ACh and Cognition

Question 1

Type of transmission in basal forebrain cholinergic pathways>?

Answer 1

both wired and volume

Question 2

cholinergic pathways in the brain

Answer 2

Question 3

Nucleus Basalis of Meynert

Answer 3

Considered to be the site of confluence of the limbic system and the ascending arousal system • Non-cholinergic cells include GABAergic, peptidergic and NADPH diaphorase positive types (nNOS?) • Receives input selectively from limbic cortices and amygdala (NOT all cortices) • Receives brain stem input – dopaminergic, tryptaminergic and noradrenergic • Receives cholinergic input – from Ch1-3, and/or pontine groups

Question 4

ACh and cognition

Answer 4

o Working memory o Attention o Episodic memory o Spatial memory

Question 5

Discovery of Alzheimer’s disease

Answer 5

First described by Alois Alzheimer in 1902. • First patient, Auguste Deter, said: “I seem to have lost myself”. She died 5 years after her diagnostic. • Alzheimer called it “Disease of forgetfulness”. • Originally considered to be pre-senile dementia, but now we know is the most common form of dementia in the elderly.

Question 6

Epidemiology of Alzheimer’s disease

Answer 6

The most common neurodegenerative disease, accounting for >80% of total dementia cases in the elderly. • There are currently 47 million sufferers worldwide and it is predicted this will grow to 130 million by 2050 because of increase in life expectancy. • In 2015, the annual societal and economic cost of dementia was US$818 billion worldwide. This amount is expected to increase to 1 trillion by 2018. • In England and Wales 163,000 new cases every year (one every 3.2 minutes).

Question 7

Clinical manifestations of Alzheimer’s disease

Answer 7

Symptom pattern begins with progressive decline in ability to remember new information. • Disruption of neuronal function usually begins in brain regions involved in forming new memories. • Progression from episodic memory problems to global decline of cognitive function.

Question 8

Anatomopathology of Alzheimer’s disease

Answer 8

Progressive loss of synaptic neurons • Atrophy of hippocampus, frontal and temporoparietal cortex • Accumulation of amyloid beta (Aβ) plaques around neurons • Hyperphosphorylated microtubules associated with tau protein in the form of intracellular neurofibrillary tangles (NFT)

Question 9

Pathogenesis of Alzheimer’s disease

Answer 9

Unknown; multifactorial • Cholinergic transmission • Excessive protein misfolding and Aβ aggregation • Oxidative stress and free radical formation • Metal dyshomeostasis • Excitotoxic and neuroinflammatory processes • Tau pathology

Question 10

Cholinergic hypothesis of Alzheimer’s

Answer 10

Degeneration of neurons from the cholinergic nuclei in the basal forebrain region (specially the nucleus basalis of Meynert) and their terminals in the hippocampus. • Hippocampal atrophy and ventricle enlargement. • No effect on Brainstem Cholinergic Pathways(?)

Question 11

Acetylcholinesterase

Answer 11

Peripheral anionic site (PAS) important in AD. • Interaction of Aβ and PAS contributes to formation of amyloid plaques

Question 12

Butyrylcholinesterase

Answer 12

Expressed in the hippocampus and temporal neocortex but at lower levels than AChE. Mainly present in endothelia, glia and neuronal cells with low affinity for ACh. • In AD brain, BuChE associates with Aβ protein and may delay onset and rate of neurotoxic Aβ fibril formation. • In AD, there is a progressive increase of BuChE:AChE ratio associated with amyloid plaques and NFTs, and with gradual loss of cognition function.

Question 13

amyloid hypothesis

Answer 13

Question 14

neuroinflammation

Answer 14

Question 15

Tau pathology

Answer 15

1. Presynaptic location: Synaptic dysfunction and loss
2. Postsynaptic location: Postsynaptic dysfunction and synaptic loss
3. Nucleus location: DNA damage
4. Tau aggregates: deterioration neuronal function and spread of tau pathology

Question 16

Tacrine

Answer 16

Competitive AChE inhibitor and mAchRs modulator competitive (withdrawn)

Question 17

Rivastigmine

Answer 17

Non-selective pseudoreversible ChE inhibitor

Question 18

Galantamine

Answer 18

1) Reversible/competitive selective AChE inhibitor and nicotinic receptor modulator 2) NMDA receptor temptation

Question 19

Donepezil

Answer 19

Reversible non-competitive ChE inhibitor

Question 20

Memantine

Answer 20

1) NMDA receptor antagonist 2) Neuroprotective and nAChRs (Aβ toxicity, tau phosphorylation, neuroinflammation, oxidative stress)

Question 21

Therapies against Aβ

Answer 21

• Anti-Aβ immunotherapy: antibodies against APP, monomeric Aβ, soluble Aβ oligomers, insoluble Aβ fibrils, Aβ carrier proteins and transport channels. • γ- and β-secretase inhibitors

Question 22

Tau-targeted therapies

Answer 22

• Tau pathology may be the cause of Aβ pathology. • Strategies: 1. Inhibition tau fibril formation (chemical) 3 2. Promotion abnormal tau clearance (antibodies, vaccination) 3. Inhibition tau aggregation