Topic 8- neurodegeneration

Question 1

What is Alzheimer’s disease?

Answer 1

Alzheimer’s disease (AD) is a neurodegenerative disease, meaning there is progressive loss of structure or function of neurons, which can result in the death of neurons.

It was first described by Alois Alzheimer in 1906. It is just one type of dementia, accounting for around 62% of those who suffer from dementia.

Prevalence (number of people with the condition at any single point in time) is around 1 in 127. In the U.K. there are around 506,000 people with AD.

Incidence rates (the number of new cases i.e. of someone becoming ill) ~¼ of the prevalence rates indicating that disease duration is about 4 yrs. There are around 125,000 new cases each year in the U.K.

It is more prevalent in women than men.

Only around 44% of those with dementia receive a diagnosis in the UK. Two thirds of people with dementia live in the community while one third live in a care home.

Question 2

How is AD diagnosed?

Answer 2

Diagnosis of AD includes several different things:

Clinical interview or assessment with patient and informant

Mental and physical health examination

Blood tests to rule out other conditions

Structural imaging (CT or MRI) is recommended for all patients

Amyloid PET imaging if available

Question 3

What are the symptoms of AD?

Answer 3

• Memory loss
• Incorrect language use (forgetting words or using them incorrectly)
• Problems speaking,
  reading, writing and understanding
• Disorientation in time and
  space
• Poor or impaired judgement
• Impaired abstract thinking
• Misplacing things
• Personality changes
• Difficulty with daily functioning

Question 4

What are some non-modifiable risk factors for AD?

Answer 4

Non-modifiable risk factors AD include:

Age is the main risk factor – your risk of developing AD doubles every five years after the age of 65 years.

Family history – there is thought to be some genetic component to AD especially the early onset kind and therefore this is a risk factor.

Down’s syndrome – individuals with Down’s syndrome are at an increased risk of developing AD.

Question 5

What are some modifiable risk factors for AD?

Answer 5

Modifiable risk factors include:

Several lifestyle factors and conditions associated with cardiovascular disease are thought to increase the risk of AD.

Alcohol and cigarette smoking may increase the risk of AD.

Obesity increases the risk of AD.

Lower levels of education can also increase risk.

Social isolation can increase risk of AD.

Physical exercise/fitness may be a protective factor.

Question 6

Explain gross changes in the brain in AD.

Answer 6

Changes have been found in the brain at both a gross and micro-structure level:

The most obvious change is a loss of volume particularly to frontal and temporal areas with enlarged sulci (gaps) between gyri (ridges).

Loss is pronounced in the hippocampus (critical for memory formation) and rate of loss of volume is correlated with the rate of loss of cognition.

Question 7

Explain cellular level changes in the brain in AD.

Answer 7

There are changes at a cellular level as well in AD:

There appears to be selective loss of cholinergic neurons. It is not clear why these neurons are susceptible to damage.

The most prominent changes are actually at a subcellular level and involve two key proteins:

• Beta Amyloid which is produced from Amyloid Precursor Protein (APP).
• Hyperphoshophylated tau protein which is formed from normal tau protein.

These two proteins form amyloid (senile) plaques and neurofibrilliary tangles throughout the cortex.

Question 8

Explain amyloid in the healthy brain.

Answer 8

Although the Amyloid Precursor Protein (APP) can turn into beta amyloid which contributes to AD pathology, APP in itself is not dangerous. It fulfils a range of useful functions including:

• Synapse formation
• Neuronal plasticity
• Iron regulation

APP is coded for on chromosome 21 (trisomy in Down’s syndrome). It is typically cut up by secretase enzymes:

• Alpha-secretase normally cuts it just outside the cell membrane.
• Gamma-secretase normally cuts it in the membrane.
• The products are not harmful in anyway.
• In healthy people, this pathway is used 90% of the time

Question 9

Exlain amyloid in the AD brain.

Answer 9

In AD it is the actions of a different secretase that is thought to give rise to plaques:

Beta-secretase normally cuts it higher up than alpha (further above the cell membrane).

Gamma-secretase normally cuts it in the membrane (no change).

This results in a longer segment. It is believed that this segment can form the plaques we see in AD.

The balance between the availability of alpha and beta secretase therefore determines the likelihood of the beta/harmful fragment being formed.

