Unit 4 - Neurodegenerative Disease And Epilepsy

What are oligodendrocytes?

Oligodendrocytes produce the myelin sheath around neurons and allow for increased signal transduction through saltatory conduction. Note that only neurons in the white matter are myelinated

What are astrocytes?

Astrocytes help to form the blood-brain barrier, they contain feet-like structures which wrap around the endothelial cells lining the blood vessels supplying the brain. This helps to control the entry and exit of substances through the brain.

What are microglia?

Microglia are the immune cells of the brain, they have a role in phagocytosis and clearing up debris.

True or false: neurons in the CNS are not as easily replaced/ renewed thasan in other tissues

True - most CNS neurons are post-mitotic meaning they are unable to undergo further mitosis and cell division

What are causes of cell death in the CNS?

Causes of cell death in the CNS include:

• Environmental

  • Cigarette smoke

  • Insecticides

  • Heavy metals such as lead

  • Alcohol - adult and during development (fetal alcohol syndrome

• Trauma

• Disease - infection, virus, neurodegenerative diseases, oxygen deprivation e.g. in the case of a stroke

True or false: The CNS has rich glycogen stores?

False: The CNS does not have rich glycogen source and relies on constant demand of oxygen and glucos e

What happens when neurons in the CNS become injured?

Neurons in the CNS can become injured resulting in loss of myelination on the axon, as a result nerve transmission is impaired. Neurons in the peripheral nervous system can regenerate whereas in the CNS most neurons are pre-mitotic meaning that they have lost the ability to regenerate and this can lead to impaired neuronal function and death of neuron.

Define apoptosis (simple definition)

Apoptosis is programmed cell death

Define necrosis (simple definition)

Necrosis is un-programmed cell death

What is necrosis/ what causes necrosis?

Necrosis is unprogrammed cell death or accidental cell death. Necrosis occurs in response to…

• trauma/ damage to the cell

• Injury

• Ischaemia

• cancer

• poisons e.g. spiders and snakes

• inflammation

Damage to one essential component of the cell causes secondary damage/ cascade of events that leads to necrosis of the cell.

What is apoptosis and what causes it?

Apoptosis is programmed cell death and is caused by physiological processes or degenerative disease. Apoptosis occurs in stages:

• Initiation - Death signals are received by the cell, causing pro-apoptotic factors to move towards the mitochondria.

• The pro-apoptotic factors migrate to the mitochondrial membrane

• Note that pro-apoptotic factors can be intracellular or extracellular

• Effector stage - cell components such as DNA repair enzymes are deactivated

• Degradation - cell corpse and organelles remain and are phagocytosed

What enzyme work as ‘executioners’ at the end of each stage during apoptosis?

Caspase enzyme

Name different types of cell death mechanisms

• DNA damage

• Ca2+ increase

• oxidative stress

• Mitochondrial dysfunction

Explain how Ca2+ kills the cell.

Glutamate receptors can be non-NMDA and NMDA. NMDA receptors include ampa and kappa and are found on the post-synaptic membrane and are permeable to Na2+. Non-NMDA receptors are permeable to Ca2+ and impermeable to Mg2+. The Mg2+ is a regulator of the cell activation. Therefore, only when an action potential is significant enough to release excessive glutamate from the pre-synaptic membrane do we see the influx of Na2+ into the AMPA receptor. This creates a significant change in the membrane voltage potential to initiate displacement of the Mg2+ from the non-NMDA receptor. This then allows for the influx of Ca2+ into the cell.

Excessive Ca2+ can trigger cell death, this is because it causes the release of proteases which causes the formation of pores in the mitochondrial membrane. This formation of pores leads to swelling of the mitochondria and the loss of production of ATP. Opening of pores on the mitochondria can initiate apoptosis/ the release of pro-apoptotic factors and the cell dies as a result.

Ca2+ can also lead to oxidative stress

What is oxidative stress?

Oxidative stress is where ROS/ reactive oxidative species cause DNA damage. Free radicals are highly regulated in the body but in excess can cause damage to the DNA and lipid membrane which eventually leads to cell death

How can we combat cell death using therapeutic implications?

