New Developments in
Understanding
Autism:
W. Ted Brown, MD, PhD
Director, New York State
Institute for Basic Research
In D...
NEW YORK STATE
AUTISM
CONSORTIUM
A public-private partnership
5 initial goals:
Professional training
Early identification ...
Epidemiology of Autism
 Rates of autism are
increasing.
 The reasons are unclear. Better diagnosis?
 Better recognitio...
How Common is Autism?
•The general observation is of a dramatic
increase.
•The standard figure up to about 1980
was ~ 1/20...
How Common is Autism?
Autistic Children in CA
System
AutismCases=f(YearofBirth,DSMDate)
DSMDateAdjustedforAsssumedAgeatDiagnosisof3Years
YEAROFBIRTH
NUMBEROFENROLLEDPERSONSWIT...
Autistic Age Distribution: 1987 vs
1998
Mental Ability and Autism
What is Autism?
 A poorly understood Developmental Disability
 Hallmark: Severe impairment in social relations
 DSM IV ...
Clinical and Research
Identification of Autism
ADI-R Autism Diagnostic Interview-
Revised
ADOS-G Autism Diagnostic
Observa...
Other PDDs
Asperger’s Disorder
- Marked impairment in social interactions &
eye contact, peer relations, social sharing.
-...
Other PDDs
Rett Syndrome
- Females
- Onset of regression >5 mo
- Hand-wringing
- MECP2 gene mutation
Other PDDs
PDD-NOS (Pervasive Developmental
Disorder - Not Otherwise Specified)
Reserved for cases not meeting the
full cr...
AUTISM
RETT’
S
CDD
ASPERGER’
S
SYNDROME
PDD-NOS
Autism Spectrum Disorders
Time to give up on a single explanation for
autism. Happe et al. Nature Neurocience, Oct 2006
• 3,400 eight year old twin ...
Syndromal vs Pure Autism
• Pure Autism (non syndromal) -Limited to
moderate mental retardation to normal
intellectual func...
Essential vs Complex Autism
Miles et al AJMG 2005
• Complex autism (260 total)
• 5% microcephalic
• 16% dysmorphic - total...
Genetics of Autism
 Identical twins with autism - 70-90%
 Sibling recurrence risk - 5%
 A high heritability relative t...
Autism: Genetic Etiologies?
• The high concordance in MZ twins
indicates a high degree of genetic
control.
• The rapid fal...
Some Genetic Disorders
associated with Autism
• Fragile X ~25%
• Tuberous Sclerosis ~25%
• Down syndrome ~10%
• Angelman s...
Linkage Studies
Folstein and Rosen-Sheidley, Nature Rev Genet, 2001
Possible Autism Susceptibility
Genes
GENE
• Immune (HLA)
• Glutamate receptor (GluR6)
• Homeobox (HOXA1)
• Reelin (RELN)
•...
Genetics of Autism
 Preliminary genome wide screenings
indicate loci on at least 21 chromosomes.
 Chrs 1, 2, 3, 4, 5, 6,...
Array-based comparative genomic hybridisation identifies
high frequency of cryptic chromosomal rearrangements
in patients ...
Strong Association of De Novo Copy Number Mutations
with Autism Sebat, et al. Science 316, 445-9, (2007)
• Sampled 264 fam...
Structural Variation of Chromosomes in Autism
Spectrum Disorder Marshall et al. AJHG 82, 477-88, (2008)
• Sampled 427 fami...
CNVs may also be involved with
Schizophrenia
Although complex disorders such as schizophrenia have
a heritable component, ...
Autistic children linked to same sperm
donor
Gwenyth Jackaway is a professor at New York's Fordham
University. She's singl...
Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46;
P<.001) more likely to have ASD c...
Advanced paternal age has been associated with several congenital
disorders, including Apert syndrome, craniosynostosis,
n...
25% of very premature babies show
autism signs
A study of toddlers found that about one-quarter (26 of 91) of
babies born ...