In healthy people this pathway is in use about 10% of the time but the beta amyloid is normally cleared away easily. In the AD brain, there is either more beta being produced or less being cleared away and this is harmful.

Question 10

Explain Tau in the healthy brain.

Answer 10

As with APP, tau has important functions in the healthy brain. In particular tau is involved in axon transport:

Because axons are quite long movement of mitochondria, lipids, synaptic vesicles, proteins, and other organelles down the axon cannot be by diffusion alone.

Additionally waste needing degrading must get back to the cell body to be broken down by lysosomes so there is designated transport processes.

Microtubules are part of the cytoskeleton and they run the length of the axons to support transport towards the terminals.

Tau protein helps stabilise the microtubules.

Question 11

Explain Tau in the AD brain.

Answer 11

It is believed that in AD the tau protein becomes hyperphosphorylated (too many phosphate molecules stick to it). This means that:

It can no longer stabilise the microtubule and instead forms clumps or tangles within the cell.

This impairs transport along the microtubules because they no longer provide a stable track.

The things needing transported get stuck in a kind of traffic jam and the axons and synapses eventually dysfunction or degenerate.

Question 12

Explain the pathogenesis of AD (how it arises in the first place).

Answer 12

Pathogenesis is distinct from pathology. Pathology are the changes in the brain whilst pathogenesis is the process by which these changes come about.
These are the different hypotheses for why AD occurs:

The Tau Hypothesis

The Amyloid (Cascade) Hypothesis

Inflammatory hypothesis: Beta amyloid (Aβ) triggers a range of inflammatory actions involving glial cells and the neuroinflammation could result in AD.

Oxidative stress hypothesis: Dysfunction in mitochondria results in high levels of reactive oxygen species which can damage cells.

Vascular hypothesis: AD arises due to increased age and vascular risk factors – cerebral microvascular pathology and cerebral hypoperfusion may trigger the cognitive and degenerative changes.

Cholesterol hypothesis: Cholesterol alters the secretase activity, increasing beta amyloid production.
Cell cycle hypothesis: The normal process of cell division is disrupted.

The different hypotheses are not mutually exclusive and note that they link back to a range of risk factors.

Question 13

Explain the tau hypothesis for AD.

Answer 13

This hypothesis puts the tau protein at the centre of the AD pathology:

Mutations result in increased phosphorylation of tau which is then found in a paired helical filament tau or tau tangle form unattached to microtubules, this can trigger various reaction including in microglia and ultimately result in neuronal death.
Stabilization of the microtubes fails and axonal transport fails – this causes neuronal death.
The cell death results in dementia.

Question 14

What evidence is there for the tau hypothesis?

Answer 14

Reports of a correlation between tau pathology and clinical picture:

AD severity correlates well with the increasing accumulation of NFTs.

There is a high correlation between the hyperphosphorylated tau species in the cerebrospinal fluid (CSF) of AD patients with the extent of cognitive impairment.

There is a decrease in tau filaments by target-directed drugs alleviate cognitive impairment.

Tau oligomers are found in those who go on to develop AD 20 years later suggesting they are early in the cascade.

In animal models of AD:

Stimulating excess production of tau protein aggregates leads to characteristic behavioural symptoms and memory loss even when Aβ is inhibited.

AD symptoms can be treated with tau aggregation Inhibitors which suppress the level of tau protein expression.

Phase 2 clinical trials suggest that a treatment targeting tau aggregation inhibitors may be effective.

Question 15

Explain the amyloid hypothesis for AD.

Answer 15

This is the dominant hypothesis of AD which puts beta amyloid (Aβ) as the primary pathology which starts everything off including tau pathology.

• Increase in production of AB which accumulates into oligomers and can have subtle effects on synapses
• AB oligomers clump together to form plaques
• Microglia and astrocytes are activated (inflammation)
• Altered neuronal functioning- stress
• Altered enzyme activity include phosphatases resulting in tau tangles
• Neuron and synapse loss and dysfunction of neuro-transmitters

Question 16

Why is there an increase in beta-amyloid in AD?

Answer 16

An increase in Aβ can arise for two reasons:
More beta secretase than alpha-secretase
Failure to remove any Aβ produced before it can form plaques

There are also two forms of AD: the dominantly inherited early onset form and the non-dominant form which includes sporadic. Both have ways to bring about an increase in Aβ:

In the genetic (early onset form) there is there can be mutations in APP or in two key genes Presenilin 1 or 2 which may affect the production of Aβ.

