Parkinson's disease Flashcards
What is Parkinson’s disease?
What is the cause?
Progressive neurodegenerative disease, disorder of the central nervous system that mainly affects the motor system
Unknown cause but is associated with:
- Ageing
- Genetic predisposition
- Exposure tot toxins/viruses
- Head injuries
- Impaired oxidative mechanisms
Epidemiology of PD?
- Occurs everywhere
- 95% age >50
- Men 1.5x more than women
- Hispanic and White > Asian and Black
What are the pathological hallmarks of PD?
- Formation of proteinaceous and intraneuronal inclusions (lewy bodies, and lewy neurites - made by alpha synuclein)
- Progressive neuronal loss particularly targeting the substantia nigra pars compacta (dopaminergic systems)
- There is neuro-melanin that form the dark parts in the substantia nigra. In PD, neuro-melanin is lost as there is lost of dopaminergic cells in the substantia nigra. Lost neurons is replaced by gliosis
What is a lewy body?
Lewy body is an intracellular inclusion made by alpha synuclein.
A protein that is normally present in the brain, although function is not well known but it’s involved in the plasticity of synapses.
However, in PD, this protein starts to have abnormal behaviour and precipitates in cells forming Lewy body, causing neuronal damage.
Describe the nigrostriatal pathway
The dopaminergic pathway that is affected in PD is the Nigrostriatal pathway.
It’s a dopaminergic pathway that connects the substantia nigra pars compacta (SNc) - where majority of the cellular bodies are, with the dorsal striatum (i.e., the caudate nucleus and putamen).
It is one of the four major dopamine pathways in the brain, and is particularly involved in the production of movement, as part of a system called the basal ganglia motor loop.
Dopaminergic neurons of this pathway synapse onto GABAergic neurons.
How does pathology of SN spread?
There is a dorsal and ventral tier in the SN. In early PD, the Ventral tier is affected - this is the one that projects to the posterior part of the putamen. But as the disease spreads, the other areas of SN are affected
How do we stage PD?
Which part of the brain is affected?
PD progresses in 6 neuropathological stages: marked by continual development of inclusion bodies e.g. Lewy neurites in cellular processes as granular aggregations and Lewy bodies in somata of nerve cells.
1 - lower brain stem, olfactory, lewy neurites and alpha synuclein aggregates (not many lewy bodies at this point)
2 - move from medulla oblongata to pontine, “ “
3 - Progression to forebrain, Lewy bodies enter SN
4 - Mesocrtex and allocortex involved (amygdala, thalamus), dopamine cell destruction in SN
5 - Neocortex (temporal, parietal and frontal lobe) involvement, Cell death in SN
6 - Fully invaded neocortex affecting motor and sensory areas
only in stage 3/4 is the mid brain affected, therefore, by the time you diagnose someone with PD, the disease has already been there for a while. Early stages responsible for non-motor systems
What are the symptoms of PD?
Motor and non motor
Motor:
- Resting tremor
- Rigidity - increased muscle tone
- Bradykinesis
- Postural instability
- Shuffling gait
Non-motor:
Sleep disorders - prodromal stage - intense fatigue especially at end of the day
Depression
Dementia
Fatigue
Hyposmia - reduced ability to smell and to detect odours
Pathological gambling - due to drug induced
What are the components of the basil ganglia?
Striatum:
- dorsal striatum (caudate nucleus and putamen)
- ventral striatum (nucleus accumbens and olfactory tubercle)
globus pallidus
ventral pallidum
substantia nigra
Sub thalamic nucleus (STN) - one of the targets of deep brain stimulation
How do we clinically evaluate PD patients?
Hoehn and Yhr stage
1: Unilateral involvement only
1. 5: unilateral and axial involvement
2: Bilateral involvement without impairment of balance
2. 5: Mild bilateral disease with recovery on pull test
3: Mild to moderate bilateral disease, some postural instability, physically independent
4: Severe disability, still able to walk or stand unassisted
5: Wheelchair bound or bedridden unless aided
What is the pull test?
Ask patient to stand still and we pull them back and see if they are able to hold themselves upright.
What imaging can we use for PD?
What are the indications?
DAT scan is the only approved scan in the market to detect the substantia nigra. SPECT - uses radio labeled ligand taken up by dopamin transporter that sits in SN synapse. can be used to see SN degeneration in PD.
- Detection of loss of functional dopaminergic neuron terminals in the striatum of patients with clinically uncertain parkinsonian syndromes
- Differentiation of essential tremor, psychogenic parkinsonism, or neuroleptic induced parkinsonism from presynaptic parkinsonian syndromes (Parkinson’s disease, multiple‐system atrophy, cortico-basal degeneration, progressive supranuclear palsy)
- Early detection of Parkinson’s disease
- Assessment of disease severity and progression
- Differentiation of dementia with Lewy bodies from other dementias
Does dementia affect PD?
Can be multifactorial in PD. It has been shown that dementia in PD is related to cholinergic dysfunction - acterlcholine esterase activity.
People with PD already have cholinergic dysfunction, therefore f you block cholinergic acitivty with an anti-cholinergic drug, might make it worse.
List the 6 main types of PD drugs
Dopamine replacement therapy:
- Levodopa
- Dopamine agonist
Reduction of levodopa/dopamine breakdown:
- Catechol-O-methyltransferase inhibition
- Monoamine oxidase isoenzyme type B inhibition
Others
- Anticholinergics
- Amantidine
Levodopa:
- MoA
- Administration
- Complications
Mechanism of Action (MoA): precursor of dopamine as dopamine isn’t taken up by BBB. Exerts its symptomatic benefits through conversion to dopamine
i. Standard release - release immediately once absorbed in intestine
ii. Slow release - never reaches maximal peak dose but more continuous
iii. Intestinal gel connected to duodenum with enteral tube (Duodopa, Slowing and digestion can be slowed in PD, esp. when disease is more advance and therefore medication takes longer to have effect. This can be given)
Have to be administered with something else as it is destroyed in the periphery, e.g. given with Carbidopa or Benserazide
Complications: motor complications
i. Motor fluctuations: (disease are not stable all day long):
- Wearing off, end-of-dose effect. The motor improvement after a dose of levodopa becomes reduced in duration
- On-off fluctuations. Rapid and unpredictable fluctuations between ON and OFF periods
ii. Levodopa-induced dyskinesia (not tremor, its twisting, twitching and rocking movements):
- Involuntary movements in response to levodopa and/or dopamine agonist intake. Most dyskinesias emerge at peak dose levels and are typically choreiform, but may involve dystonia or myoclonus
