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Medicine Year 2 > Scenario 29 > Flashcards

Scenario 29 Flashcards

1
Q

What is the mean age of PD onset?

A

65

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2
Q

What are the risk factors for PD?

A

Family history, sex, age, family history, pesticide exposure

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3
Q

How many people does PD affect worldwide?

A

4 millions

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4
Q

What are the motor symptoms of PD?

A

Shaking, stiffness, slowness and hypokinesia

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5
Q

Non motor symptoms of PD?

A

Fatigue, sleep deprivation, anxiety, depression, psychosis, dementia, constipation, pain

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6
Q

What is the role of dopamine in the brain?

A

Regulates cortical excitation of striatal neurons, stabilises the firing rate and excitability of striatal neurons and regulates their plasticity

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7
Q

Where does Parkinsons start in the brian?

A

Medulla and olfactory region- olfactory dysfunction in 70-100% of patients

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8
Q

What could differential diagnoses for PD like symptoms be?

A

Multiple system atrophy, progressive supranuclear palsy, drug induced, vascular, structural- toxins, infections, metabolic

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9
Q

Where is acetylcholine released?

A

From lower motor neurones- GI tract, preganglionic autonomic nerves, post ganglionica parasympathetic, retina
Nucleus basilis in brain to thalamus and cortex (not cerebellum)

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10
Q

How is acetylcholine synthesised?

A

Choline and acetyl CoA (synthesised in cell body and transported to terminals)

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11
Q

How is acetylcholine stored?

A

Vesicle in presynaptic terminal

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12
Q

How is ACh released?

A

Calcium dependent vesicular release at the end terminal

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13
Q

What ACh receptors are there?

A

Ligand gates ion channels (nicotinic) and GPCRs (muscarinic)- 2 subgroups M1,M3,M5 (Gq) and M2,M4 (Go)

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14
Q

How is Ach reuptaken?

A

Choline transporter (after its degraded)

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15
Q

How is Ach degraded?

A

To choline and acetic acid by acetylcholinesterase (in synaptic cleft)

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16
Q

What drugs interfere with Ach storage?

A

Vasamicol

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17
Q

What drugs interfere with Ach release?

A

Botox

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18
Q

What drugs interfere with Ach nicotinic receptors?

A

Full agonists- Ach, suxamethonium, nicotine
Partial agonists- Verenacline
Reversible agonists- Pancronium and vercuronium
Irreversible agonists- alpfa-bungrotoxin

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19
Q

What drugs interfere with Ach muscarinic receptors?

A

Ach, muscarine, oxotremotine M

Atropine, ipratropium

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20
Q

What drugs interfere with Ach reuptake?

A

hemicholinim

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21
Q

What drugs interfere with Ach degradation?

A

galantamine, rivastigmine

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22
Q

What recreational drugs interfere with Ach?

A

Nicotine, scopolamine, herbane

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23
Q

What diseases are related to Ach?

A

Dementia, Myaesthenia gravis, PD, motion sickness, analgesia

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24
Q

Where is dopamine found?

A

Located in CNS-forebrain, striatum (PD), pineal gland via hypothalamus, hippocampus amygdala (not back of cortex or cerebellum)

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25
Q

How is dopamine synthesised?

A

Tyrosine from diet–>DOPA–>Dopamine

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26
Q

How is dopamine released

A

Calcium dependent vesicular release and end terminal adn along axon

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27
Q

What dopamine recptors are there?

A

All GPCRs
D1 like- D1,5 couples to Gs (activates adenylate cyclase)
D2 like- D2,3,5 coupled to Gi (inhibits adenylate cyclase)
No ligand gating so no fast firing

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28
Q

How is dopamine reuptaken?

A

Diffuses round end terminal and taken up by DAT requiring Cl and 2Na

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29
Q

How is Dopamine degraded?

