Parkinson's

Question 1

Pathophysiology of PD

Answer 1

**Loss of Dopamine-Producing Neurons: **
* The hallmark of Parkinson’s disease is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, a region in the midbrain. These neurons are responsible for producing dopamine, as it plays a critical role in regulating movement.
**Reduced Dopamine Levels: **
* As these neurons die, the levels of dopamine in the striatum (a key part of the basal ganglia) decrease. The basal ganglia is crucial for coordinating smooth and controlled movements. Dopamine deficiency disrupts the normal functioning of the basal ganglia, leading to the motor symptoms characteristic of Parkinson’s disease.
**Lewy Bodies: **
* In the affected neurons, abnormal protein aggregates known as Lewy bodies are often found. These are intracellular inclusions made up primarily of a protein called alpha-synuclein.
**Alpha-Synuclein Misfolding and Aggregation: **
* Alpha-synuclein normally has a role in synaptic function, but in Parkinson’s disease, it misfolds and aggregates, forming Lewy bodies. These aggregates are thought to contribute to neuronal dysfunction and death.
**Impaired Mitochondrial Function: **
* Mitochondria are dysfunctional in Parkinson’s disease. This leads to impaired energy production and increased oxidative stress within neurons, contributing to their degeneration.
**Oxidative Stress: **
* The brain is particularly vulnerable to oxidative damage due to its high oxygen consumption. In Parkinson’s disease, the accumulation of ROS and reduced antioxidant defenses exacerbate neuronal damage.
**Disrupted Basal Ganglia Circuitry: **
* The loss of dopamine leads to an imbalance in the basal ganglia circuits, particularly the direct and indirect pathways. The direct pathway, which facilitates movement, becomes underactive, while the indirect pathway, which inhibits movement, becomes overactive. This imbalance results in the characteristic motor symptoms of Parkinson’s disease, such as bradykinesia, rigidity, and tremor.

Question 2

Symptoms of PD

Answer 2

1. Tremors: Often starting in a limb, usually the hands or fingers, even when at rest (resting tremor).
2. Rigidity: Muscle stiffness that can occur in any part of the body, leading to discomfort and limiting movement.
3. Bradykinesia: Slowness in initiating and executing movement, making simple tasks difficult and time-consuming.
4. Postural Instability: Impaired balance and coordination, increasing the risk of falls.
5. Other Symptoms: Speech changes, writing difficulties, and facial masking (reduced expression), freezing, gait disorder, dysphagia, dystonia, depression, dementia, etc.

Question 3

Stages of Parkinson’s

Answer 3

1. Prodromal
* when someone has symptoms that indicate a higher risk of developing the disease, but they don’t yet meet the diagnostic criteria. These symptoms are also known as early warning signs or preclinical symptoms.
2. Early Stage
* Symptoms: are mild and tend to be unilateral. Bradykinesia, rigidity, and tremors become more apparent at this stage.
* Impact on Daily Life: Minimal. May carry out ADLs without significant difficulty. Meds can control symptoms
3. Mid Stage
* Symptoms worsen and bilateral involvement begins, balance may become impaired (increase falls risk). Tremor, rigidity, and bradykinesia become more apparent, affecting both sides. Speech and facial expression change may develop
* Impact on Daily Life: ADL may take more time and effort, issues with walking and posture appear but can still live independently. May start progressing towards needing assistance. Slowness becomes more noticeable. Meds no longer adequately control symptoms
4. Late Stage
* Symptoms: Severe & disabiling. May become bedridden/confined to wheelchair. Motor symptoms are extreme, with marked rigidity & bradykinesia. Severe cognitive impairments are common. QoL severely diminished.
* Impact on Daily Life: nil independence with ADL

Question 4

Meds for PD

Answer 4

• Dopamine: madopar, sinemet
• Dopamine agonist: ropinerole, pramipexole, cabergoline, pergolide
• MAO-B inhibitor: selegiline, zelopar