In the non-dominant form there is a failure to remove Aβ so that it can build up. This can be due to some genes (ApoE) and faulty clear-up methods.

Question 17

Explain the evidence for the amyloid hypothesis of AD.

Answer 17

Genetic evidence (potential starting point):

Mutations within and adjacent to the Aβ region of APP cause aggressive forms of familial AD. Mutations which decrease Aβ give lifelong protection from AD and cognitive decline.

Those with 3 copies of Chromosome 21 (found in Down’s Syndrome) develop AD and show abundant plaques and this chromosome has APP coded on it.

Mutations in presenilin 1 or 2 are the most common cause of early‐onset AD, and presenilin is the catalytic subunit of γ‐secretase.
ApoE4 carriers, which reduces Aβ clearance have increased risk of AD.

Other evidence:
Human Aβ oligomers decrease synapse density, inhibit LTP, and enhance long‐term synaptic depression in rodent hippocampus, and their intraventricular injection impairs memory in healthy adult rats.

Human Aβ oligomers induce tau hyperphosphorylation in cultured rat neurons; co‐administering Aβ antibodies fully prevents this.
Human biomarker studies show low CSF Aβ and positive amyloid‐PET scans precede other AD‐related changes by years.

Trials of 3 different Aβ monoclonal antibodies have suggested slowing of cognitive decline in post hoc analyses of mild (but not moderate) AD patients.

But despite early signs of use in treatment, generally considered a failure clinically.

Question 18

Explain the evidence against the amyloid hypothesis.

Answer 18

Genetic evidence (potential starting point):

Onset of dementia in Down’s Syndrome is highly variable, despite plaques in 100% of Down’s individuals by fifth decade so amyloid plaques does not necessarily mean AD.

Genetic factors linked to AD can be interpreted independently of amyloid.

Other evidence:

Aβ occurs in cognitively normal older individuals (40%).

The relationship between Aβ and tau is unclear.

There is a weak correlation between plaques and cognition.

The triggers of synapse loss, neuronal loss and neuroinflammation are unclear.

This hypothesis arguably remains the dominant one even though some people believe it has been detrimental because it has been focused on for far too long without success.

Question 19

Explain the drug treatment of AD.

Answer 19

At present there is no effective treatments that halt or reverse the disease pathology. Therefore treatments are largely about minimising the symptoms and making the individual more comfortable. They fall into:

Acetylcholinesterase Inhibitors: these prevent the breakdown of ACh which is reduced in AD. By preventing breakdown it is possible to increase ACh binding to receptors, countering the loss e.g. Donepezil. This is used for mild to moderate AD and reduces anxiety, improves motivation, concentration, memory and concentration and ability to do daily tasks.

NMDA receptor antagonists: These block the glutamate receptors, possibly reducing excitotoxicity e.g. Memantine
There is also off-label, controversial use of anti-psychotic treatments. Used for moderate to non-responsive and severe AD. This slows progression including orientation and difficulties with daily activities and may help with delusions, aggression and agitation.

Question 20

What are the side effects of using

acetylcholinesterase Inhibitors to treat AD?

Answer 20

AChEIs
	Loss of appetite
	Nausea
	Vomiting
	Diarr-hoea
	Cramps
	Head-aches
	Dizziness
	Insomnia

Question 21

What are the side effects of using NMDA antagonist to treat AD?

Answer 21

NMDA antagonist
	Dizziness
	Headaches
	Tiredness
	Raised BP
	Constipation

Question 22

What is parkinson’s disease?

Answer 22

Parkinson’s disease is a neurodegenerative disease. It is named after James Parkinson, who originally described it as the Shaking Palsy in 1817:

It is the second most common neurodegenerative disorder.
Prevalence is around 1 in 500 meaning in the U.K. there are around 127,000 people with PD.

Incidence rates ~1/12 of the prevalence rates indicating that disease duration is about 12 yrs. Around 10,000 new cases each year in the U.K.
Prevalence is around 25% higher prevalence in men than women.

Question 23

How is Parkinson’s disease diagnosed?

Answer 23

In the U.K. a GP will normally refer to a specialists e.g. neurologist for assessment.