A

Via MAO/COMT/aldehyde dehydrogenase to homovalinic acid which can be measured in the blood/CSF/urine

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30
Q

What drug is involved with dopamine synthesis?

A

levo DOPA

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31
Q

What drug is involved with dopamine storage?

A

reserpine, methamphetamine

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32
Q

What drug is involved with dopamine release

A

amantadine

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33
Q

What drug is involved with dopamine receptors?

A

Full agonists- DA, apomorphin, bromocriptine

Agonists- Haloperidol, chlopromazine

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34
Q

What drug is involved with dopamine reuptake?

A

Cocaine, bupropion, methylpenidate

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35
Q

What drug is involved with dopamine degradation?

A

MAO inhibitors- phelzine, selegiline

COMT inhibitors- entacapone, tolcapone

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36
Q

What recreational drug is involved with dopamine?

A

Cocaine, amphetamines, bromocriptine

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37
Q

What diseases are linked to dopamine?

A

Durg dependence (reward mechanism), PD, schizophrenia, nausea, hormonal disturbances

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38
Q

What are the motor cortex related problems in PD?

A

Paralysis with spasticity (upper motor sign)

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39
Q

What are the IC related problems in PD?

A

Upper motor sign and sensory defecits

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40
Q

What are the basal ganglia and cerebellum related problems in PD?

A

Involuntary movements, slowness

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41
Q

What is the basal ganglia made up of?

A

Striatum and globus pallidus

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42
Q

What is the striatum made up of?

A

Caudate nucleus and putamen

43
Q

What is the lentform nucleus made up of ?

A

Globus palidus and putamen

44
Q

What are the internal pathways?

A

Afferents to the cortex from the senses and pain to the thalamus with relay neurons to the thalamus
Efferents from the cortex (dont stop at thalamus)- motor corticospinal and corticobulbar and prefrontal corticopontine pathway
Reciprocal connections- between thalamus and cortex modulated by basal ganglia (inhibit thalamus) and cerebellum (excites thalamus)

45
Q

What is the role of the IC?

A

Funnels axon connections (channel for info in and out of the cortex)

46
Q

What is most posterior part of the IC?

A

Optic and auditory radiations (most posterior)- sensory corticopontine

47
Q

What is the function of the posterior limb?

A

Motor and sensory

ARM–>TRUNK–>LEG (more ant to post)

48
Q

What is the function of the genu?

A

Motor and sensory to the face

49
Q

What is the function of the anterior limb?

A

Corticopontine (cognitive)

50
Q

What is the blood supply to the anterior and posterior limbs of IC and basal ganglia?

A

Middle cerebral artery

51
Q

What is the blood supply to the anterior limb and more medial parts and the genu?

A

Anterior cerebral artery

52
Q

What happens if the post limb aand genu are damaged?

A

paralysis, loss of sensation, vision and hearing

53
Q

What happens in the ant limb is damaged?

A

Cognitive defects

54
Q

What is the role of the basal ganglia?

A

Modulates the reciprocal connections with the thalamus (from cortex) sending inhibitory actions (lifting and pushing brakes)

55
Q

What NT modulates overall output of basal ganglia?

A

Dopamine- more DA causes less inhibitory basal ganglia output
Less dopamine- more inhibition (PD)

56
Q

What are some disorders limked to the basal ganglia (more or less inhibition of the thalamus)

A

Hyper/hypo kinetic movement disorders, PD, HD, cognitive disorders

57
Q

What is the role of the cerebellum?

A

Axons from motor and prefrontal areas to the cerebellum that reinforces responses from the cortex to the thalamus. Excitatory and rather than changing the amplitude of movements affects timing

58
Q

What are some disorders linked to damage of the cerebellum?

A

Hypertonia, astasia (cant stand or walk), ataxia (errors in coordination), action- intention tremor

59
Q

What is the link between cerebellum and cog function?

A

Corticopontine input from prefrontal areas, prenatal damage leads to cognitive disability, autistric spectrum

60
Q

What is the cerebrocerebellum?

