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Week 3 Parkinson Flashcards

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1
Q

What is Parkinson’s disease?

A
  1. A progressive disease of the nervous system marked by:
    - tremor
    - muscle rigidity
    - slow, imprecise movement
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2
Q

Who is affected with Parkinson’s disease?

A
  1. Middle aged

2. Elderly people

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3
Q

What is Parkinson’s disease associated with?

A
  1. Degeneration of the basal ganglia of the brain

2. Deficiency of the neurotransmitter dopamine

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4
Q

What did James Parkinson describe the disease?

A
  1. Shaking Palsy
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5
Q

What is the key pathology in PD?

A
  1. alpha-synuclein accumulation
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6
Q

What does large alpha-synuclein form?

A
  1. Round lamellated eosinophilic cytoplasmic inclusions - Lewis bodies
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7
Q

What does accumulation of alpha-synuclein impair?

A
  1. Function of:
    - mitochondria
    - lysosomes
    - endoplasmic reticulum
    - interfere with microtubular transport
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8
Q

What does the core pathology of Parkinson’s disease affect?

A
  1. Dopamine-producing neurons of the substantia nigra
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9
Q

What does substantia nigra Contain?

A
  1. Neuromelanin
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10
Q

What is Parkinson’s disease?

A
  1. Progressive degeneration of the dopaminergic neurons within substantia nigra
  2. Decrease in substantia nigra - decrease in motor movements
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11
Q

What are the signs and symptoms?

A
  1. T - tremors - resting
  2. R - rigidity
  3. A - Akinesia (no movement) - their face is expression less
  4. P - postural instability (hunched over posture)
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12
Q

What can the signs of Parkinson’s disease be divided into?

A
  1. Motor symptoms

2. Non-motor symptoms

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13
Q

What are the motor symptoms?

A
  1. Bradykinesia
  2. Akinesia
  3. Rigidity
  4. Tremor at rest
  5. Postural instability
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14
Q

What are the non-motor symptoms?

A
  1. Depression
  2. Cognitive impairment and dementia
  3. Insomnia
  4. Psychosis
  5. Urinary incontinence
  6. Sexual dysfunction
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15
Q

When can non-motor symptom be present?

A
  1. Before Parkinson’s patient present typical motor symptom
  2. Dysfunction in dopaminergic signalling in other parts of brain beyond the substantia nigra e.g. PFC - cognitive symptoms
  3. Issues from other neurotrasmitters e.g. ACh
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16
Q

What does the motor symptoms represent?

A
  1. Early phase of the disease
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17
Q

What is the problem with Parkinson disease?

A
  1. Abnormal motor movements
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18
Q

Where does the cortex send the message/neurons to? (Direct Pathway)

A
  1. Down to the putamen
  2. Cortical-stratial pathway
  3. Cortical stratial fibres/neurons release a neurotransmitter (stimulatory) - Glutamate
  4. Glutamate is released onto the neurons present within the putamen - stimulates neurons
  5. The neurons extend to the globus pallidus internal
  6. Neurons in GPi releases a specific chemical - GABA(inhibitory)
  7. GABA binds onto the neurons in the GPi
  8. GABA causes potassium ions to leave the cell or chloride ions to come into the cell - IPSP
  9. The neurons in GPi extends to the thalamus
  10. In the thalamus there is another group of cell bodies which extends to the cortex
  11. Less GABA - less IPSP - release thalamus from
    Inhibition and will be stimulated
  12. More AP and stimulates the cortex to come down and initiate the movement
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19
Q

What is the indirect pathway?

A
  1. Fibres from the cortex to the putamen (cortical-striatal Pathway)
  2. Release glutamate
  3. Glutamate stimulates the GABAergic neurons which are present within the putamen
  4. When stimulated, AP that releases GABA onto neurons that are present within GPe
  5. If a lot of GABA is released it inhibits this neuron
  6. It releases less AP, releasing less GABA, it releases this neuron from inhibition (subthalamus)
  7. It will stimulate this neuron which will come up and release a lot of glutamate onto GPi
  8. If there is glutamate - it is stimulatory, it stimulates the AP down the neuron, and releases a lot of GABA
  9. Causes IPSP and inhibits neurons in the thalamus - it undergoes less AP to cerebral cortex - inhibitory action
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20
Q

What does D1 receptor activate?

A
  1. G-stimulatory Pathway
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21
Q

Where does D2 receptors work?

