Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

CNS- Mechanisms, Disorders & Therapeutics.) > Parkinson's Disease & Treatments > Flashcards

Parkinson's Disease & Treatments Flashcards

1
Q

What type of disease is Parkinson’s disease?

A

A disease of the basal ganglia.

Due to degeneration of the dopamine producting (dopaminergic) neurons in the substantia nigra.

Brain analysis of patients showed significant decrease in the levels of dopamine basal ganglia.

Characterised by poverty of movement (bradykinesia), rigidity and resting tremor.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Explain dopamine metabolism.

A

Tyrosine converted to DOPA (Dihydroxyphenylalanine) by the enzyme tyrosine hydroxylase.

DOPA is then converted to dopamine by an aromatic amino acid decarboxylase called DOPA decarboxylase.

Dopamine is then converted to either DOPAC (Dihydrocyphenylacetic acid) or 3-MT (3-Methoxytyramine) by Monoamine oxidase B (MAO-B) and Catechol-o-methyltransferase (COMT) respectively.

DOPAC and/or 3-MT is then converted to HVA (homovanillic acid) (by COMT or MAO-B respectively).

Check slide 4 for diagram

DOPAC- Dihydroxyphenylacetic acid
3-MT- 3-Methoxytyramine

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the following:

  1. Bradykinesia
  2. Akinesia (related to 1)
  3. Hypokinesia (related to 1)
  4. Dyskinesia
  5. Dystonia
  6. “On-off” phenomenon
  7. Freezing
A
  1. Slow movement- tremor and rigidity (Stiffness).
  2. Loss of movement (lack of facial expression & rare eye blinking)
  3. Smaller than life movement e.g. tiny handwriting (micrographia) or a soft voice (hypophonia)
  4. unintended, involuntary and uncontrollable rapid and dance-like movement (e.g. twitching, jerking, twisting, restlessness but they are NOT tremors)
  5. When muscles do not relax after contraction
  6. Sudden changes in movement control
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What is the incidence of PD?

A

5/6 per 100, 000 people (aged 30-39)

1696 per 100, 000 people (aged 80-84)

lifetime risk of being diagnosed with PD was 2.7% in the UK in 2015. This is the equivalent to 1 in every 37 people.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the prevalence of PD?

A

145, 519 in the UK for people aged over 20 (in 2018)

There’s a rising prevalence with age and a higher prevalence & incidence for PD in men.

Prevalence rates double every 5 years for those aged between 50-69 y/o (men&women)

For men aged 50-89- prevalence is 1.5 times higher than for women in the same age-group.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

List 5 MOTOR & 12 NON-MOTOR clinical features of Parkinsons:

A

Motor:
1. Tremor
2. Rigidity
3. Slowness of Movement
4. Freezing
5. Muscle cramps & dystonia

Non-motor:
1. Pain
2. Low blood pressure
3. Restless legs
4. Bladder & bowel problems
5. Sleep
6. Eating, Swallowing & Saliva control
7. Speech & communication problems
8. Eye, Dental, Foot & Mental health problems
9. Mild memory & thinking problems
10. Anxiety & Depression
11. Dementia
12. Hallucinations & delusions

(less blinking, micrographia, drooling, greasy skin, urgent urination, erectile dysfunction, communication problems= examples)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is used to diagnose Parkinsons Disease?

A

UK’s PD Society Brain Bank Criteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Explain the pathophysiology of PD

A
  • Extensive degeneration of nigro-striatal tract
  • Cell bodies of the neurones that form this tract are located in the substantia nigra in the midbrain
  • Cause = unkown= idiopathic
  • Symptoms appear only when the degeneration is extensive (over 80%)
  • Presence of eosinophilic inclusions (lewy bodies)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Protein misfolding- what is it?

A

Many chronic neurodegenerative disease result from protein misfolding.

Mutation can occur to the external factors. this results in misfolded proteins. At this point the body will try to dispose of the protein or its oligomer via cellular mechanisms. If it isn’t disposed of it becomes an insoluble aggregate that ultematly results in extracellular deposits and intracellular deposits which leads to neurotoxicity (disease)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the 5 cellular mechanisms that might cause the spread of PD from host brain to grafted neurons?

