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Neuroscience Y2S2 > Neurobiology of Disease 5 > Flashcards

Neurobiology of Disease 5 Flashcards

1
Q

Complete the passage relating to schizophrenia. (1)

Schizophrenia is a long-term mental health condition which affects the way that people experience the world.
It is often classified as a type of ……………………

A

Psychosis

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2
Q

What is the lifetime incidence of schizophrenia? (1)

A

1%

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3
Q

At what ages is the typical onset, and typical diagnosis of schizophrenia? (2)

A

Onset in adolescence

Diagnosis in late teens

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4
Q

Why is it an issue that schizophrenia can often be diagnosed much later after its onset? (1)

A

More difficult to treat effectively

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5
Q

What is the peak age of onset of schizophrenia in males? (1)

What is the peak age of onset in females? (1)

Suggest a reason why there is a difference. (1)

A

15-25yrs in males

25-35yrs in females

Women may be protected by oestrogen

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6
Q

What proportion of people with schizophrenia make a full/big recovery? (1)

A

1 in 7

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7
Q

Schizophrenia decreases life expectancy by roughly how many years? (1)

A

Two decades (20yrs)

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8
Q

Describe two general ‘time-course’ patterns of schizophrenia symptoms. (2)

A
  • Relapsing-remitting
  • Chronic progressive
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9
Q

Give three symptom categories in schizophrenia. (3)

A
  • Positive symptoms
  • Negative symptoms
  • Cognitive symptoms
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10
Q

Give four positive symptoms of schizophrenia. (4)

A
  • Reality distortion
  • Hallucinations
  • Delusions
  • Thought disorder
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11
Q

Give five negative symptoms of schizophrenia. (5)

A
  • Self-neglect
  • Social withdrawal
  • Decreased emotion
  • Apathy / no motivation
  • Poverty of speech
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12
Q

Give four cognitive symptoms of schizophrenia. (4)

A
  • Dementia
  • Deficits in working memory
  • Deficits in attention
  • Deficits in executive function
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13
Q

Give three reasons why treating schizophrenia may be difficult. (3)

A
  • Delay between onset and diagnosis
  • Heterogenous disorder with positive symptoms more easily treated than negative and cognitive symptoms
  • Patients may have reduced ability to think and reason logically (and accept/comply with treatment)
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14
Q

Briefly describe the pathophysiology behind the positive symptoms of schizophrenia. (2)

A

Hyperactivity of dopamine neurones

in the mesolimbic pathway.

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15
Q

Briefly describe the pathophysiology behind the negative symptoms of schizophrenia. (2)

A

Hypoactivity of dopamine neurones

in the mesocortical pathway.

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16
Q

Briefly describe the pathophysiology behind the cognitive symptoms of schizophrenia. (2)

A

Cortical glutamate hypofunction

Loss of GABAergic interneurones in striatum

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17
Q

True or false? Explain your answer if appropriate. (1)

As well as changes in neurotransmission, changes in postsynaptic dopamine receptors are also seen in schizophrenia.

A

True - changes seen in D2 and D3 receptors, and may contribute to the altered dopaminergic activity

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18
Q

Changes in D2/D3 receptors are often seen in schizophrenia.

Give three possible causes of receptor changes. (3)

A
  • Drug use (recreational or therapeutic)
  • Genetics
  • Altered signalling as part of schizophrenia pathology
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19
Q

Describe when structural brain changes usually manifest in schizophrenia, and how they change throughout the course of the illness. (2)

A
  • Usually present at onset
  • Do not progress with the illness
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20
Q

Given that structural brain abnormalities usually present at the onset of schizophrenia and do not progress, what does this suggest about the aetiology of the illness? (1)

A

Aetiology is more likely to be developmental rather than degenerative.

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21
Q

Complete the passage relating to structural brain abnormalities in schizophrenia. (4)

There is usually a reduced brain volume of about 6-10%, particularly in the ………………………. and ………………………..

Another structural abnormality seen is ……………………..

There may also be dysfunctional development of the ……………………..

A

Hippocampus

Temporal lobe

Enlarged ventricles

Frontal cortex

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22
Q

What percentage of people get schizophrenia if one parent has it? (1)

A

12%

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23
Q

What is the identical twin concordance rate in schizophrenia? (1)

A

50%

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24
Q

Complete the sentence relating to the genetics of schizophrenia. (3)

A genome-wide association study (GWAS) found 8 genetic polymorphisms of strong effect, with relative risks 4-20fold.

All these polymorphisms were …………………………….., some examples being …………………… and …………………………

A

rare copy number variants (CNVs)

16p11.2 deletion syndrome

22q11.21 deletion syndrome

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25
Q

The 16p11.2 and 22q11.21 deletion syndromes are associated with schizophrenia.

True or false? Explain your answer if appropriate. (1)

These copy number variants are not disease-specific and are also associated with other neurological conditions.

