case 7/ Parkinson's disease Flashcards
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
What are the different treatment options for PD?
- dopaminergic therapies:
- levadopa
- dopamine receptor agonists (pramipexole, ropinirole)
- peripheral COMT inhibitors (entacopone, opicapone)
- monoxidase inhibitors (selegiline, rasagiline) - NMDAR antagonists (amantadine)
- surgical therapies
- GPm/STN deep brain stimulation
- GPm lesion
What are motor complications in the treatment of PD?
wearing off effect and motor fluctuations
–> L DOPA induced dyskinesia: (reduce therapeutic window: you spend time below response threshold and above dyskinesia threshold)
(occurs in 50% after 4-6 years of treatment. risk factors: young age ad disease severity, genetics)
What are the mechanisms of motor complications? What can be done?
- less able to handle the dopamine stimulation
- abnormal handling of dopamine by 5-HT neurones
- abnormal handling of synapse plasticity
- dopamine receptor agonist treatment delays dyskinesia onset
what can be done:
- continuous dopaminergic stimulation
- amantapine (NMDA receptor antagonist, reduced dyskenesia by approx 40%)
- surgical therapies
Why should you not abruptly withdraw medication?
lead to neuroleptic malignant syndrome
What is the aetiology of Hungtinton’s disease?
- expanded CAG repeat (>40) in Huntington gene (on chromosome 4)
- anticipation: as it goes down generation, it occurs at younger age
- greater expansion in male transmission
What is the pathophysiology of Huntington disease?
–> strial pathology (especially caudate):
-selective loss of D2 receptors (involuntary movements increase)
-later loss of D1 receptors (hypo kinetic movement disorder)
DIRECT PATHWAY RELATIVELY OVERACTIVE COMPARED TO INDIRECT)
- -> cortical pathology
- loss of neurones in layer 5 and 6
- -> neuropsychiatric disturbances early on in the disease
- anxiety, depression, impulsivity, apathy
Wha is Tourette syndrome?
neuropsychiatric illness that is characterised by rapid, repetitive, stereotypes movements or vocalisation (tics: motor and vocal)
-onset <20 yo
What is the pathophysiology of Tourette syndrome?
- loss of cholinergic and GABAergic stratal interneurones: reduced basal ganglia inhibition
- increased striatal dopamine D2 receptor binding in patients with TS compared to controls
What is SPECT? What does it measure?
gamma emitting radioisotope
measures blood blow
What is PET? What does it measure?
What are the different types of PET used in diagnosis of PD and Alzheimer’s?
positron emitting radioisotope
measures metabolic rate
- 18F-DOPA PET (Parkinson)
- FGD PET (radioactive glucose): shows which part of the brain is the most active (can be used in PD and Alzheimer’s disease
- 18F-Florbetapir: presence of amyloid (for Alzheimers)
- 11C-PK11195: for stroke: marker for inflammation (CRP)
What can you miss with Nervous System imaging?
-raised intracranial pressure
-cerebral venous sinus thrombosis
(which both of the above can be seen through clinical assessment: papilledema in back of eye)
-stroke
-subarachnoid haemorrhage
-Guillain Barre syndrome
-myasthenia gravis
-anything to do with neuromuscular system
