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Neuropharma Of CNS disorders > Autism > Flashcards

Autism Flashcards

1
Q

Pervasive developmental disorder (PDD)

A

Normal until interaction with environment
Delays in childhood development (eg autism) that are associated with atypical behaviours

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2
Q

Autism and rates disorders (history)

A

1943 - identification of children that showed atypical behaviours
Sounded verbal skills
Social interaction
Repetitive behaviours

Otherwise normal development until social skills and skills needing the brain

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3
Q

Autistic triad and a spectrum of disorders

A

Asperger’s - impaired social interaction, impaired restricted activity particularly focussed to inanimate objects

Autism - impaired social interactions, impaired restricted activity g focusing to inanimate objects and verbal communication or reduced language skills

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4
Q

Appears in development and sustained

A

Developmental can mature over time - diagnosis of autism may be better defined by other syndromes
Cognitive dysfunction- high functioning/low functioning confuse diagnostics
Major cognitive syndrome present with behaviours that appear autistic but major dysfunction is mental retardation Retts and fragile X not autism
Retts and fragile x - defective gene identified so used as model

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5
Q

Autism

A

Triad of dysfunction in social, communicative, repetitive behaviours
Range: 10/10000
Monozygotic twins and significant siblings = genetic component, clear complex polygenetic underpinnings, environmental interactions

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6
Q

Asperger’s

A

Autistic disorder without dysfunctional verbal communication
1-60/10000
Genetic and environmental
Genes not clear

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7
Q

PDD-NOS

A

Low level autistic spectrum, more common better prognosis
1/200
Less studied - environmental and environmental

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8
Q

Hellers childhood disintegration disorder

A

Normal development followed by dysfunction in many areas beyond autism. Social skills less disrupted but severe decline in language skills
1/100000
Unclear but neuropathology implicated

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9
Q

Fragile X syndrome

A

Mental retardation, modest autistic phenotype
1/5000
Males > females
Fragile x gene
RNA binding protein mutated

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10
Q

Retts syndrome

A

Similar early symptoms, progresses to mental retardation
1/12500
MECP nuclear methyl DNA binding protein

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11
Q

Diagnosis of autism

A. Persistent deficits in social communication and social interaction across contexts, not accounted for general developmental delays, manifests by 3 of 3 symptoms

A
  1. deficits in social emotional reciprocity
  2. Deficits in nonverbal communication behaviours
  3. Deficits in developing and maintaining relationships
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12
Q

Diagnosis of autism

B. Restricted, repetitive patterns of behaviour, interests or activities as manifested >2 of 4 symptoms

A
  1. Stereotyped or repetitive speech, motor movements, use of objects
  2. Excessive adherence to routines, ritualised patterns of verbal or non verbal behaviour or excessive resistance to change
  3. Highly restricted, fixated interests that are abnormal in intensity and focus
  4. Hyper or hypo reactivity to sensory input or unusual interest in sensory aspects of environment
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13
Q

Diagnosis of autism

C. Symptoms must be present in early childhood but may not become fully manifest until social demands exceed limited capacities

A

Pervasive developmental disorder
Adult diagnosis too

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14
Q

Ute firsth: sally anne test and theory of the mind

A

A test to recognise empathy and associated social skill in the young

2 dolls sally and Anne
Sally has a basket, Anne has a box
Sally has a marble puts it in her basket
Sally goes for a walk
Anne takes the marble and puts it in her box
Sally comes back, wants to play with her marble where will sally look for her marble?

