Dementia

Question 1

Define ‘dementia’

Answer 1

A syndrome that may be caused by a number of illnesses in which there is a progressive decline in multiple areas of function, including memory, reasoning, communication and ability to carry out daily activities

Question 2

What are the non-modifiable risk factors for dementia?

Answer 2

Age, genetic predisposition, family history and Down’s syndrome

Question 3

What are the modifiable risk factors for dementia?

Answer 3

High cholesterol, hypertension, diabetes, cognitive inactivity, head injury and depression

Question 4

What are the main types of depression?

Answer 4

Parkinsons, vascular dementia, Alzheimers, dementia with Lewy bodies, frontal temporal dementia and mixed

Question 5

What are the two components implicated in Alzheimer’s disease?

Answer 5

Neurofibrillary tangles (from hyperphosphorylated Tau protein) and amyloid plaques (B-amyloid peptide)

Question 6

What are the consequences of neurofibrillary tangles?

Answer 6

These hyperphosphorylated Tau protein segments present in cell bodies and neuritis which causes synaptic loss and dystrophy which leads to significant loss of cholinergic cells

Question 7

What is ‘early-onset’ Alzheimer’s disease?

Answer 7

When it occurs around 35 years of age

Question 8

What genes are involved in the development of early-onset Alzheimer’s disease?

Answer 8

Amyloid precursor protein (APP) on chromosome 21, PSEN1 (chromosome 14) and PSEN2 (chromosome 1)

Question 9

Which chromosome is APP on?

Answer 9

Chromosome 21

Question 10

Why is there a greater risk of developing Alzheimer’s disease in those with Down Syndrome?

Answer 10

Down syndrome is a trisomy 21 condition, APP (conveys greater risk of early-onset AD) is present on chromosome 21, so there is a greater likelihood of it’s influence

Question 11

Which chromosome is PSEN1 found on?

Answer 11

Chromosome 14

Question 12

Which chromosome is PSEN2 found on

Answer 12

Chromosome 1

Question 13

What is the function of PSEN1/2?

Answer 13

To cleave APP (amyloid precursor protein).

A subunit of gamma-secretase (aspartyl protease) for cleaving APP to Ab peptides

Question 14

What type of mutation is present in APP/PSEN1/PSEN2 to give rise to early onset Alzheimers?

Answer 14

Missense mutation

Question 15

Outline the pathogenesis of early-onset Alzheimers disease

Answer 15

Genetic mutation in APP/PSEN1/PSEN2 –> increased proteolysis of APP to Ab peptides or increased production of APP –> accumulation of A-beta peptides in interstitium –> deposition and aggregation to form plaques –> inflammatory response –> microglial activation and astryocytosis –> altered metabolism, damage, oxidative stress and altered kinase/phosphatase activity –> hyperphosphorylation of Tau –> tangles –>neuronal dysfunction and death in hippocampus and cerebral cortex

Question 16

What is ‘late onset’ Alzheimer’s?

Answer 16

Occurs in those aged 60

Question 17

What gene is associated with late-onset Alzheimers disease?

Answer 17

Apolipoprotein E on chromosome 19

Question 18

By what two pathways may APP be cleaved?

Answer 18

Non-amyloidogenic: by alpha or gamma secretes

Amyloidogenic: by beta and gamma secretase to make amyloid peptides (Abeta)

Question 19

How does the presence of ApoE4 affect a persons chance of developing Alzheimers?

Answer 19

ApoE4 increases risk for late-onset AD as it decreases the clearance of extracellular amyloidogenic Ab peptides which contribute to plaque formation

Question 20

Which iso form of ApoE may be neuroprotective against late-onset Alzheimers disease?

Answer 20

ApoE2

Question 21

How may Alzheimers disease be diagnosed from CSF?

Answer 21

Amyloid decreases in CSF and more hyperphosphorylated tau in the CSF

Question 22

Explain how acetylcholinesterase inhibitors may be used in the treatment of Alzheimers disease

Answer 22

Increase cholinergic stimulation in the forebrain –> stimulates cortical and limbic structures

Question 23

What type of drugs are donepezil, galantamine and rivastigmine?

Answer 23

Acetylcholinesterase inhibitors

Question 24

What type of drug is memantine?

Answer 24

NMDA receptor antagonist

Question 25

Explain how NMDA receptor antagonists be used in the treatment of Alzheimers disease

Answer 25

AD may be associated with slow excitotoxicity from increased glutamate causing excess calcium influx causing production of free radicals and ROS which can cause mitochondrial dysfunction. Therefore by blocking the NMDA glutamate receptor it may prevent this from happening

Question 26

Which pathways degenerate in Alzheimers disease?

Answer 26

Cholinergic pathways in the forebrain which innervate the cortical and limbic structures

Question 27

What is the normal function of tau protein?

Answer 27

Stabilises microtubules through four tubular binding domains

Question 28

Why is the phosphorylation of tau a problem for it’s function?

Answer 28

When phosphorylated it cannot bind to the microtubules to stabilise them