Week 7-Week 7-Acquired Brain Injury & Neurodegenerative Diseases

Question 1

Hippocampal lesions on the brain
What happens when the hippocampus is damaged? What it has taught us in regards to the role of the hippocampus in memory formation?

Answer 1

Patient H.M(1953)- severe epilepsy and needed surgery to remove the temporal lobe(lesion of the hippocampus) of the brain- cognitive consequences (even though above IQ no psychological illness)

-HIGH ANTEROGRADE AMNESIA(couldn’t form new long term memories; can remember things before surgery)

Removal of Hippocampus:
Not affected:
-Working memory: e.g. remembers names for as long as not distracted
-Old Procedural: e.g. language normal
-New Procedural: e.g. can learn new sports and skills
(Procedural memory not affected- learning new skills)
-Facts/events from before damage: e.g. recognises his mother. Old memories are still intact.

Affected:

• New facts/events: e.g. cannot remember new acquaintances
• ..severe anterograde amnesia – evidence that hippocampus is critical for forming new memories

Question 2

How is Korsakoff’s Syndrome caused and what does it teach us about the hippocampus?

Answer 2

Korsakoff syndrome is caused by thiamine deficiency due to alcoholism.

Results in damage to the thalamus (and general cortical atrophy). PARTICULAR DAMAGE TO THALAMUS.

Severe anterograde but also retrograde amnesia
Suggests THALAMUS IS IMPORTANT for forming but also recalling memories

But.. earlier memories are better preserved (temporal gradient in retrograde amnesia.

Suggests that, over a long time-frame, memories get stored in a way that doesn’t require thalamus

Question 3

How is Korsakoff’s Syndrome caused and what does it teach us about the hippocampus?

Answer 3

Korsakoff syndrome is caused by thiamine deficiency due to alcoholism.

Results in damage to the thalamus (and general cortical atrophy). PARTICULAR DAMAGE TO THALAMUS.

Severe anterograde but also retrograde amnesia
Suggests THALAMUS IS IMPORTANT for forming but also recalling memories

But.. earlier memories are better preserved (temporal gradient in retrograde amnesia. (memories from childhood more likely to be recalled than recent memories)

Suggests that, over a long time-frame, memories get stored in a way that doesn’t require thalamus

Question 4

Systems consolidation of memories in the hippocampus

Answer 4

Hippocampus is important in forming new memories in the brain.

Sensory information is processed in the hippocampal formation to form a memory “episode” (Hippocampus binds info together—>memory episode)

This information is then slowly transferred to cortex.. via the thalamus (which acts like a ‘bridge’)

Overtime: memories become ‘consolidated’ in the cortex, and eventually can be retrieved without the thalamus/ hippocampal structures (Squire,2006). (Recall a memory without involving the hippocampus and thalamus)

Alternative view: over time, memories become more ‘semantic’ and stored according to their meaning. Cortex alone learning new information.

Question 5

Semantic memories without a hippocampus?

Answer 5

Some evidence that cortex can learn semantic information, independent of the hippocampus. (learning new words, names and faces etc.). Some capacity of learning; cortex on its own, without hippocampus, can learn and store info as long it’s related to MEANING.

Two patients with large lesions of hippocampus and surrounding regions were given four tests of semantic knowledge.

Earlier knowledge recall confirmed to be intact.

Both patients exhibited some capacity for new learning of words, names and faces, although performance was low.

Question 6

Hippocampal damage

Answer 6

These patient studies have provided useful insight into how memory is ORGANISED in the brain- dissociable can’t form new episodic memories but motor skills can still be learnt. Different brain regions involved.

But case studies have limitations- damage is usually not confined to a single brain structure, lots of variation (in terms of the pattern of damage) between cases

Also, the brain responds to damage, as we’ll see now in relation to Stroke.

Question 7

What is a stroke?

Answer 7

Disruption of blood supply and subsequent damage to the brain tissue.

Ischemic strokes due to blood clots most common (85%). Blod clot causes constriction or blockage of blood vessels: brain starved of oxygen.

Haemorrhagic stroke:
Rupture of blood vessels (blood is toxic for cells)

Symptoms of an ischemic stroke occur suddenly because the death of brain tissue occurs within minutes – cells surrounding stroke location deprived of blood/oxygen

Question 8

How can doctors identify if someone has a stroke?

Answer 8

Doctors can usually identify where the damage occurred based on symptoms. E.g. weakness of the left leg points to damage to the right motor cortex

Brain imaging (e.g. MRI) can be used to show the extent of the damage and where.

Question 9

What happens in the brain after a stroke?