A
  1. Lack of growth factors
    causes poor protein handling which reduces antioxidant defence
  2. Inflammation
    host microgilia (IL6/ IL-1Beta/ TNF-alpha/ COX2)
    this causes iNOS to enter the cell and convert to nitric oxide.

These 2 mechanisms causes upregulation modification- meaning alpha-synuclein is imported into lewy body

  1. Oxidative stress
  2. Excitotoxity

Free radicals (caused by either oxidative stress or glutamate being converted into free radicals when transported into the cell via NMDA receptors due to excitotoxity) move into the cell

  1. Protein transfer
    When dying host neurons release alpha-synuclein. Or by living host neurons releasing alpha-synuclein. This alpha-synuclein is then uptaken by the cell via endocytosis and other unknown cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

State more info about the pathophysiology of PD

A
  • Cholineric neurones from the pedunculo-pontine nucleus also degenerate leading to postural instability, dysphagia and sleep distrurbances
  • Changes in the GABA containing neurones in the stratum are thought to play a role in development involuntary movements (dyskinesia)
  • Similarly loss of adrenergic and seratogenic neurones within coeruleus and raphe nuclei may provide the basis for depression
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the Parkinson’s Rating scales?

A
  • A means of assessing the symptoms of the condition to aid treatment and management strategies
  • There are many diff scales: Unified Parkinson’s Disease Rating Scale (UPDRS), the Hoehn and Yahr, and the Schwab and England Activities of Daily Living (ADL) Scale.
  • UPDRS combines element of several scales. It is usually used alongside other 2 of the other scales mentioned above.
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the Aetiology of PD?

A

cause of Parkinson’s disease is unknown

General belief: Environmental factors initiate the onset in genetically susceptible individuals

In the 1980s environmental factors came into focus when drug addict attempting to manufacture pethidine accidentally produced MPTP.

Ingestion or inhalation of MPTP produced a parkinsonian state (parkinsonism)- indistinguishable from advanced Parkinson’s disease. Similarly repeated exposure to pesticides like rotenone can produce symptoms similar to Parkinson’s disease. Genetics also plays a role in Parkinsons disease and the genes implicated include LRRK2, SNCA, PINK1 and PARKIN.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Non-pharmacological management of PD

A
  • Disease-specific physiotherapy for people who are experiencing balance or
    motor function problems.
  • Consider Alexander technique (AT) is a self-care approach aimed at alleviating
    stress and improving physical and emotional wellbeing. Alexander technique
    teaches improved posture and movement, which is believed to help reduce
    and prevent problems caused by unhelpful habits
  • Disease-specific occupational therapy for people who are having difficulties
    with activities of daily living
  • Speech & language therapy for people with PD who are experiencing
    problems with communication, swallowing or saliva
  • Diet: Proteins interfere with how well levodopa is absorbed by their body.
    Hence patients may benefit from taking the medication 30-60 minutes before
    a meal and opting for a protein redistribution diet
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Pharmacological management of PD

A
  • All drugs currently used are symptomatic

The two main approaches of pharmacological treatment
1. Increase [DA] of nigrostriatal system
2. Decrease influence of Ach in striatum

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

6 drugs used to treat PD motor problems

A

● Levodopa (most effective treatment)
● Dopamine agonists
● MAO-B inhibitors (monoamine oxidase-B inhibitors)

● Anticholinergic agents
● Amantadine
● COMT inhibitors

3 most commonly used medications: levodopa, dopamine agonists & monoamine oxidase-B inhibitors

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Drawbacks of Levodopa

A

– Patient developing tolerance,
– Dyskinesia,
– On-off effect

Therefore Current trends in management include
> Later administration of levodopa i.e. starting off with alternative medicines
> Combination therapy

