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Disease in the brain > ADHD (finished) > Flashcards

ADHD (finished) Flashcards

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1
Q

What is the DSM-V criteria for ADHD?

A
  • > 6 inattention and/or hyperactivity/impulsivity features for 6 months before age 12 (>5 in adults)
  • Symptoms present in at least 2 life areas: school, home, work or social setting
  • Defining criteria are developmentally inappropriate behaviours (age 4 vs age 12)
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2
Q

What are the 2 categories that ADHD symptoms are categorised by?

A
  • Inattention
  • Hyperactivity/impulsivity
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3
Q

List some of the behaviours that come under inattention in ADHD:

A
  • Lack of attention to detail
  • Difficulty to sustain attention
  • Does not listen
  • Not follow thru instructions
  • Difficulty organising tasks
  • Avoid sustained attention
  • Lose or misplace objects
  • Easily distracted
  • Forgetful
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4
Q

List some of the behaviours that come under hyperactivity/impulsivity in ADHD:

A
  • Fidgeting
  • Restless during activities
  • Running about
  • Excessively loud
  • Always “on the go”
  • Talks excessively
  • Blurts out answers
  • Interrupt or intrudes upon others
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5
Q

How many prison inmates are estimated to suffer from ADHD, why does this link?

A

Up to 20% of inmates suffer from ADHD

Ppl who suffer from ADHD are stuck in the present (consumed by the experience) –> so cannot see the concequences of their actions

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6
Q

What is the aetiology of ADHD?

A
  • Genetic & environmental
  • 70-90% heritability in twins
  • 5x increase risk in first degree relative
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7
Q

What are the main environmental factors of ADHD?

A
  • Neonatal hypoxia
  • Maternal smoking
  • Premature birth
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8
Q

What is the neurobiology of ADHD?

A
  • MRI = smaller less active front-striatal complex
  • PET = reduced striatal metabolism
  • Hyperactive sensory cortex (easily enhanced by any little stimulus)
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9
Q

What is the prevalence of ADHD?

A
  • ADHD (DSM-V) = 3-5%
  • USA defining = 0.5-1.5% (hyperkinetic disorder)
  • Boys > Girls 2:1
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10
Q

List 6 specific environmental factors that are associated w increased prevalence:

A
  • Extreme prematurity & low birth weight
  • Maternal smoking / alcohol
  • Low social class grp / social deprivation
  • Learning disability
  • Institutional rearing
  • Other brain diseases / neurologicla disorders (e.g. epilepsy)
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11
Q

How does ADHD affect someone over their lifetime?

A
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12
Q

How prevalent is ADHD alone & why?

A
  • Has a 31% prevalence
  • ADHD has a high co-morbidity so occurs alone less often than not
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13
Q

What are some disorders that ADHD is often co-morbid with?

A
  • Oppositional defiant disorder (ODD) = 40%
  • Anxiety disorder = 34%
  • Conduct disorder = 14%
  • Tics = 11%
  • Mood disorders = 4%

(Co-morbid disorders may req their own theraputic intervention)

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14
Q

What are the changes that occur in the brain in ADHD?

A
  • Smaller brian (~4%) –> right frontal lobe (~8%)
  • Smaller basal ganglia (~6%) –> normalisation (~18 yrs)
  • Smaller cerebellum (~12%) –> more pronounced (~18 yrs)
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15
Q

What are the volumetric differences in ADHD like?

A
  • Manifest early (~6 years)
  • Correlate with ADHD severity
  • Are irrespective of medication status
  • Are irresponsive of co-morbidities
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16
Q

What are the 2 key brain areas that are involved in ADHD?

A

Prefrontal cortex

Striatum

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17
Q

What is the role of the prefrontal cortex?

A

Decision making, mood regulation, conflict management

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18
Q

What is the role of the striatum?

A

Controls aspects of cognition & social behaviour

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19
Q

What is the aeitology of ADHD?