• Anti-oxidants - to reduce free radicals

• Anti-glutamatergic - Prevents excess Ca2+

• Caspase inhibitors - prevents apoptotic cascade

What are the common features of neurodegenerative diseases?

Common features of neurodegenerative diseases include:

• can be caused by genetic or environmental factors

• There is a pattern of cell death

• Deposition of proteins

• Mitochondrial changes

• No predictive testing, except genetic screening

• Treatment is symptomatic, no cure or no treatment that slows the progression of the disease

Name examples of neurodegenerative diseases

• Parkinsons disease

• Alzheimers disease

• Multiple sclerosis

• Huntingtons disease

What is protein deposition in neurological diseases?

Protein deposition can lead to apoptosis/ necrosis and ultimately cell death

• Soluble protein monomers are converted to soluble oligomers

• It is the soluble oligomers that are the toxic molecules and trigger apoptosis and cell death

What is autophagy?

Autophagy is the removal of unwanted/ excess proteins

Explain the process of autophagy

Autophagy is where we firstly have a phagophore, which forms a double membrane and is converted to an autophagosome. The autophagosome fuses with a lysosome. The lysosome then degrades/ recycles the unwanted/ excess protein. This is because the lysosome is responsible for the degradation/ recycling of organelles. Therefore, autophagy triggers cell death

True or false: Most neurological diseases are associated with possible apoptotic triggers

True: apoptotic triggers can include genetic factors or factors such as smoking, injury, trauma to the brain, reduced calorie intake, toxins etc.

How does cell death arise in stroke?

Stroke causes ischaemia and this causes cell death/apoptosis/ necrosis in regions in which ischaemia occurs.

The ischaemic conditions also also lead to vascular inflammation and the release of inflammatory mediators. These inflammatory mediators cause swelling in the brain which disrupts the BBB and causes it to become leaky.

The leaky BBB causes more inflammatory mediators to enter the cell as well as free radicals. This can all trigger apoptosis/ cell death.

There is also an excessive glutamate release, which leads to excess Ca2+ release. This excess Ca2+ can go on to cause mitochondrial dysfunction and leads to cell death

What are the 4 different types of dementia?

• Alzheimers disease

• Vascular dementia

• Dementia with Lewy bodies

• frontaltemporal dementia

What is dementia/ the characteristics of dementia?

Dementia is an umbrella term which is usually characterised by loss of memory, impaired cognitive function, loss of critical thinking, language is affected and learning capacity.

In later dementia we usually see behavioural issues, depression, agitation etc.

What are the 2 types of pathology in dementia?

• Amyloid plaques

  • Extracellular

  • Beta-amyloid accumulation

• Neurofibrillary tangles

  • Intracellular

  • Tau protein phosphorylation dysfunction

Explain how amyloid plaques lead to dementia

Amyloid plaques are produced by beta-amyloid protein. In a healthy individual, beta-amyloid protein accumulates and is removed. However, in a patient with dementia, we get an accumulation of the beta-amyloid protein. The protein monomers will form soluble beta-amyloid oligomers. The soluble oligomers are toxic and lead to cell death and neuronal death. The extracellular insoluble beta-amyloid plaques are non-toxic as they are insoluble, it is the soluble beta-amyloid oligomers that are toxic and lead to neuronal/ cell death

Explain how neurofibrillary tangles lead to dementia

Tau is a naturally occurring protein and its role is to support the function of the microtubules. In Alzheimers disease, Tau phosphorylation is dysregulated and as a result this can lead to cell death and shrinkage of the brain.

What does disease progression look like in AD?

In AD, we have early stage dementia where symptoms include mild forgetfulness, this then progresses to advanced dementia, whereby we have memory loss of recent life events and behavioural changes such as agitation and depression. In severe dementia we have loss of memory of friends and family and inability to understand language

What are risk factors of Alzheimers disease?

Risk factors of Alzheimer’s disease include:

• Strong genetic link

• Sporadic

• Trauma to the brain

• Smoking, cardiovascular disease, stroke, high cholesterol, obesity, diabetes

• Sedentary lifestyle, social isolation, hearing loss, untreated depression

• More common in females

How is dementia diagnosed?

