PH2113 - Neurodegenerative Disease and Epilepsy 3

Question 1

Can the brain repair itself?

Answer 1

Areas of cell proliferation in the adult brain
- neurogenesis
New neurones can be formed
- in healthy adults
- important for memory
Not enough to repair in diseases

Question 2

What are the two major blood vessels that supply the brain?

Answer 2

Two major vessels supply the brain
- internal carotid
- vertebral arteries

Question 3

What is the Circle of Willis?

Answer 3

A circulatory anastomosis formed from the internal carotid, anterior and posterior cerebral arteries that supplies blood to the brain and surrounding structures

Question 4

What are the four main causes of a cerebrovascular accident?

Answer 4

Thrombosis
- obstruction of a blood vessel by a locally forming clot
Embolism
- obstruction of a blood vessel by an embolus formed elsewhere
Hypoperfusion
- lack of blood supply to the brain
- systemically low blood pressure
- e.g. shock
Haemorrhage
- an accumulation of blood within the cranial cavity

Question 5

What is an ischaemic stroke?

Answer 5

Blood flow to the brain is blocked by a blood clot
Thrombotic strokes
- when a blood clot forms in an artery
Embolic strokes
- begin with a clot forming elsewhere in the body that breaks loose and travels to the brain
- heart
- neck
Combination of symptoms
- numbness or weakness on one side of the body
- trouble speaking
- difficulty with vision or balance

Treatable with tPA within 4.5 hours

Question 6

What is a haemorrhagic stroke?

Answer 6

Weak blood vessel bursts
- bleeds into the brain
Intracerebral haemorrhage
- weak blood vessel breaking inside the brain
Subarachnoid haemorrhage
- weak blood vessel breaking on the surface of the brain
Patients will likely experience a sudden onset headache or head pain

Question 7

How does a stroke cause cell death?

Answer 7

Necrosis in the ischaemic core
Apoptosis in the surrounding tissues
Vascular response activates leukocytes and other inflammatory mediators
Acute inflammatory response
- Blood-Brain Barrier injury and further infiltration of immune cells
Leaky Blood-Brain Barrier can cause oedema and worsen tissue damage
Inflammation mediated release of cytokines and free radicals contributes to cell injury and death
Evidence for excitotoxicity (low ATP leads to Ca leakage) triggers excessive synaptic glutamate release
Excess Ca leads to mitochondrial dysfunction

Question 8

What is the typical age of onset of Parkinson’s disease?

Answer 8

60s

Question 9

What is the incidence of Parkinson’s disease in the UK?

Answer 9

1 in 500
- 10,000 diagnosed each year
- 1 in 20 will be under 40
- early onset

Question 10

How is Parkinson’s disease diagnosed? (symptoms wise)

Answer 10

3 of 4 Cardinal symptoms
- TRAP
- tremor
- rigidity
- akinesia/bradykinesia
- postural instability

The tremor doesn’t develop in many people

Micrographia
- small handwriting
Altered posture
Shuffling gait
Hypomimia
- stiff face muscles

Question 11

What is the pathology of Parkinson’s disease?

Answer 11

1960, Hornykiewicz
- PD brains had < 10% of normal dopamine levels in substantia nigra and corpus striatum

Neuronal loss of the dopaminergic nigrostriatal pathway
- serotonergic
- cholinergic
- noradrenergic pathways to a lesser extent

Lewy bodies
- protein inclusions that contained alpah-synuclein, tau
- CNS
- PNS

Question 12

What is the pathological process of Lewy bodies in Parkinson’s disease?

Answer 12

Rise up through brainstem

Pattern of symptoms as disease progresses
- constipation
- sleep disorders
- loss of sense of smell

Question 13

What other symptoms are associated with Parkinson’s disease?

Answer 13

Mental changes
- dementia
- depression
- apathy - lack of interest, enthusiasm, or concern
Motor changes
- postural instability
- freezing of gait
- speech abnormalities
- dysphagia - struggling to swallow
Autonomic nervous system dysfunction
- constipation
- sexual dysfunction
- urinary problems
- sweating
Sleep disturbances
- sleep fragmentation
- sleep apnoea
- REM behaviour disordered
- restless leg syndrome
Sensory phenomena
- pain
- dysthesia

Question 14

When is the onset of Parkinson’s disease symptoms?

Answer 14

When the critical balance of dopamine in the brain is lost

Question 15

What are the general causes of Parkinson’s disease?

Answer 15

Accidental toxin administration
Pesticide/herbicide exposure
Well water
- farms
Head injury
Virus
- sleep sickness
- viral encephalitis
Antipsychotics
- dopamine receptor agonists
Food and water
- aluminium content

Decreased risk
- smoking
- caffeine

Question 16

What is the relationship between alpha-synuclein and Parkinson’s disease?

Answer 16

Identified in Greece with mutation
Found in Lewy bodies
Known to interact with dopamine system
Spreading hypothesis
- Lewy bodies found throughout brain in sequential patterning
Additional mutations in the SNCA gene

Question 17

What is the relationship between LRRK2/Park 8 and Parkinson’s disease?

Answer 17

Multiple mutations cause familial Parkinson’s disease
- 1 - 7% of idiopathic Parkinson’s disease in Western mutations have a single mutation
- increased proportions in selected populations
- 20 - 40% in Ashkenazi Jews and North African Arabs
- protein in cytoplasm and mitochondrial membrane
- role in autophagy
- may contribute to both tau and alpha-synuclein inclusions, mitochondrial toxicity and cytoskeletal dysfunction

Question 18

How do the cells die in Parkinson’s disease?

Answer 18

Genes and environment point to:
- mitochondrial dysfunction
- mitophagy
- evidence of complex 1 inhibition/mitochondrial dysfunction
- MPTP, rotenone, paraquat
- propagation, prion-like behaviour leading to mutated proteins
- lysozomes
- indicated by GBA/Gaucher’s disease
- reduced growth factors - low GDNF/BDNF