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Parkinson's Disease Flashcards

1
Q

What did Charcot term Parkinson’s disease?

A

Involuntary tremulous motion with lessened muscular power, in parts not in action and even when supported with a propensity to bend the trunk when supported with a propensity to bend the trunk forwards and to pass from walking to a running pace

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2
Q

What is they order in which parts of the CNS tend to be affected as Parkinson’s disease progresses?

A

Start with olfactory problems

then basal ganglia(balance)

then limbic system (anxiety and depression)

then cortex (Parkinson’s disease dementia)

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3
Q

What is a loss of seratonin associated with?

A

Fatigue and depression

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4
Q

Through what are most inputs into the cerebellum channeled?

A

Pontine nucleus

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5
Q

axon pathways are ordered within the internal capsule into four major streams. What are they?

A

optic and auditory radiations

posterior limb

genu

anterior limb

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6
Q

What fibres pass through the most posterior part of the internal capsule?

A

Auditory - sublenticular

Visual - retrolenticular

sensory

corticopontine

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7
Q

What fibres pass through the posterior limb of the internal capsule?

A

Motor and sensory to:

  • leg
  • trunk
  • arm

(Optic and auditory radiations)

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8
Q

What fibres pass through the genu of the internal capsule?

A

Motor and sensory to:

  • head
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9
Q

What fibres pass through the anterior limb of the internal capsule?

A

(Prefontal) Corticopontine

(To pontine nucleus)

(PREFRONTAL COGNITIVE FUNCTION)

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10
Q

Perforating arteries of what main artery supply the caudate nucleus?

A

Anterior cerebral

Medial striate aa.

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11
Q

Perforating arteries of what main artery supply the lentiform nucleus and the majority of the internal capsule?

A

Meddle cerebral

Lenticulostriate aa.

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12
Q

Perforating arteries of what main artery supply the thalamus?

A

Posterior cerebral

Thalamoperforating aa.

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13
Q

What may result for damage to the posterior limb and genu of the internal capsule?

A
  • paralysis
  • loss of sensation
  • loss of vision and hearing
Areas affected:
ARM
TRUNK
LEG
HEAD
VISION VISION 
HEARING
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14
Q

What may result for damage to the anterior limb of the internal capsule?

A

Cognitive defects

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15
Q

Summarise what is contained in the internal capsule?

A

• internal capsule contains:

  • cortical output
  • corticothalamic
  • thalamocortical axons
  • sensory/motor,
  • visual, auditory
  • prefrontal pathways
    occupy different parts of the internal capsule

• regional loss of blood supply can selectively target different functions – from vision to judgement

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16
Q

What is the role of the pars compacta of the substantia negra?

A
  • Dopamine (substantia nigra) modulates overall output of basal ganglia
  • more dopamine = less inhibitory basal ganglia output
  • less dopamine = more inhibition
Inhibits indirect (inhibitory pathway)
Activates (direct) (activating pathway)
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17
Q

Give an outline of basal ganglia disorders

A

Basal ganglia disorders

  • Hypo/hyper-kinetic movement disorders
  • Parkinson, Huntington’s
  • Disruption of amplitude and threshold for movement

• Cognitive disorders
(Eg. Reward)

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18
Q

The cerebellum is involved principally in what?

A

Timing and coordination

(Motor and prefrontal inputs (like basal ganglia)

(Excitatory)

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19
Q

What is different about how the basal ganglia and the cerebellum are involved in the initiation of movement?

A
  • basal ganglia - intitiation by internal cues

- cerebellum - initiation in response to external stimuli/cues

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20
Q

What does damage to the cerrebellum cause?

A

• Hypotonia (pendulous reflexes)

• Intention tremor in movements
(Tremor towards end of movement)

  • Errors in timing and coordination of movement (ataxia)
  • Disarthia

(Alcohol affects cerebellum short and long term)

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21
Q

Features of cerebellar ataxia and intention tremor?

A
  • delay in initiating movement ipsilateral to lesion
  • dysmetria
  • decomposition of complex movements
  • dysdiadochokinesia (rhythm)
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22
Q

Why are the cerrebellum’s abilities as a comparator so important?

A
  • Motor evaluation
  • Motor learning
  • Motor planning
  • “feed-forward” (- Anticipate corrections that will need to be made - need to have learnt the movement)

(Pontine motor inputs (mossy fibres)
versus
Spinal proprioceptive inputs (mossy fibres) )

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23
Q

Learn cerebellar structure etc

A

-

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24
Q

How is the cerebellum involved in cognitive function?