Fever Improves Autism Symptoms
Children with autism appear to improve when they have a fever,
according to intriguing new ...
What Is Autism Caused by?
Dr Tom Insel, NIMH Director
and chair of the NIH Interagency Autism
Coordinating Committee, sugg...
The recent discovery of a new class of mammalian small regulatory
RNAs termed PIWI-interacting RNA (piRNA) has extended th...
http://pirnabank.ibab.ac.in/index.shtml
piRNABank is a web analysis system and resource
Sai Lakshmi S, Agrawal S.
Nucleic ...
PIWI-interacting RNAs (piRNAs) are a novel class of small (30 nt) noncoding
RNAs identified in mammalian germline cells an...
The Fragile X Syndrome
 The leading cause of inherited mental
retardation. It is associated with autism.
 This common me...
Association of Fragile X and Autism
• 17 screening studies of 1,243 autistic
subjects for FX had a range of 0 -16%,
and a ...
Association of Fragile X and Autism
• Behavioral characteristics found in
many FX males are similar to that in
autism (per...
Chromosome 15
 A maternally inherited chromosomal
duplication of the region 15q11-q13 has
been found in 1-3% of several l...
Chromosome 15
• Angelman Syndrome –Develpmental
delay, retardation speech impairment,
gait ataxia and happy behavior. Ofte...
Chromosome 15
• Prader-Willi is the lack of paternal
contribution within the same region
15q11-13
• Hypotonia, dev delay, ...
Isodicentric 15 - idic(15)
IDIC(15)
• Phenotype includes: MR, seizures,
language disorders, autism, hypotonia
• One series- 8/9 exhibited autism
• Br...
Brain Abnormalities in
Autism
Rare postmortem studies in autism (<30).
Typically larger brain size 10-20%.
Brain size en...
Brain Abnormalities in
Autism
 Dr. George Wegiel at IBR has studied
14 autism cases and age matched
controls.
 Finds sma...
Material
14 brains of autistic subjects and
14 age matched control brains
Age range: 4 to 64 years.
Autism Tissue Program ...
Structures examined:
Striatum: Caudate
Putamen
N. accumbens
Amygdala: Lateral, basal, accessory and central nucleus
Cerebe...
IDIOPATHIC AUTISM
GRADING OF DEVELOPMENTAL DEFICITS
IN THE SIZE OF NEURONAL BODY IN
4-7 YEAR OLD AUTISTIC CHILDREN
Nucleus...
IDIOPATHIC AUTISM
PERCENTAGE OF SMALL NEURONAL NUCLEI
IN AUTISTIC AND CONTROL PEOPLE
Structure Neuronal Autism Control Rat...
Triple Hit Hypothesis
• UNDERLYING VULNERABILITY
• EXOGENOUS STRESSOR
• CRITICAL PERIOD OF BRAIN
DEVELOPMENT
Some fundamental questions
• How many autisms are there?
• Is there is a “real” autism and one or
more pretenders?
• Shoul...
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  • To obtain a crude chromosomal location of the gene or genes associated with a phenotype of interest. Genes or markers on different chromomes segregate independently. Any two genes or markers on the chromosome might be expected to segregate together especially if they are in close proximity.
  • Brown.ppt

    1. 1. New Developments in Understanding Autism: W. Ted Brown, MD, PhD Director, New York State Institute for Basic Research In Developmental Disabilities
    2. 2. NEW YORK STATE AUTISM CONSORTIUM A public-private partnership 5 initial goals: Professional training Early identification and intervention Epidemiology and registry Treatment research (lab school)
    3. 3. Epidemiology of Autism  Rates of autism are increasing.  The reasons are unclear. Better diagnosis?  Better recognition?  Better programs?  True increase?
    4. 4. How Common is Autism? •The general observation is of a dramatic increase. •The standard figure up to about 1980 was ~ 1/2000. • Since then, a consistent increase has been observed. • CDC (Feb 07) ⇒ 6.6/1000 or about 1/150 with 10.6/1000 in NJ.