Answer 9

The brain responds physically to stroke damage by repair processes:

• Creating new blood vessels
• Axonal growth and remyelination
• Creating new synapses and neurons

The brain responds functionally to stroke damage by reorganisation:
-Surrounding brain region (or opposite hemisphere) takes on the function that was lost –>Recovery of function is possible

Question 10

How long does it take to recover after a stroke?- Rehabilitation of Motor functions(movement/coordination)

Answer 10

Most recovery after a stroke occurs over the FIRST 3 MONTHS
-Rehabilitation is most important during this time period(Ward et al)

-Even after serious strokes, motor function can recover nearly completely within the first few months. esp if rehabilitation programmes followed

Question 11

How long does it take to recover after a stroke?- Rehabilitation of Cognitive functions (if affected frontal cortex)

Answer 11

Most common impairments are in psychomotor speed (34%) and executive function (27%)

Over 6 months, some recovery of function possible - particularly in exec function and visual memory

From 6 months onwards, limited scope for improvement.

Question 12

What is dementia?

Answer 12

Dementia = a loss of cognitive functioning that interferes with a person’s daily life and activities

Globally, dementia affected about 46 million people in 2015, and set to increase as populations age.

Question 13

What are the different types of dementia?

Answer 13

• Alzheimer’s Disease (AD) (most common: 50-70% cases of dementia)
• Vascular (multi-infarct) dementia
• Posterior cortical atrophy (PCA)

Also - Lewy body dementia, Frontotemporal dementia

Question 14

What is dementia?

Answer 14

Dementia = a loss of cognitive functioning that interferes with a person’s daily life and activities

Globally, dementia affected about 46 million people in 2015 and set to increase as populations age.

Question 15

PREVALENCE OF Alzheimer’s Disease (AD)

Answer 15

• Age biggest risk factor
• 0.5% prevalence at 55 years
• Risk then doubles every five years (60yrs: 1%, 70 yrs: 4%, 80 yrs ~15 to 20%
• About 7.7 million new cases of AD each year. Globally, someone is diagnosed every 4 seconds (Source: WHO)
• Early-onset familial Alzheimer’s disease (EOFAD) shows a clear inheritance pattern
• Minority of cases (1%), but studies have identified specific genes responsible

Question 16

PREVALENCE OF Alzheimer’s Disease (AD)

Answer 16

• Age biggest risk factor
• 0.5% prevalence at 55 years
• Risk then doubles every five years (60yrs: 1%, 70 yrs: 4%, 80 yrs ~15 to 20%)
• About 7.7 million new cases of AD each year. Globally, someone is diagnosed every 4 seconds (Source: WHO)
• Early-onset familial Alzheimer’s disease (EOFAD) shows a clear inheritance pattern
• Minority of cases (1%), but studies have identified specific genes responsible

Question 17

Symptoms and progression of Alzheimer’s Disease

Answer 17

AD preceded by Mild Cognitive Impairment phase (high risk of transition to AD in later years)

-Memory disturbance becomes severe. Initial AD symptoms are an in-memory domain
These progress to other cognitive domains; also mood and behavioural disturbances, in later stages

-Progression from mild to severe AD can take up to 10 years – varies by patient

Mild: Forgetfulness; difficulties in day to day function
Moderate: Memory loss becomes more severe; disorientation
Severe: Mood disturbances become apparent.

Question 18

Current treatment options for Alzheimer’s Disease

Answer 18

Main therapies are cholinesterase inhibitors which increase the levels of acetylcholine in the brain; these were discovered 25 years ago

• Acetylcholine (Ach) has an established role in learning and memory.
• In the synapse, ACh is broken down by acetylcholinesterase.
• By blocking that enzyme, acetylcholinesterase inhibitors (AChEIs) increase Ach

Question 19

What is the Cholernergic hypothesis for Alzheimer’s Disease?

Answer 19

• Cholinergic Hypothesis: loss of Cholinergic neurons(Ach) is the cause of AD
• Post-mortem studies in the mid-1970s found reduced levels of the enzyme responsible for the synthesis of acetylcholine (ACh), in the cortex of AD patients
• Cholinergic neurons in basal forebrain degenerate in AD, and worsen as the disease progresses
• Acetylcholinesterase inhibitors help to compensate for this, by boosting Ach

Question 20

Why is the cholinergic hypothesis no longer favoured for Alzheimer’s Disease?

Answer 20

• Treatments have limited effects
• ACh is not the only neurotransmitter affected by AD, nor is AD the only neurodegenerative disorder which shows cholinergic dysfunction.
• Cholinergic system failure might be due to the accumulation of other pathology

Question 21

What are the post-mortem brain-imaging studies to show neural signatures? What are the signs of damage in the Alzheimer’s brain?

Answer 21

In the brains of AD patients there are key markers:

• Amyloid-beta plaques
• Neurofibrillary tangles that build up inside the neuron
• Brain shrinkage(loss of brain tissue particularly in later stages)

Question 22

What are Amyloid-Plaques in AD patients?

Answer 22

Clump together OUTSIDE the neuron.
Amyloid-Beta causes very negative effects in the brain, abnormal breakdown of parent molecule APP such as the death of neurons.

-Amyloid-Beta is a fragment of a larger protein called APP found in healthy neurons.
In Alzheimer’s Disease APP gets broken down in an abnormal way.
-In AD, abnormal cleavage of APP leads to higher levels of Amyloid Beta (40 and 42).

