Central nervous system

Parkinson disease

• umbrella term or clinical syndrome

• Chronic neurodegenrative condition

• Disease linked with/ associated aging

• Parkinson was first described by Dr James Parkinson in 1817

• He noted ‘ involuntary tremulous motions’

• A propensity to bend forwards

Other symptoms

• sensory phenomena

• Sleep disturbances

• Autonomic nervous system dysfunctions

• Motor

• Mental changes

• Cardinal symptoms

Pathology

• Corresponding neuronal loss of the dopaminergic nigrostriatal pathways

• Lewy bodies

Lewy bodies

• present in CNS and PNS

• Intracellular cytoplasm protein aggregates

• Aggregates of alpha synuclein

  • Amino acid protein

  • Misfolded proteins

• Leading pathogenic hallmarks in brain biopsies

The Braak hypothesis

• Braak staging

• Proposed model suggest Pathology spreads through the brain over time

The role of dopamine

• neurotransmitter produced in neurons of the substantia nigra

• The nigro-striata pathway is the main pathway damaged in Parkinson’s disease

  • Due to loss of DA producing neurones in the SN

• Nuclei in basal ganglia crucial for the control/ initiation of movement

The basal ganglia

• initiate movement

  • A group of 5 bilateral nuclei lateral to the thalamus

  • Caudate

  • Putamen

  • Globus pallidus

  • Subthalamic nucleus

  • Substantia nigra

• Substantia nigra: provides dopaminergic modulation of motor pathways

Movement control

• movement is initiated in the motor cortex

• The basal ganglia modulate and fine tune that movement

• Dopamine from the substantia nigra modulates basal ganglia activity

• The thalamus relay back to the cortex

• Cortex → spinal cord → muscles

• Control how easily movement are started and how smooth they are

Direct and indirect pathways controlling movement

Direct

• facilitates movement

• Allows motor cortex to activate muscle

Indirect

• inhibits unwanted movement

• Prevents excessive motor activity

Dopamine

• released from substantia nigra

• Stimulates the direct pathway

• Inhibits the indirect pathway

• Overall effect: movement is enabled

Pathway imbalance in Parkinson’s

Direct

• becomes less active

• Less movement facilitation

Indirect

• becomes overactive

• Excess movement inhibition

Results

• thalamus provides reduced excitation to motor cortex

• Motor cortex activation reduced

• Movement become slow and rigid

How do we treat Parkinson’s

• as we lose neurons there is less and less dopamine

• Eventually symptoms appear

• Motor symptoms appear after 60% dopaminergic neuron loss

• Pharmacological treatment

• Replace the dopamine stimulation

Symptomatic therapies

• replace the dopamine

• Increase the availability of dopamine to brain

• Decrease the breakdown of dopamine

  • MAO B inhibitor

  • COMT inhibitors

• Replace the post synaptic dopamine stimulation

Motor complication of treatment

• wearing off

• On- off fluctuations

• Dyskinesias

Why they occUr

• loss of dopamine buffereing

Symptomatic therapies- non dopaminergic strategies

• anti cholinergic

  • Tremor

• Amantadine

  • NMDA receptor antagonist with mild dopaminergic effects

  • Userful for levodopa- induced dyskinesia

  • Reduce excessive glutamate activity linked to dyskinesia