Topic 8- neurodegeneration Flashcards
(42 cards)
What is Alzheimer’s disease?
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.
How is AD diagnosed?
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
What are the symptoms of AD?
- 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
What are some non-modifiable risk factors for AD?
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.
What are some modifiable risk factors for AD?
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.
Explain gross changes in the brain in AD.
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.
Explain cellular level changes in the brain in AD.
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.
Explain amyloid in the healthy brain.
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
Exlain amyloid in the AD brain.
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.
Explain Tau in the healthy brain.
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.
Explain Tau in the AD brain.
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.
Explain the pathogenesis of AD (how it arises in the first place).
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.
Explain the tau hypothesis for AD.
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.
What evidence is there for the tau hypothesis?
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.
Explain the amyloid hypothesis for AD.
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
Why is there an increase in beta-amyloid in AD?
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.
Explain the evidence for the amyloid hypothesis of AD.
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.
Explain the evidence against the amyloid hypothesis.
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.
Explain the drug treatment of AD.
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.
What are the side effects of using
acetylcholinesterase Inhibitors to treat AD?
AChEIs Loss of appetite Nausea Vomiting Diarr-hoea Cramps Head-aches Dizziness Insomnia
What are the side effects of using NMDA antagonist to treat AD?
NMDA antagonist Dizziness Headaches Tiredness Raised BP Constipation
What is parkinson’s disease?
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.
How is Parkinson’s disease diagnosed?
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).
What are the symptoms of parkinson’s disease?
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
