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Disease in the brain > Autism spectrum disorder (finished > Flashcards

Autism spectrum disorder (finished Flashcards

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1
Q

How is ASD defined (diagnosed)?

A

Deficits in these 2 core domains (3 symptoms)

a) Atypical social behaviour

b) Disrupted verbal & non-verbal communication AND restrictive interests & repetitive behaviours

Onset before age 3

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2
Q

What is used in order to diagnose autism?

A

DSM- V = diagnostic and statistical manual of mental disorders

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3
Q

How often is a delay in spoken language seen in ASD cases?

A

Delay in spoken language seen in ~50% of cases

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4
Q

What 3 previously separate diagnoses does the DSM-V combine into ASD?

A
  • ‘Autistic disorder’
  • ‘Asperger’s disorder’
  • ‘Pervasive developmental disorder - not otherwise specified (PDD-NOS)’
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5
Q

What sort of therapy is available for patients w ASD?

A

Therapy restricted to behavioural intervention as so many different traits associated with ASD and the origin is hard to treat

Can benefit IF received early

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6
Q

What are the FDA approved drugs for treating ASD and what does each one aim to do?

A

Antipsychotics:

  • Risperidone- treats aggressive and repetitive behaviour
  • Aripiprazole- reduces irritability
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7
Q

What are the 2 main treatments for ASD?

A
  • Behavioural intervention therapy
  • FDA approved drugs
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8
Q

What is the issue with using drugs to treat ASD?

A

Drugs don’t treat core social deficit just the behavioural symptoms managed

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9
Q

What is the prevalence of ASD in the early 1990s vs today?

A

Early 1990s = 1 in 1,000- diagnostics were not very developed

Today = est. 1 in 68 children under 8 in the USA

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10
Q

What is the prevalence of ASD in males vs females?

A
  • 1 in 42 for males
  • 1 in 189 in females

(5 fold for males)

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11
Q

What are the prevalent comorbidities of ASD?

A
  • Motor deficits
  • Sleep abnormalities
  • Gastrointestinal disturbances (50%) (gastrointestinal microbiome partly responsible for ASD)
  • Epilepsy
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12
Q

What level of intelligence is generally found in children w ASD?

How about the 2 minorities of intelligence?

A

MOST ASD children have normal intelligence

35-50% have intellectual disability - defined as IQ <70

Small minority - have remarkable memory/intellect e.g. Einstein

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13
Q

What is the neuropathology of ASD?

A
  • No common macroscopic or microscopic neuropathology
  • Ne specific brain region or cell type implicated

(So cannot diagnose w brain imaging)

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14
Q

How does head size differ in ASD?

A

~20% larger head size

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15
Q

Are there any biomarkers for ASD?

A

No biomarkers –> means no prediction at birth

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16
Q

How can an EEG be used for diagnosis?

A

Eye tracking movements (eye contact issues) & EEG can be helpful for diagnosis

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17
Q

What is the group of drugs that is used to treat ASD?

A

They are antipsychotics

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18
Q

Name the 3 core autism symptoms

A
  • Social deficits
  • Language impairment
  • Repetitive behaviours
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19
Q

Name the 6 associated neurological issues in ASD?

A
  • Seizures
  • Sleep deficits
  • Mood
  • Anxiety
  • Hyperactivity
  • Attention (last 2 link to ADHD as a related disorder)
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20
Q

Name the 2 associated systemic issues in ASD

A
  • GI disorders
  • Immune dysfunction
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21
Q

What are some of the typical early traits in ASD seen in children?

A
  • Inability to relate to children or adults
  • Poor speech or lack of speech
  • Inappropriate crying/laughter
  • Oversensitive or undersensitive to sound
  • Inappropriate playing w toys
  • Difficulty dealing w changes in routine
  • Oversensitive or undersensitive to touch
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22
Q

What % of cases do genetic conditions contribute to ASD?

A

Rare genetic conditions contribute to 3% of ASD cases

Very small fraction of children w ASD

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23
Q

What % of children with an autistic sibling develop ASD?

A

20%

Certain degree of inheritance

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24
Q

What is a De novo mutation?

A

A mutation that is present in the offspring but not inherited (absent) from either parent- occur after fertilisation

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25
Q

How can a De novo mutation cause ASD?

How frequent are they?