A
  1. G-inhibitory Pathway
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22
Q

What happens when you lose dopamine?

A
  1. Controls population of cells
  2. Increase in activity in the indirect pathway linking stratium to Globus Pallidus External
  3. Decrease in the pathway which projects from stratium to Globus Pallidus Internal
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23
Q

What is Parkinson’s disease?

A
  1. Heterogenous
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24
Q

What are the 2 distinct subtypes that you can detect in the basis of clinical diagnosis?

A

Tremor-dominant

Postural imbalance and gait disorder

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25
Q

What are gait disorder and postural instability a leading cause of?

A
  1. Falls

2. Disability

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26
Q

For most neurons where does the damage occur?

A
  1. Pars Compacta
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27
Q

What happens to dopamine release when the neurons in pars compacta are damaged?

A
  1. Decrease
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28
Q

What is affected in Pars Compacta?

A
  1. Pars Compacta
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29
Q

What does the Pars Compacta send messages to?

A
  1. Stratium via neurons rich in the neurotransmitter dopamine
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30
Q

What happens when the substantia nigra pars Compacta neurons die?

A
  1. The individual may be in a hypokinetic /low movement state
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31
Q

What does substantia nigra help?

A
  1. Calibrate and fine tune the way that movements happen
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32
Q

What are the clinical features of PD?

A
  1. Tremor
    - involvintary shakiness
    - pill rolling
    - resting tremor: present at rest, diminishes with movement
  2. Rigidity
    - Cogwheel Rigidity - series of catches or stalks as a persons arms or legs are passively moved by someone else
  • also responsible for the stooped posture and an almost expressionless face
    3. Bradykinesia - slow
    4. Hypokinesia - lessened movement
    5. Akinesia - absence of movement
  • difficulty initiating movement
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33
Q

What does PD not produce?

A
  1. Weakness

2. Differentiate it from diseases that affect the motor cortex or corticospinal pathways

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34
Q

What did Braak’s hypothesis state?

A
  1. Sporadic PD is caused by a pathogen that enters the body via nasal cavity
  2. Swallowed and reaches the gut
  3. Initiating Lewy pathology in the nose and digestive tract
  4. Spread of LP from peripheral to the CNS
  5. Progression you move from lower level structures towards highest level structure (cortical areas)
35
Q

What is the stages proposed by Braak Hypothesis?

A
  1. Dorsal motor nucleus of glossopharyngeal and vag nerves
  2. Locus coeruleus
  3. Substantia nigra - pars Compacta
  4. Mesocortex
  5. Higher order sensory association cortex and prefrontal fields
  6. First order sensory Association areas, promotors area and primary sensory and motor fields
36
Q

What has Lewy body aggregates been associated with?

A
  1. Spread of neuropathology from the peripheral to the CNS

2. Involved with autonomic disorders responsible for gastrointestinal symptoms of individuals afflicted with Parkinson’s

37
Q

Characterise normative expression of alpha-synuclein in innervation of GI

A
  1. Examined both the postganglionic neurons and preganglionic projections by which the disease is postulated to retrogradely invade the CNS
  2. Determine the expression of alpha-synuclein in myenteric plexus and vagal terminals
38
Q

Where is alpha-synuclein expressed?

A
  1. Subpopulation is myenteric neurons

2. Proportion of positive somata increasing from stomach through duodenum to jejunum

39
Q

What expresses alpha-synuejn

A
  1. All vagal preganglionic projections to the gut
40
Q

What does some vagal preganglionic deferents expressing alpha-synuclein form?

A
  1. Varicose terminal rings around myenteric plexus neurons that are also positive for the protein
  2. Provide a candidate alpha-expressing pathway for retrograde transport of putative Parkinson’s pathogens or toxins from ENS to CNS
41
Q

What is able to reproduce the PD pathological staging as found in patients?

A
  1. Intragastrically administered rotenone

Commonly used pesticide that inhibits complex I of mitochondrial respiratory chain

42
Q

What does low doses of chronically and intragastrically administered rotenone induce?

A
  1. Alpha-synuclein accumulation in ENS, dorsal motor nucleus of vagus (DMV), the intermediolateral nucleus of spinal cord and substantia nigra in WT nice
43
Q

What induces PD-like progression and reproduce the neuroanatomical and neurochemical features of PD staging?

A
  1. Local effects of pesticide on ENS

2. Provides new insight into how environmental factors could trigger PD

44
Q

What is the hypothesis of PD?