A
  • Corticopontine input from a wide range of areas
  • Judgement of elapsed time
  • Complex temporo-spatial judgements
  • Dyslexia?
  • Autism
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25
Q

What are the three regions of the cerebellum and what are their functions and outputs?

A

cerebrocerebellum (“neocerebellum”)

  • motor planning
  • cognition
    ouput: thalamus (ventrolateral nucleus)

spinocerebellum (“paleocerebellum”)

  • posture
    output: red nucleus (midbrain)

vestibulocerebellum (“archicerebellum”)

  • balance
    output: vestibular nuclei
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26
Q

On what side of the body would a cerebellar lesion cause problems?

A

Ipsilateral - see page 53 of internal capsule, basal ganglia, cerebellum lecture

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27
Q

A few stats on dementia?

A
  • Dementia currently affects >24 million people worldwide people worldwide
  • Expected to reach 80 million by 2040
  • Alzheimer’s accounts for >60% of all dementias

If you reach 80, you have a 20% chance of developing Alzheimer’s

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28
Q

What causes neurodegenerative disease?

A
  1. environmental or man made neurotoxins:
    - heavy metals
    - pesticides
    - MPTP
  2. inherited or sporadic gene mutations:
    • 10% of Motor Neuron disease is inherited with mutations identified in SOD1, TDP-43, FUS1 and a hexanucleotide repeat identified in C9ORF72
    – together these account for ~50% of the familial cases.
  • The same mutations account for ~ 15% of the sporadic disease with C9ORF72 being most common.
  • Mutations in other genes cause other diseases (e.g. mutations in alpha-synuclein can cause Parkinson’s disease, and mutations in APP can cause Alzheimer’s disease)
  • Mutated proteins that cause disease are often involved in sporadic disease in the absence of any mutation. For example, APP is implicated in Alzheimer’s disease and TDP-43 aggregates are a very common feature of MND and frontotemporal dementia (FTD).
  • Huntington s Chorea is an unusual example of a pure genetic disorder.
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29
Q

What is unusual about Huntington’s Disease?

Give an outline of the condition

A

• Huntington s Chorea is an unusual example of a pure genetic disorder.

• A disease of mid‐adult life
– Onset 38‐42 years

– Personality disturbance

– Twist and turn in dance like motion (chorea – Greek for dance) (chorea Greek for dance)

– Dyskinesia & Parkinson’s like symptoms

– Death (mean 17 years post onset)

(- Massive degeneration in striatum in HD due to the loss of GABAergic neurons
- At least initially indirect pathway of basal ganglia disproportionately affected - degraded)

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30
Q

What do you know about the genetics and prevelance etc. of Huntington’s disease?

A

• Autosomal dominant (50% chance of receiving gene regardless of sex of parent or child)

– Prevalence is

  • 1 per 10,000 of population of Western European decent and
  • 1 per Western European decent and 1 per 1,000,000 of Asian and African decent

– ~ 30,000 people in USA have the disease

– ~ 150,000 have a 50% risk

• 1983 Linkage analysis of a large family in 1983. Linkage analysis of a large family in Venezuela localised gene to chromosome 4.

Reverse genetics applied to isolate the Huntingtin gene which has a polyglutamine repeat sequence caused by a trinucleotide repeat expansion

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31
Q

Table of Huntingtin gene CAG repeat length vs. risk

A

Repeat length determine status of the disease

No. of CAG repeats Outcome

< 28 Normal range; individual will not develop HD

29-34* - Individual will not develop HD but the next generation is at risk g

35-39 - Some, but not all, individuals in this range will develop HD; next generation is also at risk

> 40 - Individual will develop HD, the greater the number of repeats, the earlier the onset

Note: * When the gene has more than 36 copies of the repeated trinucleotide sequence, the DNA replication process becomes unstable and the number of repeats can change in successive generations. This can mean that in a parent without HD but with a count close to 36, the count may increase above the threshold that causes HD in their children

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32
Q

Some aspects of abnormal Huntingdon?

