case 7/ Parkinson's disease Flashcards
(35 cards)
What constitutes the striatum?
putamen and caudate nucleus
What constitutes the lentiform nucleus?
putamen and globus pallidus
What are the different neurone in the striatum?
- medium spiny neurones: 96% striatal neurones, projects to other regions of the basal ganglia, are all GABAergic
- interneurones: GABAergic and cholinergic: modulate activity of there neurones
What are the different pathways that input into the striatum?
-corticostriatal pathway:
glutamergic (excitatory)
input from cerebral cortex
-nigrostriatal pathway:
dopaminergic (modulates medium spiny neurones)
from substantial nigra pars compacta
How is input to the medium spiny neurones modulated?
- glutamate activates spine causing excitation of neurones (driving neuronal activity)
- dopamine receptors modulates amount of signal (level and eventual output)
What is the direct dopaminergic pathway in the basal ganglia?
facilitating of desired movements
- D1 receptors (G protein coupled receptor)
- activates GaS which increases adenylyl cyclase activity
- catelyses cAMP from ATP:
- phosphorilation/activation of intracellular substrates
- -> turn up motor learning/synaptic plasticity
What is the indirect dopaminergic pathway in the basal ganglia?
inhibition of unwanted movements
- D2 receptors (G protein coupled receptors)
- activation of Gi/o which inhibits adenylyl cyclase activity:
- no catalysis of cAMP from ATP:
- decrease phosphorylation/activation of intracellular substrates
- -> turns down motor learning/synaptic plasticity
What are the neuropeptides transmitters of the direct and indirect pathways?
- direct pathway: dynorphin
- indirect pathway: enkephalin (opioid molecule)
what happens when there is no activity (background)
activation of indirect pathway:
-tonic dopamine release –> low synaptic and extra synaptic levels –> preferential D2R activation (high-affinity receptors) –> action inhibition “no-go” long term depression (lowering of synaptic strength)
What happens when doing a learned action?
activation of direct pathway:
-phasic dopamine release -> preferential D1R activation –> motor initiation, long term potentiation
What are the different functions of the basal ganglia and where are the loops placed?
limbic (behavioural, reward)
associative (executive: learning, memory, attention, motivation, emotion and volition: strong input from DLPFC)
sensory
motor
–> ventromedial to dorsolateral gradient (from limbic to motor)
What is chorea?
rapid, multifocal irregular movements
- flitting between various muscle groups and body parts
- motor impersistence (relative overactivity of direct pathway and relative under activity of indirect pathway)
What are examples of choreiform disorders?
Huntington’s disease
Levodopa-induced dyskinesia
What is dystonia?
abnormal twisting, distortion movements of the neck and limbs
What is the age of onset of Parkinson’s disease?
> 60 yo
young onset PD in 5% of people <40yo
What are the genes involved in Parkinson’s disease?
parkin (recessive) SNCA LRRK2 (dominant)
What are the movement symptoms seen in PD?
-bradyskinesia
(increased inhibitory output to brainstem, thalamus and motor cortex + abnormal 20 Hz (beta band) oscillations in basal ganglia: increased activity at that frequency)
-resting tremor
(absent in approx 30% of people, less responsive to drugs, not just basal ganglia output: thalami-cortical-cerebellar loops and non dopaminergic pathways (5-HT))
-rigidity (cogwheel)
(increased muscle tone, more obvious during slow movements
–> peripheral: reduced inhibition from type 1b fibres and overactive type II fibres (connected to muscle spindles): muscle tense up
–> central: altered GABA an ACh interneurones: altered inhibition in indirect pathway: increased responsiveness of STN/GPi firing to peripheral stimulation)
-postural instability (late)
What are the non-movement symptoms n PD?
- anosmia (PD starts in olfactory bulb)
- gut problems
- REM sleep behaviour disorder
- depression
- prominant pain
What is the Braak staging for PD?
- Break stage 1 and 2: autonomic and olfactory disturbances
- Braak 3 and 4: sleep and motor disturbances
- Braak 5 and 6: emotional and cognitive disturbances
What are the behavioural impairments in PD?
- cognitive disturbances (executive planning: associative loops, thinking ability)
- impulsive behaviour (dopaminergic deficit in limbic stratal areas)
- depression anxiety (related to monoamine loss in brainstem)
What are the risk factors for impulse control behaviours in PD?
- dopamine agonist use> high dose levodopa
- smoking, male
- young onset Pd
- depression
- novelty seeking behaviour
- family history of gambling, alcoholism
What is the pathophysiology of PD?
-abnormal deposition of Lewy bodies causing death of the cells and loss of dopamine: alpha synuclei aggregate
-(caudal postal spread through the -brain)
(alpha synuclei is a protein that is involved in normal cellular functions such as synaptic functions)
--> reduced D1 and D2 stimulation: direct pathway underactive and indirect pathways is overactive (relative)
+ increased levels of proenkephalin: causing parkinson symptoms
What do you need for a diagnosis of PD?
- -must have bradykinesia + one of the following
- rigidity
- resting tremor
- postural instability - unilateral onset and persistent asymmetry
- good levodopa response > 5 years
- levodopa induced chorea
What are red flags for idiopathic PD diagnosis?
- absent tremor, symmetrical onset
- early gait abnormality and falls
- pyramidal tract signs
- poor levodopa response
- supranuclear gaze palsy
- dysautonomia, ataxia, stridor
- apraxia, myoclonus, alien limb
- early dementia