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Levodopa preparations

A
  • Administered along with peripheral dopa- decarboxylase inhibitor carbidopa
    or benserazide
  • Immediate release levodopa:
    – Cocareldopa (Sinemet®)
    – Cobeneldopa (madopar®)
  • Usually commenced on 50mg 2-3 times a day, gradually increasing 50 -100mg
    to a maximum maintenance dose of 2g/day
  • Beneficial to take about 30mins before food
  • Both drugs are available as controlled release levodopa (e.g. Sinemet CR)
  • Duodopa
19
Q

Side effects of Levodopa

A
  • Common side effects: Nausea, vomiting and orthostatic hypotension
  • These can be overcome through:
    – Gradually increasing levodopa dose or
    – Use of an anti-emetic such as domperidone
    – 20-30mg three times a day

Comparison with immediate release levodopa:
* Bioavailability is less and response duration is longer
* Patient’s perception of quality of life during on period poorer
* Should not be prescribed more than 4 times a day

20
Q

What are dopamine agonists

A
  • They stimulate pre-synaptic and post-synaptic dopamine receptors
  • Not as effective as levodopa
  • Ergot derivatives (Cabergoline) have a plasma half life of 63-65 hrs. Dosage
    can be taken once daily.
  • Non ergot derivatives (Ropinirole & pramiprexol) have a shorter half life.
    Hence administered 3 times a day. Prolonged release form enables once daily
    dosing.
  • Rotigotine another non ergot derivative can be administered trans dermally
    via 24hr patchs
  • Apomorphine is another agonist administered parenterally
  • Studies show that some patients are benefitted by dopamine agonist monotherapy in the form of lower incidences of dyskinesia
21
Q

Advantages of using dopamine agonist

A
  • Dopamine agonists provide an effective alternative to levodopa for the
    treatment of Parkinson’s disease.
  • Successfully used as monotherapy & they allow initiation of levodopa therapy
    to be delayed so deferring onset of levodopa associated treatment
    complications, a problem mostly seen in younger patients.
  • Addition of dopamine agonists to these patients on levodopa allows around
    a 20%-30% reduction in the dose of levodopa in practice and leads to
    improvement in the disabling complications.
  • As dopamine agonists are not metabolised by oxidative pathways it does not
    lead to production of the cytotoxic free radicals that may be associated with
    metabolism of dopamine.
22
Q

Side effects dopamine agonists

A
  • Nausea, Vomiting, orthostatic hypotension, confusion, hallucinations
  • Ergot derivatives tend to cause pleuro-pulmonary fibrosis
  • High frequency of cardiac valvulopathy especially the tricuspid valve with
    pergolide & cabergoline
  • Ropinirole & pramiprexole implicated in “sleep attacks” (sudden spells of
    drowsiness)
  • Impulse control disorders (excessive gambling , hypersexuality, excessive
    shopping)
23
Q

What are Apomorphines?

A
  • Apomorphine is a strong dopamine agonist
  • Useful in patients experiencing sudden or unpredictable changes in
    symptoms or have severe ‘off’ periods that aren’t controlled by other
    Parkinson’s medication
24
Q

How are Apomorphine given to a patient?

A
  • Given by subcutaneous injection or infusion as follows:

– APO-go PEN for intermittent injections
– APO-go PFS for Infusion over a period of several hours via a syringe driver
using a pre-filled syringe.
– Apomorphine in ampoules for infusion over a period of several hours using a
syringe driver and a syringe. The ampoules need to be diluted using saline

25
Q

What are the benefits & side effects of apomorphine?

A

Benefits:
* Significant reduction in the number of ‘off’ periods

Side effects:
* Severe short term nausea and vomiting
* Impulsive/ compulsive behaviour: E.g. gambling, binge eating, ‘shopaholic’ etc.
* May experience hallucinations & delusions

26
Q

What are COMT inhibitors?

A
  • COMT (catechol-o-methyl tansferase)
  • An enzyme that catalyses the conversion of dopamine to homovanillic acid
  • COMT inhibitors reduce Parkinson’s symptoms by blocking an enzyme that
    breaks down levodopa

Examples:
– Entacapone (Comtess) can be taken with levodopa.
– Tolcapone (more potent) was withdrawn from the UK in 1998 due to its
hepatotoxicity.
– However, in 2005, prescribing procedures were heavily modified and
tolcapone was reintroduced.

