2. Parkinson's Disease Flashcards
who first described PD
James parkinson
- described it as a shaking palsy
what is the mean age of onset
65 years
what percentage of people are diagnosed before the age of 40
4%
how many people does PD affect worldwide
10 million
describe the clinical features of PD
rigidity
bradykinesia
tremor at rest
impaired gait
mask-like face
cramped handwriting
what are the pathological features of PD
degeneration of DA neurons in the substantial nigra or caudate-putamen
presence of Lewy bodies
what are Lewy bodies composed of
aggregated alpha-synucleiun protein
where are Lewy bodies found
in the cell body and axons of neurons in the basal ganglia
what dark substance from the substantia nigra is lost in PD
neuromelanin
what is the difference between PD and dementia with lewy bodies
in DLB - cognitive symptoms appear either at the same time or before the onset of motor problems
in PD- motor problems arise at least a year before cognitive symptom
what is the direct pathway of the motor circuit responsible for
increased movement
describe the processes occurring in the direct pathway:
- motor cortex releases excitatory glutamate into the caudate putamen
1b. substantia nigra releases dopamine to the caudate putamen, it stimulates the caudate pathway
- caudate putamen releases GABA to the substantial nigra and globus pallidus
- GABA binding to the globus pallidus and substantial nigra means less GABA is released to the thalamus
- this means glutamatergic neurons of the thalamus can fire and stimulate increased movement
what does dopamine bind to in the caudate putamen
d1 receptors
what additional structure is featured in the indirect pathway
the sub thalamic nucleus
describe the indirect pathway of motor movement.
- glutamate release from the motor cortex
- GABA is released from the caudate putamen to the globus pallidus. this creates an internal feedback within the globus pallidus whereby the pars internal and subthalamic nucleus are disinhibited
- glutamate release from the sub thalamic nucleus to the substantia nigra and the pars interna of the globus pallidus
- increases the GABA release from the globus pallidus and substantia nigra to the thalamus = decreased activation of the motor cortex
what happens when the substantia nigra releases dopamine in the indirect pathway
binds to D2 receptors to inhibit the caudate pathway
GABA neurons are inhibited - and less GABA is released onto the thalamus = increased movement
what happens to the direct and indirect pathways in PD
there is a loss of dopamine - this shifts the balance towards the indirect pathway, where stronger inhibition of the system reduces voluntary movement
name 3 non-modifiable risk factors for PD
age
sex
genetics
what is the sex ration for PD
male bias
male to female = 1.5:1
what percentage of cases does genetics account for
~10%
how many regions does alpha-synuclein protein have
3
what are the 3 regions of a-synuclein
- ampiphatic region
- the non-amyloid component
- acidic tail
which region is associated with familial PD
the ampiphatic region
which region confers aggregation properties
the non-amyloid component
what mutation is a relatively common cause of autosomal dominant PD in caucasians
G2019S
describe the G2019S mutation
elevates LRKK2 activity - a large protein kinase
what % of cases does the g2019S mutation account for
4% of familial PD cases
describe the evidence proving a role of LRKK2 in PD
anti-LRKK2 antibodies strongly label brainstem and cortical levy bodies
- could play a role in alpha-synuclein and levy body formation
what is Parkin part of
the ubiquitin E3 ligase complex
what does UCH-L1 encode
a de-ubiquitinating enzyme
what does a point mutation to UCH-L1 cause
late-onset PD
- as there is a build up of aggregating proteins
name 2 more mutations that cause early-onset PD
DJ-1 and PINK1
what is the role of DJ-1
a mitochondrial protein that acts as a sensor for oxidative stress
how many DJ-1 mutations have been identified in PD
19
what is the role of PINK1
a protein kinase that protects cells from stress-induced mitochondrial dysfunction
how many PINk1 mutations found in PD
70
what do PINk1 and DJ-1 mutations elude to?
the role of mitochondrial dysfunction and oxidative damage in the pathogenesis of PD
name 3 modifiable risk factors that increase the risk of PD
traumatic brain injury
heavy metals
pesticides
name 2 things that can decrease risk of PD and by what % compared to non-users
smoking - 60% lower compared to non-smokers
caffeine - 30% lower compared to non-caffeine drinkers
describe the case study in 1982 where heroin users developed irreversible parkinsons
7 young people (aged 20-40) injected synthetic heroin containing MPTP.
this molecule crossed the blood brain barrier where it was converted into MPP+
MPP+ gets transported into DA neurons where it can impair the electron transport chain and result in cell death
what molecule converts MPTP into MPP+
glial cells
what did the 1982 heroin fiasco suggest
could PD be caused by an environmental trigger similar to MPTP
describe how a 1/3 of the Chamorro tribe came to be affected by PD
they indirectly ingested BMAA from flying foxes who had consumed the dangerous chemical from cycad palm nuts
BMAA is a glutamate agonist - causes excitotoxicity and neurodegeneration
= deficits
during 1915-1926, an outbreak of which disease triggers Parkinsonism in 50% of its survivors
encephalitis lethargica
what is L-dopa
a precursor to dopamine
why can’t you just inject dopamine into the brain
it cannot pass the BBB unlike L-dopa
how long does L-dopa effects last for? why?
last for approx 5 years
this is because neurons are continuing to die, so the relief will only last so long
what is the effect of administrating carbidopa
its is a dopa decarboxylase inhibitor - so it prevents premature conversion into dopamine
what can also be given to inhibit dopamine degradation
COMT and MAO-B inhibitors
name a non-pharmaceutical option of managing PD
deep brain stimulation
describe how deep brain stimulation works in PD
electrode is imparted into the pars interna of the globus pallidus, this attempted to increase input to the subthalamic nucleus
(the idea is that it bypasses the substantial nigra
name 3 drugs in the pipeline for PD
antioxidants
immunotherapy
inhibiting alpha-synuclein aggregation
