Parkinson’s Disease

Contents Definition Symptoms and diagnosis Causes and pathogenesis Treatment

What is Parkinson’s Disease? Result of damage to substantia nigra and the globus pallidus Caused by selective degeneration of substantia nigra (pigmented substantia nigra neurons) A shortage of dopamine in substantia nigra leads to an excess of Acetyl choline which leads to a subsequent increase of GABA in striatum. The result is an increase effect of basal ganglia causing a suppression of motor cortex. This is visible as hypokinesia. The damage to globus pallidus causes a reduced inhibitory effect in reticular formation which can be seen as rigidity. Hence the term ‘hypokinetic - hypertonic disease’

Symptoms 4 major symptoms: Non-motor symptoms Rigidity – muscles are tensed and contracted Resting tremor – trembling which is most obvious when the patient is at rest or when stressed Bradykinesia – slowness in initiating movement Loss of postural reflexes or instability – poor balance and coordination Non-motor symptoms Anxiety disorders, depression, sleep disturbances, orthostatic hypotension, olfaction dysfunction, dysphagia, sialorrhoea, dementia, psychosis and visual hallucinations

Diagnosis Diagnosis: Neurological examination Autopsy of brain to find lewy bodies (trademark characteristic) Judgement of physicians

Causes and Pathogenesis Degradation of dopaminergic neuron. Free radicals. Neurotoxin - MPTP Genetic factors.

Degradation of Dopaminergic Neuron Substantia nigra pars compacta. Death of neuron. Symptoms of PD don’t appear until 50-80% of the neurons in the pars compacta have died. Cause of death of neuron is not known.

Free Radicals Unpaired electrons that can easily react with surrounding molecules and destroy them. Metabolism of dopamine by MAO produce hydrogen peroxide. Glutathione normally breaks down the hydrogen peroxide quickly. Reduced glutathione = loss of protection against free radicals  cell damage

Neurotoxin - MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) – neurotoxin. MPTP crosses the blood-brain barrier and oxidized to 1- methyl-4-phenylpyridinium (MPP+) by monoamine oxidase B (MAO)-B MPP+ selectively enters dopamine neurons via the dopamine transporter. MPP+ inhibiting Complex I  leads to cell death via energy deficit. This leads to the degeneration of dopamine neurons.

Genetic Factors Mutation of SNCA genes in chromosome 4. 2 types of alterations: Alanine is replaced with threonine. Cause alpha-synuclein to misfold. SNCA genes is inappropriately duplicated or triplicated. Extra copies of the gene lead to an excess of alpha-synuclein. Aggregate (Lewy bodies) and attract other protein. Clog neuron and impair the function of neuron.

Treatment Levodopa Dopamine agonists Levodopa is absorbed by the nerve cells in your brain and turned into the chemical dopamine, which is used to transmit messages between the parts of the brain and nerves that control movement. Increasing the levels of dopamine using levodopa usually improves movement problems. Dopamine agonists Dopamine agonists act as a substitute for dopamine in the brain and have a similar but milder effect compared with levodopa. They can often be given less frequently than levodopa.

Monoamine oxidase-B inhibitors They block the effects of an enzyme or brain substance that breaks down dopamine (monoamine oxidase-B), increasing dopamine levels. Catechol-O-methyltransferase inhibitors Catechol-O-methyltransferase (COMT) inhibitors are prescribed for people in later stages of Parkinson's disease. They prevent levodopa from being broken down by the enzyme COMT.