Unveiling the White Matter Microstructure in 22q11.2 Deletion Syndrome. Julio Villalón
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1 Unveiling the White Matter Microstructure in 22q11.2 Deletion Syndrome Julio Villalón
2 What is 22q11.2 Deletion Syndrome?
3 Yes, there is a mouse model!! Modified from Meechan et al. 2015
4 How are neurons affected by the deletion? Modified from Meechan et al. 2015
5 ENIGMA 22q11.2 Deletion Consortium Project Leader: Carrie Bearden Largest neuroimaging study of 22q11.2 delegon syndrome 10 internagonal samples 466 delegon subjects, 21 duplicagon subjects and 374 healthy controls 5 acgve consorgum projects
6 Demographics of ENIGMA-22q DTI a. Diagnosis b. Sex Upenn UCLA SUNY Newcastle Maastricht IoP Davis2 Davis1 Cardiff Utrecht HC 22q11.2 Upenn UCLA SUNY Newcastle Maastricht IoP Davis2 Davis1 Cardiff Utrecht Females Males Frequency Frequency Site Country 22q11.2DS Controls Sex Age Total N Univ. California Davis #1 CA, USA M / 32F (SD ± 2.27) 67 Univ. California Davis #2 CA, USA M / 46F (SD ± 2.44) 87 Inst. of Psychiatry London, UK M / 25F (SD ± 6.73) 48 Univ. of Newcastle NSW, Australia M / 19F (SD ± 2.85) 33 Univ. California Los Angeles CA, USA M / 40F (SD ± 5.61) 81 State Univ. New York NY, USA M / 21F (SD ± 1.88) 45 Univ. of Pennsylvania PA, USA M / 36F (SD ± 3.16) 92 Maastricht Univ. Netherlands M / 26F 3 (SD ± 9.16) 60 Cardiff Univ. WAL, UK M / 15F (SD ± 3.48) 27 Utrecht Univ. Netherlands M / 16F (SD ± 4.21) 54 Total M / 276F (SD ± 7.16) 594
7 Age Distribution of ENIGMA -22q DTI c. mean HC mean 22q Age Upenn UCLA SUNY Newcastle Maastricht IoP Davis2 Davis1 Cardiff Utrecht 10 4 Sites
8 Cognitive, clinical and genetic info a. Psychotic Disorders d. Upenn UCLA SUNY Newcastle Maastricht IoP Davis2 Davis1 Cardiff Utrecht Yes No Frequency Upenn UCLA SUNY Newcastle Maastricht IoP Davis2 Davis1 Cardiff Utrecht AD AB & Others Frequency Deletion Type c mean HC mean 22q11.2 AD delehon 195 AB/AC delehon 22 Intelligence [IQ] psychohc non-psychohc Sites
9 Diffusion Tensor Model Isotropic Unrestricted Diffusion Anisotropic Restricted Diffusion λ 1 λ 2 λ 3 Diffusion Tensor D D D D xx D xy D xz D yx D yy D yz D zx D zy D zz Diffusion Trajectory Diffusion Ellipsoid z y x z y x 0 FA 1
10 ENIGMA DTI Protocol ENIGMA-DTI Protocol Site 1 Site 2 Site 3 Site 4 Site i è n... ENIGMA-Template Jahanshad et al. NeuroImage, 90: , Smith et al. NeuroImage, 31: , 2006.
