Whats New on the Frontier

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Whats New on the Frontier?

• Nancy Minshew, MD
• Director, NIH Collaborative Program of Excellence
  in Autism at the University of Pittsburgh
• "Center for Autism And Related Disabilities"
• January 22, 2006

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University of Pittsburgh Carnegie-Mellon
University University of Illinois-Chicago Collabor
ative Program of Excellence in Autism (CPEA)

• Nancy J. Minshew, M.D.
• Director Child Neurologist
• 3811 OHara Street, Webster Hall Suite 300
• Pittsburgh, PA 15213
• 412-246-5485, Fax [phone]
• Email minshewnj_at_upmc.edu

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What We Have Learned in A Decade

• Prevalence
• Diagnostic methods (screening tools)
• Longitudinal stability of diagnosis
• Age at acquisition of language
• Cognitive neurologic basis of behavior
• Re-defining the syndrome beyond the DSM triad
• Brain basis from single structure to connections
• Brain keeps developing into early adulthood at
  least
• Developing new treatments based on new findings
• Gene hunt-far future treatments prevention

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Prevalence 3 Fold Increase

• 1

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Diagnostic Methods

• Screening tools are not diagnostic (quick
  dirty)
• Autism Diagnostic Interview (2 hours, history)
• Autism Diagnostic Observation Schedule (1 hour)
• Standardized questions coding of answers
• For adult LFA modified PL-ADOS
• For Aspergers ADI-ADOS w/o language delay,
  adult historian present but does it matter?
• See December Journal of Autism Developmental
  Disorders for articles on these topics

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Not A Triad Anymore

• DSM stipulates 3 symptom areas
• Our studies of 150 HFA 150 controls also show
  involvement of memory for complex material,
  higher order motor abilities, cortical sensory
  perception, oculomotor control and postural
  control.
• Symptoms are related to the demands placed on the
  brain for processing appear in proportion to
  these processing demands

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Not Just A Social Disorder The Second Bite

• Non-social or cognitive aspects equal impact
• Repetitive behavior, rigidity, obsessions
• Preoccupation with parts of objects or details
• Impaired problem solving, inflexibility, rigidity
• Impaired face and emotion recognition
• Impaired attribute labeling, rule-learning,
  concept formation
• Impaired common sense, function outside structure
• Impaired adaptive behavior-use of information to
  function

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Social Emotional Immaturity A Key Concept Not
Included in Diagnosis

• Social deficit in autism characterized by gaze
  and theory of mind impairments, which have been
  extended to eyes voice expression, face
  emotion, face recognition, gender
• Capacity to experience and comprehend emotions at
  a basic and cognitive level under investigated
  and underconsidered in treatment despite frequent
  brain imaging studies of amygdala, an emotion
  structure of the brain
• Many verbal ASD individuals socially-emotionally
  as young as 12-18 months to 4-5 years of age
  causing major problems in life. Failure to
  consider this in treatment worsens behavior and
  function.

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Diagnosis Over Time 2-9 years

• Courtesy of
• Dr. Catherine Lord

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Redefining Intervention

• Intervention is not over at 5
• Studies in autism show the brain is developing
  into adulthood
• Studies show language develops in most
• Many improving throughout childhood
• Temple Grandin has clearly improved as an adult

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Intact or Enhanced Abilities Deficits

• Intact or Enhanced
• Attention
• Elementary Sensory
• Elementary Motor
• Simple Memory
• Formal Language
• Rule-learning
• Visuospatial processing

• Cognitive Weaknesses
• Complex Sensory
• Complex Motor
• Complex Memory
• Complex Language
• Concept-formation
• Face recognition

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Dual task performance deficit in autism(but
matched performance in single task conditions)
Garcia-Villamisar Della Sala, 2002 Cognitive
Neuropsychiatry
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And then problems with face recognition were
reported. Is this focal brain dysfunction?
Cognitively the problem is with prototype
formation and automatic processes as opposed to
conscious verbally mediated reasoning.
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Infants are born with automatic mechanisms that
allow them to form Prototypical Representations
of Information
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Which of these is the best example of a dog?
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Recognition of average symmetrical faces are most
dependent on prototype formation

• detail or feature processing is not very helpful.

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Re-Crafting DSM Criteria

• Add category for social emotional immaturity
• Incorporate sensory, motor, gait, memory sxs
• Provide background before each symptom about
  underlying cognitive neurologic impairments to
  the extent they are now known with references
• Then provide symptom examples in order of
  severity so that all levels and ages included

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fMRI Activation During a SpatialWorking Memory
Task

• Healthy Individuals
  Individuals with Autism

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Language Profile in HFA

• Superior to age-, IQ-, gender- matched controls
  on word non-word decoding, spelling,
  vocabulary, fluency
• Inferior to controls on comprehension of
  sentences, idioms, metaphors, stories

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Brain activation during sentence comprehension in
high-functioning autistic subjects
Marcel Just Nancy Minshew Tim Keller Vlad
Cherkassky Jennifer Roth

• Center for Cognitive Brain Imaging
• Carnegie Mellon

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Sentence reading task and comprehension probe
Center for Cognitive Brain Imaging
The player was followed by the parent
Who was following? player parent
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• Brain activation during sentence comprehension in
  autism In Brain, 2004
• Autism group has less activation in Brocas area
• (a sentence integration area)
• than the control group and more in Wernickes
  area
• (a word processing area)
• Results are consistent with poorer comprehension
  of complex sentences, coupled with good word
  reading (spelling bee champs)

