Parkinson's Flashcards
What is Parkinson’s
Loss of dopaminergic neurons of the Substantia Nigra pars compacta
Breakdown of nigrostriatal pathway
What are the primary motor symptoms of Parkinson’s Disease, and how do they differ from non-motor symptoms?
The primary motor symptoms of Parkinson’s Disease include:
1. Bradykinesia: Slowness of movement, which is a cardinal feature and can impact daily activities. 2. Resting Tremor: Typically starts in one hand or limb and may appear as a "pill-rolling" tremor. 3. Rigidity: Stiffness in muscles that can affect movement and cause discomfort. 4. Postural Instability: Impaired balance and coordination, leading to falls in later stages.
In contrast, non-motor symptoms include:
* Cognitive Impairment: Memory issues, difficulty concentrating, or dementia in advanced stages. * Mood Disorders: Depression, anxiety, and apathy. * Autonomic Dysfunctions: Constipation, orthostatic hypotension, and urinary issues. * Sleep Disorders: REM sleep behaviour disorder, insomnia, and excessive daytime sleepiness. * Sensory Symptoms: Loss of sense of smell (anosmia) or pain.
Explain the Lewy body pathology in terms of Parkinson’s
Presence of abnormal aggregates of the protein alpha-synuclein in the cytoplasm of neurons
Aggregates are known as Lewy bodies
Present in sporadic and genetic PD
Mainly consisting of alpha-synuclein
○ 140 aa protein highly enriched in presynaptic terminals
○ Point mutations in SNCA cause familial PD
Typical spreading pattern
In the Substantia Nigra, Lewy bodies contribute to the loss of dopaminergic neurons, leading to the motor symptoms of Parkinson’s disease
What is the significance of alpha-synuclein in Parkinson’s disease pathology, and how do mutations in SNCA contribute to the disease?
Lewy bodies primarily consist of misfolded alpha-synuclein protein
Misfolding and aggregation of alpha-synuclein disrupt normal cellular functions
First pathogenic mutations in familial PD, Autosomal dominant mutations
○ 3 mutations now exist: A53T, A30P and E46K
SNCA locus duplications and triplications found on chr. 4:
○ Duplication at one locus: Results in a total of 3 copies 1.5x elevation in protein expression
○ Triplication at one locus: Results in a total of 4 copies 2x elevation in protein expression
How does neuron loss in Parkinson’s disease differ from normal aging?
Controls: linear loss of pigmented neurons in SNpc. Average of 4.7% per decade
In PD: exponential loss of pigmented neurons 45% loss in first decade
What changes occur in brain circuitry, such as the thalamus and motor cortex, in Parkinson’s disease?
Loss of substantia nigra neurons lead to a reduction of dopamine in the striatum
Causes over inhibition of the thalamus
Ultimately leads to fewer excitatory signals being sent to the motor cortex
What is the mechanism of dopamine synthesis and storage
Tyrosine diffuses down the pre-synaptic membrane
Tyrosine hydroxylase (rate-limiting step in dopamine synthesis) converts it into L-DOPA (L-3,4-dihydroxyphenylalanine).
○ Requires tetrahydrobiopterin (BH4) as a cofactor.
L-DOPA is converted to dopamine (DA) by aromatic amino acid decarboxylase (AADC)
DA is contained in a vesicle by vesicular monoaminergic transporter 2 (VMAT2)
VMAT2 actively transports dopamine from the cytoplasm into vesicles using a proton gradient generated by a vesicular ATPase.
What is the purpose of storage of Dopamine
Dopamine in the cytoplasm is prone to degradation by monoamine oxidase (MAO) and can form reactive oxygen species (ROS).
Stored dopamine is available for rapid release into the synaptic cleft in response to an action potential.
