Lecture 19 - Neurodegeneration Introduction

Question 1

At which point is onset of Parkinson’s disease seen?

Answer 1

When 50-70% of Substantia Nigra cells are lost

Question 2

What is the most important pathological marker observed in PD?
Describe some features of this

Answer 2

Lewy Bodies
 • Abnormal aggregates of protein that develop inside nerve cells
 • Displace other cell components
Primarily composed of:
 • α-synuclein

Question 3

When was the role of Dopamine in PD observed?

When was it observed that α-synuclein is the primary component of Lewy bodies?

Answer 3

Dopamine: 1960’s

α-synuclein: 1998

Question 4

What is the generic progression of disease?

Apply this to PD

Answer 4

1. Risk factors
   • Environmental: ?
   • Genes
2. Disease onset
   • Disturbance in α-synuclein → Lewy bodies
3. Active disease
   • Loss of Substantia nigra
   • Loss of Dopamine transmission
4. Failed organs
   • Motor symptoms of PD

Question 5

Describe the single aetiology of PD

Answer 5

Doesn’t work for PD

Question 6

What is the significance of ‘phenotype’ in neurodegeneration?
Give some examples

Answer 6

The clinical signs / phenotype give an indication of the brain region that has been affected

1. Amyotrophic sclerosis / Motor neurone disease
   Weakness; paralysis; increased reflexes
   → Upper motor neurone disease

Loss of reflexes; Fasciculations
→ Lower motor neurone disease

Question 7

What are Fasciculations?

Answer 7

Small, local, involuntary muscle twitches

Question 8

What is the ‘tantalising observation’ in the Chesapeak retriever breed?

Answer 8

SOD1 mutation seen in:
• Human familial MND
• Chesapeak breed also has mutations in SOD1

However, in the dog we see:
• Sensory spinal neuron pathology

Question 9

What are the clinical signs of late PD?
What is important to remember about this?

Compare symptom onset & associated brain locations

Answer 9

‘More than motor symptoms!’

• Sleep disorder
• Autonomic failure
• Motor disorder
• Dementia
• Impulsivity
• Neuro-psychiatry

Onset:
• These signs have varied onset; whether it be before disease onset, or only after the organ has failed

Brain locations; i.e. regions where the Lewy bodies are found:
• Autonomic failure: brain stem
• Impulsivity, dementia, neuro-psychiatry: pre-frontal cortex
• Motor loss, sleep disorder: mid brain

Question 10

What is ‘Parkinsonism’?

Answer 10

Completely unrelated aetiology (eg. brain trauma to SN) that shows the same symptoms as PD

Question 11

What is the connection between neurodegenerative disease and ‘misbehaving protein’, in general?

Answer 11

Each neurodegenerative disease tends to have a specific ‘misbehaving protein’

For example:
• PD: α-synuclein
• Alzheimer’s: A-β: Amyloid beta
• MND: SOD1 (plus others)

Question 12

Discuss cell involvement in Neurodegenerative disease

What are the common mechanisms of late onset ND?

Answer 12

• Each Neurodegeneration affects a system of cells
• Progressive death of specific subsets of cells

Common mechanisms:
 • 'spread' to neighbouring neurons
 • Inclusion formations
 • Axon transport problems
 • "Energetics component'

Question 13

What can be said of the genetic basis of late onset neurodegenerative disease?

Answer 13

• It is too late for there to be a strong, classical genetic causality
• Possibility of a selective advantage in this abnormality (?)

Question 14

Compare dementia in PD and AD

Answer 14

PD:
 • Executive dementia
 • Corresponding to Frontal lobe
- Executive function: problem solving
- Impulsivity

AD:
 • Amnestic dementia & language
 • Corresponding to posterior cortex
- Memory
- Language

However:
• Some PD patients have Amnestic dementia
• w/ increased levels of Amyloid-β

Question 15

Describe the spread of disease in PD

Answer 15

Spread of disease (Lewy bodies) up the neuro-axis from brain stem to the pre-frontal cortex

Question 16

If there are all these other Parkinson-like diseases (Parkinsonism), how do we ascertain that a disease is PD?

Answer 16

Insufficient to say that α-synuclein is the cause of the disease, because there are other diseases that involved these proteins

Question 17

What is Dementia?

Answer 17

Neurodegeneration does not equal Dementia
And vice versa

Dementia:
• Dysfunction of the association cortex

Fixed and progressive dementias:
• Car crash, damaged frontal cortex: disturbances of executive function
• ND: symptoms progress over time

Not all dementias are the same; combination of dysfunction in various domains:
• Memory
• Attention
• Language
• Executive function
• Impulsivity

Each of these functions has its root in various regions in the brain

Question 18

What can be said about aetiology in the following onsets of neurodegeneration:
• Juvenile onset
• Early onset
• Late onset?

Answer 18

Junvenile onset:
• Strong genetic predisposition

Early onset:
• Genetic component + environmental exposure

Late onset:
• Genetic component only evident late in life
• Strong environmental component