    5. 5. How Common is Autism?
    6. 6. Autistic Children in CA System
    7. 7. AutismCases=f(YearofBirth,DSMDate) DSMDateAdjustedforAsssumedAgeatDiagnosisof3Years YEAROFBIRTH NUMBEROFENROLLEDPERSONSWITHAUTISM 100 200 300 400 500 600 1960 1965 1970 1975 1980 1985 1990 1995 DSM DSM-II DSM-III DSM-III-R SCHIZOPHRENIA CHILDHOODTYPE INFANTILE AUTISM AUTISTIC DISORDER California Data and Changes in DSM Criteria
    8. 8. Autistic Age Distribution: 1987 vs 1998
    9. 9. Mental Ability and Autism
    10. 10. What is Autism?  A poorly understood Developmental Disability  Hallmark: Severe impairment in social relations  DSM IV - 5 different Pervasive Dev Disorders 1. Autism - 6 or more of 12 features involving social interactions, communication, repetitive & stereotypical behaviors 2. Onset prior to three yrs of age 3. Not Rett syndrome or CDD (childhood disintegrative disorder)
    11. 11. Clinical and Research Identification of Autism ADI-R Autism Diagnostic Interview- Revised ADOS-G Autism Diagnostic Observation Schedule-Generic PDD-BI Pervasive Developmental Disability – Behavior Inventory
    12. 12. Other PDDs Asperger’s Disorder - Marked impairment in social interactions & eye contact, peer relations, social sharing. - No delay in language, self help skills, or general cognitive development. - Apparently very common, but still is little known.
    13. 13. Other PDDs Rett Syndrome - Females - Onset of regression >5 mo - Hand-wringing - MECP2 gene mutation
    14. 14. Other PDDs PDD-NOS (Pervasive Developmental Disorder - Not Otherwise Specified) Reserved for cases not meeting the full criteria for autism because of later age of onset, atypical or subthreshold symptoms. Concept of a broader spectrum: Autistic Spectrum Disorders
    15. 15. AUTISM RETT’ S CDD ASPERGER’ S SYNDROME PDD-NOS Autism Spectrum Disorders
    16. 16. Time to give up on a single explanation for autism. Happe et al. Nature Neurocience, Oct 2006 • 3,400 eight year old twin pairs were studied. • Modest to low correlations between autistic-like traits in the three core areas (social, language, sameness). • Autism like traits are in a smooth continuum between individuals with ASD and the general population-no humps separating disease from not disease. • Social/communication impairments correlated in the range of 0.2-0.4 • Considerable numbers showed isolated difficulty in one area - 59% with social difficulty had only social difficulty. • Around 10% of all children showed only social impairment. • Conclusion: largely nonoverlapping genes act on each of these three traits.
    17. 17. Syndromal vs Pure Autism • Pure Autism (non syndromal) -Limited to moderate mental retardation to normal intellectual functioning and no associated signs or symptoms (except seizures). • Syndromal autism- one or more morphologic signs- estimated at ~20% Cohen et al JADD 2005
    18. 18. Essential vs Complex Autism Miles et al AJMG 2005 • Complex autism (260 total) • 5% microcephalic • 16% dysmorphic - total 21% • Lower IQ p<.006 • More seizures p<.0008 • Less sib reoccurence 0 vs 4% • Less relatives with autism 9 vs 20% • Lower male to female ratio 3.2:1/6.5:1
    19. 19. Genetics of Autism  Identical twins with autism - 70-90%  Sibling recurrence risk - 5%  A high heritability relative to diabetes, asthma, schizophrenia, hypertension, etc  A polygenetic (8-15 genes), multi- factorial disorder with M:F ratio of 4:1
    20. 20. Autism: Genetic Etiologies? • The high concordance in MZ twins indicates a high degree of genetic control. • The rapid fall off of concordance in DZ twins suggested a multilocus, epistatic model. • Caveats: Epigenetics & Mitochondria