A

Coding differences occurring after fertilisation (not inherited from either parent)

Occur in 5-10% of all cases

A sporadic form - not inherited

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26
Q

How often do genetic mutations cause ASD?

A

80-85% = no clear genetic cause

  • 3% mendelian single gene inherited
  • 5% chromosome anomalies & CNVs
  • 5-10% De novo single gene mutations
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27
Q

How can chromosome anomalies & CNVs cause ASD & how common are they?

A

5% of cases caused by copy number variations

Large sections of the genome replicated/deleted

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28
Q

Which gene has been found to be affected by de novo mutations in ASD?

A

The gene producing the protein TRIO

It is responsible for the early formation of dendritic spines of glutamatergic neurons

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29
Q

What % of children w an autistic sibling develop ASD?

A

20% = certain degree of inheritance

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30
Q

What is the main factor that results in ASD?

A

predominantly due to difficulties in early development that is mainly neuronal networks which then in adulthood will be showing as behavioural abnormalities

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31
Q

What are the 3 levels at which ASD develops on?

A
  • Neuroanatomical
  • Systems-level
  • Cellular and molecular
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32
Q

What are the neuroanatomical ways that ASD differs?

A
  • Brain growth- ASD have larger brains in early stages but throughout development this normalises
  • Cortical columns- neurons form these networks in very early stages but these are altered in ASD (malfunctions)
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33
Q

How does brain growth differ in those w ASD?

A

Children w ASD tend to have larger brains

Thru development this normalises again in adolescence

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34
Q

How do cortical columns differ in those w ASD?

A
  • There is disorder of neuronal connectivity esp in the cerebral cortex
  • Malfunctions occur in the formation of these early networks
35
Q

How does pathfinding differ in ASD both prenatal & postnatal?

A

Prenatal –> neuronal migration & axonal pathfinding is different

Postnatal –> dendritic development, synaptic pruning & neurogenesis differs- involved in forming networks in brain

36
Q

What are the systems-level ways that ASD differs?

A
  • White matter tracts & functional connectivity
  • Balance of excitations/inhibition
37
Q

How does the balance of excitations/inhibition lead to ASD?

A

Some genes cause different prenatal pathfinding

So more excitatory than inhibitory neurones forming

38
Q

What are the genes involved in systems-level ASD causes?

A
  • NRXN1
  • NLGN2&3
  • SHANK3 (excitatory) - has been shown to have particular links to ASD
39
Q

How many genes are involved in malfunction of circuits in ASD?

A

> 100 susceptible genes covering on pathways involving synaptic transmission

(Different genes may contribute to the 3 distinct symptoms)

40
Q

What are the cellular & molecular ways that ASD differs?

A
  • Activity-dependent protein synthesis
  • Neuronal activity
  • Neuronal cell adhesion
41
Q

What are the genes found at a cellular & molecular level that contribute to ASD & what do each of them do?

A
  • SCN2A &1A - related to VGSCs
  • GRIN2A & B - NMDA receptors
  • GRIK2 - kinase receptors
  • CACNA1C & H - VGCCs

(Genes encoding for these proteins shown to be associated w ASD)

42
Q

What does the biological convergence of genes & pathways affect?

A
  • Synapse formation
  • Neuronal activity
  • Neuronal cell adhesion
43
Q

What 6 areas of genes are affected in ASD?

A
  • Synaptogenesis
  • Protein synthesis
  • Chromatin remodelling & transcription
  • Protein degredation
  • Phospholipid homeostasis
  • Cytoskeleton dynamics
44
Q

What is synaptogenesis?

A

= formation of synapses between neurons

45
Q

What are the genes that are affected in synaptogenesis in ASD?

A
  • Neurolexin
  • Neuroligin
  • Neurobeachin
  • DAT
  • mGluR
  • Neulexin IV
  • Synaptojanin
46
Q

What is the gene in ASD that affects both cytoskeleton dynamics & synaptogenesis?

A

SHANK gene

47
Q

What is the main function of neuroligin and neurexin?

A

= cell adhesion proteins responsible for forming appropriate synaptic connections

48
Q

What are neuroligins + their function?

A

= synaptic cell-adhesion molecules at postsynaptic neuronal membranes and interact with either glutamate (NMDA receptors – excitatory) or GABA receptors (– inhibitory) to the synapse and maintain the excitatory/inhibitory balance

49
Q

What is a neurexin?