A

Environmental & genetic

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20
Q

What is the genetic risk of ADHD?

A
  • 70-90% heritability in twins
  • 5x increase risk in first degree relative

(Among the most heritable of psychological disorders)

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21
Q

What are the 6 genes that are linked to ADHD?

A
  • SLC6A3
  • DRD4
  • DRD5
  • SLC6A4
  • HTR1B
  • SNAP25
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22
Q

What are the proteins coded by each of these genes that are linked to ADHD:

  • SLC6A3
  • DRD4
  • DRD5
  • SLC6A4
  • HTR1B
  • SNAP25
A
  • SLC6A3 = DAT
  • DRD4 = D4 receptor
  • DRD5 = D5 receptor
  • SLC6A4 = SER-T
  • HTR1B = 5-HT1B receptor
  • SNAP25 = vesicle protein
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23
Q

What do most of the genes that are linked to ADHD cause?

A

Candidate genes are linked to dopaminergic or serotonergic neurotransmission

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24
Q

Why are the 6 genes linked & not causal for ADHD?

A

They have low odds ratios (relative risk)

No single gene is sufficient or causal (multiple genes w low risk)- combinations of mutant genes along with environmental impacts leads to more likely to develop several traits of ADHD

-

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25
Q

Give an example how one gene mutation is linked to a phenotypic trait in ADHD

A

Each gene may code a specific phenotypic trait- Dopamine D4 receptor (DRD4) linked to novelty seeking behaviour

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26
Q

What is odds ratio?

A

Odd ratios = chances that mutations in these genes are related to ADHD

Odds ratio of 1 = no association

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27
Q

What are the 2 main candidate genes in ADHD?

A
  • D4 (Dopamine D4 recpetor) gene 11p15.3
  • DAT1 (Dopamine transporter 1) gene 5p15.3
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28
Q

Where are D4 genes mainly expressed?

A

In cortical area networks

(Repressed cAMP response)

29
Q

How does DAT4 gene affect ADHD?

A

Means there is more DAT expressed –> more transmitters = less dopamine in synaptic cleft

30
Q

5 points about D4 gene causing ADHD:

A
  • 7Repeat allele: Pooled Odds Ratio = 1.9 (1.4-2.2)
  • Prevalent in frontal-cortical networks
  • High risk allele: 48 bp repeat
  • Results in an attenuated (weakened) cAMP response to dopamine
  • May correlate w symptoms of innatention
31
Q

4 points about DAT1 gene causing ADHD:

A
  • Pooled Odds Ratio = 1.16
  • Site of action = stimulant drug & elevated in ADHD
  • High risk allele = 480 bp repeat
  • May affect striatal DAT expression?
32
Q

How do DAT levles change in ADHD pateints?

A

They have significantly increased DAT levels

(Inc striatal binding)

33
Q

How can inc DAT levels in ADHD patients be treated?

A

Methylphenidate

= increased striatal binding to DAT is reduced following FOUR weeks of treatment using this

(Fixes amt of dopamine in synaptic cleft & treats the patient in the short term)

34
Q

Although methlphenidate decreased DAT binding in the short term what happens with prolonged use?

A

Ventral striatal DAT is ELEVATED 12 months after use

Shows neuroplasticity which could decrease treatment efficacy

35
Q

How does short vs long exposure to methylphenidate affect DAT levels?

A

Short = reduced DAT binding in striatum

Long = may increase DAT striatal binding –> a compensatory increase

36
Q

What are the 2 environmental factors with the strongest association to ADHD?

A
  • Extreme prematurity & low birth weight
  • Intrauterine exposure to nicotine (or alcohol - FAS)
37
Q

List all the environmental factors linked to ADHD:

A
  • Extreme prematurity & low birth weight
  • Intrauterine exposure to nicotine (or alcohol - FAS)
  • Neonatal hypoxia
  • Lead exposure
  • Acquired brain disorders (e.g. encephalitis, brain trauma)
  • Food allergies (i.e. sugars??) - no causal convincing evidence - no guidelines
38
Q

What are the top 3 environmental/genetic factors for ADHD?