A
  1. There may be a nasal route penetration of pathogen
  2. Pathogen accessing the brain through nose
  3. Viral pathogen - neuroinflammation
45
Q

What does the PD effect (evidence)?

A
  1. Dorsal motor nucleus of vagus nerve
  2. Olfactory bulbs and the nucleus
  3. Locus coeruleus
  4. Substantia nigra
46
Q

What are the pathological features of PD?

A
  1. Loss of cells

2. Presence of Lewy bodies enriched in alpha synuclein

47
Q

Where can alpha synuclein be apparent?

A
  1. Certain neuritis in diseases neurons
48
Q

What are the pathophysiologicsl mechanisms in PD (1)

A
  1. Defect in mitochondrial complex I (transfer of elections from NADPH to CoQ)
  2. Toxicity of MPTP results from action of metabolite MPP+ on mitochondrial complex I
49
Q

What is pathophysiological mechanism in PD (2)

A
  1. Oxidative stress
  2. 95% of molecular oxygen is metabolised in mitochondria
  3. Oxygen radicals generated through respiration can induce mitochondrial dysfunction
  4. Increased dopamine turn-over leads to increase oxidative stress
  5. Reactive oxygen species can lead to lipid peroxidation
50
Q

What does substantia nigra pars Compacta receive?

A
  1. Strong glutamatergjc innervation
51
Q

Activation of NMDA glutamate receptors

A
  1. Trigger excitotoxicity
  2. Increased influx of calcium
  3. Activation of NOS
  4. Secondary intramitochondrial accumulation of calcium and disturbances of ATP synthesis
52
Q

What does Amantadine have?

A
  1. Anti-viral compound

2. NMDA receptor blockade properties and efficacy in early Parkinson disease

53
Q

What is pathophysiological mechanism of PD (3)

A
  1. Excitotoxicity
54
Q

What happens to us in normal senescence?

A
  1. Have some dysfunction of dopaminergic neurons
55
Q

What is associated with PD?

A
  1. Many locus which code for specific proteins with special functions
  2. Describe dominant or recessive inheritance of these genetic loci
56
Q

SNCA (alpha-synuclein;PARK1)

A
  1. Alpha-synuclein is a pre-synaptic protein involved in vesicle recycling and neurotransmitter storage
  2. Missense mutation and also gene duplication or triplicating can occur
  3. The C-terminal region of the molecule is a regulator of aggregation
  4. Is the aggregated misfolded protein in LB neurotoxic or protective
57
Q

What is typical biosynthesis of dopamine?

A
  1. Tryosine is converted to L-dopa and finally into dopamine in the presynaptic dopaminergic terminal
  2. Dopamine will be concentrated through the vesicular transporter V-MAT into vesicles and they will be released
  3. Dopamine will be pumped back through the DAT transporter and will be repackaged into vesicles
58
Q

What are the house keeping system in the body?

A
  1. Ubiquitin proteosome

2. Lysosome dependent autophagy system

59
Q

What is one way to get rid of the alpha-synuclein aggregation risk?

A
  1. Enhance the activity of the house keeping ensembles of proteins
  2. Stabilise the non-toxic alpha-synuclein species
  3. Antibody-mediated approach
60
Q

What is Parkin (PARK2)?

A
  1. E3 ubiquitin protein ligase
  2. Enhances ubiquitination and degradation of misfolded proteins
  3. It targets the misfolded proteins to the ubiquitin proteosome Pathway (UPS)
  4. Mutations and also post-translational changes can comprise its activity
  5. It has neuroprotective functions
  6. Parkin and PINK1 May target the damaged mitochondria for autophagy
61
Q

What are the other mutations and functions associated with the encoded proteins?

A
  1. PINK1
    - protects against mitochondrial dysfunction
  2. DJ-1
    - it has chaperone functions and protects against oxidative stress
  3. LRRK2 (dardarin)
    - involved in synaptic vesicles and neurite growth
62
Q

LRRK2 -Dardarin

A
  1. 30% of PD patients carry the G2019S mutation
  2. Disease penetrance is incomplete - strong disease modifiers
  3. 2527 as protein: it has a kinase domain and a GTPase activity domain
  4. Role in autophagic process
63
Q

What is Gaucher’s disease?