    21. 21. Some Genetic Disorders associated with Autism • Fragile X ~25% • Tuberous Sclerosis ~25% • Down syndrome ~10% • Angelman syndrome ~40% • Prader-Willi syndrome ~25% • San Filippo syndrome ~90% • Smith-Magenis (del 17p11.2) ~90% • VCF/ DiGeorge (del 22q11) ~25%
    22. 22. Linkage Studies Folstein and Rosen-Sheidley, Nature Rev Genet, 2001
    23. 23. Possible Autism Susceptibility Genes GENE • Immune (HLA) • Glutamate receptor (GluR6) • Homeobox (HOXA1) • Reelin (RELN) • Speech1 (FOXP2) & MET • WNT2 & EN2 • Serotonin Receptor (5-HTR-7) • GABA Receptors (GABRB3) • Ubiquitin-P Ligase (UBE3A/E6-AP) • Serotonin Transporter (5-HTR7) • Neuroligins (NLGN3 & 4) LOCATION 6p 6q 7p 7q22 7q31 7q32 10q 15q 15q 17q X
    24. 24. Genetics of Autism  Preliminary genome wide screenings indicate loci on at least 21 chromosomes.  Chrs 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 22, X  Cytogenetic Abnormalities have been reported in 5-7% of cases IMGSAC et al. Hum. Mol Genet. 7(3):571-578, 1998 Philippe et al. Hum Mol. Genet. 8(5);805-812, 1999 Liu et al. Am. J. Hum. Genet. 68;327-340, 2001 Yonan et al. Am J. Hum. Genet. 73(4):2003
    25. 25. Array-based comparative genomic hybridisation identifies high frequency of cryptic chromosomal rearrangements in patients with syndromic autism spectrum disorders. Jacquemont et al. J Med Genet, 43: 843-9, 2006 Abnormalities found in 8/29 (27.5%) patients: 6 deletions and 2 duplications. Altered segments ranged in size from 1.4 to 16 Mb.
    26. 26. Strong Association of De Novo Copy Number Mutations with Autism Sebat, et al. Science 316, 445-9, (2007) • Sampled 264 families, 118 simplex, 47 multiplex, and 99 control families. Majority came from AGRE. Genome scans were performed by a form of comparative genomic hybridization (CGH) providing a mean resolution of 35 kb. • CNVs were identified in 12 of 118 (10%) of simplex, 2 of 77 (3%) multiplex, and in 2 of 196 (1%) of controls. • CNVs were in the range of 100kb-12mb. • Adding the known rate of cytogenetically visible abnormalities, the total frequency of de novo variation detectable in sporadic cases is ~15% at this resolution. • Affected genomic regions were highly heterogeneous and included mutations of single genes. • These findings establish de novo germline mutation as a more significant risk factor for ASD than previously recognized.
    27. 27. Structural Variation of Chromosomes in Autism Spectrum Disorder Marshall et al. AJHG 82, 477-88, (2008) • Sampled 427 families. Genome scans were performed by CGH arrays. • 277 unbalance CNVs were found in 44% of ASD families, not present in controls,. • de novo CNVs were identified in ~7% of simplex, ~2% of multiplex • CNVs were in the range of 100kb-20mb. • Affected genomic regions were highly heterogeneous and included mutations of single genes (NLGN4, SHANK3, NRXN1,, etc) and regions previously associated with syndromes (22q11.2, 16p11.2, etc).
    28. 28. CNVs may also be involved with Schizophrenia Although complex disorders such as schizophrenia have a heritable component, identifying the genetic components associated has been very difficult. Walsh et al (Sci April 08) found that multiple, individually rare, structural mutations (genomic microdeletions and microduplications) occurred more frequently in 150 individuals with schizophrenia than in controls. The enrichment was more than threefold among schizophrenia cases generally and more than fourfold among schizophrenia cases with onset by age 18. The genes disrupted by the genomic breakpoints of mutations in the schizophrenia patients were not random, but were disproportionately members of pathways controlling neuronal signaling and brain development.