Patient usually presents with mild forgetfulness,

• diagnosed by CT scan, PET scan or MRI

• Mini-mental state examination MMSE

• There are new diagnostic measures which measure the levels of beta-amyloid soluble oligomer toxins. However, these toxins are usually produced years before onset of symptoms so not very useful.

Briefly outline the major treatments used in AD

• Anticholinesterase inhibitors - rivastigmine, donepezil

• NMDA inhibitors - Memantine

• Psychiatric medications

• Antidepressants

• Benzodiazepines

• Very important care/ support is provided to the patient but also to friends, family and carers.

What neuron is affected in AD?

Cholinergic neurons - there is loss of cholinergic neurons in AD

Explain how acetylcholinesterase inhibitors work in the treatment of A

In AD, there is loss of cholinergic neurons. Therefore, we can increase acetylcholine levels to increase neuronal transmission. We can do this by inhibiting the enzyme acetylcholinesterase which is responsible for the breakdown of acetylcholine in the synapse. By inhibiting this enzyme, we increase levels of Ach and therefore increase neuronal transmission. An example in donepezil and rivastigmine

Explain how NMDA antagonists work in the treatment of AD

If we inhibit NMDA receptors we inhibit glutamate binding. Usually, glutamate binds to the NMDA receptor and causes displacement of Mg2+ allows for influx of Ca2+. This leads to excitatory neuronal transmission. However, if we have excessive Ca2+ it can cause mitochondrial dysfunction, inability to form ATP and the accumulation of reactive oxidative species/ free radicals which leads to oxidative stress. Therefore, by inhibiting NMDA receptors, we inhibitor excess Ca2+ so prevent mitochondrial dysfunction and accumulation of ROS (Reactive oxidative species).

An example of an NMDA antagonist is: memantine

What are side effects of acetylcholinesterase inhibitors: rivastigmine/ donepezil?

• GI side effects including nausea, vomiting, diarrhoea, loss of appetite, weight loss

• Insomnia, fatigue, abnormal dreams

• Take medication with food to reduce GI side effects

• Start at lowest dose and titrate upwards

What are the side effects of NMDA antagonists: memantine?

• GI side effects such as nausea, vomiting, constipation

• dizziness, headaches, raised blood pressure

• Start at lowest dose and titrate upwards

What new treatments are being developed for AD?

New monoclonal antibodies are being developed for use in AD with the target to slow disease progression and not just providing symptomatic relief - treats underlying disease

When would we consider using psychiatric medication in AD?

Psychiatric medications should only be used in mild-advanced dementia where behavioural therapy has already been tried. Should use at the lowest dose possible for the shortest duration of time

True or false: SSRIs are effective in AD when treating depression

False: SSRIs are not effective in AD - The reason for this is unclear

What region of the brain is affected in AD?

The hippocampus - this is where memories develop

The amygdala - emotional response unit of the brain

Both are affected in AD

We also see shrinkage of the brain

What is epilepsy?

Epilepsy is a chronic condition characterised by recurrent seizures

What are seizures?

Seizures are a symptoms of epilepsy due to excess neuronal discharge. They can be localised or spread to different regions of the brain.

In which area does the seizure originate?

Epileptic focus - this is the region of the brain in which the seizure originates.

What are the causes of epilepsy?

Most cases of epilepsy are idiopathic and we cannot identify a cause

Epilepsy could be due to a genetic factor - in a healthy person, the seizure threshold is very high whereas in epileptic threshold, the seizure threshold is very low.

May also be due to stroke, trauma to the brain, injury, infection etc

What can trigger seizures in patients with epilepsy?

Seizures can be triggered by

• Alcohol

• Illicit drug use

• Flashing lights

• Dehydration

• Lack of sleep

• Stress

• Skipping meals causing reduced blood glucose levels

• Illness

• Infection - e.g. meningitis

• Trauma/ injury to the brain

What are the 2 classifications of seizures?

• Focal seizures

  • Focal aware

  • Focal unaware

• Generalised seizure

  • Absent seizure

  • Tonic-clonic seizure

What are focal seizures?