A

Lateral parts- motor planning and cognition, output to thalamus

61
Q

What is the spinocerebellum?

A

Middle section responsible for posture and output to midbrain (red nucleus) and thalamus (ventrolateral)

62
Q

What is the vestibulocerebellum?

A

flocculonodular lobe- balance and output to vestibular nuclei

63
Q

Where is damage to each part seen?

A

Same side of the body
Cerebrocerebellum(opp motor cortex) and spinocerebellum (opp red nucleus) cross over and back vestibulo is locally ipsilateral

64
Q

What is the mean time until death in HD?

A

17 Years

65
Q

What is the cause of HD?

A

Degeneration in the striatum due to the loss of GABAergic neurons

66
Q

What are the genetics of HD?

A 
Autosomal dominant (50% chance)
Normally 10-30 CAG in HD >40 CAG
67
Q

What is the result of increased CAG?

A

Gain of toxic function- inclusion bodies build up in vulnerable neurons eventually in the nucleus interacting with transcription factors and modulate gene expression- cell death follows

68
Q

What is the mechanism in MND?

A

Excessive loss of motor neurons in spinal cord, brain stem and/or motor cortex
Severe muscle atrophy- compensatory muscle fibre sprouting not enough

69
Q

When is the normal age of onset and how long to live?

A

50-60 and 5 years

70
Q

What causes MND?

A

10% familial SOD1 C90RF72 and 15% sporadic

SOD1 and TDP-43 can form toxic aggregates and nuclear inclusions

71
Q

What other non neuronal inputs exacerbate the disease?

A

Microglia activating and releasing toxic factors, astrocytes activated and release toxic factors and lose ability to recycle glutamate resulting in excitotoxicity, loss of trophic support from target, reactive response in target

72
Q

How does excitotoxicity kill neurons?

A

Only ionotropic glutamate receptors not metabotropic
Glutamate accumulates at synapses (excessive release, defective uptake, reversal of transporters) and Ca accumulates at synapse damaging mitochondria, proteases, endonucleases, stress activated kinases, phospholipases and NO synthase

73
Q

How do we mitigate against the disease or limit damage?

A

Replacement- Ldopa/ cholinesterase inhibiors in AD
Inhibit excitotoxicity- glutamate receptor agonists, Na channel agonists, V gates calcium agonists
Accumulation of toxic proteins- beta and gamma secretase inhibitors
Trophic support- NGF, GDF, VEGF
Anti-inflamm- Cox inhibitors

74
Q

What are the stages of PD?

A

Starts at the medulla, raphe and locus coruleus affects (sleep), dorsal motor nucleus of the vagus (GI problems), olfactory bundle, then nigra (motor symptoms- phase 3)

75
Q

What % of PD suffer NMS?

A

99

76
Q

What % of PD is familial?

A
77
Q

What are possible causes of the other 95%

A

environmental toxins (MPTP), agrochemical persistent accumulation

78
Q

What part of the brain degenerates in PD?

A

Dopaminergic nigrostriatal tract- loss of pigmented bodies in substantia nigra pars compacta

79
Q

By how much is dopamine innervation of the striatum reduced in PD

A

60-80%

80
Q

What are Lewy bodies?

A

Pathological hallmark of PD found in many remaining dopaminerfic neurons in SNc in PD
Consequence of cells ready to die? Contain ubiquitin

81
Q

What factors contribute to SNc degradation in PD?

A

Oxidative stress, excitotoxicity

82
Q

What are the two main components of oxidative stress?

A

Free radical production increasing and antioxidant defences decrease

83
Q

How does free radical production increase?

A

Normally autooxidatin of DA to form neuromelanin and DA is metabolised by mono-amine oxidase producing H2O2
In PD high Fe levels (possibly frm microglial cells) in SNc drive the Fenton reaction causing OH- to be produced. Free radical damage to proteins, lipids and DNA bases

84
Q

Why does antioxidant defence decrease?