    29. 29. Autistic children linked to same sperm donor Gwenyth Jackaway is a professor at New York's Fordham University. She's single but had always wanted to have a child. So she contacted California Cryobank, one of the largest sperm donor banks in the country. Cryobank doesn't reveal the identities of donors but allows people to choose based on the traits they'd like their child to have. Jackaway decided on "Donor X". What she couldn't know then is that her son would have autism. So she started to wonder whether Donor X might carry a gene that could have contributed. In six families Jackaway contacted that had used Donor X, three of the children are autistic, and one is showing signs of autism. The cause or causes of autism are not known and are hotly debated. Most experts believe that genetics are a component, making a child predisposed to autism or responsive to an environmental trigger. Researchers have found some genetic areas associated with autism, but it could take years before the gene or genes that cause autism or contribute to it will be determined. Until then, Geri Dawson, chief science officer for Autism Speaks, says there's no way to screen for those genes and prevent them fromCNN April 04
    30. 30. Offspring of men 40 years or older were 5.75 times (95% confidence interval, 2.65-12.46; P<.001) more likely to have ASD compared with offspring of men younger than 30 years, after controlling for year of birth, socioeconomic status, and maternal age. Advancing maternal age showed no association with ASD after adjusting for paternal age. Advancing Paternal Age and Autism. Reichenberg et al. Arch Gen Psych 63:1026,2006. Paternal age US 'controls' a AGRE autistic first child n=2 492 308 n=312 20–29b 55.1 41.6c 30–39 41.9 54.7 40–49 3.0 3.7 Paternal age and autism are associated in a family-based sample. Cantor et al. Mol Psych 12:419-21,2007. c P<0.005 PATERNAL AGE AND AUTISM
    31. 31. Advanced paternal age has been associated with several congenital disorders, including Apert syndrome, craniosynostosis, neurofibromatosis, progeria, situs inversus, syndactyly, cleft lip and/or palate, hydrocephalus, and neural tube defects . In addition, advanced paternal age has been associated with schizophrenia and decreased intellectual capacities in the offspring. The most widely proposed mechanism underlying these congenital anomalies is known as the “copy error” hypothesis, first proposed by Penrose. After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals. Prenatal and perinatal risk factors for autism: a review and integration of findings. Kolevzon A, Gross R, Reichenberg A. Arch Pediatr Adolesc Med. 161:326-33. 2007 Advancing paternal age has been consistently associated with increased risk of autism and ASDs.
    32. 32. 25% of very premature babies show autism signs A study of toddlers found that about one-quarter (26 of 91) of babies born very prematurely had signs of autism on an early screening test. The research is preliminary since formal autism testing wasn't done. But the results are provocative, suggesting that tiny preemies may face greater risks of developing autism than previously thought. That suggests autism may be an under-appreciated consequence of medical advances enabling the tiniest of premature babies to survive, said lead author Dr Limperopoulos, a researcher at McGill University in Montreal and Children's Hospital in Boston. Pediatrics April 08
    33. 33. Fever Improves Autism Symptoms Children with autism appear to improve when they have a fever, according to intriguing new research that could lead to a better understanding of the disorder. Fever was associated with less hyperactivity, improved communication, and less irritability in the study involving children with autism and related disorders. Anecdotal reports of improvements in autism symptoms related to fever have circulated for years, but the research represents the first scientific investigation into the observed association. While kids with autism might be expected to be calmer and less hyperactive when they have fevers, the improvement in communication and socialization seen in the study suggests that fever directly affects brain function says pediatric neurologist Andrew Zimmerman, MD, of Baltimore's Kennedy Krieger Institute Curran et al. Pediatrics Dec 07
