Lecture 22: Parkinson’s Disease

Question 1

What are the neurodegenerative disorders?

Answer 1

• Alzheimer’s Disease (AD)
• Parkinson’s Disease (PD)
• Others e. g. Creutzfeldt-Jakob disease (CJD), Huntington’s disease (HD)

Question 2

What is parkinsons disease?

Answer 2

Neurodegenerative disorder featuring accumulation of a damaged protein

Often associated with the toxic deposition of proteins in the brain: Alpha synuclein within ‘lewy bodies’

Question 3

What toxic proetiens are deposited in the brains of patients with alzheimers disease?

Answer 3

Amyloid beta into ‘plaques’ + Tau into ‘neurofibrillary tangles

Question 4

What causes neurodegeneration?

Answer 4

1. Gene mutation/ environement
2. Misfolded protein
3. Aggregation/ Deposition/ Failure to clear
4. Synapses loss, neurodegeneration

Question 5

What are lewy bodies?

Answer 5

toxic alpha-synuclein aggregates found in PD neurons

Question 6

What are other risks for neurodegenerative diseases

Answer 6

Oxidative stress and mitochondrial dysfunction

Question 7

What are the types of parkinsonisms?

Answer 7

Parkinson’s Disease
‘Parkinson’s plus’ (=‘atypical’)
-Vascular Parkinson’s
- Lewy body dementia
- Fronto-temporal dementia
- Multiple system atrophy
Progressive supranuclear palsy

Question 8

What are the parkinsonism features?

Answer 8

A dysregulation of motor functions

• Bradykinesia: slowness of movement
• Tremor at rest: caused by alternative contraction of opposing muscle groups
• Rigidity/freezing/being ‘stuck’/expressionless face
• Postural instability
• Alkinesia: no normal unconscious movement (arms swinging while walking)
• Hypokinesia; reduced amplitude of movement (handwriting smaller)

Question 9

What is the mean age of onset of PD

Answer 9

55

Question 10

What are the mechanisms that cause parkinsons disease?

Answer 10

1. Movement inhibition - In PD, most ventral/compacta substantia nigra cells die, resulting in severe disruption of these pathways and disorganised muscular activity
2. Other neurotransmitter systems and regions show some degeneration too
3. Gut-Brain axis - Incorrectly folded alpha-synuclein may enter the brain via the vagus nerve. Bacterial infection creates chronic inflammatory state driving brain inflammatory changes
4. Inflammation - caused by breakdown of neurons containing lewy bodies. degeneration of dopamine neurons is associated with massive microglial activity - this causes phagocytosis of debris and apoptotic cells ans initiation of repair processes but uncontrolled inflammation results in production of neurotoxic factors that worsen neurodegenerative pathology. Increased levels of released inflammatory cytokines and NO production + recruitment of other immune cells (gliosis). Antibodies to proteins modified by dopamine oxidation products. Use of NSAID decreases risk of developing PD by 45%

Question 11

What controls the initiation of movement?

Answer 11

Substantia nigra to striatum by dopaminergic neurons occurs, and this is fed back to the reticulata region and eventually the cortex

Question 12

What is neuromelanin?

Answer 12

safely stored waste product of dopamine oxidation

Question 13

What are the 2 regions of the straitum?

Answer 13

putamen
caudate

Question 14

What is braak stage 1&2 of pd?

Answer 14

Lewy bodys in the brain stem - autonomic and olfactory disturbances

Question 15

What is braak stage 3&4 of pd

Answer 15

Lewy bodies spread to mid brain and cause motor symptoms/ sleep disturbnaces

Question 16

What is braak stage 5&6 of pd?

Answer 16

Lewy bodys have spread extensively throughout the brain resulting in emotional and cognitive disturbances

Question 17

What are the factors that may trigger PD?

Answer 17

• Normal dopamine metabolism: Generates reactive oxygen species (ROS) that damage mitochondria and damaged mitochondria produce more ROS: ‘oxidative stress’
• Environemental: Toxins, Pyridine and related compounds
• Genetic variants: Familial forms – genes identified, Population risk – genes identified

Question 18

What is MPTP?

