Lecture 19 - Neurodegeneration Introduction Flashcards Preview

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Flashcards in Lecture 19 - Neurodegeneration Introduction Deck (18):

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

When 50-70% of Substantia Nigra cells are lost


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

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


When was the role of Dopamine in PD observed?

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

Dopamine: 1960's

α-synuclein: 1998


What is the generic progression of disease?

Apply this to PD

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


Describe the single aetiology of PD

Doesn't work for PD


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

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


What are Fasciculations?

Small, local, involuntary muscle twitches


What is the 'tantalising observation' in the Chesapeak retriever breed?

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

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


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

Compare symptom onset & associated brain locations

'More than motor symptoms!'

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

• 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


What is 'Parkinsonism'?

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


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

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)


Discuss cell involvement in Neurodegenerative disease

What are the common mechanisms of late onset ND?

• 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'


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

• It is too late for there to be a strong, classical genetic causality

• Possibility of a selective advantage in this abnormality (?)


Compare dementia in PD and AD

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

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

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


Describe the spread of disease in PD

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


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

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


What is Dementia?

Neurodegeneration does not equal Dementia
And vice versa

• 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


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

Junvenile onset:
• Strong genetic predisposition

Early onset:
• Genetic component + environmental exposure

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