    34. 34. What Is Autism Caused by? Dr Tom Insel, NIMH Director and chair of the NIH Interagency Autism Coordinating Committee, suggested: In Autism, the phenotype is diverse: Language development is diverse. Social cognition is variable. Regressive form seen in ~30%. CNV differences multiplex vs. simplex. Male only vs. female in family. Male ratio of 4:1 – higher in high functioning. }  piRNA
    35. 35. The recent discovery of a new class of mammalian small regulatory RNAs termed PIWI-interacting RNA (piRNA) has extended the diverse family of small regulatory RNAs. piRNAs are a novel class of small RNAs isolated from mammalian germline cells. piRNAs interact with the Piwi subfamily of proteins and form a ribonucleoprotein complex called Piwi-interacting RNA complex (piRC). piRNAs consist of more than 50,000 (perhaps >200,000 @ Betel PLoS 07) different species, in contrast to several hundred species of miRNAs. http://pirnabank.ibab.ac.in/index.shtml piRNAs
    36. 36. http://pirnabank.ibab.ac.in/index.shtml piRNABank is a web analysis system and resource Sai Lakshmi S, Agrawal S. Nucleic Acids Research 2007 Sep 18 Small non-coding RNAs may play a key role in Autism
    37. 37. PIWI-interacting RNAs (piRNAs) are a novel class of small (30 nt) noncoding RNAs identified in mammalian germline cells and constitute the most abundant known class of genes with over 32,000 elements in humans. We have examined piRNAs' organization in the human genome and have found that currently known human piRNAs map to 70,736 sites and are structured in about 400 clusters, containing each at least 10 piRNAs. A large proportion of the piRNA loci (about 65%) are located within repeat sequences, mainly LTRs and LINE sequences, and over 50% contain repeated units of a single piRNA, 71 being composed of tandem copies of a unique piRNAs. Surprisingly, over 25% of total piRNAs are located in regions that contain segmental duplications (SDs) and about 37% are within copy number variant (CNVs) regions. In addition, 233 (58%) and 220 (55%) piRNA clusters are within SDs and CNVs, respectively. Similarly, a significant subset of SDs (43%), especially those with the highest level of nucleotide identity, contains piRNAs. Finally, we have confirmed experimentally that the genomic sequences in which piRNAs are embedded in vary in copy number in humans. Since SDs and CNVs account for 5% and 12% of the human genome sequence, respectively, the significant enrichment of piRNAs is suggestive of a functional role of these elements. This association provides the first link between SDs and CNVs with elements that could have a putative functional role in the integrity of the genome. Enrichment and variability of PIWI-interacting RNAs (piRNAs) in segmental duplications and copy number variants (CNVs) suggest a functional role in the integrity of the genome. Armengol, Caceres, Brunet, X. Estivill (#153 ASHG)
    38. 38. The Fragile X Syndrome  The leading cause of inherited mental retardation. It is associated with autism.  This common mental retardation syndrome is due to the silencing of the FMR1 gene on the X chromosome.  The FMR1 protein (FMRP) is an RNA binding protein and modifies the expression of a set of other genes.
    39. 39. Association of Fragile X and Autism • 17 screening studies of 1,243 autistic subjects for FX had a range of 0 -16%, and a mean of 4%. • 14 studies of 479 FX males had a range of 7- 60%, and a mean of 24% with autism. • A recent study by Don Bailey of 57 boys with FX found 25% with autism.
    40. 40. Association of Fragile X and Autism • Behavioral characteristics found in many FX males are similar to that in autism (perseveration, stereotypies, regulating affect, attention, hyperactivity). • Anxiety-based symptoms more common in FX (gaze aversion). • Social interests, perception of others emotions, attachment to parents are higher in FX.
    41. 41. Chromosome 15  A maternally inherited chromosomal duplication of the region 15q11-q13 has been found in 1-3% of several large autism samples.  This region is paternally deleted in Angelman syndrome, and maternally deleted in Prader-Willi syndrome.  Contains several potentially relevant genes: Gaba receptor, Ubiquitin related gene.
