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Revision PD

Revision PD. Key Facts 1. Mostly diagnosed after the age of 50 years but some individuals diagnosed earlier-in their 30s. Genetic differences between late onset (PARK 1 and early onset (PARK 2) genotypes. About 200 per 100,000 in UK have PD. More men than women

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Revision PD

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  1. Revision PD

  2. Key Facts 1 • Mostly diagnosed after the age of 50 years but some individuals diagnosed earlier-in their 30s. Genetic differences between late onset (PARK 1 and early onset (PARK 2) genotypes. • About 200 per 100,000 in UK have PD. More men than women • Causes progressive disability characterised by tremor and stiffness and later cognitive decline. • Pathology is initial significant loss of dopamine producing cells and development of insoluble synaptic vesicle protein inclusion bodies (Lewy bodies) in cells. May be a secondary event.

  3. Key facts 2 • Damage to brain initially confined to the specific target of the Pars Compacta of the Substantia Nigra (SN) with loss of dopamine producing cells and affecting function of the basal ganglia • Reduction of dopamine producing cells and lowered dopamine content in SN and Corpus striatum • Loss of dopamine has profound “knock-on” effects in connections from the SN that radiate from the corpus striatum to the Pars Reticulata of the SN and then directly to the Thalamus and Cerebral Cortex. • An indirect pathway relays through the Golbus Pallidus and Sub Thalamic Nuclei to the Pars Reticulata to reduce output to Thalamus and Cortex

  4. Effects in Basal Ganglia Clinical symptoms when 50% neurones in Pars Compacta of SN damaged In Corpus striatum dopamine D1 receptors predominate, are excitatory and cause excitation of inhibitory Striatal projections that release GABA D1 receptors predominate in striatum and activate inhibitory GABA-energic neurones that project to SN Pars Reticulata and from Pars Reticulata to Thalamus and Cerebral Cortex Activity in Thalamus and Cortex decreased Other aminergic transmitters are probably involved

  5. Neurotransmitters in the basal ganglia17 Neurotransmitter Action Site of action Excitatory to D1 receptors (direct pathway) Inhibitory to D2 receptors (indirect pathway) Striatum Dopamine Excitatory Acetycholine Striatum Links with direct and indirect pathways GABA Inhibitory Substance P Inhibitory Localised with GABA in the direct pathway Enkephalin Inhibitory Localised with GABA in the indirect pathway

  6. Basal ganglia structure9 Subthalamic nucleus acts like a car brake on the basal ganglia Substantia nigra acts like a car accelerator on the basal ganglia Adapted from www.stanford.edu/group/hopes/basics/braintut

  7. Normal motor control12 Normal movement Dopamine increases the inhibitory activity of the direct pathway Motor cortex GPi inhibitory activity is reduced Thalamus Striatum Dopamine Dopamine decreases the excitatory activity of the indirect pathway Excitatory (indirect) Substantia Nigra (SN) Inhibitory (direct) Adapted from Swinn, Parkinson’s disease, Theory and practice for nurses.

  8. Changes in the basal ganglia in Parkinson's12 The motor cortex receives diminished excitatory output from the thalamus so movement is inhibited Dopamine depletion results In decreased inhibitory activity of the direct pathway GPi inhibitory activity is increased Inhibition of the thalamus Striatum Dopamine depletion Dopamine depletion Increases the excitatory activity of the indirect pathway Excitatory (indirect) Substantia Nigra (SN) Inhibitory (direct) adapted from Swinn, Parkinson’s disease, Theory and practice for nurses.

  9. Key facts Clinical symptoms Akinesia occurs in the final stages of the disease Bradykinesia – slow movements. Affected person requires much concentration to perform a movement Postural difficulties – push to the shoulders causes overbalance, failure to throw limbs out to protect body during a fall Shuffling gait Face has a mask-like appearance Arms do not swing while walking Can sit or stand motionless-may “freeze” Micrographia Difficulty swallowing food or drink - marked weight loss Dementia may occur in later stages

  10. Key facts. Models of PD • Parkinson like symptoms may be seen following injury like in boxing or other brain injuries • MPTP N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine A neurotoxin contaminating heroine in the 1980s caused PD like freezing and loss of function. Post mortem examination showed loss of SN dopamine producing cells and gave clues to the causes of PD symptoms • Some herbicides may have a similar neurotoxic effect

  11. Treatment • Replacing dopamine • Dopamine is not absorbed across the blood brain barrier Therefore L-dopa (levodopa) a precursor of dopamine is given • Can help restore dopamine levels for up to 5 years but may cause profound side effects • Monoamine oxidase B (MAO-B) inhibitors-reduce dopamine metabolism • Dopamine receptor agonists (Bromocriptine, lisuride, pergolide etc.) Newer drugs may have fewer side effects. • Possible cellular implants of dopamine producing cells • Deep brain stimulation to help with tremor (but no other impact)

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