Parkinson's Disease Flashcards
What is parkinson’s disease?
neurodegenerative movement disorder, predominantly of old age
Often sporadic /idiopathic
Describe the clinical presentation of parkinsons
Resting tremor
Akinesia - loss of power of voluntary movement
Bradykinesia - slowness of execution of movement
Dementia in later stages
Psychiatric symptoms - depression and anxiety
Describe the epidemiology of parkinsons
1-2% of the population over the age of 65 have PD
Increases to 3-5% over the age of 85
Cause of death usually linked to incapacitation
What are the two key pathological hallmarks of parkinsons?
- Loss of neurons, predominantly dopaminergic and in the Substantia nigra
- The accumulation of intracellular inclusions, called Lewy bodies, made up of the protein alpha synuclein
What research did Arvid Carlson find out?
Carried out studies in rabbits showing that depletion of dopamine was critical for control of movement, and that it acted as a neurotransmitter in the substantia nigra
Subsequent studies revealed decreased dopamine levels in the basal ganglia of PD patients
What are the environmental factors that are linked to parkinsons?
Pesticide exposure
MPTP (street/drug/meth?) exposure
Also exposure to influenza and repeated head trauma
What is MPTP?
Identified in Californian drug addicts who used a ‘synthetic heroin’
contaminated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
The toxic species is MPP+ which enters mitochondria in neurons
What are the genetic factors linked to parkinsons?
Inherited forms of Parkinson’s disease (familial parkinson’s)
Genetic susceptibility in sporadic Parkinson’s disease
Give an example of a gene observed in familial parkinsons
LRRK2 gene
What are some of the gene that cause Parkinson’s (7)
VPS35 PARK7 SNCA LRRK2 PARK2 PINK1 ATP13A2
What are the two key insights from genetics and toxin research?
Mitochondrial biology
Protein aggregation
What causes mitophagy? Degradation of mitochondria
Factors such as oxidative stress, aging, pesticides
Genes such as Parkin
Fbxo7 and PINK1
What was found regarding Protein aggregation that is linked to familial parkinsons disease?
Identification of mutations in alpha synuclein - quickly followed by the realisation that Lewy bodies were made up of this protein
Alpha synuclein readily aggregates and forms toxic lumps of sticky protein (amyloid) similar to that found in Alzheimer’s
What is the currnt hypothesis about alpha cynuclein causing parkinsons?
Current hypothesis is that small aggregates of synuclein (oligomers) can spread from cell to cell, and cause cell death
May be analogous to prion diseases such as BSE (Mad Cow disease) and CJD (Creutzfeldt–Jakob disease)
Describe the Dopamine pathway treatment?
Natural DA precursor which, unlike DA, can cross BBB.
L-DOPA is converted to dopamine by DOPA decarboxylase (DCC).
BUT L-DOPA is ~90% converted by DDC in intestinal wall
Given with peripherally-acting DDC inhibitors, carbidopa or benserazide
L-DOPA also ~5% metabolised by plasma Catechol O-Methyl Transferase
COMT inhibitor, entacapone, may be used as adjunct
Ensure majority of L-DOPA enters brain unchanged for conversion to DA
L-DOPA raises striatal DA levels to normalise activity in BG circuits
What is an acute and chronic side effect of dopamine treatment?
Acute: psychosis
Chronic: excess movements (dyskinesia)
L-dopa used as the first drug and most effective at symptom relief
What are some common preparations?
carbidopa/levodopa (co-careldopa) (e.g. Sinemet, Parcopa, duodopa)
benserazide/levodopa (co-beneldopa) (e.g. Madopar)
carbidopa, levodopa and entacapone (Stalevo)
Describe the surgical intervention that can take place
Targeted lesion of subthalamic nucleus and globus pallidus brain areas
Decreases neuronal activity that is raised due to loss of signal from the substantia nigra
Destructive lesions are associated with significant side effects (neurologic deficits)
Deep brain stimulation using implanted electrodes in these brain regions increasingly being used as an alternative
How can stem cell therapy be used? What issues are there?
- Replacement of cells in the basal ganglia to correct the underlying cause of lowered dopamine levels
Procedures carried out in Sweden (illegal in the US) with moderate success
Subsequent studies with sporadic PD patients have proved less successful, with some severe reactions to stem cell implantation
Key question is what cells to use: initial studies used fetal brain cells (from aborted embryos), more recently embryonic stem cells and induced pluripotent cells have been suggested as alternatives