A

= components of the presynaptic neuronal membrane and their intracellular domain interacts with proteins involved in exocytosis- to allow synaptic vesicle recyling

50
Q

Explain how immunostaining was used to see the effect of neuroligin + results

A

Effect neuroligin by introducing a mutation (R451C) will alter GABAergic activity
Can look at via immunostaining- stain for VGAT in the presynaptic vesicles
- mutate protein = increased signal of GABA presynaptic neuron (more green dots)
= neuroligin is responsible for expression of GABAergic neurons

51
Q

Explain how electrophysiological data was used to see the effect of neuroligin + results

A

Can study functional effects of same mutation
can measure spontaneous activities of neurons:
- EPCs = excitatory postsynaptic currents mediated by glutamate
- IPCs = inhibitory postsynaptic currents mediated by GABA

Increased activity of GABAergic activity following mutation = more GABA activity as neuroligin affected = direct link

52
Q

Explain how behavioural was used to see the effect of neuroligin + results

A

Measure social interactions in mice via time spent with a partner
But mutants spent less time interacting with their partners

53
Q

What other protein is important in ASD?

A

dopamine receptors

54
Q

Describe an experiment that suggests D2 receptors are involved in ASD

A

Human brain samples have been used for experiments with a radio-label (mRNA)
ASD vs controls = Dopamine receptor 1 is unaltered but DR2 in ASD have higher levels of these receptors

55
Q

What do D2 receptors lead to and where are they found?

A

= pre and post synaptic neurons- high levels in striatum
lead to reduction in cAMP signalling

56
Q

What is another protein associated with ASD?

A

DAT = dopamine transporter

57
Q

Describe an experiment that suggests DAT is involved in ASD

A

Mutation inserted into Human DAT protein (T356M)- showed DAT has impaired ability to transport dopamine (shown in graph)
No effect on expression (shown on bar graph)

58
Q

What is this multi sequence alignment showing?

A

threonine = preserved across different species- suggesting important function involving DAT

59
Q

What happens when there is a T356M mutation and where is it located?

A

Knock threonine amino acid = reduce activity of DAT as mutation is located on transmembrane domain 7

60
Q

Describe an experiment on drosophila that suggests DAT is involved in ASD

A

Drosophila- assess activity
Put flies into tube with infrared beam going through, which measures how many times fly crosses beam = readout of fly activity
Insert T356M into flies or knockout DAT = activity increases / hyperactive

61
Q

Outline the causes and risk factors of ASD

A
62
Q

Is age a risk factor for developing ASD + explain?

A

Yes- increased risk with increasing maternal age = age 25 to 40 the risk of developing ASD doubles
- same applies to male- if father is >10 years older than mother = increased risk

63
Q

What is another neurotransmitter that is implicated in ASD?

A

serotonin

64
Q

How is serotonin implicated in ASD?

A
  • hyperserotonemia
65
Q

What is hyperserotonemia and how many people with ASD does this occur in?

A

Elevated whole blood serotonin levels (particularly in platelets)- Elevated whole blood serotonin levels (particularly in platelets) occur in approximately 25% of children with autism

66
Q

What other disorders are associated with hyperserotenemia?

A

OCD

67
Q

What is hyperserotonemia caused by?

A

Increased 5-HT production by enterochromaffin cells in the intestine, increased uptake of 5-HT into the platelet, decreased metabolic breakdown of 5- HT

68
Q

Outline some evidence that suggests 5-HT is involved in ASD

A

Tryptophan depletion which decreases synaptic 5-HT, worsens repetitive behaviours and irritability in autism

69
Q

Outline some neuroimaging evidence that suggests 5-HT is involved in ASD

A

Neuroimaging studies found decreased 5-HT2A receptor binding in adults with Asperger’s syndrome and parents of children with autism

70
Q

What other 5-HT mechanisms have been shown to altered in ASD?

A

deactivation mechanisms- SERT and MAO-A

71
Q

What does the genetic knock out of SERT do?

A

Genetic knock-out of SERT alters brain development, including overall brain growth and interneuron migration into the cortex
- affected early on during development = impacts on path finding and synaptogenesis events

72
Q

Name a treatment involved in increasing serotonin levels in the brain and does it have any benefits for ASD?

A

SSRIs = have little therapeutic benefit on ASD

73
Q

Where are serotonergic neurons expressed?

