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

Ratio of “hidden cortex”

Local Gyrification Index 5

4

3

2

Quantify surface in circular region of interest (Schaer et al, IEEE Transactions on Medical Imaging, 2008)

Early

Sensitive to maturational

changes

Thickness Later

Gyrification in VCFS

Right

Left

Several regions of reduced surface

expansion,

which may explain the volume reduction

44 patients with VCFS, 53 typically developingCorrected for multiple comparisons using FDR<0.01

Gyrification within VCFS

Parental origin of the deletion

27 patients with maternal origin, 19 with paternal originUncorrected for multiple comparisons

Right lateral

Right medial Left medial

Left lateral

Gyrification within VCFS

Right lateral

Left lateral

18 with CHD (who underwent surgery), 17 withoutUncorrected for multiple comparisons

Defect of expansion along watershed territories suggests hypoperfusion during cortical development

Effect of congenital heart disease

Right medial

Left medial

Psychotic symptoms in VCFS

65 patients with 22q11DS

Gyrification within VCFS

44 patients (6-37yo)53 controls (6-37yo)

22 psychotic patients (10-37yo)22 matched controls

7 with hallucinations7 without

5 with delusion9 without

14 patients (12-16yo)

… on to the maturation of the cortex

2mm

4mm

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

Right hemisphere

Cortical thickness changes

Trajectories of cortical thickness

Longitudinal measures of cortical changes over 3 years

Delayed thinning in preadolescents

(younger than 9 at T1)

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

Study-specific template, Covarying for gender and agecorrected for multiple comparisons using FDR<0.05

Thicker cortex in patients compared to control…

… but a faster thinning with age in patients

Uncorrected for multiple comparisons

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 Bronwyn GlaserMartin Debbané

Marie Schaer

Maude Schneider

Annalaura Lagioia

Mélanie Chabloz Michal Epstein

Catherine Pasca

Astrid Flahault Marie-Christine OttetCatherine Audrin

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

Cross-sectional: 29 Met / 28 Val

Yellow: thinner in Met compared to ValBlue: thinner in Val compared to Met

Yellow: faster thinning in Met than ValBlue: faster thinning in Val than Met

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