    42. 42. Chromosome 15 • Angelman Syndrome –Develpmental delay, retardation speech impairment, gait ataxia and happy behavior. Often microcephaly and seizures. 1/12000 • Silence or disruption of UBE3A maternally derived gene • Autism in Angelman ~40%
    43. 43. Chromosome 15 • Prader-Willi is the lack of paternal contribution within the same region 15q11-13 • Hypotonia, dev delay, and MR. • Prevalence 1/29,000 • Autism in PW =25%
    44. 44. Isodicentric 15 - idic(15)
    45. 45. IDIC(15) • Phenotype includes: MR, seizures, language disorders, autism, hypotonia • One series- 8/9 exhibited autism • Brain size tends towards small 20% microcephalic • Autism shown to have larger brain size on neuropathologic exam, neuroimaging and is present in first degree relatives.
    46. 46. Brain Abnormalities in Autism Rare postmortem studies in autism (<30). Typically larger brain size 10-20%. Brain size enlarged by 10-20% using MRI during 2-4 yrs, then falls off after 8-10 yrs. Smaller nerve cell size and more dense packing seen in internal regions: limbic system and brain stem nuclei. Minicolumns are smaller and less compact. More white matter in frontal lobes, the cerebellum, various other areas, and associated with signs of inflamation.
    47. 47. Brain Abnormalities in Autism  Dr. George Wegiel at IBR has studied 14 autism cases and age matched controls.  Finds smaller and decreased numbers of neurons in many areas. Finds elevated levels of intracellular Beta-Amyloid in 40% of autistic specimens, unrelated to age.
    48. 48. Material 14 brains of autistic subjects and 14 age matched control brains Age range: 4 to 64 years. Autism Tissue Program (Princeton) coordinated selection of material for morphometric study of cortical and subcortical subdivisions in several European and US research centers engaged in Autism Brain Atlas Project. Inclusion/exclusion criteria. Selection of brains was based on clinical, neuropathological and technical inclusion and exclusion criteria. This study of historically the largest collection of brains of autistic individuals and age matched control subjects is the product of coordinated efforts of several institutions and dozens of unnamed contributors.
    49. 49. Structures examined: Striatum: Caudate Putamen N. accumbens Amygdala: Lateral, basal, accessory and central nucleus Cerebellum: Purkinje cells Dentate nucleus Brain stem: Nucleus of facial nerve and Nucleus olivaris inferior Entorhinal cortex: Layers II (stellate neurons), III, V, and VI. Structures to be examined: Examination of 11 other structures (in progress) will complete comprehensive mapping of developmental and age-associated changes in brains of autistic subjects.
    50. 50. IDIOPATHIC AUTISM GRADING OF DEVELOPMENTAL DEFICITS IN THE SIZE OF NEURONAL BODY IN 4-7 YEAR OLD AUTISTIC CHILDREN Nucleus accumbens: -46% Amygdala (lateral basal nucleus): -29% Putamen: -27% Dentate nucleus: -25% Caudate: -20% Nucleus of facial nerve: +5% (not significant)
    51. 51. IDIOPATHIC AUTISM PERCENTAGE OF SMALL NEURONAL NUCLEI IN AUTISTIC AND CONTROL PEOPLE Structure Neuronal Autism Control Ratio nucleus autism/ volume μm3 control Amygdala. Lateral n <300 45% 15% 2.5x Amygdala. Lat.Bas.n. <300 46% 15% 3.0x N. accumbens <200 82% 12% 6.8x Putamen <200 66% 31% 2.1x Caudate <200 72% 27% 2.7x Dentate n <300 55% 18% 3.0x N. olivaris <400 47% 16% 2.9x Average 59% 20% 3.0x N. Facial n. <1,500 50% 58% 0.9x
    52. 52. Triple Hit Hypothesis • UNDERLYING VULNERABILITY • EXOGENOUS STRESSOR • CRITICAL PERIOD OF BRAIN DEVELOPMENT
    53. 53. Some fundamental questions • How many autisms are there? • Is there is a “real” autism and one or more pretenders? • Should autism be studied as an entity or as part of a continuum? • Where do we draw the lines? Who are we excluding? • What do words like co-morbid and dual diagnosis really mean?
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