A

expressed in dorsal and median raphe neurons

74
Q

What is gene encoding SERT and what chromosome is it located on?

A

Gene encoding serotonin transporter [member of’solute carrier family 6’(SLC6A4)] on chromosome 17 = mutation in this potentially leads to ASD

75
Q

How is the SLC6A4 gene altered in ASD?

A

Promotor region of the SLC6A4 gene contains a polymorphism leading to “short 14” and “long 16” repeats; the short 14 repeat reduces transcription and is associated with anxiety-related traits and altered brain structure.

76
Q

Describe how the most common SERT amino acid variant was examined in mice

A

SERT Gly56Ala knock-in mouse (=mutation reducing SERT activity) has elevated blood serotonin, altered serotonergic raphe neuron firing (reduced firing)
+ altered social behaviours- 3-chamber crawley sociability test:
= Put mice into 3 chambers
1. one chamber has mouse in glass
2. One chamber has no mouse in glass
3. Mouse placed into middle chamber and allowed to explore
= usual behaviour = mouse spends time investigating chamber with other mouse
Measure time mice spent investigating- compare times with wildtype and those with Gly56Ala mutation = mutant mice reduced time spent investigating other mouse

77
Q

How is the Gut brain axis involved in ASD?

A

Changes in the gut microbiota composition and resultant altered gut-derived microbial products and neurotransmission can over-activate the immune system producing increased oxidative stress and impact on serotonin signalling.

78
Q

Describe the basic structure of the gut-brain axis

A
  1. microbiome in gut produces many chemicals- some beneficial and some toxic
  2. Communcation via vagus nerve that signals from the gut to the brain
  3. communication via bloodstream from gut into brain

Gut biota can produce a huge range of chemicals including serotonin, inflammatory molecules etc - which signal into brain

Happens in both mammalian systems and drosophila

79
Q

Outline some gastro-intestinal disturbances associated with ASD

A

Whole range of gastro-intestinal disturbances in ASD- which specifically interact with the serotonergic pathways
- Certain bacteria able to intefere with cascade of serotonin synthesis e.g. clostridium

80
Q

Which neurotransmitters are effected (produced/interferred with) by the gut brain axis

A

Whole range of neurotransmitters
- Noradrenaline(Escherichiaspp (E coli),Bacillusspp.andSaccharomycesspp.)
- Dopamine (Bacillusspp.)
- Serotonin- (Candidaspp.,Streptococcusspp.,Escherichiaspp. (E coli) andEnterococcusspp.)
- GABA (Lactobacillusspp. andBifidobacteriumspp.)
- Acetylcholine(Lactobacillusspp.)

81
Q

How is the gut-brain axis implicated in ASD

A
  1. changes in microbiome
  2. = changes activity of endochromaffin cells- produce neuro-inflammatory molecules
  3. Via vagus nerve this is signalled to brain + also can be via bloodstream to brain where the BBB is crossed = cytokines are able to interfere with neuronal function
    = cascades responsible for dis-development of the brain- that has worse impacts if it occurs in early development
82
Q

Name some examples of bacteria that have been shown to be beneficial to neuronal development + what do they do?

A
  • Lactobacillus reuterihas the capacity to upregulate plasmaand brain levels of oxytocin (increases social behaviour in mouse models of ASD).
  • Lactobacillus rhamnosusproduces GABA and regulates GABA receptors in the brain.
  • Bifidobacterium longumupregulates brain-derived neurotrophic factor (BDNF), augments neuronal plasticity in the enteric nervous system (ENS) and reduces anxiety and depression-like behaviours in mice.
  • Bacteroides fragilisimproves anxiety-like behaviour, repetitive behaviour and communication in mice.
83
Q

Describe an experiment which shows the effect of bacteroides fragilis on ASD

A

Bacteroides fragilis used as a treatment can releive autism like behaviour abnormalities in mice:
1. Immune activation induced in mother during pregnancy = injected with inflammatory molecule, so offspring exposed to maternal immune activation
2. Then measured anxiety-like behaviours in off-spring- had open platform that is usually fully explored but if anxious they hide
3. Hiding behaviour was associated when off-spring exposed to maternal immune activation
4. But treatment with bacteroides fragilis = increase in exploratory behaviour despite still experiencing maternal immune activation = suggests early developmental abnormalities can be reversed by beneficial bacteria

Disease in the brain (22 decks)

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