Dementia - Lecture

Question 1

What is delirium?

Answer 1

A state of mental confusion that starts suddenly and is caused by a physical condition. Acute. Often interruption of glucose/blood to brain.
‘Acute confusional state’ - aka not knowing where you are, whats happening, what time it is?

Question 2

What is the cerebral metabolic insufficient hypothesis of delirium?

Answer 2

Neurons have a very high metabolic rate
So very susceptible to interruptions in the microvasculature
During hypoxia, metabolic dysregulation causes lactate secretion from neurons.

Question 3

How do astrocytes help support neurons meet their metabolic needs?

Answer 3

Astrocytes uptake glucose via GLUT1 - uptake more than needed
Converterd to pyruvate then lactate within the cell.
Lactate is then shuttled to neurons, converted back to pyruvate and enters the TCA cycle to release energy from oxidative phosphorylation.
This is the astrocyte-neuron lactate shuttle.

Question 4

How is the astrocyte-neuron lactate shuttle system deregulated during hypoxia?

Answer 4

Lactate transported from astrocyte to neuron
Converted to pyruvate rather than entering the TCA (as no oxygen to act as terminal electron acceptor) is converted back into lactate.
Then excreted from the neuron (due to very high intracellular conc)

Question 5

What is the role of peripheral inflammation in delirium?

Answer 5

Trigger
Inflammatory molecules and cell infiltrate the CSF by crossing the BBB
Activate quiescent microglia - becomes primed - release further inflammatory mediators (TNF) and NOS?ROS - leads to neuronal dysfunction and injury
Inflammatory mediators also prime astrocytes - so loss of metabolic support to neurons
Astrocytes release more inflammatory mediators causing chemotaxis of more monocytes and leukocytes into the area (positive feedback loop)
Causes delirium and accelerated dementia

Question 6

What is a summary of contributing factors to delirium?

Answer 6

Primed astrocytes due to degenerative pathology - leads to increased immune cells and decreased metabolic support
Primed microglial due to degenerative pathology - neuronal dysfunction and injury
Vascular dysfunction (endothelial and BBB) - metabolic insufficient
Neuronal networks undergo neurodegenerative pathology - reduced integration of brain networks
Neurotransmitter distrubance - from drugs or abnormalities in brain circuits.

Question 7

How is the brainstem affected in delirum?

Answer 7

Dysregulated arousal systems/nuclei - including cholinergic, seratonergic, histamingergic and adrenergic.

Many drugs that affect these neurotransmitters can exacerbate delirium.

Question 8

What drugs can be associated with delirium?

Answer 8

GABAergic sedatives
Anticholinergic drugs
Antihistamine drugs

Question 9

What is the key difference between delirium and dementia?

Answer 9

Delirium = acute and sudden onset, identifiable cause
Dementia - chronic, progressive, slow decline

Question 10

What are the most common types of dementia?

Answer 10

Alzheimers Disease (50%)
Vascular dementia (20%)
Both can co-exist

Question 11

What is the main difference between Alzheimer disease and Vascular dementia?

Answer 11

Vascular - cerebrovascular disease - small multiple cortical and subcortical infarcts - results in step-wise progression, varying intervals between deterioration each episode vary in severity
Alzheimers - Gradual onset and progression, continuous but slow deterioration.

Question 12

What type of dementia is present in this image?

Answer 12

Parkinson’s Dementia
Loss of dopamine active transporters signals in the right dorsal striatum.

Question 13

What type of dementia is present in this image?

Answer 13

Vascular dementia
Presence of cerebrovascular disease - indicate many small infarcts - imaging modality of choice - susceptibility weighting MRI

Question 14

What type of dementia is present in this image?

Answer 14

Frontotemporal dementia
Atrophy of the left temporal lobe (slight enlargement of the left lateral ventricle)
Some atrophy of the right frontal lobe

Question 15

What type of dementia is seen in this image?

Answer 15

Alzheimers
Enlargement of the ventricles
Atrophy of the hippocampus
Enlargement of sulci, decreased gyri, particularly of the lateral fissure

Question 16

What type of dementia is seen in this image?

Answer 16

Dementia with Lewy bodies
Mild atrophy of the frontal lobe
MRI poor diagnostic image - often found by exclusion of vascular or Alzheimers dementia.
PET scan would be better to confirm

Question 17

How do the different types of dementia tend to present at diagnosis?

Answer 17

Memory loss - AD, VD
Language - AD, FTD, VaD
Visuospatial function - AD, VAD, DLB
Attention/executive function - AD, VaD, DLW
Behavioural/personality/social change - AD, FTD, VaD, DLB, PD
Motor function - VaD, DLB, PD

Question 18

What are the main players in the pathology of Alzhimers?

Answer 18

Amyloid beta plaques (considered main agent) - extra-cellular space short polypeptide abnormally folded into plaques.
Neurofilamentary tangles - made of phosphorylated Tau a microtuble binding protein - form inside the neuron.

Question 19

What is the basic pathophysiology of Alzheimers Disease?

Answer 19

Amyloid precursor protein in membrane cells regulate synaptic transmission - when cleaved incorrectly forms insoluble amyloid beta.
Decreased clearance of amyloid beta groups together to form extracellular amyloid plaques
Act as a trigger for increased inflammation
Activate kinases leading to phosphorylation of tau proteins which support microtubules, pTau is no functional and forms neurofilmant tangles inside the neuron
pTau can release extracellular and undergone pathogenic spread to nearby neurons
Leads to neuronal dysfunction, loss of synapsis and neuronal death.