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Lower functional connectivity in autism between
pairs of key language areas during sentence
comprehension
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Autism group has lower functional connectivity
but same rank order
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Mental Imagery in Autism Seeing Pictures to
Understand Words
Rajesh Kumar Nancy Minshew Tim Keller Vlad
Cherkassky Marcel Just
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FMRI News

• Speak in sentences-think in words pictures
• Brain operates in systems, systems underconnected
• Local connections over-developed
• Distant connections under-developed
• Key Qs
• Does ABA develop local connections?
• Can new cognitive paradigms be designed to
  develop distant ones?
• Compensatory strategies obvious left side of
  table

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Total Brain Volume Morphometrics

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Brain Volume as a Function of Age

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Brain Growth During Childhood

• Courtesy Dr. Eric Courchesne
• Need for multi-center studies to achieve n1,000
• International standardization of imaging

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Not All Growth is Equal in the Brain

• Courtesy
• Dr. Martha Herbert

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Amygdala in Autism

• Courtesy of
• Aylward et al

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Minicolumnar Pathology in the Brains of Autistic
and Aspergers Patients

• MF Casanova, MD
• D Buxhoeveden, PhD
• RE Switala, PhD
• This research was funded by grants from the
  Theodore and Vada Stanley Foundation and the VA
  Merit Review Board.

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Diagram of the arrangements of neurons and their
processes within cortical modules
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Stereoscopic Observations

• Perspective schematic drawing based on
  stereoscopic observations of Nissl-counter
  stained Golgi sections. Column-like units, formed
  by elongated aggregates of cells and their
  processes, are shown.

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Stereoscopic Observations

• Minicolumnar
• Width

Neuropil Space
Relative Dispersio Ratio
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Total Brain Volume Morphometrics

• 1

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Re-Thinking Treatment

• Think in terms of connections
• Information comes to sensory or motor receiving
  centers of brain and then is connected to
  adjacent areas to interpret for purposes of
  understanding or generating a response
• Brain connections spread out and then to other
  regions close by and far away to enhance the
  sophistication of the processes

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Brodmans Brain
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Genetics of Autism

• Recurrence risk 4.5
• Estimates of 5-100 genes involved, vary in cases
• 41 male to female
• Fathers have protective protein expressed in
  daughters and missing sons (see Turner syndrome)
• Risk genes on y chromosome
• Heterogeneity present different genes or
  variations in same genes, clinical subgroups

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Epigenetics

• Genetic effects due to modifications of secondary
  or tertiary structure of DNA rather than primary
  changes in sequence e.g. genes
• These changes in the genetic code result in
  modifications of covalent bonds (eg methylation)
  and histones ( eg methylation, phosphorylation,
  acetylation)
• e.g. MECP2 functions at an epigenetic level as a
  gene silencer

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Linkage studies

• Philippe 99 51 ASP 3
• Risch 99 97/47 ASP 3
• Barrett 99 81 ASP 3
• IMGSAC 01 152 ASP 5
• Buxbaum 01 97 families 3
• Alarcon 02 152 families 5 (Y3)
• Shao 02 97 families 5
• Auranen 02 38 families 4 ?
• Yonan 03 345 families 5

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Linkage Studies Enriching Autism Samples for
Language Delay

• Chr 2 signal strengthens when enriching for
  language delay
• Also happens when linkage finding on chromosome 7
  is studied
• Caveat language function correlated with other
  features of autism, e.g. may not be language, but
  overall level of function

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Chromosome 7q31-35

• Autism chromosome 7
• language deficit
• increased risk of leukemia
• increased risk of autoimmune
• diseases

Genes within this region SPCH1 influences
speech and language development TCRB rearranged
in T-Cell leukemia IFRD1 associated with IgA
deficiency PDS thyroid deficiency associated with
congenital deafness
q31-35 Associated with Autism
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LOD logarithm of odds linked/odds not linked
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15q11-13 Deletion Syndromes
Deletion syndromes Paternal ? Prader-Willi (mild
MR, severe obesity, OCD) Maternal ? Angelman
syndrome (severe/profound MR, 100 autism
spectrum disorders)
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Chromosome 15q11-13
Autistic Disorder Duplication q11-13 Deletion
q11-13 Prader Willi Syndrome
Genes within this region SNRPN expressed in
brain development Immunoglobulins deficient in
Autism GABRA associated with Affective
Disorder UBE3A helps breakdown substances in the
brain during development, localized to
hippocampus, purkinje neurons and olfactory
regions

• Shared Features
• reciprocal social impairment
• language and motor delay
• light sound sensitivity
• obsessive compulsive disorder
• upset by change
• skin picking

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Promising candidate region 15q11-13

• Prader-Willi Angelman Syndrome region
• Experts suggest 3-4 of ASD trace to 15q11-13
• Sensitivity of assessments low my guess much
  larger
• Promising candidate genes
• 5-HTT S/L and (?) Intron 2 VNTR both functional
  
• NLGN4 a neuroligin
• Others MECP2 (Rett), HOXA1 (Head size), RELN
• (Mouse phenotype, etc), AGC1 (Asp/Glu carrier 2q)

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Well-controlled Candidate Gene Studies in autism
with at least one positive

• Two positive family-based studies in independent
  samples, no independent follow-up yet EN2
  (engrailed 2 involved in cerebellar development)
• Two or more studies nominally positive with some
  studies negative Serotonin transporter, GABA-A
  beta 3 subunit, vasopressin 1A receptor, Reelin
• Evidence equivocal, most carefully done studies
  are negative-HOXA1