Lecture 8: Parkinsons

Question 1

What is parkinsons?

Answer 1

Parkinson’s disease is a movement disorder of middle and old age that affects 1-2% of the elderly population

It is 2.5 times more prevalent in males than females

Question 2

Symptoms of Parkinson’s

Answer 2

Initial symptoms are mild, no more than slight stiffness or tremor of the fingers

Most common symptoms of full-blown disorder;

• a tremor that is pronounced during inactivity but not during voluntary movement or sleep
• muscular rigidity
• difficulty initiating movement slowness of movement
• masklike face

Patients often display cognitive deficits although dementia is not typically associated with disorder. Patients are thinking people trapped inside bodies they cannot control

Question 3

Causes of Parkinson’s

Answer 3

Seems to have no single cause; - faulty genes
- brain infections
- strokes, tumours
- traumatic brain injury -neurotoxins
…have all been implicated in specific cases

Associated with widespread degeneration but particularly in the substantia nigra – midbrain nucleus whose neurons project via the nigrostriatal pathway to the striatum of the basal ganglia

Question 4

Dopamine and Parkinson’s

Answer 4

Dopamine is a major neurotransmitter released by neurons of substantia nigra… there is little dopamine in substantia nigra and striatum of long term Parkinson’s patients

Autopsy often reveals clumps of proteins in the surviving dopaminergic neurons of the substantia nigra – clumps are called Lewy Bodies

Symptoms can be alleviated by injections of L-dopa – the chemical from which the body synthesises dopamine, becomes less and less effective however with continued use

Question 5

Mutations and Parkinson’s

Answer 5

About 10 different gene mutations have been linked to Parkinson’s, mutations have been found to disrupt the function of the mitochondria (the energy creating structures in each cell)

Question 6

Brain stimulation and Parkinson’s

Answer 6

Controversial treatment is brain stimulation, treatment in which low intensity electrical stimulation is continually applied to an area of the brain through a stereotaxically implanted electrode, involves chronic bilateral electrical stimulation the subthalamic nucleus (lies just beneath the thalamus and is connected to the basal ganglia)

Effectiveness of deep brain stimulation slowly declines, improvement relative to the patient’s pre-treatment status is often still apparent 2 years after stimulation begins

Deep brain stimulation can also cause side effects such as cognitive, speech and gait problems (i.e. walking)

Question 7

MPTP Model of Parkinson’s Disease

Frozen Addicts

Answer 7

Cases of the Frozen Addicts:

Parkinson’s rarely occurs before the age of 50 but young drug addicts had developed severe and irreversible parkinsonism, only link was new synthetic heroin.

The addicts exhibited classic triad of:
- bradykinesia (slowness of movement)
- tremor
- rigidity of their muscles 
As well as subtle features such as seborrhea (oiliness of the skin) and micrographia (small handwriting) that are typical of Parkinson patients 

• Offending agent was 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
• No sign of remission, most problems became increasingly severe in terms of management

This lead to the development of an animal model of Parkinson’s

Question 8

MPTP Model of Parkinson’s Disease

Development of Animal Model of Parkinson’s

Answer 8

Quickly established that non-human primates respond to MPTP the same way humans do…

• Brains of non-human primates exposed to MPTP have cell loss in the substantia nigra similar to that observed in Parkinson’s patients
• Substantia nigra major source of brains dopamine, not surprising the level is greatly reduced in both MPTP model and in the naturally occurring disorder
• Few monkeys produced major depletion of dopamine without production of any gross motor symptoms

**MPTP Animal Model benefited patients as it was discovered that deprenyl, a monoamine agonist, blocks the effects of MPTP in an animal model

• Deprenyl administered to early Parkinson’s patients slows down the progression of the disease
• Model does not however model etiological factors in the disease (cause)

Question 9

Transplanting Foetal Tissue

Answer 9

Bilateral transplantation of foetal substantia nigra cells was successful in treating the MPTP monkey model of Parkinson’s disease

Transplants survived in the MPTP treated monkeys, transported cells innervated (supplied with nerves) adjacent striatal tissue, released dopamine, alleviated severe poverty of movement, tremor and rigidity produced by MPTP

Neurotransplantation was offered as a treatment for Parkinson’s disease at major research hospitals:

• Results were promising, foetal substantia nigra implants survived, released dopamine into host striatum
• Results triggered large scale double-blind evaluation study of patients, after a year 15% of treated patients who had shown some improvements started displaying a variety of uncontrollable writhing and chewing movements a year after surgery, these adverse motor effects limit any further development of neurotransplantation as a treatment, researchers do not yet know how to maximise the survival and growth of neurotransplants and how to minimise their side effects

Question 10

Roberto Garcia d’Orta case study:

Answer 10

• Described himself as a great lizard frozen in a dark, cold, strange world because he is suffering from Parkinson’s disease
• Initially responded to 3 years of L-Dopa therapy, after 3 years of therapy condition worsened
• Responded to treatment with dopamine agonist but improvement was only temporary
• Heard about Adrenal Medulla Autotransplantation (transplanting a patient’s own adrenal medulla cells into their striatum, usually for the treatment of Parkinson’s disease)
• Adrenal medulla cells release small amounts of Dopamine, was some small early indications it may alleviate symptoms
• Subsequent research found procedure to be ineffective, study has been abandoned