L17: Parkinson's Disease Flashcards
What is Parkinson’s DIsease (PD)?
- a chronic & progressive neurodegenerative condition
- resulting from the loss of the dopamine-containing cells of the substantia nigra
what are the motor symptoms of PD?
- Resting Tremor: A tremor that occurs when the affected limb is at rest & subsides during voluntary movement.
- Rigidity: Stiffness & resistance to movement in the muscles.
- Akinesia/Bradykinesia: Akinesia= loss of voluntary movement, bradykinesia= slowness of movement.
- Postural Instability: Difficulty maintaining balance and posture
What is the pathological basis of Parkinson’s disease?
- characterized by the loss of dopaminergic neurons in the substantia nigra
- this neurodegeneration leads to a reduction in dopamine levels, which affects the normal functioning of the basal ganglia (brain area involved in motor control)
- PD more common in the aging population (rarely occurring in individuals under 40 years of age)
- tends to affect more males than female, no specific racial or environmental risk factor
Describe the non-motor symptoms of Parkinson’s disease
- Gastrointestinal (GI) and Genitourinary (GU) Dysautonomia: dysfunction of the autonomic nervous system, leading to issues like constipation, urinary problems & difficulty swallowing.
- Orthostatic Hypotension: drop in BP upon standing - can cause dizziness/fainting
- Cognitive Decline: Problems with memory, attention, & other cognitive functions
- Depression
- Sleep Disturbance
- Anxiety
What are some pathological findings in Parkinson’s disease?
Pathologically, PD characterized by following:
- Loss of Dopamine Neurons:
- Post-mortem examination reveals a reduction in dopamine-producing neurons in the substantia nigra - Formation of Lewy Bodies: Lewy bodies (abnormal protein aggregates that are considered a marker of dying cells) - found in affected brain regions & associated with neurodegeneration
- Involvement of CNS & PNS:
- PD affects CNS (hypothalamus, cerebral cortex, dorsal motor nucleus of the vagus) & PNS (autonomic ganglia). - Imaging Techniques:
- PET (positron emission tomography) and SPECT (single-photon emission computed tomography) scans can show ↓ in dopamine neurons in the brain
- aiding in diagnosis of PD - Causes of Cell Death:
- exact cause of cell death in PD not fully understood
- but involves oxidative stress, inflammation, proteosome dysfunction, altered mitochondrial function & impaired autophagy
How is Parkinson’s disease diagnosed?
- Pathological examination at post-mortem showing loss of dopamine neurons in substantia nigra & formation of Lewy bodies
- Imaging techniques like PET and SPECT scans that reveal ↓ in dopamine neurons in brain.
What are some of the known causes of Parkinson’s disease?
The causes of Parkinson’s disease include:
- Most cases are sporadic, with no specific known cause.
- 10-20% of cases are inherited and associated with specific genes, such as Parkin, alpha-synuclein, UCHL-1, LRRK-2, and Glucocerebrosidase (susceptibility gene).
What mechanisms are involved in the cell death of neurons in Parkinson’s disease?
Oxidative stress
Inflammation
Proteosome dysfunction leading to the formation of inclusion bodies (e.g., Lewy bodies)
Altered mitochondrial function, impairing complex I, reducing ATP production, and increasing free radical formation
Altered lysosomal pathways, leading to impaired autophagy and removal of damaged proteins and organelles from the cell.
What are the two pathways that enhance movement in Parkinson’s disease?
- The direct pathway
- The indirect pathway
How does the direct pathway work in enhancing movement?
- Dopamine acts through D1 receptors in Striatum
- inhibits inhibitory GABAergic neurons & enhances glutamic output from the thalamus to the cortex
- leading to enhanced movement
How does the indirect pathway work in enhancing movement?
- Dopamine acts through D2 receptors in the Striatum to cause disinhibition by inhibiting inhibitory neurons
- this disinhibition decreases glutamate output to the cortex, which results in enhanced movement
- activation of the D2 receptors leads to decreased activation of mACh receptors in the striatum, contributing to the enhancement of movement
What is the main goal of using L-DOPA in the treatment of Parkinson’s disease?
Increase dopamine levels in the brain (substantia niagra)
Enhance dopamine action
Improve motor function
What are the common side effects of L-DOPA?
- Anorexia, nausea, and vomiting
- Insomnia and agitation
- Tachycardia and arrhythmias
- Dyskinesia (involuntary hyperkinetic movements)
- chronic use may result in the “on-off effect” & “wearing off” of efficacy - which are related to fluctuations in L-DOPA concentration in the plasma
What are COMT inhibitors
- drugs used in treating PD
- they block the enzyme catechol-O-methyltransferase (COMT) which breaks down dopamine
- so COMT inhibitors enhance the effects of L-DOPA and prolong its action
- Examples: entacapone and tolcapone.
What are examples of COMT inhibitors used to treat Parkinson’s disease?
Entacapone: Peripherally active, increases the duration of L-DOPA response.
Tolcapone: Centrally active, allows reduction in L-DOPA usage, but has hepatotoxic side effects