Diagnosis will look at symptoms and consider differential diagnosis.

A diagnosis may be made if two of the following are found:

shaking or tremor in a part of your body that usually only occurs at rest

slowness of movement (bradykinesia)

muscle stiffness (rigidity)

There is no scan but SPECT scans may be used (similar to PET).

Question 24

What are the symptoms of parkinson’s disease?

Answer 24

The symptoms of PD can be classified as motor and non-motor.

Motor symptoms include:
Rigidity and tremor in extremities and head
Forward tilt of body
Shuffling gait
Reduced arm swing

Non-motor symptoms:
Impaired memory
Fluctuating attention
Impaired perception
Enhanced distractibility
Mood problems 
Increased likelihood of dementia

Question 25

What are the non-modifiable risk factors for parkinson’s?

Answer 25

Non-modifiable risk factors PD include:

• Age is a key risk factor – PD affects around 1% of people at 60 years old and this increases to 5% by 85 years.
• Gender is another risk factor; men are more likely to get PD than women. Various reasons have been suggested for this including protection by oestrogen and increased head trauma or occupational hazards for men.
• Family history; PD does have some genetic component, this is stronger in some forms.
• Ethnicity; Prevalence is greater in white populations compared to black and Asian.

Question 26

What are the modifiable risk factors for parkinson’s?

Answer 26

Modifiable risk factors include:

Head trauma – injury to the head and neck area may be a risk factor. Obviously these are rarely intentional but they are technically modifiable.

Environmental pesticides have been proposed as a risk factor, research is not conclusive.

Question 27

Explain changes in the brain in Parkinson’s.

Answer 27

Despite the widespread symptoms in PD, the initial pathology is very localised. There is loss of dopaminergic neurons:

Primary pathology is believed to be in the substantia nigra pars compacta where 80% of DA neurons can be lost prior to diagnosis.

Secondary pathology is in the ventral tegmental area where up to 50% of DA neurons may be lost.

There are other, believed to be secondary changes, to other neurons.

As well as loss of DA neurons, there are cellular inclusions called Lewy Bodies which are abnormal clumps of alpha-synuclein, which can be present in the brain in a range of neurologic diseases.

Question 28

Explain the impact of loss of dopamine in PD.

Answer 28

Dopamine neurons in the SNc send their axons to the dorsal striatum (consists of caudate and putamen), forming the nigrostriatal pathway. The striatum is a key structure in the basal ganglia:

The basal ganglia is a set of nuclei that work together to perform specific functions.

Key structures include: striatum, globus pallidus (internal and external sections), substantia nigra pars reticulata and the associated subthalamic nucleus.

These structures form a set of loops with the thalamus and cortex.

Question 29

Explain the direct pathway for a motor loop in a healthy brain where there is ample dopamine.

Answer 29

The cortex excites the striatum- dopamine acts via D1 to enhance this excitation of the striatum.

The striatum is full of GABAeric neurons which are inhibitory so when it is excited, it inhibits the basal ganglia output (the globus paalidus internal and the substantia nigra pars reticulata). Dopamine results in the stronger inhibition of the GPi and SNr.

This results in an even greater reduction of inhibition of the thalamus, which frees the thalaums up and enhances the excitation of the cortex and results in movement.

In the healthy brain, dopamine adds to the actions of the cortex and makes an even stronger push for movement.

Loss of dopaminergic inputs results in an overall reduction in movement, as seen in Parkinson’s disease.

Question 30

Explain the indirect pathway of a motor loop if no dopamine were present.

Answer 30

The indirect pathway is the one that takes a detour.

The cortex excites the striatum. The striatum inhibits inhibits the GPe (globus pallidus-external). This segment normally acts to inhibit the subthalamic nucleus (STN) however it cannot do that if it is inhibited itself so the STN experiences disinhibition- it is no longer inhibited.

This leaves the STN free to excite the basal output of the ganglia (GPi and SNR).

The GPi and SRN become very excited and pass all their inhibitory strength onto the thalamus.

The thalamus is then unable to do it’s normal job of exciting the cortex which results in a suppression in movement.

The lack of suppression in the absence of dopamine results in less movement.

Question 31

Explain the indirect pathway of a motor loop if dopamine were present.

