Pathophysiology of PD Flashcards
Outline the aetiology of PD
-Age-related neurodegenerative disorder
-Most cases are sporadic with late onset and no known cause
Possible causes=
-Genetics ( mutations in genes encoding alpha-synuclein, LRRK2, DJ-1,PINK1)
-Environmental toxins (MPTP; agrochemicals eg pesticides-persistent accumulations)
Outline the neuropathology of PD
- Dopaminergic nigrostriatal tract degeneration
- Loss of pigmented cell bodies in substantia nigra pars compacta
- The dopamine cells in the midbrain SNc contain neuromelanin which is why the SNG appears as black lines
where does the neuromelanin come from
-breakdown/oxidation of dopamine
What are the characteristics of the LEWY BODY
- pathological hallmark of PD-not exclusive; DLB,PDD
- contain alpha-synuclein which form large aggregates in lewy bodies
- Lewy bodies are inclusions that form in the neurones in PD
- Abs for ubiquitin & caspase (apoptosis marker) co-stain Lewy bodies
- Lewy bodies are found in many remaining dopaminergic neurones in SNc in PD
- Stain for many proteins including alpha-synuclein, ubiquitin
What is the function of ubiquitin
-Tags damaged proteins and signals their transport to the ubiquitin proteosome system for breakdown
How can the progressive clinical path of PD be divided ?
- ) Preclinical PD~10yrs
- )Early treated PD (stable) ~5yrs
- ) advanced PD~10yrs
Outline the preclinical stage of PD
- olfactory loss
- RBD
- constipation
- anxiety
- depression
- Impaired colour vision
Outline the early treated PD (Stable) stage of PD
-Bradykinesia
-Rigidity
-Resting tremor
+/- non-motor symptoms
Outline the advanced PD stage
Motor complications:
- weaning off/dyskinesias
- gait& balance problems
- Axial deformities
- Dysarthria/dysphagia
Non-motor complications:
- Cognitive decline/dementia
- depression
- psychosis
- autonomic dysfunction
- sleep-awake dysfunction
what distinguishes preclinical PD from early treated PD
-the onset of motor symptoms
What is the role of activated microglia in the pathogenesis of PD
- microlglia are cells of the immune system in the brain
- In PD there’s an infiltration of microglia into the substantia nigra that can lead to the release of inflammatory mediators
What is the role of glutamate in the pathogenesis of PD?
- There’s increased transmission of glutamate at the NMDA receptor
- There is a pacemaker channel which is very dense and active in the SN, so you get an increase of intracellilar calcium in substantia nigra as a result of excess glutamate
- The increased calcium activates excitotoxic pathways which cause neuronal dysfunction & death
What is possible the role of neurotrophic factors in pathogenesis of PD?
- These are important for maintaining neural survival
- May not be functioning efficiently in PD
What is the role of increased ROS (reactive oxygen species) in pathophysiology of PD?
- leads to increased oxidative stress
- Leads to alpha-syn misfolding and thus accumulation of alpha synuclein
What is responsible for accumulation of alpha-synuclein?
-May be linked to oxidative stress or may be due to genetic malfunctions