A
  • Prematurity
  • Low birth weight
  • Maternal smoking

(Not genes! Environmental facotrs have a much higher Odds Ratio so are the strognest 3 factors)

39
Q

What do gene polymorphisms & early life adversity (environmental) combine to cause?

A

Fronto-striatal monoamine dysfunction

This causes:

Devleopmentally inappropriate hyperactive, impulsive, inattentive behaviour

=

ADHD

40
Q

Describe the neurobiology ADHD:

A
  • Fronto-striatal dopaminergic (DAergic) hypo-function
  • Higher density of dopamine transporter (DAT) in striatum
41
Q

Describe the molecular genetics of ADHD:

A
  • 7 repeat form od dopamine D4 receptor linked novelty
  • 480 bp repeat (x10) of dopmaine transporter (DAT) associated ADHD
  • Marginal linkage dopamine D5 recpetor gene polymorphisms in TMR
42
Q

Where do dopminergic neurones mainly originate from & project to?

A

Originates = midbrain (ventral tegmental & substantia nigra)

Projects to = striatum & nucleus accumbens + prefrontal cortex

43
Q

Where does glutamate originate from?

A

In Glial cells- Glutamate from glucose during the Krebs cycle and is converted into glutamine by glutamine synthetase

44
Q

How does glutamine enter the presynaptic terminal?

A

Produced by glial cells

Transmits to presynaptic neuron via glutamine transporter

Glutamine is then oxidized back to glutamate and packed into vesicles by vGLUT

45
Q

What are the 3 ionotropic glutamatergic synaptic subgroups in ADHD?

A
  • GluN2A
  • GluN2B
  • GluK2
46
Q

What role do the 3 ionotropic glutamatergic synaptic sub-groups have in ADHD?

A
  • Role in ADHD susceptibility & attentional impairment in ADHD patients
  • Hyperactive-impulsive symptoms
47
Q

What are the 2 metabotropic glutamatergic synaptic sub groups in ADHD?

A
  • mGluR5
  • mGluR7

(They use cAMP signalling –> mutation of these cause attention deficit)

48
Q

Outline some interactions associated with glutamate and dopamine signalling

A

Glutamate receptors (especially iGluRs) and dopamine receptors interact in many ways:
- When dopamine receptor D2 is activated = inhibition of NMDARs (glutamate receptor)
- Activation of dopamine receptor D4 = reduces activity of AMPARs (glutamate receptor) on excitatory neurons in the prefrontal cortex
- Activation of D4 reduces presence of AMPARs at synapses
- Glutamate release in striatum enhances release of dopamine acting on NMDARs

49
Q

outline when these interactions between glutamate and dopamine signalling were observed (in mice)

A

Mice lacking GluA1 (a subunit of AMPAR) or with deficient GluA3 (another subunit of AMPAR) show increased levels of dopamine in the striatum.

50
Q

Overall, what do interactions between glutamate and dopamine signalling result in?

A

Hypo-dopaminergic state in the ADHD may be expected to lead to more active NMDARs/AMPARs and a subsequent increase in glutamate output = take home message

51
Q

What are the 4 types of medications for ADHD?

A

Psychostimulants

Non-stimulants (sub-groups:)

  • Recently liscenced treatments
  • Glutamatergic targets
52
Q

What action do Psychostimulants have?

A

Bind to DA-transporters (DAT)

53
Q

Give examples of psychostimulants used to treat ADHD:

A

Mehtylphenidate - Ritalin tabelt

Equasym, Concerta XL slow release preperations - DAT & NAT inhibitors

Equasym, Concerta XL, slow release preparations - DAT & NET inhibitors

Dexamphetamine - Dexedrine & Adderall

Lis-dexamphetamine - Vyanse (prodrug to be converted in the body)

54
Q

Give examples of Non-stimulant drugs used to treat ADHD:

A

Atomoxetine - Strattera (slow onset less addiction?) NAT inhibitor

55
Q

What action do non-stimulant drugs used to treat ADHD have?

