Memory disorders

Question 1

What is amnesia

Answer 1

1. drug induced - alcohol!
2. head trauma - temporary or permanent
3. retrograde or anterograde
4. retrograde- erase stored memories
5. anterograde- can’t make new memories

Question 2

What is dementia

Answer 2

1. “A syndrome characterized by a decline in cognitive functions sufficient to cause impairment in social and occupational performance”
2. Loss of multiple memory categories
3. Inability to form new memories (learning)
4. Associated with general cognitive decline
5. memory impairment first presenting symptom

Question 3

What is Alzheimer’s disease

Answer 3

1. Alois Alzheimer - 1907
2. Most common dementia at >65 yrs
3. 2:1 female:male
4. memory deficits - presenting symptom
5. Initiation deficits
6. Visuo-spatial deficits
7. Language deficits - word finding - comprehension - paraphasia
8. Impaired judgment and executive functions - risk assessment
9. Psychotic episodes

Question 4

What is the gross pathology of Alzheimer’s

Answer 4

1. Early shrinkage - temporal poles, frontal cortex
2. Earliest damage in entorhinal cortex - memory and speech defects
3. progressive spread to whole cortex and subcortical structures

Question 5

What are some Diagnostic hallmarks of Alzheimer’s

Answer 5

1. Neuritic plaques (NP) - extracellular - amyloid-beta-protein
2. End up clumping into plaques extracellulary surrounding neurons
3. Neurofribrillary tangles (NFT) - intracellular - abnormal cytoskeletal protein Tau
4. Plaques can introduce intracellular tangles
5. Together they cause neurodegeneration of neurons
6. Primarily affect glutamate and acetylcholine neurones and terminals
7. Aberrant function - synapse loss - neuronal death - brain shrinkage

Question 6

What is APP

Answer 6

1. Every neuron has APP
2. Amyloid precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons.
3. Its primary function is not known, though it has been implicated as a regulator of synapse formation, synaptic plasticity and iron export.

Question 7

How is APP normally cleaved

Answer 7

1. Normally APP is cleaved by alpha-secretase to form two different peptides one of which is soluble - APPalpha which is extracellular
2. Has trophic effects -Trophic generally nourishing or stimulatory – POSITIVE EFFECTS
3. If not present brains don’t function
4. What is left in membrane is cleaved by gamma-secretase

Question 8

How is APP cleaved abnormally

Answer 8

1. Beta secretase cleaves APP instead of alpha
2. Cleaves in different part
3. When gamma cleaves what is left
4. Beta amyloid is produced
5. Causes beta amyloid plaques
6. Enhanced by apoE4
7. Thought that formation of plaque activates intracellular kinases
8. Causes hyperphosphorylation of tau
9. Tau when hyperphosphorylated clumps together to form tangles

Question 9

What are causes of AD

Answer 9

1. ABETA40/42 not normally produced
2. 90 % of AD cases are sporadic- not sure how happens
3. Beta-secretase may be enhanced - environmental, disease, inflammation
4. Genetic mutations identified in early onset AD (<65 years)
5. In presenilin genes - excess beta-secretase activity – make more Abeta42 which is MOST likely to form plaques
6. Genetic risk factor in late onset
7. ApoE4 mutations - increased aggregation

Question 10

What causes memory loss

Answer 10

1. Memory loss - loss of neurones and their connections
2. Probably not direct impairment of memory mechanisms (LTP)
3. But - Abeta40/42 MAY block LTP

Question 11

What is possible basis of neuronal death

Answer 11

1. Plaques and metal ions (Cu + Fe) react to form H2O2
2. This peroxidates membrane lipids
3. React with reactive oxygen species and disrupt their function -disrupt function of receptors
4. Excess Ca accumulation cell damage and death- caused by glutamate receptor disruption and Ca channel
5. Causes death by excitotoxicity – stroke lecture
6. Amyloid plaques hyperphosphorylated Tau which forms tangles which disrupts microtubular transport so more disruption of receptors and channels etc
7. Ca accumulation thought to phosphorylate tau even more

Question 12

How do we treat Alzheimer’s – A symptomatic

Answer 12

1. Cholinesterase inhibitors - cholinergic neurons damaged early in Alzheimer’s- first neurons to die-
   disease
2. Memantine
3. Nootropics (general cognitive enhancers)- Nothing effective yet….

Question 13

How do cholinesterase inhibitor help treat AD

Answer 13

1. Inhibit cholinesterase increases acetylcholine
2. donepezil, rivastigmine, galantamine
3. enhance ACh at nicotinic and muscarinic receptors
4. small improvements in cognition
5. not on progression- don’t stop progression of

Question 14

How does memantine help treat AD

Answer 14

1. non-competitive NMDA receptor blocker
2. Neuroprotective?
3. slight improvements in cognition

Question 15

How do we treat Alzheimer’s? B. disease progression

Answer 15

1. Secretase inhibitors - in trials
2. Anti-amyloid-beta vaccine / monoclonal antibodies – in trials
3. Anti-tau vaccine / monoclonal antibodies – in trials- just recognizes hyperphosphorylated tau
4. Copper and zinc chelators - metal ions promote plaque formation – toxic
5. Growth factors - not feasible for routine therapy
6. Antioxidants – limited evidence – eg. Vitamin C, flavinoids
7. Statins – some epidemiological evidence- cholesterol promotes amyloid deposition
8. biomarkers- for early diagnosis - very expensive- to do brain scans
9. blood test- would be ideal