Answer 31

Dopamine actually inhibits the striatum because instead of binding to D1 receptors it is binding to D2 receptors. Instead of contributing excitation as it does in the direct pathway, dopamine actually counters the excitation from the cortex.

This reduces the inhibition of the GPe which, in turn, reduces the inhibition of the STM.

This decreases the excitation of the GPi and SNR, resulting in decreased inhibition of the thalamus.

This means the thalamus is able to provide more excitation to the cortex, resulting in more movement.

Question 32

Explain the early onset form of Parkinson’s disease.

Answer 32

The early onset familial form of PD is considered to be an autosomal dominant form (strong genetic component) and several genes have been identified:

SNCA - α-synuclein
LRRK2 - Leucine-rich repeat kinase 2
VPS35 - Vacuolar protein sorting 35
EIF4G1 - Eukaryotic translation initiation factor 4-γ 1
DNAJC13 - Receptor-mediated endocytosis 8 (REM-8)
CHCHD2 - Coiled-coil-helix-coiled-coilhelix domain containing 2

Question 33

Explain the later onset form of Parkinson’s disease.

Answer 33

The later onset autosomal recessive form, although not considered genetic in the same way has had several key genes identified:

Parkin - Parkin
PINK1 - PTEN-induced putative kinase 1
DJ-1 - DJ-1

Question 34

What are some processes that are disrupted in Parkinson’s disease?

Answer 34

Protein aggregation

Protein and membrane trafficking

Neurite structure

Ubiquitin-proteasome system

Mitochondria function

Lysosome function

Question 35

Explain oxidative stress as a factor in PD.

Answer 35

Oxidative stress is a state of imbalance between production of reactive oxygen species (ROS) and their clearance from within the cell. Excess ROS can cause damage to cell DNA, lipids and proteins.

Question 36

Why do dopamine cells in particular die in PD?

Answer 36

DA neurons are 4x more susceptible to ROS damage, possibly due to high calcium loading.

Post mortem changes in brains of PD patients relate to ROS: decrease in antioxidant activity and evidence of ROS-mediated damage to lipids and DNA.

Calcium channel blockers which reduce oxidative stress appear to be protective.

Question 37

Explain inflammation as a factor impacting PD.

Answer 37

Inflammation is another possible factor but it is not clear whether the inflammation found in PD is a reaction to the condition or part of it.

Neuroinflammation is a feature of the pathology of PD.

Use of anti-inflammatory medication is associated with a reduced risk of PD.

Question 38

Explain the spread of lewy body pathology in PD.

Answer 38

This is the order in which the lewy body pathology spreads- this appears to spread once in the nervous system:

Peripheral nervous system, olfactory system, medulla

Locus coeruleus, reticular formation, raphe nuclei, spinal cord

Pedunculopontine nucleus, substantia nigra pars compacta, basal forebrain, limbic system

Limbic system, thalamus, temporal cortex

Multiple cortical regions

Question 39

Explain the multifactor pathogenesis of PD.

Answer 39

There could be multiple causes of the starting of hte pathology for PD.

It could be genetic, due to environmental factors such as pesticides, or beacuse of oxidative stress from increased ROS. It is likely at some point to involve mitochondrial dysfunction. All these factors can lead to the death of dopaminergic neurons.

Question 40

Explain the treatment of PD.

Answer 40

Even with unanswered questions over the pathogenesis, it is clear that reduction in dopamine drives many of the symptoms so addressing this is critical. This can be done by:

increase production

increase release

Mimic action

decrease reuptake

decrease breakdown

Question 41

Explain deep brain stimulation in PD.

Answer 41

This involves passing a very thin electrode into the brain which can stimulate a region of the brain.

The exact region used can vary slightly. The STN, GPi and SNR, and thalamus can be used.

Rather than just stimulating and exciting, deep brain stimulation seems to impose a rhythm on the structure. In PD, the loss of dopamine seems to have created an asynchrony which deep brain stimulation may help synchronise.

Question 42

Explain transplantation treatments for PD.

Answer 42

Foetal DA cells can be transplanted into the striatum where they show good survival and form connections to host neurons.

In animal models and some patients there is some signs of restoration of function, but major ethical issues make use limited.

Stem cells may provide an alternative approach. These can also be from an embryo but it may be possible to harvest stem cells from the individual patient.

Issues here include how to control the cell differentiation and division appropriately because these are pluripotent cells.