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					Thank you:
   NIMH, NINDS and NICHD
     Simons Foundation
       Autism Speaks
                            Sierra
      Cure Autism Now
      NICHD Brain Bank
   ATP/Harvard Brain Bank




             Taran
NEURODEVELOPMENTAL STUDIES OF AUTISM:
   FROM MRI AND FMRI
       TO NEURONS AND GENES




    UCSD Autism Center of Excellence
         Eric Courchesne, Director
       Karen Pierce, Assistant Director
      Three Phases of Growth Pathology in ASD
                                                        Frontal
 Overgrowth           Arrested
                                 Possible
                      Growth     Decline/Degeneration
         SIZE

                ASD
                        NORMAL

                                       Temporal

                           AGE

                                                        Amygdala
Courchesne et al 2001
Courchesne et al., 2003
Courchesne & Pierce 2005
Courchesne et al., 2007
Abnormal Brain Overgrowth in
                                     Courchesne et al., 2003 JAMA
ASD in First Two Years of Life       Dementieva et al., 2005
                                   Dissanayaki et al., 2005
                  x        xxx x     Hazlett et al., 2005
 90                       xxx       Dawson et al., 2007
                                     Mraz et al., 2007
                          xx x x
                               x     Webb et al., 2007
 70               x                  Elder et al., 2007
                            x
 50           x                          Data from Webb, Dawson 2007 = *
             x                          And Courchesne 2003
          xx xxx
             xx             x
 30                         x
             xx
              x                                        * *
 10           x 
                                                 *
          

  -0.5                      0.5
                                           *
          Birth           6-12 mos   *
      Dementieva et al 2005
                Abnormal Brain Overgrowth
              in Autism by 2 to 4 Years of Age
                     Courchesne et al., 2001

                         Autism
              1500
Volume (ml)




                                  l
                                        l
                             l l                 Autism case Macrencephaly
                                l   l l l
              1300             l     l
                          ll l l l l l                Recent MRI Studies Also
                                   l       l
                            l
                            l    ll l                 Showing Abnormal Brain
                               l       l l                   Overgrowth
              1100                        ll      in Autism by 2 to 4 Years of Age
                                        l
                                                         Sparks et al., 2002
                          Normal Mean                     Carper et al 2002
                          1179 ml                    Carper & Courchesne 2005
               900                                       Hazlett et al., 2005
                                                  Schumann, Pierce, Courchesne
                     2      3      4                       in prepapration
                          Age (years)              Average Normal
                                          Gray Matter Overgrowth in ASD
                                  p<0.05                             1. Carper et al. 2002         3.4 years
                              *
                                                                     2. Bloss&Courchesne, 2007 3.8 years
                              *
Standard deviations




                                                                     3. Kates et al. 2004          7.6 years
                          *                           *
   from normal




                                                                               *
                                                                     4. Palmen et al. 2005     11.1 years
                      *
                                      *                              5. Hazlett et al. 2005 n.s.19.1 years
                                                                                        *
                                                                         (left cerebrum only)
                                           n.s.
                                                  *   n.s.
                                                             *              *
                                  *                              *

                                                                                                     n.s.


                      1 2 3 4 5                   1 2 3 4 5          1 2 3 4 5     1 2 3ç 5
                                                                                         4     ç
                       Frontal                    Temporal            Parietal     Occipital
                                          Gray Matter Overgrowth in ASD
                                  p<0.05                                 1. Carper et al. 2002     3.4 years
                              *
                                                                         2. Bloss & Courchesne, 2007 3.8 years

                              *                                          3. Kates et al. 2004       7.6 years
Standard deviations




                          *                           *
   from normal




                                                                         4. Palmen et al. 2005
                                                                                   *               11.1 years
                      *
                                                                         5. Hazlett et al. 2005 n.s.19.1 years
                                      *                                                     *
                                                                             (left cerebrum only)
                                           n.s.                          6. Schumann, Pierce et al. 2010 2 years
                                                  *   n.s.
                                                             *       *          *
                                  *       *                      *

                                                                                                      n.s.


                      1 2 3 4 5 6                 1 2 3 4 5 6            1 2 3 4 5 6   1 2 3 4 5 6
                       Frontal                    Temporal                Parietal     Occipital
       Overgrowth
SIZE                                 Major Goals of the
        ASD                                UCSD
               NORMAL                Autism Center of
                                        Excellence

                 AGE
   (1) Identify the neural and genetic defects that cause
      early brain overgrowth in ASD
      a) theorize defects in prenatal regulation of neural
          genesis and apoptosis

   (2) Discover powerful and reliable behavioral and
      biological markers of ASD in the first years of life
What Causes Early Brain Overgrowth in ASD?
Overgrowth
                                 Autistic (N=7) vs Control
       ASD                              (N=6) Males
               NORMAL                   Ages 2 to 15 years
SIZE




                 AGE more
                 68%
                 neurons

                                                    34% more
                                                    neurons

             Mouton, Calhoun, Arhens-
             Barbeau, Courchesne
                    What is the
                    Cause of
68% more            Excess Cells?
neurons                             Gene
            What are the            Expression
            Resulting               and CNV
            Cortical                analyses
            Defects?
           Anatomic
           Microstructure
Abnormal Frontal Cortex Gene Expression
at Young Ages (2 to 14 years) in Autism
102 differentially expressed genes

Prenatal Pathways Governing
Cell Numbers and Functional Integrity
DNA damage responses
     Cell cycle regulation
     Cell proliferation
     Apoptosis and survival

Prenatal Processes Governing Patterning
Left/Right neural patterning
       Anterior/Posterior neural patterning

                      Chow, Pramparo et al., in
                      manuscript
    Abnormalities in Neural Patterning, Cellular
    Specification, Cell Division and Proliferation
Downregulation       Processes
neural patterning genes (e.g., DLX4, HOXD1, NDE1, NODAL, PCSK6, GREM1) that
affect left/right asymmetry patterning processes and anterior/posterior axis
specification (p=2.63E-04)
Hum Mol Gen, 2010: PCSK6, a genetic link between cerebral asymmetry and
language disorder




Upregulation
proliferation regulators (e.g., WNT3)                     Chow, Pramparo et al., in
                                                          manuscript
                 Abnormal Laterality to Language
                    in ASD Infants & Toddlers
        TYPICAL              Eyler, Pierce and Courchesne
    13 to 45 months
                                  1.0
                       L
                  Temporal                   Effect
                   cortex                    Size
    R                                        (Eta2)
                                                                           Fw Bw Fw Bw Fw Bw Fw Bw

                                  0.0

                                                               0.08
                                                                              TYPICAL
                                                               0.06



                                    Left-Right Difference in
           ASD                                                                 L>R


                                     Mean FIt Coefficient
                                                               0.04
     14 to 47 months                                           0.02
                                                                  0
                                                               -0.02
                                                               -0.04
                                                                            ASD
                                                                            R>L
R                                                              -0.06
                                                               -0.08
Temporal
                                                                -0.1
cortex                                                                 0       10       Age
                                                                                        20       30   40   50
                                                                                        Age in
                                                                                        months
White Matter                  CTGF
Boundary



                          NTNG2

                       PCP4


                 RORB
                                     Layer 1 - Pial
                                     Surface

               CALB1

				
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