Parkinson's Disease Flashcards
Symptoms of PD?
Bradykinesia Resting tremor Rigidity (cogwheel/lead pipe) Sleep disturbances (flailing out) Excessive salivation Shuffling gait Falls Freezing of gate Masked faces Impaired swallowing Anosmia Micrographics
Risk factors?
Family history
Smoking
pesticide exposure
Age (17.4 per 100,000 person years between 50 and 59 increases to 93 per 100,000 person years between 70-79)
What compensatory changes mean PD only manifests when a significant proportion of neurons have been lost in the nigrostiatal pathway?
Increase in TH activity
Increase in postsynaptic dopamine receptors in the striatum
What other dopaminergic pathway may degenerate in PD?
Those from the VTA (mesolimbic may degenerate up to 50%)
What other neurons may degenerate other than dopaminergic ones?
Noradrenergic (locus coeruleus)
Cholinergic (basal forebrain)
These may be responsible for the non motor symptoms of PD
What are the cognitive dysfunctions in PD?
Mood disturbances
Cognitive defects
Dementia
What mood disturbances are seen in PD?
Depression (increases risk of developing dementia)
May be organic or reactionary
Could be due to morphological changes in NA and 5-HT pathways in locus coeruleus and dorsal rap he nucleus
What are the cognitive defects seen in PD?
Degeneration of the mesolimbic pathway
Disturbed processes under frontal lobe control
What factors in PD increase th risk of developing dementia in PD?
Depression
Prominent gait and speech disordered
Poor L-dopa response
What dementias may be associated with PD?
Lewy body dementia
Alzheimer’s (degeneration of the basal nucleus of meynert)
What is psychosis?
The inability to distinguish between the subjective experience and external reality
How many PD patients develop psychoso due to l-dopa treatment?
20-30%
Those with preexisting cognitive defects are at increased risk
How do you treat PD psychosis without making the PD worse?
Reassess patients medication
Pimavanserin (selective serotonin inverse agonist)
Quitiapine
What are Lewy bodies?
The hallmark of PD
Insoluble aggregates of alpha Synuclein
Which stain heavily for eosin
Wha factor determines LB morphology
The neuroanatomical location
Where else can LB be found?
DwLB
multiple system atrophy
Incidental LB pathology (patient who do not have PD…will they have gone on to develop PD?)
What did Braak et al suggest?
LB disseminates throughout the brain affecting specific neuroanatomical areas in various stages. Not all PD cases show this progression though
What is hypothesised to be the toxic species of PD?
Alpha Synuclein oligomers
What might LB do?
May have a neuroprotective role acting as an aggresome for misfolded proteins which causes neurodegenration
What are the aetiologcal theories of PD?
Familial (hereditary) Viral Pesticides and chemicals MPTP (MPP+) Industrial exposure
What genes are associated with monogentic variants of PD
SNCA LRRK DJ-1 PARKIN PINK1
How may SNPs are associated with PD
~28 (over 20)
Found via genome wide association studies
What viral aetiology is associated with a parkinsonian like syndrome?
Encephalitis lethargia
Why is MPTP useful?
Provides a animal model for PD as is selective for mono amino neurons, particularly those in the SN
What industrial chemicals cause degeneration of striatum and its outputs producing a PD like syndrome?
Manganese
Carbon disulphide
Ultimately, do we know what causes Parkinson’s disease?
No.
However RNAi studies have indicated that several genes involve din protein trafficking are genetic modifiers for this disease e.g. The RabGTPases
How can we treat PD with medications?
Dopamine therapy (give L-DOPA as dopamine cannot cross BBB) + carbidopa Dopamine agonists MAO-B inhibitors COMT inhibitor Anticholingerics Amantidine
What are the problems with L-Dopa?
ADRS (psychosis, dyskinesia, N+V, hypotension)
Effect decrease overtime
Deietary considerations
?neurotoxic
What are the different types of dopamine agonists? Give an example
Ergot derived - Bromocryptine
Non ergot - ropinirole
Subcutaneous - apomorphine
What are the disadvantages of dopamine agonists?
Increased risk of psychosis
Less efficacious than L-Dopa
Impulse control disordered i.e. Pathological gambling
name a MAO-B inhibitor
Selegiline
How do MAO-B inhibitors work?
Bloc dopamine break down in DOPAC
Can be used alone or in combination with LDopa to prolong its effects
name come COMT inhibitors
Tolcapone Entacapone (does not cross BBB)
How does entacapone work?
Breaks peripheral break down of Ldopa to a compound which competes with it for entry into the CNS
Thus needs to be even with L-Dopa
Prolongs L dopa effects and helps eliminate wearing off
What is procyclidine useful for?
Anticholingeric good for treating tremor
What does Amantadine do?
Increases dopamine release
?inhibits uptake
Unclear mechanism
where can graft to treat PD come from?
Stem cells and the adrenal medulla
What do grads from the adrenal medulla show?
Variable results and graft do not survive well
What do graft from foetal stem cells show?
Short lived improvements
May accumulate alpha Synuclein themselves over time
What surgical interventions are there for PD?
Lesions (thalamus, STN, globus pallidus)
Deep brain stimulation (electrodes often placed in subthalamic nucleus to cause depolarisation block of Gpi)