27
Q

Advantages and disadvantages of COMT inhibitors

A

Advantages:
* Combinated with levodopa, COMT inhibitors can reduce the daily ‘off’ time and increase the ‘on’ time.
* In many cases, enables reduction in the dose & frequency that levodopa is taken

Disadvantages:
* Can increase the side effects caused by levodopa, notably dyskinesia, nausea
and vomiting.
* Abdominal pain, diarrhoea and discoloured urine.
* Interactions with other drugs especially apomorphine

28
Q

What are Monoamine oxidase type B inhibitors

A
  • Monoamine oxidase A (MAO A)
  • Metabolises tyramine, norepinephrine (NE), serotonin (5-HT), and dopamine (DA).
  • Monoamine oxidase B (MAOB) metabolises dopamine (DA) mainly
  • MAOA inhibitors typically used to treat depression
  • MAOB inhibitors typically treat Parkinson’s disease (Selective MAO-B inhibitor)
  • These may increase dopaminergic activity by interfering with dopamine
    reuptake at the synapse
  • MAO-B inhibitors are used on its own in early Parkinson’s, or in combination
    with other drugs at all stages
29
Q

What type of MAO-B inhibitor is Selegiline (l-deprenyl) & Rasagiline?

A

Selegiline= irreversible MAO-B inhibitor

Used as an adjunctive therapy to levodopa in patients with PD.

Rasagiline= also a selective, irreversible inhibitor of MAO-B

More potent enzyme inhibitor than selegiline

Rasagiline is approved by for both monotherapy (1 mg once daily) & as an adjunct to levodopa (0.5 or 1 mg once daily) in patients with PD.

30
Q

what side effects does Selegiline (l-deprenyl) cause?

A

Nausea, dizziness, dry mouth, headaches, confusion & hallucination

It is Contraindicated in patients taking meperidine and similar opioids.
(as both increase serotonin levels in blood).

31
Q

What are the 4 modes of action for Amantidine?

A

Modes of action:
1. facilitation of presynaptic dopamine release
2. inhibition of dopamine reuptake
3. anticholinergic
4. effect and NMDA antagonism

32
Q

What is the usual administration dose of Amantidine?

A

100-400mg/day

(lower max dose in elderly)

33
Q

Side effects of Amantidine?

A

nervousness, anxiety, agitation, insomnia, difficulty in concentrating, exacerbations of pre-existing seizure disorders & psychiatric symptoms

Worsening of parkinsonism upon withdrawal

34
Q

What do Anticholinergic drugs do and give 2 examples

A

Effective in reducing tremor but not bradykinesia

Example: Trihexyphenidyl and Orphenadrine

35
Q

Side effects of Anticholinergic drugs?

A

constipation, urinary retention, cognitive impairment and confusion

Low doses of tricyclic antidepressants e.g. amitriptyline are useful
in reducing nocturnal akinesia and improving sleep

36
Q

State the following for levdopa, dop agonists, MAO-B inhibitors, COMT and amantadine:

  1. Motor symptoms
  2. Activities of daily living
  3. Motor complications
  4. Off time (for Dopamine agonists, MAO-B inhibitors, COMT & Amantadine ONLY)
  5. Side effects
  6. Risk of hallucinations
A

Using slide 15 & 16 explain using the whiteboard.

37
Q

4 Surgical treatments for PD?

A
  1. Lesioning
    Destruction of targeted areas of the brain to control the symptoms of Parkinson disease.

In this process, a specific deep brain target is destroyed by thermocoagulation. A radiofrequency generator is used most commonly to heat the lesioning electrode tip to the prescribed temperature in a controlled fashion

This has been replaced by deep brain stimulation (DBS).

  1. Deep brain stimulation (DBS)
    A pulse generator (like pacemaker) is placed under the skin around the chest or stomach area. It is connected to 1/2 fine wires that are inserted into specific areas of your brain.

