1. Brain development in VCFS: a longitudinal study
Stephan Eliez

2. 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

3. 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)

4. 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

5. 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

6. 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

7. 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

8. Psychotic symptoms in VCFS
65 patients with 22q11DS

9. 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.

10. … on to the maturation of the cortex
4mm
2mm

11. The Geneva cohort 61 patients with VCFS (36F/25M)
Mean age 15.6 ± 8.9 (range: )
Average FSIQ 68.7 ± 12.0
80 matched controls (44F/36M)
Mean age 15.9 ± 8.4 (range: )
Average FSIQ ± 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

12. 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.

13. 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.

14. 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

15. 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

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

17. 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

18. 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

19. 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

21. 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