PD Causes and Disease Mechanisms Flashcards
What are the clinical symptoms of PD
Pre-Motor symptoms (constipation, loss of smell and depression) and Post Motor Symptoms (Hallucinations, Psychosis, Postural instability)
Motor symptoms - Bradykinesiia, Akinesia
Responsive to L-Dopa therapy
What are the pathological features of PD
Lewy bodies (Perikyra) and Lewy neutrites (processes), these are intraneuronal inclusion bodies which invole asyn aggregates Loss of dopaminergic neurons in the Substania Nigra The neuropathology of PD appears to spread through anatomically connected regions of the brain in accordance to Braak's Model
What is the Incidence of PD
1-5 in 1,000
Onset variable, early (~40s) or late (~65)
What are other diseases with the histopathological features of PD?
MSA
Dementia with Lewy Body Disease
Incidental LBD
Genetic Risk Factors?
The genetic risk factors are relatively uncommon (11 risk loci and 5 extra upon meta analysis)
Monozygotic and Dizygotic studies in twins - low concordance, except between mono with early onset
Environmental Factors
Smoking, Coffee = protective
Industrialisation is associated with a higher incidence in population
P450 detoxification defects (CyP2D6) - 2.4 times higher risk
In Guam a higher incidence, associated with the type of meat they eat there
Environmental factors that are complex I inhibitors e.g. MPTP and rotenone
What does MPTP stand for
N-Methyl-4-phenyl-1,2,3,6-tetrapyrimidine
What is MPTP’s pathogenic mechanism in teh brain
It passes through the blood brain barrier thanks to its highly lipophilic characteristics. Here it is converted by monoamine oxidase B to MPTP+ –> MPP+ via spontaneous oxidation
Describe Oxidative Stress in PD patients
- Increased Iron Levels
- Decreased reduced glutathione
- Decreased copper/zinc superoxide dismutase activity
Describe proteasomal defects in PD patients
UPS
- Decreased proteasomal activity
- LB are ubiquitinated, suggesting an inhibited UPS pathway
- Decreased UPS activity in patients
- Injecting proteasome inhibitors in rats results in SN degeneration
Describe the lysosomal defects in PD patients
- Decreased CMA proteins (LAMP2A and Hsc70)
- Decreased lysosome number lysosomal proteins (LAMP1 and Cathespin D)
- Increased number of autophagosomes, possibly due to decreased clearence by lysosomes
In the Braak (2003) staging of PD where do the aggregates begin - and where do they spread to (name 6 stages)
- Dorsal Motor Nucleus
- Lower Rophe nuclei
- Sub. Nigra (Motor Symptoms)
- Temporal mesocortex
- Temporal Neocortex
- Neocortex
- -> this notion suggested the idea of prion-like hypothesis, supported by grafting (li et al. 2008/2010) –> Hansen et al. 2011 –> Angot et al. 2012 –> Reyes et al. 2011/2013 - specifically reyes who showed that injection into olfactory and mapped for 72 hours demonstrated spread through anatomically connected regions, suggesting potential for environmental exposure
Where is asyn phosphorylated?
Serine 129
What are the pre-motor symptoms
Loss of smell
Depression
REM sleep disorder
Constipation (suggestive of environmental toxins orginating in the stomach) (supported by findings of LB in enteric nervous systems
Motor symptoms?
Bradykinesia - slowness of movement
Akinesia - Loss of Movement
Tremor
Post motor symptoms
Dementia (80% after having PD for 20 yrs)
Visual halucinations
Postural instability
Speed problems
What did Tanner et al. 1999 describe
No correlation in twins (di or mono)
Except that for earlier onset PD there was a greater correlation between mono - this is supported by the fact that many AR mutations cause earlier onset, finding since been supported by improved genomic technology