A

Some aspects of abnormal Huntingtin

  • Mice lacking the gene do not get the disease
  • Expression of the mutant gene or the extended CAG repeat, can induce disease in mice – and this classifies it as a “gain-of-toxic function” disease
  • Inclusion bodies containing fragments of mHtt build up selectively in vulnerable neurons – eventually in the nucleus
  • Aggregates can interact with transcription factors and modulate gene expression • Cell death follows – but mechanism not clear
  • There are 8 other PolyQ diseases (including 6 types of spinocerebellar ataxia) with CAG repeats in other genes
  • There are other trinucleotide repeat diseases (e.g. CGC in Fragile X syndrome)

Huntington’s disease is very unusual as we know the cause in all patients – Motor Neuron Disease is a good example of a neurodegenerative disease where we know the cause in some patients, but not all patients

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33
Q

What is the role of abnormal Huntingtin in the Huntington’s disease?

A
  • Inclusion bodies containing fragments of mHtt build up selectively in vulnerable neurons – eventually in the nucleus
  • Aggregates can interact with transcription factors and modulate gene expression
  • Cell death follows – but mechanism not clear
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34
Q

How does motor neurone disease typically progress?

A

A motor neuron will innervate many muscle fibers – this is the motor unit

If a motor neuron dies, others take over the territory by a process called compensatory sprouting, and this increases the size of the motor unit.

However, capacity to do this is limited and motor units are eventually lost.

The disease state is characterised by the excessive loss of motor units and severe muscle atrophy.

The Important point is that in all disease states a considerable amount of damage is done before symptoms become apparent - major problem in developing therapies

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35
Q

How can Non-neuronal cells be involved in neurodegenerative diseases such as MND, Alzheimer’s, Parkinson’s, Huntington’s

A

(1) Microglia become activated and release toxic factors (eg. NO, TNFalpha
(2) Astrocytes become activated, release toxic factors, and lose their ability to recycle glutamate (loss of EAAT2) resulting in glutamate excitotoxicity
(3) Loss of trophic support from target
(4) Reactive response in target: e.g. APP and Nogo-A

36
Q

Give a brief summary of Alzheimer’s Disease

A

– Massive loss of cholinergic neurones
– Loss of glutamatergic synapses and serotonin nerve fibres

  • Impaired cognitive function
  • Memory loss
  • Mood and emotional disturbances
37
Q

Give a brief summary of Parkinson’s Disease

A
  • Loss of dopaminergic neurones in the basal ganglia

- Loss of control of voluntary movement, tremor

38
Q

Give a brief summary of Alzheimer’s Disease

A
  • Massive loss of GABA neurons in the striatum
39
Q

(1) Protein aggregation is common in neurodegenerative diseases, but protein species is unique. Give examples

A
  • SOD1 or TDP-43 protein aggregates in motor neurons in ALS
  • Synuclein aggregates in dopaminergic neurons in Parkinson’s disease
  • Huntingtin aggregates in GABAergic neurons in Huntington’s disease
  • Amyloid plaques and neurofibrillary tangles in Alzheimer’s disease

All of these compromise neuronal/synaptic function

40
Q

What are three common features of neurodegenerative diseases such as MND, Alzheimer’s, Parkinson’s, Huntington’s

A
  • probably be masked by compensatory sprouting
  • exacerbated by activation of microglia and astrocytes and/or loss of trophic support/reactive changes in the denervated target
  • and importantly by excitotoxicity
41
Q

How to glutamate receptors work?

A

NMDA, AMPA and Kainate receptors are permeable to Ca++ and/or Na+

Na+ influx will depolarise cells and open voltage gated calcium channels

Metabotropic receptors couple to calcium release from internal stores

Calcium has normal functions e.g. regulating receptor activity by phosphorylation to control synaptic plasticity

42
Q

What mechanisms cause to excitotoxicity arise?

A

Excitotoxicity arises when glutamate accumulates at synapses

• Excessive release

  • Epilepsy
  • Loss of Ca++ homeostasis due to ATP rundown after stroke

• Defective Uptake
- Loss of EAAT (astrocyte uptake) (e.g. in MND/ALS) can lead to increased synaptic levels

• Reversal of transporters
- Energy depletion after stroke

43
Q

What is the role of Ca++ in exicitotoxity?

Eg’s of what conditions exicitotoxity is significant in?