Answer 18

Contaminnat found in a batch of synthetic heroin - several people developed PD. Similar to paraquat and other herbicides.

MPTP crosses the BBB and is taken up by astrocytes. It is oxidized to a toxic metabolite MPP+ by glial MAO-B. MPP+ is taken up via dopamine transporter into dopaminergic neurons but also may enter via binding to neuromelanin - causes Inhibition of mitochondrial Complex I: increased free radical production and oxidative stress

Question 19

What is the management of PD?

Answer 19

Medication
Levodopa:
- Co beneldopa - levodopa and benserazide: ‘Madopar
- Co careldopa - levodopa and carbidopa: ‘Sinemet’

Dopamine agonists :
- Pramipexole, Ropinirole
- Rotigotine skin patch (Neupro)
- Apomorphine

MAO-B inhibitors (rasagiline, selegiline, safinamide)

COMT inhibitors (entacapone, opicapone)

Amantadine

Anticholinergics
(procyclidine, trihexyphenidyl)

General managemnet:
- Manipulation of standard oral drug therapy which aims to boost dopamine neurotransmission
- No response, or severe ‘on-off’ issues Then move on to… More invasive drug treatments (such as apomorphine injection/infusion or an intraduodenal levodopa [Duodopa] pump), Neurosurgery, most commonly deep brain stimulation.

Question 20

How does levodopa treatment work?

Answer 20

Lack of dopaminergic signalling between substantia nigra and Striatum/ caudate is countered by flooding CNS with the dopamine precurson levodopa

Dopamine itself does not cross the BBB and would cause peripheral side effects if administered

The lowest effective Levodopa concentration possible should be used to avoid side-effects

Levodopa and dopamine are metabolised and removed by COMT, AADC (dopa decarboxylate) and MAO (monoamine oxidase) - hence administered with an enzyme inhibitor

Question 21

What happens if dopamine is in the periphery?

Answer 21

cardiac conduction abnormalities, tachycardia, angina, palpitation, bradycardia, vasoconstriction, hypotension, hypertension, dyspnea, nausea, vomiting, headache, and anxiety etc.

Question 22

What is the action of carbidopa and benserazide?

Answer 22

Inhibits AADC so prevents levadopa being converted to dopamine in the periphery.

Question 23

What are the side effects of levodopa?

Answer 23

• Sleepiness
• Hypotensive reactions
• Impulsive control disorders: gambling, binge eating, hypersexuality

Treatment must not be stopped suddenly due to the small risk of neuroleptic malignancy syndrome – Life-threatening symptoms include high fever, sweating, unstable blood pressure, stupor, muscular rigidity, and autonomic dysfunction. Also occurs as a reaction to antipsychotic/neuroleptic medication.

Question 24

What is the on off state of PD? And what is the drug response to this?

Answer 24

Off state – tremours, untreated form of PD
On state – l dopa administered and relief of symptoms – lasts 4 or 5 hours

As the disease progresses – neaurodegenerative progress continues – there are less synapses for the l dopa to work on, so the on stage lasts much less – need to increase dosage frequency, give slow release form.

Question 25

How do you manage off periods?

Answer 25

• Intraduodenal gel infusion of Levodopa avoids erratic gastric emptying in PD…faster time to ON effects.
• Dopamine agonists: Non-ergot-based drugs: pramipexole, ropinirole, rotigotine (older ergot-based drugs such as bromocriptine no longer used because they promoted lung/heart fibrosis)
  Apomorphine: titrated in patient during ‘off-stage’. Once titrated, can be used in conjunction with levodopa. Subcutaneous injection, fast acting but only lasts 100 minutes. Infusion is possible but risks side-effects.
• COMT inhibitors like entacapone – try to stop dopamine broken down in the brain
• MAO-B inhibitors like selegiline that reduce ‘off’ time and prolong levodopa action
• Anticholinergic drugs: orphenadrine, procyclidine, trihexyphenidyl…but side-effects (saliva, bladder constriction etc)