Autistic child - will look in the box, told the story so knows where it is. Can’t put themselves in the position of sally who would be unaware it was taken

Normal child - will look in basket, can put themselves outside of themselves

Empathetic, feeling outside yourself

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15
Q

Reality is that most with ASD diagnosis are not high performing

A

Sheldon - Big Bang theory probably Asperger’s
Non verbal, intense focus, hyper-hypo sensitivity, weird positioning system

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16
Q

When does neurotypical becomes neuroatypical

A

More prevalent or diagnosed in males
Human females empathise: do well in behavioural scores of ability to predict and respond appropriately to others mental state (verbal fluency)
Human males systemise: predict and respond to behaviour of nonagentive deterministic systems by predicting rules that govern the system (map reading)

Quantitative tests - series of questions, score if individual empathiser or systemiser

Extreme male brain (autistic) = focused go against empathising nerve activity

17
Q

Change in diognosis

A

More balanced view of male and females
Females more likely to be empathisers , autistic = non empathetic so might miss diagnosis without the balance

18
Q

Does the triad represent a unique spectrum or overlap of traits?
Social, verbal and motor (repetitive) behaviours

A

Fractionable in normal population but some linkage between some but not significant
Poor expression of traits in the triad of autism- not completely fractionated as some socially biased test tease out association

Genetic inheritance of individual traits in triad (twin studies) argues for fractionation of traits

19
Q

Social brain areas

A

Cortical regions:
medial frontal cortex, temporparieatal junction, temporal suculus and poles

20
Q

Verbal brain areas

A

Voice centres of cortex

21
Q

Repetitive brain areas

A

Caudate putamen

22
Q

Biological basis of autism

A

Infer that underpinned by changes in brain structure and function
Electroencephalograms in autistics identify unusual patterns of electrical activity - reinforced by string association with seizures in autism (30%)
Changes in brain size relative to control pops (slow neonatal and rapid post natal growth)

23
Q

Imagining of abnormal development and connectivity of autism in post mortem brains

A

Cerebral cortex - cell number increased
Cerebellar cortex - cell number decrease
Deep cerevellar nuclei - size change
Inferior oil art nucleus - cell densit

24
Q

Normal brain development

A

Progenitor
Neurogenesis (proliferation)
Migration
Neural differentiation
Neurone outgrowth
Synapse formation
(Retraction and shrinkage during synapse formation)
Maturation and stabilisation
(Pruning synaptic sculpturing so retraction and shrinkage)

Done by 6/7 yrs old but connectivity continues
Matched with cell death to keep numbers of neurones as required

25
Q

Genetic basis providing insight to a synaptic locus for autism

A

Monozygotic twins have 90% coincidence of autism
Siblings association too - polygenetic jn nature or complex regulation of de novo mutations

Mutations can be followed by tracking in heritability of genes
Chromosomal rearrangements cutoarchitecture identified and mutant associated with rearrangement
Linkage or association using markers in genome to track regions of genome associated with grainy and infer molecular associated with this

26
Q

Genome wise association studies (GWAS) using genomic variation to map disease associated alleles

A

Powerful in autism not powerful in depression
Patients DNA vs non patients DNA
SINGLE NUCLEOTIDE POLYMORPHISMS
Track single nucleotide polymorphisms
Compare position and abundance
Map of where they are associated with atypical
Weight of genetic contribution of that gene

27
Q

Genetic architecture of autism

A

Strong genetic association

Genetic variation
Rare, highly penetrant variations 1 allele involved to > 1000 in low penetrant variations present at high frequency

Complexity and spectrum

> 1000 genes implicated so far

28
Q

Many genes but good rationale to describe synaptopathy

A

Support a neurobiological and particularly synaptic basis for pathophysiology- often involved in nervous system (neurones)
Synapse

29
Q

FMRP

A

Control transcription and express of genes involved in formation and stabilisation of synapses

30
Q

NLGN4 & 3

A

Cell - cell and synaptic contacts

31
Q

Other mutations

A

Regulate cytoskeleton and form and function of dendrites
Protein organisation of synapse
Directly control chemical transmission and excitibility
Cell signalling (synapse function)
Developmental processes that lead to synapse formation
Control transcription and express of genes involved in formation and stabilisation of synapses
Cell - cell and synaptic contacts