When the pulse generator is switched on, the electrodes deliver high frequency stimulation to the targeted area. This stimulation changes some of the electrical signals in the brain that cause the symptoms of Parkinson’s.

  1. Stem cell therapy
    Replaces lost neurons and restore normal movement
  2. Foetal cell transplant
38
Q

How many researches into PD do you need to know? what are they?

A

6

  1. Parkinson’s Progression Markers Initiative (2020-2033)
  2. Caffeine metabolism as a diagnosis for parkinson’s
  3. Alpha synuclein & parkinson’s
  4. Tapeworm drug (niclosamide) as parkinson’s treatment
  5. Clinical trial of GDNF
  6. Parkinson’s disease ‘may’ start in gut
39
Q

What is the Parkinsons Progression Markers Initiative

A
  1. The Parkinsons Progression Markers initiative.
  2. Observational research study to identify Biomarkers of PD progression. Study done in the US & Europe in July 2020. Will be completed in 2033.

Aim: Assess progression of clinical features, digital outcomes, imaging, biologic and genetic markers of PD progression in participants with manifest PD, prodromal PD and healthy controls.

Overall goal: Identify markers of disease progression for use in clinical trials pf therapies to reduce progression of PD disability.

40
Q

Explain caffeine metabolism as a means of diagnosing Parkinsons

A

Research done in Japan

Found: People with parkinson’s may have lower levels of caffeine in their blood after drinking tea and coffee

Results suggest that caffeine may be processed differently by those with PD. This could lead to simple diagnostic blood tests.

International researchers (Parkinson’s UK) discovered that a particular type of alpha-synuclein may be to blame for damaging cells in the condition.

41
Q

ALPHA SYNUCLEIN AND PARKINSON’S

A

Alpha-synuclein = a protein that was first linked to Parkinson’s 20 years ago.

It is one of the main proteins found inside the Lewy bodies (which are sticky bundles of proteins that appear inside the brain cells of everyone with PD). But how this protein (or at least the clumps it produces) causes damage to the cells has remained a mystery.

International researchers used specialist equipment to study the shape of the various alpha-synuclein clumps and found that a layered form. This layer is called an oligomer. This oligomer was toxic to cells.

This form of alpha-synuclein was able to insert itself into and puncture the cell membrane.

The team found that when the membrane was punctured by layered alpha-synuclein, it had dire consequences causing the contents of the cells to leak out, eventually leading to cell death.

42
Q

Tapeworm drug (niclosamide) as parkinson’s treatment

A

Cardiff & Dundee university researchers discovered niclosamide increases the activity of a key protein, called PINK1, inside brain cells.

PINK1 is found inside cells which plays an important role in recycling damaged mitochondria.

Research has shown that damaged mitochondria build up inside affected brain cells in Parkinson’s, and that mutations in the PINK1 gene cause a rare inherited form of the condition.

This suggests increasing PINK1 activity could protect cells from damage.

43
Q

Clinical trial of glial cell line-derived neurotrophic factor (GDNF)

A

GDNF is a special protein that is naturally produced inside the brain and supports the survival of many types of brain cells – including the cells lost in Parkinson’s.

Research suggests that GDNF has the ability to encourage these cells to grow again and may be able to stop the progression of Parkinson’s.

An experimental new treatment involving GDNF has been tested in a clinical trial funded by Parkinson’s UK.

44
Q

Parkinson’s disease “may” start in GUT

A

Research in USA suggest that Parkinson’s may actually start in the
depths of the digestive system. In their study, people whose appendix
had been removed were less likely to develop the neurodegenerative
disease.
* Analysis of the contents of people’s appendixes showed they contained
the same toxic protein - called alpha synuclein - that is found in the
brains of Parkinson’s patients. Researchers argue the guts are a
breeding ground for the protein, which then travels up the vagus nerve
and into the brain. Cutting the vagus nerve is also linked to a lower level
of Parkinson’s and animal studies have suggested bacteria that live in
the gut are key.

CNS- Mechanisms, Disorders & Therapeutics.) (15 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions