parkinson's Flashcards
symptomatic hallmarks of movement disorders
- tremor
- athetosis
- chorea
- dystonia
- tics
athetosis
slow movements, twisting and writing
chorea
brief, jerky, rapid, unpredictable movements
dystonia
sustained muscle contraction
repetitive movements
tics
sudden repetitive, non-rhythmic motor movement
synucleinopathy
- mutation of alpha-synuclein > duplication/triplication of normal alpha-synuclein gene
- mutation of leucine-rich repeat kinase-2-gene (LRRK2) > autosomal dominant familial parkinsonism
- mutation in parkin gene > early onset; autosomal recessive familial parkinsonism
risk factors
high risk;
- pesticides (rotenone)
- environmental or endogenous toxins
- vitamin D deficiency
- people working in teaching, health care, farming, exposed to lead or manganesse
low risk;
- cigarette smokers
- coffee
- anti-inflammatory disease
- high serum uric acid levels.
progression of PD
Braak stages
- olfactory nucleus, lower brianstem
- higher brainstem
- substantia nigra
- mesocortex and thalamus
- entire neocortex
symptom classification
- symptoms only on 1 side
- symptoms on both sides, NO balance problems
- symptoms on both sides, balance problems, patients can still function independently
- symptoms on both sides, balance problems, patients need daily help
- severly disabled state; nursing care
hallmarks of PD
- cell death in dopaminergic neurons; less dopamine available
- lewy bodies with a-synuclein aggregation in the cell body of neurons
extracellular a-synuclein
interacts with microglia and astrocytes, release of cytokines, which affects other neurons.
dopamine pathways
- nigrostriatal pathway
- mesolimbic pathway
- mesocortical pathway
- tuberohypophyseal pathway
dopamine synthesis and metabolism
tyrosine > dopa > dopamine
metabolized by MAO and COMT
dopamine receptors
D1 - D1, D5
Gs activation > increase cAMP and PK
stimulation of AMPA-, NMDA-receptor and L-Ca2+-channels.
D2 - D2, D3, D4
Gi activation > decrease cAMP, increase K+ channel conductivity
pre and postsynaptic inhibition
functional aspects
- motor control > nigrostraital system
antipsychotic drugs are D2 antagonist, blocking D2 in mesolimbic pathway - behavioral aspects > mesolimbic and mesocortical system
amphetamine releases both dopamine and noradrenaline - endocrine control > tuberohypophyseal system
dopamine inhibits prolactin secretion and promote growth hormone production - vomiting, nausea
dopamine agonists induce nausea
D2 receptors associated with initiation of nausea
direct basal ganglia pathway
cause movement, thalamus is activated
substantia nigra is inhibited, less GABA to the thalamus, thereby LESS inhibition, causing movement
indirect basal ganglia pathway
no movement, thalamus is inhibited
by activation of globus, more GABA to thalamus, inhibited > no movement
therapy
- restore dopamine activity;
levodopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors. - restoring balance between cholinergic and dopaminergic system
- blocking acetylcholine
levodopa
can cross the BBB, metabolised in the brain by D1-3 receptors to dopamine.
» source of dopamine, restoring dopamine activity
in combination with carbidopa 10% in brain
dopamine receptor agonists
increase the uptake of dopamine
do not compete for active transport into the blood and across the BBB
first in line therapy
bromocriptine; D2 agonist
pergolide; D1 and D2 agonist
pramipexole; D3 agonist
ropinirole; D2 agonist
rotigotine;
MAO inhibitors
blocks the metabolism of dopamine, increasing dopamine levels
selegiline
rasagiline; early treatment
COMT inhibitors
inhibition of DOPA decarboxylase leads to upregulation of other pathways;
COMT turns dopamine into 3-OMD, 3-OMD competes with L-DOPA for transport proteins to cross BBB.
tolcapone
entacapone
» prolong actions of levodopa
stalevo; combination of tolcapone, entacapone and levodopa
other procedures
surgery
neuroprotection
gene therapy
drug-induced PD
