Brain development in VCFS: a longitudinal study Stephan Eliez

Outline Introduction and a few words on methods Impact of genetic factors and heart malformations How do early and maturational brain changes relate to psychosis Conclusion

Cortical volume changes in VCFS Reduction of gray matter volume in 60 patients with VCFS compared to 80 typically developing individuals (6-40 y/old)

Measuring cortical changes Local Gyrification Index 5 4 3 Early 2 Quantify surface in circular region of interest (Schaer et al, IEEE Transactions on Medical Imaging, 2008) Ratio of “hidden cortex” Thickness Later Sensitive to maturational changes

Gyrification in VCFS Several regions of reduced surface expansion, Right Several regions of reduced surface expansion, which may explain the volume reduction Left 44 patients with VCFS, 53 typically developing Corrected for multiple comparisons using FDR<0.01

Gyrification within VCFS Parental origin of the deletion Left lateral Right lateral 27 patients with maternal origin, 19 with paternal origin Uncorrected for multiple comparisons Left medial Right medial

Gyrification within VCFS Effect of congenital heart disease Right lateral Defect of expansion along watershed territories suggests hypoperfusion during cortical development Right medial Left lateral Left medial 18 with CHD (who underwent surgery), 17 without Uncorrected for multiple comparisons

Psychotic symptoms in VCFS 65 patients with 22q11DS

Gyrification within VCFS 22 psychotic patients (10-37yo) 22 matched controls 7 with hallucinations 7 without 5 with delusion 9 without 14 patients (12-16yo) 44 patients (6-37yo) 53 controls (6-37yo) When we further analyse the data comparing those participant with 22q11DS reporting psychotic symptoms versus controls, we find that the gyrification index is also decreased in the frontal areas, right around Broadmann areas 10 and 46. Although our adolescent group was relatively small, we still cared to provide an initial withing group comparison between those reporting hallucinations or delusions compared to those not reporting any symptoms. We find that reduction in te gyrification index in the frontal areas and the precentral areas can still be observed in these preliminary analyses, but they are perhaps too premature to draw general conclusions. What is important to remember is that gyrification index patterns CAN be observed between adolescents with 22q11ds that report positive symptoms of psychosis when compared to those that don’t.

… on to the maturation of the cortex 4mm 2mm https://surfer.nmr.mgh.harvard.edu/fswiki/LGI

The Geneva cohort 61 patients with VCFS (36F/25M) Mean age 15.6 ± 8.9 (range: 6-37.4) Average FSIQ 68.7 ± 12.0 80 matched controls (44F/36M) Mean age 15.9 ± 8.4 (range: 6-39.7) Average FSIQ 111.8 ± 12.8 Control VCFS 6 to 9 16 17 9 to 12 22 11 12 to 15 8 10 15 to 18 7 4 18 + 27 19

Cortical thickness changes Let’s break this down into the age bins in order to understand what might be going on with cortical thickeness from childhood through adolescence. Early on, we see increased thickness in 22q11DS, and this might be due to the fact that our controls’ gray matter may already be involved in a marurational process of pruning, as we can see on the plot. Towards middle adolescence, the slope takes an important shift and fast thinning occurs, which ultimately may lead to localized regions of cortical thinning, as seen here on the temporal lobe.

Cortical thickness changes Right hemisphere Here is another look at the trajectory from our cross-sectional results. We have preliminary longitudinal analyses that seem to corroborate these findings, but the sample sizes are still insufficient in some of the bins to get a clear comparison between the cross-sectional and longitudinal datasets.

Trajectories of cortical thickness Delayed thinning in preadolescents (younger than 9 at T1) Longitudinal measures of cortical changes over 3 years Faster thinning in adolescents (older than 9 at T1) 32 patients younger than 18 at first time-point (T1) & 31 matched controls

Thickness changes in 22q11DS … but a faster thinning with age in patients Uncorrected for multiple comparisons Thicker cortex in patients compared to control… Study-specific template, Covarying for gender and age corrected for multiple comparisons using FDR<0.05

Cortical thickness & schizophrenia 19 adult patients (6 with schizophrenia, 13 without) - 27 healthy adults

Conclusion Brain changes in VCFS are complex because they are caused by: Early changes in cortical folding & Later changes during cortical maturation (dysmaturation) In addition, there is an important variability in inter-individual brain development resulting from genetic factors and environmental factors (e.g. heart malformation) Greater dysmaturation is associated with psychosis. This opens new avenues for prevention and treatment

Stephan Eliez Martin Debbané Bronwyn Glaser Marie Schaer Annalaura Lagioia Catherine Pasca Catherine Audrin Astrid Flahault Marie-Christine Ottet Maude Schneider Mélanie Chabloz Michal Epstein

Thank you for your attention... Additional thanks go to: Participating parents and their families Connect 22 & Génération 22 family associations VCFS Educational Foundation Service Médico-Pédagogique The Swiss National Fund Fondation Gertrude von Meissner

COMT in patients with 22q11DS Yellow: thinner in Met compared to Val Blue: thinner in Val compared to Met Yellow: faster thinning in Met than Val Blue: faster thinning in Val than Met Cross-sectional: 29 Met / 28 Val Longitudinal: 15 Met / 18 Val Study 6 - Schaer, Debbané, Bach Cuadra, Ottet, Glaser, Thiran & Eliez, Deviant trajectories of cortical maturation in 22q11.2 deletion syndrome: a cross-sectional and longitudinal study, in revision