A

Excitotoxicity is caused by Ca2+ accumulation at the synapse

Ca2+ can damage mitochondria and in addition can activate:

  • proteases
  • endonucleases
  • stress activated kinases
  • phospholipases
  • Nitric Oxide Synthase

 Head Trauma
 Cerebral ischemia (Stroke)
 Alzheimer’s, Parkinson’s and Huntington’s diseases
 Motor Neurone Disease (ALS)
 Damage following intense seizure activity (epilepsy) and alcohol withdrawal
 Age related cognitive decline

44
Q

What are the therapeutic targets for neurodegenerative disease?

A

Replacement therapy
•L dopa for Parkinson s disease
•Cholinesterase inhibitors for Alzheimer’s

Excitotoxicity
• glutamate receptor antagonists (AMPA, NMDA)
• Na channel antagonists
• Voltage gated-calcium channel antagonists

Accumulation of toxic proteins
• secretase inhibitors to prevent generation of toxic peptides
• Immunisation strategies to remove toxic ABeta peptides

Trophic support
• NGF, BDNF, GDF, VEGF to support neurons

Anti-inflammatory drugs
• COX1/2 inhibitors

45
Q

What are the current and future therapies for Alzheimer’s disease and at what points in the neurodegenerative process to they work?

A 
Amyloid deposition: 
• Abnormal APP metabolism 
• Beta-amyloid deposition
• Beta-amyloid plaques
- Beta-secretase inhibitors
- Gamma-secretase inhibitors 
- Immunisation strategies

Excitotoxicity
- NMDA inhibitor

Increased Inflammation:
• Inflammatory response
• Cytokines & Chemokines
- NSAIDs (COX1/2)

Loss of synapse and neurons

Neurotransmitter disturbance
- Cholinesterase inhibitors

Alzheimer’s disease

46
Q

What is the The 2S 3R 2D (SSRRRDD) system?

A
  • S – Synthesis
  • S - Storage
  • R - Release
  • R - Receptors
  • R – Reuptake
  • D - Degradation
  • D – Drugs & Disease
47
Q

What are the main centres of Ach transmission in the brain?

A

Th - thalamus

Hyp – hypothalamus

Am - amygdala

C – cerebellum

Sep – septum

Sn –substantia nigra

Str – striatum

Hip - Hippocampus

48
Q

Outside of the CNS where does Ach transmission occur?

A

Lower motor neurones

GI tract

Preganglionic autonomic nerves

Post ganglion parasympathetic

Retina

49
Q

He and where is Ach synthesised?

A

1.Choline (diet + recycled) + Acetyl-CoA (Krebs cycle)

Enzyme: ( Choline acetyltransferase (ChAT) )

Gives: Acetylcholine

Occurs in the nerve terminal

ChaT synthesised in the cell body and transported to the terminals

50
Q

How is Ach stored?

A

1 Ach+ into vesicle in exchange for 2H+

Cytosol conc: 1mM

Vesicular conc: 100mM

51
Q

How is Ach released from the presynaptically terminal?

A
  • Calcium dependent vesicular release
  • End terminal - exocytosis
  • Vesicular pool types: releasable, recycling and reserve
52
Q

What Ach receptors are there?

A 
• Ligand gated ion channel nicotinic (pentameric) 
– Muscle nAChRs mature (α1)2 + β1+δ+ε) 
– Embryonic muscle (α1)2 + β1+δ+γ)
– Neuronal nAChRs ganglion (α3)2 +(β4)3 
– Neuronal nAChRs CNS (α4)2 +(β2)3
– Neuronal nAChRs CNS (α7)5

• GPCRs (class A, rhodopsin type), muscarinic
– M1 - Gq/Gll
– M2 - Go/Gi
– M3 - Gq/Gll
– M4 - Go/Gi
– M5 Gq/Gll
(Even numbers And Odd numbers - different second messenger system)

53
Q

How is Ach reuptaken?

A

• Choline transporter (note ACh must be degraded to choline before it can be reuptaken – this is unusual for a t neurotransmitter)
- acetylcholinesterase

54
Q

How is Ach degraded and where?

A
  • Acetylcholine

Enzyme: Acetylcholinesterase

  • Gives: Choline + Acetic Acid

Mostly located in the synaptic cleft (extracellular)

55
Q

What drugs affects Ach synthesis, storage or release?

A
  • Synthesis - ?
  • Storage - vesamicol
  • Release - botulinus toxin(s) - (Cleaves protein from vesicle and presynaptic membrane to stop Ach release)
56
Q

Give examples of full nicotinic Ach agonists

A

suxamethonium

nicotine

57
Q

Nicotinic Ach partial agonists?