• Amyloid-Beta 42 (insoluble) aggregates into ‘clumps’: plaques. Visible in Alzheimer’s brain.
• Plaques trigger an inflammatory response (ie. they are toxic).
• Leads to synaptic dysfunction and neuronal death
• Amyloid-Beta 40 is soluble and now thought to also be highly toxic.

Question 23

What are Neurofibrillary tangles in AD patients?

Answer 23

Clump together inside the neuron.

• Tau protein is an intracellular protein which stabilises the microtubules that transport nutrients and molecules from the cell body to the axon and dendrites.
• In AD abnormal chemical changes cause tau to become ‘hyperphosphorylated’ and clump together, which then leads to the formation of neurofibrillary tangles (NFT). These impair microtubule function and causes the cell to die.

Question 24

PROGRESSION OF AMYLOID PLAQUES IN AD

Answer 24

PET brain imaging can detect Aβ plaques in someone’s brain:
BEGIN IN HIPPOCAMPUS(in-memory domain)
-Plaques detectable very EARLY in the disease process
-The ‘amyloid cascade hypothesis’ states that β-amyloid is the initiating event in AD, which then triggers symptoms and other pathology (e.g. NFTs, loss of brain volume)

• Plaques follow a characteristic pattern as AD progresses
• Begins in hippocampal regions, then spreads into the temporal lobe, frontal; eventually affecting the entire cortex
• Tau pathology similar to that seen with amyloid, but seems to build up AFTER amyloid.

Question 25

What is the amyloid cascade hypothesis?

Answer 25

Has been the dominant theory of AD pathogenesis since the 90s.

-Familial AD implicates genes involved in the production of the precursor of beta-amyloid protein, or its processing.

But- amyloid load does not link well to symptom severity in AD (tau neurofibrillary tangles levels correlate better; causes the problems more)

Question 26

Amyloid: Predictive utility

Answer 26

High levels of amyloid plaques without any major consequences. Initiating event that causes a cascade of problems.

Problem: Up to 30% of cognitively normal controls show elevated amyloid, measured by PET scans.

But – high amyloid does link to the risk of later cognitive decline.
And predicts conversion from MCI to AD.

Question 27

How do anti-amyloid drugs work to remove amyloid from the brain?

Answer 27

Strategies include:

• Block/inhibit the overproduction or aggregation of Aβ -inhibit the enzymes which break down APP into Aβ
• Promote clearance of Aβ from brain

Question 28

How does STRATEGY 1 inhibiting overproduction of Aβ -inhibit the enzymes help AD?

Answer 28

Strategy: inhibit the enzymes which break down APP into Aβ
SEMAGACESTAT – evidence for enhanced clearance of Aβ into plasma
Increased risk of skin cancer and infections. Significant negative effects on function and cognition

Question 29

How does STRATEGY 2 promoting clearance of Aβ from brain help AD?

Answer 29

Strategy: use antibodies which bind to Aβ peptide and prevent aggregation or speed up clearance
SOLANEZUMAB - some evidence for enhanced clearance, but no effect on symptom progression

All drug treatment strategies based on Amyloid hypothesis have so far failed. To improve we should be focusing on amyloid removal earlier in life? Or target Tau( neurofibrillary tangles)?

Question 30

What is Posterior cortical atrophy dementia?

What are the symptoms?

Answer 30

PCA: An atypical variant of Alzheimer’s disease
FOCAL, affecting posterior parietal cortex ONLY.
Alzheimer- like pathology (amyloid plaques and neurofibrillary tangles).

Symptoms:

• blurred vision; light sensitivity.
• progressive inability to recognise faces and objects (“agnosia”).
• problems with spatial skills such as dressing or driving.
• impaired reading and writing.
• memory, spoken language and reasoning better preserved until the late stages.

Question 31

What is vascular (multi-infarct) dementia? What are the symptoms?

Answer 31

SILENT STROKE-small unnoticed strokes that build-up

A second most common cause of dementia
Loss of cognitive functioning due to a series of small ‘silent’ strokes

• Symptoms: progressive cognitive impairment, that occurs step-wise, after each stroke Some improvement between each event possible
• Risk factors for vascular dementia include age, hypertension, smoking, high cholesterol, diabetes
• Early detection essential: treatment involves reducing these risk factors, but diagnosis can be difficult since features overlap with other dementias

Question 32

Summary of Dementia

Answer 32

• Many forms of dementia – all can have severe effects on daily function.
• Alzheimer’s Disease most common form. Impairments begin in the Memory domain and then progress.
• The cholinergic hypothesis of AD no longer favoured- Cholinergic treatments have limited effects. (Tau-neurofibrillary tangles are probably the root cause of AD)
• Amyloid plaque buildup begins in the hippocampus and has been proposed as the initiating event in AD (amyloid cascade hypothesis) - but drugs to remove amyloid have not been effective. (treating patients too late, go back before symptoms start becoming apparent)
• Vascular dementia and PCA are other less common dementias.