Neurological Diseases

Question 1

List some similarities between Parkinson’s and Huntington’s disease

Answer 1

• Neurodegenerative
• Affect the basal ganglia
• Overt motor impairments
• Early non-motor impairments
• No cure

Question 2

What is the cause of Parkinson’s disease?

Answer 2

Multifactorial
Sporadic (80%)
Degeneration of dopamine neurones in substantia nigra and striatum - neuronal loss of the dopaminergic nigrostriatal pathway
Could be genetic cause, pathogen, toxic agents, injury/trauma

Question 3

Name the 4 cardinal symptoms of Parkinson’s disease

Answer 3

Tremor
Bradykinesia (slow movement)
Rigidity
Postural instability

Question 4

List 7 classical symptoms of Parkinson’s disease (excluding the 4 cardinal symptoms)

Answer 4

Micrographia
Dysphagia
Altered posture
Shuffling gait
Forward tilt of the trunk
Reduced arm swinging
Speech disabilities

Question 5

Explain the diagnosis of Parkinson’s disease

Answer 5

Need to show 3/4 cardinal symptoms for a preliminary diagnosis
Then do a PET scan for loss of dopamine in the brain
Can then do a test treatment to see if you response well to dopamine

Question 6

List 4 non-motor symptoms of Parkinson’s disease

Answer 6

Mental changes (e.g. dementia, depression)
Autonomic nervous system dysfunction (e.g. sexual dysfunction, constipation)
Sleep disturbances
Sensory phenomena

Question 7

Which is the primary pathway lost in Parkinson’s disease?

Answer 7

Nigro-striatal - from the substantia nigra to the striatum - sensory stimuli and movement

Question 8

Which system degrades later on in Parkinson’s disease

Answer 8

Mesolimbic system - involved in cognitive/emotional behaviour

Question 9

Explain the neurological pathway function in Parkinson’s disease

Answer 9

Degeneration of domanine neurones in the substantia nigra results in less dopamine projection to the striatum. Therefore there is loss of the direct pathway (usually stimulated by dopamine), this leads to
Increased indirect pathway activity (medium spiny neurones), which inhibits the external Globus Pallidus (GPe) through GABA release from the striatum
This increased inhibition means lesser activity/less GABA release from the GPe, so there is less inhibition of the sub thalamic nucleus (STN)
This increases the STN’s stimulatory glutamate output to the internal Globus Pallidus (GPi)
The GPi is also receiving less inhibition from the striatum due to the loss of the direct pathway
Therefore there is an increase in the inhibitory GABA output from the GPi to the thalamus
This decreases the excitatory glutamate output from the thalamus to the striatum and cerebral cortex
This results in reduced output to the brainstem and spinal cord, leading to reduced movement

Question 10

What is the cause of Huntington’s disease?

Answer 10

Autosomal dominant inherited mutation (100 penetrance) in huntingtin protein - misfolds and aggregates in the brain. Also medium spiny neurones degenerate.

Question 11

Which disease, Huntington’s or Parkinson’s, is fatal?

Answer 11

Huntington’s

Parkinson’s will eventually lead to death but due to related causes

Question 12

Which disease, Huntington’s or Parkinson’s, is hyperkinetic?

Answer 12

Huntington’s

Parkinson’s = hypokinetic

Question 13

Describe the huntingtin protein and the changes that occur due to the mutation

Answer 13

Huntingtin is a 348kDa cytoplasmic protein encoded by the HTT gene on chromosome 4. It is ubiquitously expressed and involved in many processes such as neurogenesis, metabolism, transcription regulation, intracellular signalling and transport, and synaptic activity.
When mutated, there is a CAG (glutamine) repeat expansion - the length of the PolyQ expansion can vary. This results in misfolding of the protein and aggregation in the brain.

Question 14

What can be used to treat Parkinson’s disease?

Answer 14

Dopamine drugs - but take with caution as can also cause dyskinesia

Question 15

Which regions of the brain are lost in Parkinson’s and Huntington’s disease?

Answer 15

Parkinson’s: substantia nigra

Huntington’s: striatum and cortex, then other regions

Question 16

What are the first motor signs of Huntington’s disease?

Answer 16

Abnormal eye movements, inappropriate hand and toe movements, general restlessness. Neuropsychiatric conditions can occur many years prior but these may not be noticed until the motor signs develop.

Question 17

What are the mid-course motor signs of Huntington’s disease?

Answer 17

Onset of involuntary movements (chorea), hypertonic rigidity and dystonia, difficulty moving

Question 18

What are the late stage motor signs of Huntington’s disease?

Answer 18

Impaired involuntary movements, rigidity, Bradykinesia (slowness in movement execution), convulsions, weight loss, dystonia, muscle contraction cause twisting, repeptitive movements, abnormal postures.
At this stage the appearance overlaps with Parkinson’s.

Question 19

How many CAG repeats are needed in the expansion to cause Huntington’s disease?

Answer 19

Greater than 40 (35-39 at greater risk). More than 70 will cause juvenile Huntington’s - the more repeats, the earlier the onset.

Question 20

What is are the usual ages of onset of Parkinson’s and Huntington’s disease?

Answer 20

Parkinson’s: ~60 y/o

Huntington’s: ~40 y/o

Question 21

What are the cognitive symptoms of Huntington’s disease?

Answer 21

Executive function: planning, rule acquisition, abstract thinking, initiating appropriate actions and inhibiting inappropriate actions
Psychomotor function
Perceptual and spatial skills of self surrounding and environment affected
Learning new skills is affected

Question 22

What are the neuropsychiatric symptoms of Huntington’s disease?

Answer 22

Prevalent and varied
Apathy in later stages, irritability, depression, affective disorders, psychotic symptoms (delusions, hallucinations), compulsions (which can often lead to addictions).

Question 23

Explain the neurological pathway function in Huntington’s disease

Answer 23

Due to the degeneration of medium spiny neurones in the striatum there is reduction in the indirect pathway to the external Globus Pallidus (GPe).
This decreased of inhibition of the GPe causes increased GABA output from the GPe, which inhibits the activity of the sub thalamic nucleus (STN)
This results in decreased stimulatory glutamate output from the STN to the internal Globus Pallidus (GPi)
There is a reduction in inhibitory GABA output from the GPi to the thalamus
Therefore there is greater excitatory output of glutamate from the thalamus to the striatum and the cerebral cortex.
This results in increased output to the brainstem and spinal cord, leading to increased movement

Question 24

Which region of the brain increases in Huntington’s disease?

Answer 24

Ventricle

Question 25

Which medium spiny neurones are lost first in Huntington’s disease?

Answer 25

Enkephalin containing medium spiny neurones - project from the striatum to the GPe

Question 26

Which medium spiny neurones are lost in the later stage of Huntington’s disease?

Answer 26

Substance P containing medium spiny neurones - project from the striatum to the GPi

Question 27

Does the brain have regenerative capacity?

Answer 27

Yes, there is a constant low level of neurogenesis. There is a high level of neurogenesis in the dentate gyrus and sub ventricular zone. There is not enough neurogenesis or differentiation to over come brain trauma or disease.

Question 28

What are Lewy bodies?

Answer 28

Spherical eosinophilic inclusions present in the CNS and PNS in Parkinson’s disease