Question 5

Treatment for PD

Answer 5

• Optimum Ex is undetermined.
• Multimodal approach required
• individualised approach, task-specific
• Ex may improve factors such as cognition, depression, sleep, balance, gait, strength, endurance, drug efficacy

Question 6

Interventions

Answer 6

• Gait Training
• Balance Training
• Strength Training
• Flex & ROM training
• Coordination

Question 7

Direct & indirect pathways

Answer 7

In Parkinson’s disease (PD), the direct and indirect pathways of the basal ganglia are central to understanding the motor symptoms associated with the disorder. These pathways are part of a complex network that regulates movement, involving several brain regions, including the cortex, basal ganglia, thalamus, and brainstem.

Function:
- The direct pathway facilitates movement by promoting the initiation and execution of voluntary motor activities. It is often referred to as the “Go” pathway.

Normal Functioning:
- In a healthy brain, the direct pathway begins with excitatory signals from the motor cortex to the striatum (caudate and putamen).
- The striatum contains neurons that express D1 dopamine receptors. When dopamine is released from the substantia nigra pars compacta (SNc) and binds to these D1 receptors, it excites the striatum.
- The striatum then sends inhibitory signals to the internal segment of the globus pallidus (GPi) and substantia nigra pars reticulata (SNr).
- Inhibition of GPi/SNr reduces their inhibitory output to the thalamus.
- With less inhibition, the thalamus becomes more active, sending excitatory signals back to the motor cortex, thus promoting movement.

In Parkinson’s Disease:
- PD is characterized by the degeneration of dopaminergic neurons in the SNc, leading to reduced dopamine levels.
- With less dopamine binding to D1 receptors in the striatum, the excitatory influence on the direct pathway is diminished.
- As a result, the GPi/SNr remains more active, exerting stronger inhibitory effects on the thalamus.
- This increased inhibition of the thalamus results in reduced excitatory output to the motor cortex, leading to difficulty initiating and executing movements, which manifests as bradykinesia (slowness of movement) and akinesia (difficulty in initiating movement).

Function:
- The indirect pathway inhibits movement by preventing unnecessary or excessive motor activity. It is often referred to as the “No-Go” pathway.

Normal Functioning:
- The indirect pathway also starts with the motor cortex sending excitatory signals to the striatum.
- However, this pathway involves neurons in the striatum that express D2 dopamine receptors. Dopamine from the SNc normally inhibits these neurons.
- When these striatal neurons are activated, they send inhibitory signals to the external segment of the globus pallidus (GPe).
- Inhibition of the GPe leads to reduced inhibition of the subthalamic nucleus (STN).
- The STN then sends excitatory signals to the GPi/SNr, increasing their inhibitory output to the thalamus.
- This heightened inhibition from the GPi/SNr to the thalamus decreases thalamic excitatory output to the motor cortex, thereby suppressing movement.

In Parkinson’s Disease:
- Due to the loss of dopaminergic neurons in PD, there is less dopamine to inhibit the D2-expressing neurons in the striatum.
- This disinhibition results in increased activity of the striatal neurons that project to the GPe, thereby increasing inhibition of the GPe.
- With the GPe more inhibited, the STN is less inhibited and becomes more active.
- The overactive STN sends stronger excitatory signals to the GPi/SNr, leading to even greater inhibition of the thalamus.
- The excessive inhibition of the thalamus results in reduced stimulation of the motor cortex, contributing to the rigidity and bradykinesia observed in PD.

• Direct Pathway Dysfunction: Leads to reduced facilitation of movement due to excessive inhibition of the thalamus, contributing to motor symptoms like bradykinesia and akinesia.
• Indirect Pathway Dysfunction: Results in increased suppression of movement due to enhanced inhibition of the thalamus, contributing to rigidity and bradykinesia.

Together, these dysfunctional pathways contribute to the hallmark motor symptoms of Parkinson’s disease: bradykinesia, rigidity, tremor, and postural instability. Understanding these pathways is crucial for developing treatments that aim to restore the balance between these two pathways, such as dopaminergic medications and deep brain stimulation (DBS).