A
  1. Lysosomal storage disorder (autosomal recessive)
  2. Mutation in the glucocerebroside (GBA) gene
  3. Deficit in lysosomal function in mononuclear phagocytes
  4. Parkinsonism is a common feature of certain forms of GD
  5. Mutations in GBA are more common than mutations in alpha-synuclein, dardarin or Parkin
64
Q

Impairment in GBA function

A

Affect lysosome function

65
Q

What are lysosomes involved in?

A
  1. Clearance of alpha-synuclein
66
Q

What are increases risk of PD?

A
  1. Pesticide exposure
  2. Prior head injury
  3. Rural living
  4. Beta-blocker use
  5. Agricultural occupation
  6. Well water drinking
67
Q

What are the decreases risk of PD?

A
  1. Tobacco smoking
  2. Coffee drinking
  3. NSAID use
  4. Calcium channel blocker use
  5. Alcohol consumption
68
Q

What are the treatment for PD?

A
  1. Strategy: increase dopamine signalling in the brain
  2. Dopamine itself cannot cross the blood brain barrier but it’s precursor L-dopa can
  3. Use amantadine - antiviral medication that increases endogenous dopamine production
  4. Dopamine agonist that can stimulate dopamine receptors e.g. bromocriptine
  5. Inhibitors of COMT
  6. Anticholinergixs can be used to balance the of dopaminergic and cholinergic signalling
  7. Deep brain stimulation
69
Q

Levo-dopa in treatment of Parkinson’s

A
  1. Typically helps most with bradykinesia and rigidity but not balance problems
  2. Combined with drug carbidopa to diminish nausea, vomiting and other side effects
  3. Precursor of dopamine in the biosynthetic pathway
  4. Administered with peripherally acting DOPA decarboxylase inhibitors
  5. Block the conversion at the periphery so you maximise the conversion of these precursors to dopamine in the brain
  6. Combine DOPA-decarboxylase and COMT inhibitors - amplifies the dopaminergic signal
70
Q

What are the many different ways of giving L-dopa?

A
  1. Intermittent

2. Sustained release preparations

71
Q

What are the motor fluctuations of L-Dopa Therapy

A
  1. End of dose wearing off
  2. Delayed on response
  3. No “on” response
  4. “On-off” phenomenal
72
Q

What are the dyskinesias complication with L-Dopa therapy

A
  1. Peak dose dyskinesia
  2. Diphasic dyskinesia
  3. Off period dystonia
73
Q

What are the dopaminergic agonist?

A
  1. Ropinirole (high affinity D2)
  2. Pramipexole (high affinity D3)
  3. Pergolide (D1=D2)
74
Q

Rotigotine

A

Can be given as transdermal patch

75
Q

Apomorphine

A

Injectable form in advanced disease

76
Q

What are the problems with current therapies?

A
  1. Short “honey-moon” with L-dopa followed by motor fluctuations
  2. Development of additional symptoms
  3. Decline in cognition and postural reflexes
  4. Major unwanted drug effects (psychosis, hallucinations)
77
Q

What are examples of surgical procedures?

A
  1. Lesion is the Globus Pallidus internum
  2. Lesion of the ventral intermediate nucleus of the thalamus
  3. Electrical stimulation of subthalamic nucleus
  4. Electrical stimulation of ventral intermediate nucleus of thalamus
78
Q

What are the pros of the surgical procedures?

A
  1. Decrease dyskinesia

2. Reduce motor fluctuations

79
Q

What are the cons of surgical procedure?

A
  1. Do not slow disease progression
  2. Do not affect the worsening of balance and gait
  3. Do not decrease cognitive impajrmdnt
  4. Do not affect dysphagia
80
Q

What are the types of transplanted cells?

A
  1. embryonic stem cells
  2. Neural precursor cells isolated from human fetal midbrain
  3. Induced pluripotent cells derived from adult human tissues
  4. Cells derived from adult neural stem cells
  5. Mesenchymal stem cells
81
Q

What are other issues linked to cell therapies?

A
  1. Improvement in the first year but recurrence of dyskinesia and dystopia in 15% of patients
  2. Alpha-synuclein inclusions appears in the transplanted cells in some patients
82
Q

Transplantation and stem cells

A
  1. ethical concerns of using feral tissue
  2. Variability in the procedure
  3. Stem cells
83
Q

What are the mechanisms underlying the effect of potential neuroprotective agents?

A
  1. Anti-oxidant effect
  2. Anti-inflammatory effect
  3. Chelation of metal ions
  4. Suppression of apoptosis
  5. Support of mitochondrial function
  6. Reduction in free radical species

Brain PD (15 decks)

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