A

Noradrenaline uptake inhibitor

56
Q

Give examples of recently licensed treatments for ADHD:

A

Clonidine & Guanfacine - aplha 2 adrenoceptor agonists

Tricyclic antidepressents (desipramine, imipramine) - NAT inhibitors

57
Q

Give examples of glutamatergic targets treatments for ADHD:

A

Mematine - an NMDA recpetos antagonist, improve ADHD symptoms in patients

Fasoracetam - a nonselective mGluR activator, showed clinical improvement

58
Q

What are the 2 main divisions of ADHD treament drugs?

A
  • Stimulants
  • Non-stimulants
59
Q

What general action do stimulants vs non-stimulants have on ADHD?

A

Stimulants = bind to DAT transporter (amphetamines used)

Non-stimulants = Target noradrenaline uptake (more noradrenaline in synaptic cleft)

60
Q

Name some drugs associated with the treatment of ADHD + what effect do they have

A

Differential Pharmacology of Drugs
Variety of drugs target different pathways and receptors
Some effects on dopamine some on noradrenaline to positively impact ADHD

61
Q

Norepinephrine & dopamine are used to treat ADHD - what is the efficacy of these being used?

A
  • Cognitive function ↑
  • Attentiveness ↑
  • Distractibility ↓
  • Hyperactivity ↓
  • Behavioural disruption ↓
62
Q

Norepinephrine & dopamine are used to treat ADHD - what are the adverse effects of these being used?

A
  • Insomnia ↑
  • BP/HR ↑
  • Nausea/vomiting ↑
  • Abdominal pain ↑
  • Tics ↑?
  • Appetite ↓
  • Bodyweight ↓
  • Growth rate ↓
63
Q

Describe the main way of action of the drugs used in the treatment of ADHD

A

How does medication work?
Dopamine transporter mutated in ADHD = less dopamine in synaptic cleft
Less receptor activity = less dopamine activity
Drugs block transporter = more dopamine in synaptic cleft that can target receptors
= MAIN CHARACTERITIC OF DRUGS

64
Q

Describe the normal physiology of dopamine signalling (no drugs involved)

A

Dopamine in the synaptic cleft is reuptaken by pre-synaptic terminal and packed into vesicles by VMAT

65
Q

Describe how methylphenidate works

A

Inhibits DAT transporter = more dopamine in synaptic cleft (less reuptaken)

  • dependent on the firing rate
66
Q

Describe how amphetamine works

A

Also inhibits DAT- but blocks differently at certain site = reduces uptake and more dopamine in synaptic cleft

Also get introduced into the neuron- so can now block the VMAT = more dopamine present in cytosol of neuron that can be released into synaptic cleft

  • independent on the firing rate
67
Q

Which has a stronger effect: methylphenidate or amphetamine

A

Amphetamine

68
Q

Describe a study showing the effect of methylphenidate + the results

A

Study = methylphenidate given to patients + raclopride (= radio labelled compound that binds to DAT) = PET scan:

Normal patients = very strong signal in straitum as raclopride binds to DAT transporter

Treat patients with methylphenidate = blocks DAT transporter = more dopamine in synaptic cleft = more dopamine can bind to receptor and outcompete raclopride = reduced signal

69
Q

Describe the outcomes of taking methylphenidate

A

Outcomes: both, stimulants and reward, enhance dopaminergic function
- Elevate DA in the ventral striatum
- Enhance DA and Nuc.accumbens in the frontal cortex.
- Increased frontocortical transmission reinforce executive function, focus attention and improve inhibition of impulsivity = IMPROVES ADHD symptoms

Disease in the brain (22 decks)

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