Parkinson’s disease Flashcards
What are the symptoms and diagnosis of PD
Bradykinesia
AND
Either rest tremor and or rigidity
(When passively moved)
Clinically established PD
1 absence of absolute exclusion criteria
2 at least 2 supportive criteria
3 no red flags
Clinically probable PD
1 absence of absolute exclusion criteria
2 presence of red flags counterbalanced by supportive criteria
(1 red, need 1 supportive)
(2 red, need 2 supportive)
No more than 2 red flags allowed
Clinical presentation
- bradykinesia/ akinesia
- rigidity
- tremor
- postural abnormality
What are the supportive criteria for PD diagnosis
- Clear and dramatic beneficial response to dopaminergic therapy
- Presence of levodopa dyskinesia
- Rest tremor
- Olfactory loss or cardiac denervation on MBIG scintigraphy
Name some of the absolute exclusion criteria for a PD diagnosis
- vertical supranuclear gaze palsy (loss of up and down eye movement)
- Behavioural variant of FTD or primary progressive aphasia
- Absent response to high dose L-dopa
- Lower body only Parkinsonism for 3 years
- Cortical sensory loss
What are the red flags for a PD diagnosis
- Wheelchair use within 5 years
- Inspiratory dysfunction
- Severe autonomic failure in first 5 years
- Recurrent falls within 3 years
- Absence of non motor features of PD
What are the pathological findings in PD
A-syn
Lewy bodies
Dopaminergic loss in SN
- leads to striatal dopamine deficit
What are the non-motor prodrome (early signs) of PD
- olfactory loss
- constipation
- depression
- REM sleep behaviour disorder
What are braaks stages and how may they present
Braak
Stage 1 and 2
Autonomic and olfactory disturbances
Stage 3 and 4
Sleep and motor disturbances
Stage 5 and 6
Emotional and cognitive disturbances
Often at stages 5/6 do individuals seek medical attention
Discuss the aetiology of PD
Genetics
- alpha synuclein LRRK2
- Parkin, Pink1, DJ1, FBx7
- GBA, causes PD in adults
-Additional loci (SNCA, tau, COMT)
Environment
- mitochondrial toxins
- smoking, caffeine, head injury
- rural living, pesticides, well water
What is bradykinesia / akinesia
Core feature of Parkinsonism
Encompasses
- slowness of movement
- poverty of movement
- progressive fatiguing and decrement of repetitive movement
- difficulty initiating movement
How does postural instability present in pd
Often seen in later stages of Parkinson’s disease
Early postural instability suggests an atypical Parkinsonian condition
How gait is affected in PD
Festinating (hurrying)
Patients may have:
- Difficulty initiating gait
- Poor arm swing
- Small shuffling steps
- Difficulty turning (lots of small steps, not pivoting)
- Freezing
What investigations should be done for PD patients
Bloods
- thyroid, B12, MMA, genetics (adult onset)
MRI scan
- structural mimics, features of atypical
DaTScan
- exclude dystonic / essential tremor, drug induced parks
What are the treatment options for PD
MAO-B inhibitors
(Selegiline, rasagiline)
Dopamine agonists
(Ropinirole, pramipexole)
Levo-dopa
(Madopar, sinemet, stalevo)
What are the differences between treatment options
MAO-B inhibitors
(Selegiline, rasagiline)
- lowest efficacy
- well tolerated
Dopamine agonists
(Ropinirole, pramipexole)
- less potent
- side effects (nausea, paranoia, swollen legs, psychiatric problems)
Levo-dopa
(Madopar, sinemet, stalevo)
- most effective
- side effects (short term = nausea / Long term = dyskinesia)
What is levodopa and what does it do
Levodopa is a drug treatment for PD
Short & long duration responses to L-dopa
- worse condition = drug works for a shorter duration of time
- patients fluctuate between on and off symptoms
Typically given with a peripheral dopa-decarboxylase inhibitor, stopping the breakdown of levodopa in the periphery, helping prevent side effects of nausea
Motor fluctuations due to long term levodopa use
-as fuses progresses, there are more frequent fluctuations
Types of disease progression- accessory drugs ?
COMT inhibitor
(Role to increase action of levodopa)
Side effects:
- increased dyskinesia, diarrhea, orange urine
Amantadine
(Role to reduce dyskinesia, help freezing)
Side effects:
-hallucinations, swollen legs, insomnia
Anticholinergics
(Role, tremor, dystonia)
Side effects:
- memory, concentration, dry mouth
What types of treatments are available for non-motor symptoms
Depression/ anxiety
- SNRIs
Insomnia
- nocturnal sedatives
Ed
-sildenafil
Pain
-analgesics
Hallucinations/ dementia
- cholinesterase inhibitors
What are non-drug treatment options for PD?
SALT assessment
- speech and swallowing
- LSVT (voice training)
- diet manipulation - dietician advice/ PEG
Physiotherapy
- prevention of falls
- prevention of contractures from dystonia
Occupational therapy
- home adjustments, ergotherapy
- weights, splints
What are the advanced treatments for PD
Apomorphine
1.pump 2.injections 3. Infusion
1.lasts daytime, trickles through body
- Short action 45 mins, sudden severe off
(30mg pens, vary between 1 & 10 mg)
Advantage of often is less skin irritation)
Negatives = bruising, nodules)
DBS
- STN target
Duodopa intestinal gel
Larger pump but useful for dyskinesia
- needs maintenance
- interferes with B12, which can increase risk of peripheral neuropathy
What are gene therapy approaches to PD
Restoring dopaminergic signalling
Compensating for loss of dopamine
Rescuing the neurodiverse apaches
(Broad and precision approaches)
what is GBA gene therapy
GBA therapy is a precision genetic therapy approach to replace the missing gene
(AAV9-GBA)
Done via cisterna injection
What are the cellular and molecular processes of PD
- protein misfolding/ aggregation
- lysosomal clearing/ dysfunction
- mitochondrial dysfunction
Also
- synaptic dysfunction
- oxidative stress, role of dopamine ?
- immunity/ inflammation
Genetic involvement in PD
Rare Mendelian PD
- Usually dominant ( LRRK2 most common)
- Recessive (Parkin, Pink1)
Overall heritability (~30%)
- part explained by SNPs detected by GWAS
A-synuclein (SNCA)
- ~ 5 missense mutations
- >99% PD patients do not have SNCA mutation
What is alpha-synuclein and its presence in PD
It is a presynaptic protein
Regulates vesicle fusion/ recycling?
It is natively unfolded
What are the aims for the progression of PD
The aims are to slow, stop or reverse the neurodegeneration of PD
Risk factors
- age
- diet
-diabetes
- toxins
Alpha-synuclein aggregation
Lysosomal dysfunction
Mitochondrial dysfunction
Neuroinflammation
^ cell/ survival
Cell to cell propagation
What is LRRK2 gene therapy
LRRK2 (gain of function gene) is a precision genetic therapy approach)
LRRK2 ASO (antisense oligonucleotide) designed to bind to LRRK2 mRNA and mediate its degradation, reducing LRRK2 protein levels and potentially slowing the disease progression
- lumbar puncture