Focal seizures are seizures which originate in a specific area of the brain

• Focal aware - This is where there is no loss of consciousness

• Focal unawareness - This is where you may see confusion, distortion of time, trouble remembering the event, loss of consciousness, may get some involuntary movements such as licking of lips, fidgeting with clothes etc.

• Typically there is confusion of amnesia after the event

What are generalised seizures?

Generalised seizures are bilateral and occur across the brain, they can be:

• Absent seizures/ non-motor: absent seizures are seizures which last for seconds or minutes and are characterised by periods of interruption in normal brain activity. Often the patient does not know they have had a seizure. Very brief “attacks”

• Tonic-clonic seizures - Tonic-clonic seizures are classified by the tonic phase which is where we see muscle contraction and the clonic phase where there is rhythmic shaking of the extremities. Before the seizure occurs there is an episode of unconsciousness which lasts for a few moments after the seizure. When the patient regains consciousness there is often confusion and memory loss

What is status epilepticus?

Status epilepticus is when we have seizures which run into each other or seizures lasting more than 5 minutes - in this case you need to call 999

What are the three acronyms which tell us what to do if someone is experiencing a tonic-clonic seizure?

Calm, Cushion, Call

True or false: To be diagnosed with epilepsy you have to have experienced more than 1 seizure.

True

Treating epilepsy: What is the aim for most patients in terms of polypharmacy?

For most patients, the aim is to reduce polypharmacy and provide seizure relief using monotherapy.

For most patients, monotherapy will be effective

Combination therapy may be considered if monotherapy fails where 2 AEDs are used.

3 different AEDs is exceptional are is rarely needed

Why is monotherapy preferred when treating epilepsy?

Monotherapy allows for:

• reduced risk of adverse effects

• increases compliance

• fewer adverse events

• lower cost

Why is there a need for new epileptic drugs?

A need for new epileptic drugs because current therapies do not treat the underlying disease, but instead helps to control symptoms.

Epileptic drugs currently have not helped to reduce mortality rates and can cause severe side effects which can reduce compliance of medication, hence there is growing need for new anti-epileptic drugs.

What is the general aim of anti-epileptics?

To prevent seizures, ideal using monotherapy

What should be considered before initiating anti-epileptic drugs?

• The type of seizures you are treating

• Other medications the patient is taking/ co-morbidities

• The age of the patient

• The sex of the patient

• Whether a women is of child-bearing age

What is the aim for anti-epileptic drugs?

Anti-epileptic drugs aim to:

• Reduce initition: This will reduce the frequency of seizures

• Reduce the region of the brain they affect by reducing transmission: This will reduce the severity of the seizures

What is the mechanism of actions of anti-epileptic drugs?

Anti-epileptics aim to reduce excitatory neuronal discharge - in epilepsy, there is excess neuronal discharge which causes seizures. The anti-epileptics aim to reduce this excitation through:

• Inhibition of Na+ voltage-gated channel

• Inhibition of Ca2+ voltage-gated channel

• Activation of GABAa receptor

• Inhibition of AMPA and Kainate receptors

• Inhibition of synaptic vesicle protein

Explain the mechanism of action of anti-epileptic drugs that work on the GABAa receptor - in your answer you should include drug examples.

The GABAa receptor is responsible for GABA binding and allows for the influx of chloride ions (Cl-) into the cell. This causes a negative membrane potential, hyperpolarisation, and prevents neuronal depolarisation and therefore prevents signal transmission.

In epilepsy, there is excess neuronal discharge, therefore, we can increase GABAa activation to increase the influx of chloride ions into the cell and therefore allows for hyperpolarisation and the prevention of neuronal transmission. Essentially, we are exploiting the GABA inhibitory neurotransmitter to prevent excess neuronal discharge and the firing of an action potential.

Examples of drugs which target the GABAa receptor include benzodiazepines, barbiturates and topiramate

Benzodiazepines, for example, bind to the allosteric site of the GABAa receptor and therefore agonise GABA binding to upregulate Cl- influx and hyperpolarise the cell, prevent depolarisation of the membrane.

