 0.15:0.71, p = .0029), where a negative slope of striatal volume over time was associated with lower depression/anxiety.

Conclusions: The current findings show that GE children may have lower depression/anxiety compared to their peers. Previously, we observed a unique pattern of early striatal hypertrophy and continued decrement in volume over time among GE children and adolescents. In contrast, GNE individuals largely show striatal volume growth. These findings suggest that the lower scores of depression and anxiety seen in GE children and adolescents may be associated with differential growth of the striatum.

Keywords: Huntington disease; anxiety; depression; neostriatum; neuropsychological tests; pediatric psychology.

FIGURE 1

Consort Diagram. Of the initial Kids‐HD sample, 281 observations included usable magnetic resonance imaging (MRI) data (82%), composing the sample of our previous analysis (van der Plas et al., 2019). Two‐hundred thirty‐six of these observations were over 20 years from onset and included behavioral data for subsequent analysis (an 84% overlap between samples)

FIGURE 2

Parent‐behavioral measures in gene‐expanded (GE) and gene nonexpanded (GNE) groups. Mean age‐ and sex‐adjusted estimates for Behavior Rating Inventory of Executive Function (BRIEF) and Pediatric Behavior Scale‐30 (PBS) t‐scores in GNE (light gray) and GE (dark gray) groups were determined via linear mixed effects model, while controlling for the random effects of family relations and repeated visits. Filled circles indicate the marginal means and the underlying lines indicate the 95% confidence interval

FIGURE 3

Age‐dependent effect of striatal volume on Anxiety/Depression trait. Smoothed age‐dependent change of striatal volume in low‐Depression/Anxiety (solid) and high‐Depression/Anxiety (dashed) groups. Combined observations from all gene expanded (GE) and gene nonexpanded (GNE) were used to create a distribution of Pediatric Behavior Scale‐30 (PBS) Anxiety/Depression t‐scores. For visualization purposes only, this plot shows striatal trajectory from the lower (≤45; n = 70) and upper quantiles (≥60.25; n = 59) of the sample distribution, independent of gene status

FIGURE 4

Age‐dependent change in striatal volume by group (adapted from van der Plas et al., 2019). Previous analysis of the Kids‐HD dataset revealed a significant group difference in age‐dependent change of striatal volume. The patterns of overall striatal growth among gene nonexpanded individuals (GNE; N = 162; light gray) and loss of striatal volume among gene‐expanded individuals (GE; N = 119; dark gray) reflect the differential trajectories of high and low depression/anxiety groups observed in the present analysis