Scenario 29 Flashcards
1
Q
What is the mean age of PD onset?
A
65
2
Q
What are the risk factors for PD?
A
Family history, sex, age, family history, pesticide exposure
3
Q
How many people does PD affect worldwide?
A
4 millions
4
Q
What are the motor symptoms of PD?
A
Shaking, stiffness, slowness and hypokinesia
5
Q
Non motor symptoms of PD?
A
Fatigue, sleep deprivation, anxiety, depression, psychosis, dementia, constipation, pain
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
7
Q
Where does Parkinsons start in the brian?
A
Medulla and olfactory region- olfactory dysfunction in 70-100% of patients
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
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)
10
Q
How is acetylcholine synthesised?
A
Choline and acetyl CoA (synthesised in cell body and transported to terminals)
11
Q
How is acetylcholine stored?
A
Vesicle in presynaptic terminal
12
Q
How is ACh released?
A
Calcium dependent vesicular release at the end terminal
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)
14
Q
How is Ach reuptaken?
A
Choline transporter (after its degraded)
15
Q
How is Ach degraded?
A
To choline and acetic acid by acetylcholinesterase (in synaptic cleft)
16
Q
What drugs interfere with Ach storage?
A
Vasamicol
17
Q
What drugs interfere with Ach release?
A
Botox
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
19
Q
What drugs interfere with Ach muscarinic receptors?
A
Ach, muscarine, oxotremotine M
Atropine, ipratropium
20
Q
What drugs interfere with Ach reuptake?
A
hemicholinim
21
Q
What drugs interfere with Ach degradation?
A
galantamine, rivastigmine
22
Q
What recreational drugs interfere with Ach?
A
Nicotine, scopolamine, herbane
23
Q
What diseases are related to Ach?
A
Dementia, Myaesthenia gravis, PD, motion sickness, analgesia
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)
25
How is dopamine synthesised?
Tyrosine from diet-->DOPA-->Dopamine
26
How is dopamine released
Calcium dependent vesicular release and end terminal adn along axon
27
What dopamine recptors are there?
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
28
How is dopamine reuptaken?
Diffuses round end terminal and taken up by DAT requiring Cl and 2Na
29
How is Dopamine degraded?
Via MAO/COMT/aldehyde dehydrogenase to homovalinic acid which can be measured in the blood/CSF/urine
30
What drug is involved with dopamine synthesis?
levo DOPA
31
What drug is involved with dopamine storage?
reserpine, methamphetamine
32
What drug is involved with dopamine release
amantadine
33
What drug is involved with dopamine receptors?
Full agonists- DA, apomorphin, bromocriptine
| Agonists- Haloperidol, chlopromazine
34
What drug is involved with dopamine reuptake?
Cocaine, bupropion, methylpenidate
35
What drug is involved with dopamine degradation?
MAO inhibitors- phelzine, selegiline
| COMT inhibitors- entacapone, tolcapone
36
What recreational drug is involved with dopamine?
Cocaine, amphetamines, bromocriptine
37
What diseases are linked to dopamine?
Durg dependence (reward mechanism), PD, schizophrenia, nausea, hormonal disturbances
38
What are the motor cortex related problems in PD?
Paralysis with spasticity (upper motor sign)
39
What are the IC related problems in PD?
Upper motor sign and sensory defecits
40
What are the basal ganglia and cerebellum related problems in PD?
Involuntary movements, slowness
41
What is the basal ganglia made up of?
Striatum and globus pallidus
42
What is the striatum made up of?
Caudate nucleus and putamen
43
What is the lentform nucleus made up of ?
Globus palidus and putamen
44
What are the internal pathways?
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
What is the role of the IC?
Funnels axon connections (channel for info in and out of the cortex)
46
What is most posterior part of the IC?
Optic and auditory radiations (most posterior)- sensory corticopontine
47
What is the function of the posterior limb?
Motor and sensory
| ARM-->TRUNK-->LEG (more ant to post)
48
What is the function of the genu?
Motor and sensory to the face
49
What is the function of the anterior limb?
Corticopontine (cognitive)
50
What is the blood supply to the anterior and posterior limbs of IC and basal ganglia?
Middle cerebral artery
51
What is the blood supply to the anterior limb and more medial parts and the genu?
Anterior cerebral artery
52
What happens if the post limb aand genu are damaged?
paralysis, loss of sensation, vision and hearing
53
What happens in the ant limb is damaged?
Cognitive defects
54
What is the role of the basal ganglia?