Explain the mechanism of action of anti-epileptic drugs that work on the sodium voltage-gated channel receptor - in your answer you should include drug examples.

The sodium voltage-gated ion channel is. an excitatory channel and allows for depolarisation and the initiation of an action potential when Na+ ions influx the cell. The sodium voltage-gated channels can be inhibited by preventing the influx of Na+ ions to prevent depolarisation of the membrane and therefore inhibition of neuronal transmission.

Examples of drugs which target the sodium-voltage include sodium valproate, carbamazepine, lamotrigine and phenytoin

Sodium channel blockers have a use-dependent action: what does this mean?

• Use dependent blockade means that they only target sodium channels which are excessive neuronal discharge. High-frequency discharge occurs in an epileptic seizure, whereby you have excessive stimulation of the receptor. Sodium blockers are use-dependent which means that they do not effect normal functioning sodium channels/ do not affect low frequency discharge.

Explain the mechanism of action of anti-epileptic drugs that work on the calcium voltage-gated channel receptor - in your answer you should include drug examples.

Anti-epileptic drugs which target the calcium channel will vary depending on the type of calcium receptor they bind to.

L-type - found in the thalamus e.g. clonazepam and ethosuximide)

P/Q type - skeletal muscle - gabapentin and pregabalin

By inhibiting Ca2+ influx, we inhibit neuronal transmission and decrease excitatory signals

Explain the mechanism of action of anti-epileptic drugs that work on the AMPA receptor - in your answer, you should include drug examples.

AMPA receptor inhibitors - AMPA receptors are a type of non-NMDA glutamate receptor and are permeable to Na+ influx. This influx of Na+ will allow for a chnage in potential difference of the cell which will lead to influx of calcium into the cell through NMDA receptors on post synaptic membrane - leading to action potential and nerve transmission. If we inhibit binding to the AMPA receptor, we prevent nerve transmission of excitatory neuronal impulse. An example of a drug which targets AMPA receptor is perampanel

Explain the mechanism of action of anti-epileptic drugs that are SV2A inhibitors - in your answer you should include drug examples.

SV2A - Synaptic vesicle protein inhibition - if we inhibit the synaptic vesicle binding to the pre-synaptic membrane, we inhibit glutamate release and therefore prevent transmission of neural impulse. Drugs which inhibit SV2A include levetiracetam and bravercitam.

State the different mechanism of actions seen in topiramate

• Sodium voltage-gated channel inhibition

• Calcium influx inhibition

• Activation of GABAa receptors

• Inhibition of AMPA receptors

State the first-line drug for tonic-clonic (generalised seizures)

The first-line drug for tonic-clonic seizures is:

Sodium valproate - in men and women over 55 and children under 10. Not favoured in men and women below 55 - Na+ inhibitor, GABAa activator

Lamotrigine (Na+ inhibitor) or Levetiracetam (SV2A inhibitor)- Can be used in women of child-bearing age

State the first-line drug for focal seizures

Levercitam/ lamotrigine

State the first-line drug for absent seizures (generalised seizures)

ethosuximide (Ca2+ inhibitor)

State the first-line drug for status epilepticus

Benzodiazepine- diazepam - buccal or rectal delivery

What is the mechanism of action (brief) of levetiracetam and what are some side effects?

Levetiracetam is an SV2A inhibitor: inhibits synaptic vesicle protein preventing glutamate release and action potential transmission

Side effects: dizziness, diarrhoea, abdominal discomfort, neasea, vomitting, headache, insomnia

What is the mechanism of action (brief) of lamotrigine and what are some side effects?

Lamotrigine: Na+ voltage-gated channel inhibitor

Side effects: dizziness, headache, GI including diarrhoea, fatigue, irritability, changes in behaviour, sleep disorders

What is the mechanism of action (brief) of carbamazepine and what are some side effects - comment on special precautions surrounding this drug

Carbamazepine is a Na+ voltage-gated channel inhibitor

Carbamazepine is a CYP inducer and this means that it can metabolise contraceptives so women should use other forms of contraception

Carbamazepine can cause side effects such as: dizziness, headaches, sleep disorders, gastrointestinal discomfort, nausea, vomiting

What is the mechanism of action (brief) of sodium valporate and what are some side effects?