What is the mechanism of dopamine reuptake and catabolism
DA passes out into the synapse by a dopamine transporter
It can act on dopamine receptors on the post-synaptic membrane
It is reup taken by the astrocyte where it is catabolised by monoamine oxidase (MAO) and catechol-o-methyltransferase (COMT)
Why are dopaminergic neurons susceptible to PD (3)
High metabolic demand
○ In a human the nigrostriatal dopamine neuron is 4m long and has 2 million synapses
○ Small changes in critical cellular pathways have a big effect
Dopamine is a highly cytotoxic chemical
○ Oxidation: forms reactive oxygen species in the cytoplasm
○ Taken up by dopamine transporter (DAT) and sequestered in vesicles by VMAT2 for storage until release
Vulnerability of dopaminergic neurons in PD is region-specific
○ Lose substantia nigra pars compacta neurons:
§ High DAT, low VMAT2 levels
○ Preserve ventral tegmental area (VTA) neurons:
§ Low DAT, high VMAT2 levels
How does dopamine synthesis change in Parkinson’s disease
Dopamine synthesis decreases due to the loss of dopaminergic neurons in the Substantia Nigra.
How does dopamine storage change in Parkinson’s disease
Dopamine storage is reduced as fewer vesicles are available to store dopamine in the remaining neurons.
How does dopamine metabolism change in Parkinson’s disease
Compensatory upregulation of dopamine metabolism occurs, leading to increased breakdown by enzymes like monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT), further depleting dopamine levels.
What is the MoA for Levodopa
dopamine precursor that crosses the blood-brain barrier and is converted into dopamine by the enzyme aromatic amino acid decarboxylase (AADC)
Replenishing depleted dopamine levels in the brain to alleviate motor symptoms of Parkinson’s disease
Why does levodopa therapy become less effective over time
fewer dopamine nerve terminals
What are the common side effects of Levodopa?
L-DOPA induced dyskinesia can develop involuntary movements
○ Affects half of people using L-DOPA
○ Likely due to changes in glutamatergic neurotransmission which becomes overactive
Can cause nausea and hypertension at high doses
What is the MoA of Carbidopa and other levodopa associated therapies
Carbidopa: Inhibits dopamine catabolism by inhibiting dopamine decarboxylase
Rasagiline, selegiline, safinamide: MAO-B inhibitors
Entacapone, tolcapone: COMT inhibitor
What is the purpose of levodopa associated therapies?
Prolong the action of L-DOPA, prevents “wearing off”
Best used in the early stages of disease
Only helpful as long as L-DOPA therapy is useful
What are the common dopamine receptor agonists and what is their MoA?
Can be given alone or in combination with L-DOPA
- Apomorphine - Bromocriptine - Pramipexole - Ropinirole - Rotigotine
Mimic the way dopamine works by binding and activating dopamine receptors
Work on D2-like receptors
What are the side effects of dopamine receptor agonists
Similar side effects to L-DOPA
Impulsive and compulsive behaviours such as gambling, binge eating etc
What is the mechanism of action of amantadine and what is it used to treat
Glutamate antagonist with mild effect in PD
Used to treat L-DOPA induced dyskinesia
Low affinity, noncompetitive antagonist of the NMDA receptor
Can reduce motor fluctuations
Evidence that it can increase dopamine biosynthesis
What is the purpose of anticholinergics in the treatment of PD (MoA, results, side effects)
Competitively inhibit the binding of Ach
Reduce tremor and can ease dystonia which is associated with “wearing off”
Benztropine - also reported as a dopamine uptake inhibitor
Not commonly used in PD due to side effects of confusion and hallucinations
What is the purpose of adenosine A2A antagonists in the treatment of PD (MoA, results, side effects)
Adenosine A2A receptors are located next to dopamine receptors in the striatum
Blocking these receptors seems to limit “off time”
Given in combination with L-DOPA
Istradefylline
What is deep brain stimulation?
Neurosurgical technique
Electrodes are implanted into specific brain regions and connected to a pulse generator
○ Requires highly specific placement of electrodes
DBS can measure pathological brain activity and deliver adjustable stimulation for therapeutic effect
