Lecture 19 - Neurodegeneration Introduction Flashcards
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
- Risk factors
• Environmental: ?
• Genes - Disease onset
• Disturbance in α-synuclein → Lewy bodies - Active disease
• Loss of Substantia nigra
• Loss of Dopamine transmission - 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
- 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
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
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
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
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
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
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