Sodium valproate inhibits sodium voltage-gated channels, and Ca2+ influx

Sodium valproate is teratogenic and therefore is preferred not to be used in women and men under 55. Preferred use is in women and men over 55 and under 10. Can be used as last resort in those under 55 if no other treatment has been effective. Patients must comply with pregnancy prevention programme to prevent congenital foetal malformations.

What is the mechanism of action (brief) of phenytoin and what are some side effects- extra information required here?

Phenytoin is a Na+ voltage gated channel receptor blocker and inhibits the influx of sodium into the channel to prevent depolarisation and the transmission of excitatory signals

Drug doses do not correlate with plasma blood concentrations, and as a result, small dose alterations can lead to large changes in plasma blood concentrations.

Phenytoin can cause side effects such as: blood disorders, bone disorders, headache, insomnia, joint disorders, vertigo, vomiting etc

What is the mechanism of action (brief) of ethosuxomide and what are some side effects?

Ethosuximide is a calcium influx inhibitor

Mostly used in absent seizures

Side effects: reduced appetite, weight loss, diarrhoea, GI upset, nausea, skin reactions, vomiting

What is the mechanism of action (brief) of benzodiazepines - when would we use a benzodiazepine in epilepsy

Benzodiazepines are GABAa activators so increase influx of Cl- which increases inhibitory transmission by maintaining hyperpolarisation.

Benzodiazepines are mostly used for acute seizures and status epilepticus

clonazepam for example used in children for acute use

Should not be used for maintenance.

Comment what type of seizure would be treated by each of the following drugs:

Lamotrigine

Levetiracetam/ brivaracetam

Sodium valproate

Carbamazepine

Phenytoin

Ethosuximide

Lamotrigine - tonic-clonic and focal seizures

Levetiracetam/ brivaracetam - tonic-clonic and focal seizures

Sodium valporate - tonic-clonic/ focal/ absent seizures

Carbamazepine - focal and tonic-clonic seizures

Phenytoin - focal and tonic-clonic seizures

Ethosuximide - absent seizures

What is anti-epileptic hypersensitivity?

Anti-epileptic hypersensitivity reaction is where a patient takes an anti-epileptic medication and gets a rash/ fever - this is a sensitivity reaction. Once this hypersensitivity reaction occurs with one medication, this reaction will occur with many anti-epileptics. If anti-epileptic hypersensitivity occurs, withdrawal of drug is needed.

What are the special considerations when starting a patient on sodium valporate?

Patients taking sodium valproate should ideally be under 10 and over 55

Used in under 55’s as a last resort if treatment failure occurs with other anti-epileptics

Patients taking sodium valproate under the age of 55 need to follow the pregnancy prevention programme

Women need to be on long term highly reliable form of contraceptive

Men whos partner is able to have children should use condoms - the partner should also be on long-term reliable contraceptive

This is because sodium valporate is teratogenic and can cause congential fetal malformations

The advice for men changed where they have to use condoms because there was evidence to suggest that children born to men taking SV has neurodevelopmental issues.

Which anti-epileptics are CYP inducers? Why do we need to know this?

• Phenytoin

• Carbamazpine

• Phenytoin

All of which are CYP inducers so they increase the metabolism of contraceptives - women should therefore switch to alternative reliable form of contraception

Is combination therapy advised in epilepsy?

In epilepsy, it is preferred to use monotherapy as this prevents side effects and adverse reactions - also increases compliance. We only use combined therapy where necessary

What is the advice when switching between brands of AED?