A

varenacline

(α4β2) - Common combo in the brain

  • stops nicotine from acting on receptors
  • competes
  • stops withdrawal symptoms by acting enough to stop that but without giving the buzz
58
Q

Give examples of reversible nicotinic Ach antagonists

A

pancronium

vercuronium

59
Q

Do you know of any irreversible nicotinic Ach antagonists?

A

α-bungarotoxin

60
Q

What full muscarinic Ach agonists do you know?

A

muscarine

oxotremorine M

61
Q

What partial muscarinic Ach agonists do you know?

A

McN-A-343

62
Q

What muscarinic Ach antagonists do you know?

A

atropine

ipratropium

63
Q

Do you know any drugs that affect reuptake of Ach?

A

hemicholinium

64
Q

What drugs do you know that affect Ach degradation?

A

Donepazil

Rivastigmine

Galantamine

Memantine - severe

endophonium

neostigmine

physostigmine

(Cholinesterase inhibitors)’

65
Q

What recreational drugs affect the Ach system?

A

Nicotine

Scopolamine “truth drug”

Henbane

66
Q

What diseases involve Ach transmission?

A
  • Dementia
  • Myaesthenia gravis
  • Parkinson’s
  • Motion sickness
  • Analgesia
67
Q

Ach is involved in what functions?

A
  • Learning & Memory
  • NMJ
  • Motor control
  • Vestibular control
  • Pain
68
Q

Where is dopamine located?

A

Th - thalamus

Hyp – hypothalamus

Am - amygdala

C – cerebellum

Sep – septum

Sn –substantia nigra

Str – striatum

P – pituitary

Ac – nucleus accumbins

Hip – hippocampus

And the retina

69
Q

Which dopamine pathway is first to degenerate in Parkinson’s Disease?

A

Nigrastriatal pathway

70
Q

How is dopamine synthesised?

A
  1. Tyrosine (diet)

Enzyme: Tyrosine hydroxylase (rate limiting)

  1. DOPA

Enzyme: Dopa decarboxylase

  1. DOPAMINE
71
Q

How is dopamine stored?

A

VMAT - vesicular monoamine transporter 1 or 2 can be cell type specific

One DA+ into vesicle for 2H+ out

72
Q

How is dopamine released?

A

Calcium dependent vesicular release

  • End terminal
  • En passant varicosities
73
Q

What dopamine receptors are there?

A

• All GPCRs (Class A, rhodopsin-like)

• “DI-like” D1, D5 coupled to Gs
- Increase andenylate cyclase

• “D2-like” D2 D3 D4 coupled to Gi
- Decrease andenylate cyclase

74
Q

How is dopamine reuptaken?

A

DAT – dopamine active transporter

Cl- 2Na+

75
Q

See page 18 of dopamine and Ach lecture for degradation of dopamine?

A

-

76
Q

What is the main breakdown product of dopamine?

A

Homovanillic acid

Measure in CSF

77
Q

Do you know any drugs that work via the synthesis of dopamine?

A

Levo-dopa?

78
Q

Do you know any drugs that affect dopamine storage?

A

reserpine

methamphetamine

79
Q

Do you know any drugs that affect release of dopamine?

A

amantadine

(Causes release selectively from terminals
- use in early stages of Parkinson’s whilst terminals are still present)

80
Q

What full agonists of dopamine do you know?

A

apomorphine

bromocriptine

81
Q

What dopamine antagonists do you know?

A

haloperidol

chlopromazine

82
Q

What drugs do you know that work by affecting dopamine reuptake?

A

cocaine

bupropion

methylpenidate (Ritalin®)

83
Q

What drugs affect dopamine degradation?

A

MAO inhibitors

  • phenelzine
  • selegiline (MAO-B)

COMT inhibitors
– entacapone
- tolcapone

(Can reduce required dose of L-Dopa)

84
Q

What recreational drugs act via the dopaminergic system?

A

Cocaine

Amphetamines

Bromocriptine (fungal contamination of grain)

85
Q

What diseases is dopamine transmission involved in?

A
  • Drug Dependence
  • Parkinson’s disease
  • Schizophrenia
  • Nausea/Vomiting
  • Hormonal disturbance
86
Q

What functions is dopamine transmission important for?

A

 Reward?

 Motor control

 Mood/thought

 Control of CTZ (monitoring of blood contents)

 Pituitary control

Neuroscience (16 decks)

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