Modulates the reciprocal connections with the thalamus (from cortex) sending inhibitory actions (lifting and pushing brakes)
55
What NT modulates overall output of basal ganglia?
Dopamine- more DA causes less inhibitory basal ganglia output
Less dopamine- more inhibition (PD)
56
What are some disorders limked to the basal ganglia (more or less inhibition of the thalamus)
Hyper/hypo kinetic movement disorders, PD, HD, cognitive disorders
57
What is the role of the cerebellum?
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
What are some disorders linked to damage of the cerebellum?
Hypertonia, astasia (cant stand or walk), ataxia (errors in coordination), action- intention tremor
59
What is the link between cerebellum and cog function?
Corticopontine input from prefrontal areas, prenatal damage leads to cognitive disability, autistric spectrum
60
What is the cerebrocerebellum?
Lateral parts- motor planning and cognition, output to thalamus
61
What is the spinocerebellum?
Middle section responsible for posture and output to midbrain (red nucleus) and thalamus (ventrolateral)
62
What is the vestibulocerebellum?
flocculonodular lobe- balance and output to vestibular nuclei
63
Where is damage to each part seen?
Same side of the body
Cerebrocerebellum(opp motor cortex) and spinocerebellum (opp red nucleus) cross over and back vestibulo is locally ipsilateral
64
What is the mean time until death in HD?
17 Years
65
What is the cause of HD?
Degeneration in the striatum due to the loss of GABAergic neurons
66
What are the genetics of HD?
```
Autosomal dominant (50% chance)
Normally 10-30 CAG in HD >40 CAG
```
67
What is the result of increased CAG?
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
What is the mechanism in MND?
Excessive loss of motor neurons in spinal cord, brain stem and/or motor cortex
Severe muscle atrophy- compensatory muscle fibre sprouting not enough
69
When is the normal age of onset and how long to live?
50-60 and 5 years
70
What causes MND?
10% familial SOD1 C90RF72 and 15% sporadic
| SOD1 and TDP-43 can form toxic aggregates and nuclear inclusions
71
What other non neuronal inputs exacerbate the disease?
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
How does excitotoxicity kill neurons?
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
How do we mitigate against the disease or limit damage?
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
What are the stages of PD?
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
What % of PD suffer NMS?
99
76
What % of PD is familial?
77
What are possible causes of the other 95%
environmental toxins (MPTP), agrochemical persistent accumulation
78
What part of the brain degenerates in PD?
Dopaminergic nigrostriatal tract- loss of pigmented bodies in substantia nigra pars compacta
79
By how much is dopamine innervation of the striatum reduced in PD
60-80%
80
What are Lewy bodies?
Pathological hallmark of PD found in many remaining dopaminerfic neurons in SNc in PD
Consequence of cells ready to die? Contain ubiquitin
81
What factors contribute to SNc degradation in PD?
Oxidative stress, excitotoxicity
82
What are the two main components of oxidative stress?
Free radical production increasing and antioxidant defences decrease
83
How does free radical production increase?
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
Why does antioxidant defence decrease?
SNc has 30% reduced glutathione levels in PD
85
What is the mechanism of weak excitotoxicity?
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
What is the mechanism of strong excitotoxicity?
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
What takes place in the direct circuit?
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
What takes place in the indirect circuit?
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
Why do we need dopamine>
Both of these pathways are contradictory so need DA
90
What is the role of DA on the direct pathway?
Activated D1 DA receptors (Gs) increase firing of the pathway and produce more movement
91
What is the role of DA on the indirect pathway?
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
What happens in PD?
Direct underactive, indirect overactive due to decreased DA
93
What is the effect of PD on thalamocortical feedback?
Reduced- motor defecits
94
What are some examples of anticholinergic/ muscarinic receptor antagonist drugs and how do they work?
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
What are some s/e of anticholinergic drugs?
confusion, modd changes, constipation, blurry vision, dry mouth (useful if dribbling present)
96
How does LDOPA work
DA precursor that crosses BBB using AA transporters convered to DA using Dopa decarboxylase.
97
Why is L-DOPA administered with DDC inbitors?
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
What are the benefits of L-DOPA?
Imporves rigidity, bradykinesia, facial expression, speech and handwriting
99
What are acute s/e of L-DOPA?
Nausea, postural hypotension, hallucinations insomnia nightmares
100
What are chronic s/e of LDOPA?
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
What are some examples of DA receptor agonists and how do they work?
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
What is an example of a MAO-B inhibitor and how do they work?
Selegilline and blocking DA metabolism
| Dont cause cheese reaction
103
What surgical approaches are there to treat PD?
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