A

SNc has 30% reduced glutathione levels in PD

85
Q

What is the mechanism of weak excitotoxicity?

A

Impairement of mitochondrial complex I leads to reduced ATP and therefor depolarisation of the membrane (lack of NA/K ATPase activity) and a small amount of glutamate can now activate the receptor

86
Q

What is the mechanism of strong excitotoxicity?

A

Increased Ca entry through NMDA activation. Neurons in ventral tier have low calbindin levels (cant mop up excess Ca) Elevated glutamine levels found in SNc due to increased firing of STN

87
Q

What takes place in the direct circuit?

A

Motor cortex fires and glutamate activates the striatum where it causes increased GABA release and increased inhibition of the GPi/SNrso the thalamic relay neuron is disninhibited causing movement

88
Q

What takes place in the indirect circuit?

A

Motor cortex firs releasing gluabate whihc stimulates GABA switching off inputs to the STN therefore disinhibiting glutamate release to the GPi/SNr causing GABA inhibition of thalamic relay neuron inhibiting movement

89
Q

Why do we need dopamine>

A

Both of these pathways are contradictory so need DA

90
Q

What is the role of DA on the direct pathway?

A

Activated D1 DA receptors (Gs) increase firing of the pathway and produce more movement

91
Q

What is the role of DA on the indirect pathway?

A

Activated D2 DA receptors (Gi) suppress cAMP and decrease neuronal firing so the pathway is inhibited, less GABA release and less inhibition of movement

92
Q

What happens in PD?

A

Direct underactive, indirect overactive due to decreased DA

93
Q

What is the effect of PD on thalamocortical feedback?

A

Reduced- motor defecits

94
Q

What are some examples of anticholinergic/ muscarinic receptor antagonist drugs and how do they work?

A

Benshexo, benzatropine and loss of DA disinhibits the striatal cholinergic interneurons increasing striatal Ach levels activating muscarinic receptors further increasing the overactivity of the indirect pathway- tremor

95
Q

What are some s/e of anticholinergic drugs?

A

confusion, modd changes, constipation, blurry vision, dry mouth (useful if dribbling present)

96
Q

How does LDOPA work

A

DA precursor that crosses BBB using AA transporters convered to DA using Dopa decarboxylase.

97
Q

Why is L-DOPA administered with DDC inbitors?

A

90% converted by DCC in intestinal wall so administered with peripherally acting DCC inhibitor (e.g. carbidopa) to avoid nausea
5% metabolised by COMT so can be administered with inhibitor entacarpone

98
Q

What are the benefits of L-DOPA?

A

Imporves rigidity, bradykinesia, facial expression, speech and handwriting

99
Q

What are acute s/e of L-DOPA?

A

Nausea, postural hypotension, hallucinations insomnia nightmares

100
Q

What are chronic s/e of LDOPA?

A

Motor fluctuations- less DA neurons as disease progresses so less storage and less controlled release, dykinesia- increased thalamocortical feedback (use NMDA receptor blocker amantadine)

101
Q

What are some examples of DA receptor agonists and how do they work?

A

Bromocriptine and activate D2 receptors normalising the indirect pathway (less inhibition of movement) not affected by neurodegeneration and same s/e as LDOPA but longer half life so less chronic effects

102
Q

What is an example of a MAO-B inhibitor and how do they work?

A

Selegilline and blocking DA metabolism

Dont cause cheese reaction

103
Q

What surgical approaches are there to treat PD?

A

Neuroablative surgery- lesion made in basal ganglia motor loop to restore normal thalamocortical feedback but risk of visual impairment, intracerebral haemmorhade and mild speech and cognitive impairment
Deep brain stimulation- normalise firing in motor loop by increasing RMP in the STN- reversible

Medicine Year 2 (19 decks)

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