Question 20

What is an early onset Alzheimer’s Disease?
How common is it?
What causes it?

Answer 20

5-10% of AD
Classed as onset before 65%
10% of these have autosomal dominant mutations in APP, PSEN1, or PSEN2
Some show APOE e4 variants this supports the Amyloid hypothesis of Alzheimers.

Question 21

What is the amyloid hypothesis of Alzheimer’s disease?

Answer 21

Amyloid Precursor protein - processed and digested in intracellular lysosomes
Forms monomers - clump together to form clumps
Lead to phosphorylation of tau and formation of neuro filamentary tangles
Triggers a cascade of many events (inflammation, alteration of calcium signalling) - that leads to neuronal death

Question 22

How can a PET scan be used to show the role of amyloid in Alzhimers?

Answer 22

More severe/closer to death
More amyloid beta in the brain
However, note that not a lot of amyloid beta in the hypothalamus.

Question 23

How does a PET scan show the role of Tau in Alzheimers?

Answer 23

Increased metabolic stress coralates to increased Tau deposition in areas of problem - particular the hippocampus in memory loss, PFC for executive function etc.
Pattern of Tau predicts the symptoms and regions of hypometabolism.

Question 24

What tends to be the current treatments for Alzheimers? Reasoning?

Answer 24

Target symptoms not pathology
Very poor outcomes
Acetylcholinesterase inhibitors - donepezil, rivastigmine, galantamine (increase brain activity)
NMDA receptor antagonist - memantine. (prevent excitotoxicity)

Question 24

What are some adverse effects of the use of NMDA receptor antagonists in Alzhimers treatment?

Answer 24

Dizziness
Headache
Lethargy

Question 25

What are some adverse effects of using acetylcholinesterase inhibitors to treat Alzheimers disease?

Answer 25

Diarrhoea
Nausea
Vomitting
Bradycardia
Muscle twitching
Nightmare - affects brainstem sleep regulation
Affects the autonomic nervous system balance - acts on PANS

Question 26

How are Amyloid beta targeting drugs being used in Alzhiemer treatment?

Answer 26

Monoclonal antibody drugs in trials - aim to prevent Abeta accumulation into plaques.
Aducanumab was approved by the FDA in June 2021 - blocks second phase of aggregation
Not approved by the European Medicines Agency

Question 27

What different types of monoclonal antibody drugs targeting amyloid beta exist?

Answer 27

Solanezumab - stops first phase aggregation
Gantenerumab - blocks fibril elongation (no protofibril formation)
Lacanemab - binds to protofibrils
Aducanumab - blocks second phase of aggregation (no fibril formation)
Donanemab - binds to plaques

Question 28

How is lecanemab indicated to treat Alzheimers?

Answer 28

Monoclonal antibody against amyloid beta
Binds to protofibrils - decreases conc of amyloid beta in the brain
Slows the rate of decline in Alzheimer’s disease by reducing the amyloid beta burden
Note improvement in dementia progression is to a less extent than decrease in amyloid.
Approved by FDA in 2023
EU banned
UK approved as safe but deemed to expensive by NICE so not offered on NHS.

Question 29

What are the risks of the use of amyloid beta targeting monoclonal antibodies?

Answer 29

Can clump together in arteries - resulting in cerebrovascular disease
Lead to rupture of blood vessels, death by stroke - occurred when being treated with the drug.

Question 30

What is the indication of donanemab for the treatment of Alzhimers disease?

Answer 30

The monoclonal antibody binds to Amyloid beta plaques - causes host immune system to clear amyloid plaques - data promising
Decrease rate of decline by 1/3
However 11 fold increase in cerebrovascular abnomalities in imaging - increased risk of cerebral haemorrhage (but none occurred)
FDA approved

Question 31

How can Tau pathology be utilised to target Alzheimer’s?

Answer 31

No drugs made it past phase 3 trial
Difficult as must make it past BBB and cell membrane into neuron.

Question 32

What is the role of APP gene in Alzheimers?

Answer 32

Codes for amyloid precursor protein
APP is processed by two pathways.
1) by alpha-secretase and gamma-secretase - forms soluble derivatives (alpha fragment) no role in Alzhiemers
2) by beta secretase and gamma secretase - forms amyloid beta as one of products - role in Alzheimers
Changes in APP gene - overexpression of APP or mutation to change structure - can increase the level of pathway two and amyloid beta formation

Question 33

What is the role of the PSN1 /PSN2 genes in Alzheimers?

Answer 33

Presenilin 1 or Presenilin 2 - are used in the protein complex of 4/5 proteins to form y-secretase.
This breaks down APP into amyloid beta.

Question 34

What is the role of ApoE allele in Alzheimers disease?

Answer 34

ApoE regulates amyloid metabolism, deposition and clearance
Apolipoprotein E4 - 20% pop but 65% AD - inc risk as inc deposition
ApoE2 (5% pop) - protective- dec Abeta
ApoE3 - 75% pop

Question 35

How is the ApoE3 Christchurch mutation protective against Alzheimer’s disease development?

Answer 35

Observed in one individual - who also have PSEN1 mutation for AD EOAD
Protective - did not develop mild cognitive impairment until 70yrs
Loads of amyloid deposition but hardly any tau - tau present was anti-correlated with amyloid
Theory mutant APOE3 not reducing amyloid beta plaque formation (leading to high levels than without) instead prevent p-tau accumulation reducing tau pathology.