11 JHU White Matter Atlas y=-12 x=-20 z=9 GCC = Genu of corpus callosum RLIC = Retrolenticular part of internal capsule EC = External capsule BCC = Body of corpus callosum ACR = Anterior corona radiata CGC = Cingulum (cingulate gyrus) SCC = Splenium of corpus callosum SCR = Superior corona radiata CGH = Cingulum (hippocampus) TAP = Tapetum of the corpus callosum PCR = Posterior corona radiata FXST = Fornix (crus) / Stria terminalis ALIC = Anterior limb of internal capsule PTR = Posterior thalamic radiation SLF = Superior longitudinal fasciculus PLIC = Posterior limb of internal capsule SS = Sagittal stratum SFO = Superior fronto-occipital fasciculus
12 Statistical Analysis y = β 0 + β 1 x 1 + β 2 age + β 3 sex + β 4 age sex + β 5 age 2 + β 6 age 2 sex FA Diagnosis MD AD RD Meta-analysis COMBAT harmonisation Fortin, J.-P., Parker, D., Tunç, B., Watanabe, T., Elliott, M.A., Ruparel, K., Roalf, D.R., Satterthwaite, T.D., Gur, R.C., Gur, R.E., Schultz, R.T., Verma, R., Shinohara, R.T., Harmonization of multi-site diffusion tensor imaging data, NeuroImage (2017), doi: / j.neuroimage
13 Diagnostic differences: MetaAnalysis and Harmonization * Positive effect sizes = 22q11.2 > HC Significant differences between 22q11.2 and HC [MetaAnalysis & Harmonization, Bonferroni corrected (p <.05)] MetaAnalysis Harmonization FA * * * * * * * * * * MD * * * * * * * * * * * * * AD * * * * * * * * * * * * * * * * * RD * * * * * * * * * * * * * -1.4 TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC
14 BRAIN MAPS FA AD MD RD
15 Diagnostic differences across sites * Positive effect sizes = 22q11.2 > HC Significant differences between 22q11.2 and HC [MetaAnalysis, Bonferroni corrected (p <.05)] MetaAnalysis Upenn UCLA SUNY Newcastle Maastricht IoP Davis2 Davis1 Cardiff FA * * * * * * * * * * 0.9 MD * * * * * * * * * * * * * AD * * * * * * * * * * * * * * * * * RD * * * * * * * * * * * * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC
16 Diagnostic differences across age groups [Sample size at each age group = 78] * Positive effect sizes = 22q11.2 > HC Significant differences between 22q11.2 and HC [MetaAnalysis, Bonferroni corrected (p <.05)] MetaAnalysis 6-10 yrs yrs yrs yrs yrs. FA 1.5 * * * * * * * * * * MD * * * * * * * * * * * * * AD * * * * * * * * * * * * * * * * * RD * * * * * * * * * * * * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC
17 Age-DTI measures correlations in HC and 22q11.2 [Utrecht Excluded (Age- & Sex-Matched Sample; q11.2 and 230 HC)] * Significant associations [Bonferroni corrected (p<.05)] FA HC 22q11.2 * * * * * * * * * * * * * * * * * * * * * * * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC MD HC 22q11.2 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC AD HC 22q11.2 * * * * * * * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC RD HC 22q11.2 * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC [Pearson s r] 0
18 Influence of deletion type, psychotic disorders and IQ in DTI measures Positive effect sizes = 22q11.2 with psychotic disorders > 22q11.2 without psychotic disorders OR 22q11.2 deletion type AD > 22q11.2 deletion type AB-Others, OR 22q11.2 higher IQ > 22q11.2 lower IQ Significant group differences (uncorrected, p<5) Significant group differences (Bonferroni corrected, p<5) * Deletion type Psychotic Disorder * * IQ ** Deletion type ** Psychotic Disorder ** IQ Psychotic Disorder vs. No Psychotic Disorder [Harmonization-All Sites Included] AD vs. AB-Others [Harmonization-All Sites Included] Higher IQ vs. Lower IQ [Harmonization-All Sites Included] 0.5 FA * TAP PLIC ALIC GCC PCR SCC BCC SLF CGH EC * MD 0.5 AD * * * * * TAP GCC PCR SCC BCC SCR ACR RLIC CGC SS PTR SLF EC RD ** ** * * * * * * ** * * * * * GCC PCR SCC BCC SCR ACR RLIC CGC SS UNC PTR SFO FXST SLF CGH EC * * TAP PLIC ALIC GCC PCR SCC BCC SCR ACR RLIC SS PTR SLF
19 What is DTI telling us? PGSE acquisi0on protocol: Low q-values Low diffusion 0mes PGSE signal detected from: Hindered extracellular space Medium sized axons 3-10 μm Diffusion Trajectory Diffusion Ellipsoid Isotropic Unrestricted Diffusion z x y Anisotropic Restricted Diffusion z x y 0 FA 1 At current resolu0on of dmri, around 2/3 of WM voxels contain mul0ple fiber crossings Axon Bundles
20 Differential Cortical Projections
21 a. Uniform distributions c. DTI metrics from uniform and gamma distributions 0.7 IVF 0.6 IVF FA 8.0E-01 Uniform Distribution 0.7 IVF Gamma Distribution 0.7 IVF Uniform Distribution 0.6 IVF Gamma Distribution 0.6 IVF 7.8E E E-01 b. Gamma distributions: Corpus Callosum 7.1E-01 GCC BCC SCC 0.7 IVF 0.6 IVF MD 3.0E E-10 GCC 2.8E E E-10 GCC BCC SCC AD 6.1E E-10 BCC 6.0E E E-10 GCC BCC SCC RD 1.5E E-10 Aboitiz et al, 1992 SCC 7.5E E-11 E+00 GCC BCC SCC
22 Thank you!
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