32
Q

Structure and function of Neuroligin

A

Post synaptic molecule in cell cell adhesion with presynaptic neurone

Sits in membrane, faces synaptic cleft, associated in transymnatic fashion with neurexins (presynaptic)
Removal of these expect synapse will fall apart

Neurologin 1-4
Neurolexin 1-4
Neurexins thousands due to splicing

33
Q

Neurologin deficiency in animal models does not give expected effect but has autistic phenotype

A

Mice lacking neuroligin have brain, synapses and expected number of synapses (hippocampus/cortex)
Die due to brain stem disrupted neural activity when all neuroligin removed (balanced +ve & -ve neural circuit)
Brainstem normal number of synapses but glutamate and GABA transmitters reduced (fucundenty)
Normal- inhibitory dominates in respiratory system
Neuroligin deficient - excitatory dominates

Synaptic dysfunction without loss of cells or synapses appears possibility (synaptic maturation?)
Neurexin key susceptible gene
EEG disrupted, imbalance characteristic

34
Q

Clarity and complication in human and animal models of autism

A

Neuroligin - expressed broadly but can have selective effect
Mutated - neuroligin-3 in humans (R451C) Arginine to cysteine
Neuroligin 3 mutation = increase inhibitory synaptic transmission
Knock in mice showed no effect on social interaction

2 brothers: severe ASD symptoms including seizures early diagnosis, ASP with DSM diagnosis but milder diagnosis later

35
Q

Neuroligins mouse models of human condition

A

Neuroligin 3 mutated - protein made but not trafficked to cell surface so post synaptic neurone that lacks the neuroligin important in the signalling (10% gets to surface) INCREASED INHIBITION, IMPAIRED SOCIAL BEHAVIOUR, MODIFIED (IMPROVED) LEARNING

Neuroligin 3 knock out - similar in outcome but phenotypivally distinct INCREASED METABOTROPIC GLUTAMATE RECEPTOR, DISRUPTED PLASTICITY IN CEREBELLUM

36
Q

Animal studies of genetic lesion to define key circuits underpinning fractionable pathophysiology of autism circuits

A

NLG-3 knock out and functional null NLG3R451C do not directly overlap
Motor learning indicate shared ability for hyper function in motor control
No difference in performance, learning process - stays on for longer each time
X2 mutants falling off quicker than wild type- can’t compensate, dysfunction arises
Disruption in motor control and learning

Motor control: cerebellum, motor cortex, striatum (dorsal striatum)
Selective rescue gene - none of the regions rescued the motor phenotype
But ventral striatum (nuclear accumbens projects to VTA)

37
Q

Neuroligin 3 loss of function (KO & mutant) reduced inhibitory signals from GABA releasing onto D1 but not D2 neurones without effecting excitation

A

NL3 loss of function excitation to D1 and D2 pathways
No change in excitation in D1 or D2 pathway
Reduction in inhibition to D1, D2 still normally inhibited
Less variable, increased performance based on repeat behavioural sequence

Mutation profound enough to change behavioural response - repetitive behaviours - autism associated

38
Q

Therapy/treatment in autism

A

No cure

Behavioural therapies to induce behavioural plasticity
1.sensory or play therapies to bring individual out of oneself
2. Encourage interaction with environment and others
3. Cognitive therapy: identify deficiencies, awareness and teach strategies to overcome these

Drug therapies
1. Target neuro chemistry that underpin autistic triad (serotenergic and dopaminergic drugs eg haloperidol and resperidone) for social impairment and stereotypic behaviour, SSRIS for repetitive behaviours
2. Transmitter pathways that underline behavioural disorders associated with autism eg sleep disorders and aggression - propranolol or clonidine (adregergic antagonist)

39
Q

Issues with treatments

A

Evidence for efficacy tends to be clinical/anecdotal
Few full trials on efficacy of drug or behavioural treatments

Neuropharma Of CNS disorders (5 decks)

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