Different brands have different bioavailabilities and therefore switching between brands may induce seizures. Generally it is advised not to switch brands as patients often think this will induce a seizure which of course we want to avoid, especially when patient is stable. The MHRA advice on switching between brands is:

Category 1 - carbamazepine - CLINICALLY RELEVANT DIFFERENCES between brands. Do not switch between brands

Category 2 - Lamotrigine - This is for drugs which do not fit into category 1 or 3: clinical decision can be made as to whether switch is appropriate e.g. patient will go without drug if switch is not made due to supply shortage so switching brands is only way in which patient will receive anti-epileptic drug

Category 3 - levetiracetam - can switch between brands as no clinically relevant differences between brands

When is it suitable to withdraw an anti-epileptic

Withdrawal of an anti-epileptic can only be done by specialise if patient has not had a seizure in 2 years

What is the advice when withdrawing a patient from anti-epileptic?

Withdrawal should be gradual: typically 3 months but may be longer, e.g. when using benzodiazepines withdrawal will take more than 3 months

Withdrawal should not be abrupt as this can trigger severe seizure or result in status epilepticus

If a seizure occurs during discontinuation or following discontinuation, then the patient often has to contact DVLA and a driving ban for 2 years. Re-initiation of anti-epileptics may take a while to see stabilisation.

Non-drug treatments for epilepsy: Explain what diet may be recommended in children

In children, where there is a failure to response to 2 different AEDs may result in advising the patient (typically a child) to try ketogenic diet which is a high fat/ low carb diet and forces the brain to use ketones as major energy supply rather than glucose.

At what age is a patient likely to be diagnosed with Huntington's disease?

30-50 years old

What is the time frame between diagnosis and death in Huntington's disease?

15-20 years following diagnosis, the patient will die

What protein is affected by a change in gene expression in Huntington's disease?

Huntington protein

What does a typical brain with Huntington's disease look like?

10-20% lose of brain weight

insertion of Huntington protein

Loss of GABAenrgic neurons

DOPAminergic and cholinergic receptors remain mostly unaffected

What neurone is affected in Huntington's disease?

GABAergic neurons

True or false: the huntingtin protein is widely expressed in brain and periphery

TRUE

What is the role of Huntington protein?

• vital for embryonic development

• used in transcription and signalling metabolism

How does a mutation in the Huntington's protein lead to Huntington's disease?

If we have a mutation in the Huntington protein, this means we have an increased risk of having over 40 CAG repeating units. If we have over 40 CAG repeats/ lengthening of the chain, it increases the risk of Huntingtons disease. This is because the mutant protein looses its normal function and forms a toxic function. The mutant protein will cause mitochondrial dysfunction, apoptosis cascade, the production of free radicals and glutamate toxicity

Huntington's disease is caused by…

A mutation in the huntington protein where we have over 40 repeating units of CAG (cytosine, adenosine and guanine) and lengthening of the gene which causes the protein to go from functional protein to a toxic protein and induces:

• mitochondrial dysfunction

• apoptopic pathways

• the production of reactive oxidative species/ free radicals

• glutamate toxicity

Describe the symptoms seen in early stages of Huntington's disease?

In early stage Huntington's disease we may see:

• abnormal eye movements

• abnormal hand and feet movements

• general abnormal movements

Describe the symptoms seen in mid-stage Huntington's disease?

Mid-stage Huntingtons disease may present as:

• Rigid movements

• Involuntary movements

Describe the symptoms seen in late-stage Huntington's disease?

Motor impairment

• Rigid movements

• Bradykinesia - slowed movements

• stiffened movements

• involuntary movements

• impaired control over voluntary movements

Cognitive decline

• cognitive decline is selective: it is impaired in some regions by not others.

• impaired critical thinking, abstract thinking, planning etc

• language is not impaired by speech is

Psychological

• Anxiety, egocentrism, depression, compulsions which lead to addiction such as gambling or alcohol, mood affected, aggression, hypersexuality

What are the pharmacological treatments used in Huntington's disease?

Pharmacological treatments used in Huntington's disease will depend on the symptoms you are treating:

• Depression - antidepressants

• Anxiety- anti-anxiety

• Mood disturbances - anti-psychotics

• Compulsions/ addictions and aggression: anti-epileptics

• Muscle contraction/ rigidity - anti-parkinsons

What needs to be considered before initiating medication in Huntington's disease?

• We need to consider the patient and the type of symptoms they are displaying and we need to consider the disease stage as this will all affect the course of action we take