U14W3: Parkinson Disease Flashcards
How does the pattern of action potentials change in different basal ganglia neuronal population?
Happy -
How is the basal ganlia circuitry affected in Parkinson disease?
Damage to substantia nigra pars compacta
Axonal projection that synapse with dorsal striatum, reduced dopmaine release at these synapses
Reduced binding of dopmaine to D1 receptors - less increased activity of the direct pathway
Reduced binding of dopamine to D2 receptors - less inhibition of the indirect pathway.
Overall there is a relative increase in activity along the indirect pathway compared to the direct pathway, results in suppression of wanted movements = bradykinesia.
What is the evolutionary aetiology of parkinsons disease?
Human evolution - midbrain relatively small, similar size in other animals
Large growth in cerebral cortex, increase in axonal folding and projections from the midbrain to the cerebral cortex
Substantia nigra in midbrain communicates to the basal ganglia in the prosencephalon.
High metabolic demand - increased risk of degeneration
Parkinsons disease is a compromise or price for rapid evolution of human cerebral cortex at the population level.
What are some risk factors for Parkinsons disease?**
Male - twice as common - protective sex hormones or environmental exposure.
Lower in caffeine and smoke exposure
Higher in pesticide exposure and traumatic brain injury.
Ashkenazi jews and Israel - LRRK2 and GBA mutation.
Age - 60-90yrs - age related decline in proteolytic defence mechanisms - lead to accumulation in alpha synuclein.
How does Parksons disease affect energy levels?**
Increase fatigue
Prodromal Parkinsons can present with REM Sleep disorder (enacted dream behaviours)
Degeneration of the thalamic reticular nucleus - regulates sleeping/inhibits arousal
Associated with poorer neurophysical functioning hence outcomes in PD
Why is it important to consider family history when a patient presents with a neurological movement disorder?
Up to 15% of Parkinsons can be genetic, some of there’s are early onset (younger than 50yrs)
Huntingtons tend to appear in middle age - AD - is anticipatory (earlier in each generation), number of CAG repeated tends to realte to progression of disease.
What is the genetic underpinning Parkinsons Disease?
Indicated in mutation of around 25 genes including the SCNA gene (encodes for alpha-synuclein)
All genes are implication in cellular metabolism, malfunction leads to autophagy or mitochondrial respiratory dysfunction.
Causes accumulation of ROS - leads to misfolding of alpha-synuclein.
Impaired axonal transport and neuroinflammation mediated by microglia to progressive neuronal death
What are the range of symptoms in Parkinsons Disease?
Motor - quadrad - bradykinesia, tremor, postural instability, rigor.
Congitive impairement - gambling, poor understanding of social clues
Autonomic dysfunction
Disorders of sleep
Depression
Hyposmia
Non motor symptoms such as REM sleep behaviour, depression and constipation tend to make up prodromal parkinsons disease.
What is the neuropathological process underpinning Parkinsons Disease?
Dopaminergic neuronal loss in the substantia nigra pars compact - becomes more widespread as the disease progresses
Intracellular protein (alpha synuclein) accumulation throughout the brain, these can form Lewy bodies (insoluble clumps of abnormal protein), initially in cholinergic and monoaminergic brainstem neurons can spread - also in olfactory system and limbic region etc.
Misfolding of alpha synculine can be due to range of factors - mutation to increase expression, decrease degradation or encourage misfolding.
Note not specific to Parkinsons disease - e.g Lewy Bodies Dementia.
Progression from SN lewy body to cortical lewy body (not cerebellum is normally spared)
What are some genetic mutations causing Parkinsons Disease?
Autosomal domiant -
PARK1/4 - SNCA gene
Early onset Parksinsins dsease (AR) - PARK2
What is a DatScan? What does it show? How does it relate to parkinsons disease?
Is a type of SPECT scan
Label dopaminergic synapses
Inject patient with radioactive ioflupane.
Wait four hours
Binds to dopaminergic transport protein at the site of SNpc axon termination at the striarum
Normal scan - essential tremoe - comma shaped
Abnormal scan - full stop shaped - possible parkinsonian syndrome.
What nuclei in the thalamus are affected in the limbic/pain basal ganglia circuits?
Midline thalamic nuclei
Medual nuclear group (mediodorsal nucleus)
Intralaminal nuclei
What is the link between olfactory anatomy and Parkinsons disease?
PRimary olfactory sensory neurons live in the olfactory epithelium in the roof of the nasal cavity beneath the cribiform plate of the ethmoid bone.
Their axons penetrate that plate and project to the olfactory bulb
Lewy bodies or misfolding of alpha synuclein can be found in olfactory bulb - originate hear before movement to SN.
How can Parkinsons disease present histopathology?
SNpc normal - lots of melainin containing neurons
Snpc PD - not many melanin containing neurons left
Lewy bodies are accumulations of alpha-synuclein (immunostained in brown) .
What is the connection between drug use and Parkinsons disease?
Specifically cannabis, cocaine and ecstasy.
Drugs affect the dopaminergic VTA signalling to the nucleus accumbens in order to create addiction
Can also affect the SN dopaminergic neurons.
Cocaine - dopamine overload - damage to dopamine responding cells - the striatum
Cannabis - acute increase dopamine release, chronic blunting dopamine release
Ecstacy - increased dopamine transmission.
Alcohol - down regulation of GABAergic neurons.
Parkinsonism is related to drugs that affect brainstem modulatory systems