A

True - also associated with autism, mental retardation, and epilepsy

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26
Q

Give some examples, apart from the rare copy number variants found by the GWAS, of other genes thought to be involved in schizophrenia. (9)

A
  • Neuregulin
  • Dysbindin
  • D-amino acid oxidase
  • Proline dehydrogenase
  • Catechol-O-methyltransferase
  • Regulator of G protein signalling (RGS-4)
  • 5HT2a receptor
  • Dopamine D3 receptor
  • mGluR3
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27
Q

Give a gene/chromosomal site related to the immune system which is known to harbour genetic risk factors for schizophrenia. (1)

A

C4

(immune system complement component 4)

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28
Q

Complete the sentence relating to the genetics of schizophrenia. (2)

The SNP most significantly associated with schizophrenia lies within the …………………………….. locus on chromosome 6, near the …………………… genes.

A

major histocompatibility complex

C4

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29
Q

Mutations in (or near) the C4 genes are known to be associated with increased risk of schizophrenia.

Give two cellular/molecular consequences of mutations in the C4 genes. (2)

A

Higher expression of C4

Altered brain development (C4 KO mice show altered synaptic pruning)

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30
Q

Complete the passage relating to the C4 genes and environmental interactions in the development of schizophrenia. (3)

Higher C4A expression has been associated with ………………. (more/less) severe psychopathology symptoms, likely due to …………………………….. in the brain of schizophrenia patients, which disrupts …………………………..

*** 2 and 3 are phrases

A

More

excessive complement activity

normal synaptic pruning processes

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31
Q

Describe how mutations in the C4 gene may interact with the environment to increase risk of schizophrenia. (2)

A

C4 is a complement component of the immune system

Can interact with environmental risk factors such as infection or maternal immune activation

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32
Q

Briefly describe the ‘early lesion hypothesis’ when talking about environmental risk factors for schizophrenia. Give examples where appropriate. (5)

A

Foetal or perinatal event interacts with normal development,

particularly synapse formation.

Examples include maternal virus/infection, hypoxia, and premature birth.

Also, development can be affected by early life stress,

for example maternal neglect, inflammation, malnutrition, and urban rearing.

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33
Q

Briefly describe the ‘late lesion hypothesis’ when talking about environmental risk factors for schizophrenia. Give examples where appropriate. (2)

A

Deviation in neuronal maturation during adolescence

for example, caused by drug use, stress, social isolation

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34
Q

Complete the sentence relating to cannabis use and schizophrenia. (2)

Compared with non-cannabis users, daily use of ……………………………….. is associated with a ……………………………… risk of developing psychosis.

A

High-potency, skunk-like cannabis

fivefold increased

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35
Q

Give a hypothesis explaining why there is a 2-fold increased risk of schizophrenia for babies born in the winter. (1)

A

Thought to be due to maternal infection during pregnancy

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36
Q

Describe a mechanism of how infection in pregnancy and genetic factors may interact to cause schizophrenia. (5)

A
  • Infection causes maternal immune activation
  • Cytokine/chemokine induction
  • Activated placenta, fetal meninges, and fetal brain and blood vessels
  • Temporarily halted fetal brain development
  • No genetic susceptibility = recovery
    genetic susceptibility = immune hyperresponse and schizophrenia`
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37
Q

Maternal immune activation may cause an immune hyperresponse in foetuses with a genetic susceptibility, leading to development of schizophrenia.

Describe the mechanism of how foetal immune hyperresponse can lead to the development of schizophrenia. (5)

A
  • Chronic expression of inflammatory proteins and neurochemical changes
  • Altered developmental trajectory and connectivity
  • Increased synaptic pruning
  • Disrupted information processing
  • Altered behaviour, cognition, and emotion
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38
Q

In terms of maternal immune activation and the development of neurological illness, different phenotypes are seen, depending on the age of the embryo when the maternal immune system is activated.

What main effect on brain development (cellular/molecular), and what neuropsychiatric disorders are seen if the embryo is very young? (3)

A

Impact on neurogenesis

Positive symptoms of schizophrenia

Autism spectrum disorder

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39
Q

In terms of maternal immune activation and the development of neurological illness, different phenotypes are seen, depending on the age of the embryo when the maternal immune system is activated.

What main effect on brain development (cellular/molecular), and what neuropsychiatric disorders are seen if the embryo is close to birth? (3)

A

Impact on synaptogenesis

Negative symptoms of schizophrenia

Cerebral palsy

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40
Q

In terms of maternal immune activation and the development of neurological illness, different phenotypes are seen, depending on the age of the embryo when the maternal immune system is activated.

Why do different phenotypes arise depending on embryonic age? (1)

A

Because different events in brain development (eg, neurogenesis, axonal growth, migration, synaptogenesis) happen at different times.

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41
Q

Describe how repeated ‘hits’ over time may lead to the development of schizophrenia. (3)

A

Repeated hits (especially inflammatory or immune insults) couple with underlying genetic predisposition

which causes inappropriate inflammatory cascade

which increases risk of schizophrenia

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42
Q

How is the nigrostriatal dopamine pathway altered in schizophrenia? (1)

A

Remains unaltered

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43
Q

How is the mesocortical dopamine pathway altered in schizophrenia? (1)

A

Hypodopaminergic activity

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44
Q

How is the mesolimbic dopamine pathway altered in schizophrenia? (1)

A

Hyperdopaminergic activity

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45
Q

How is the tuberoinfundibular dopamine pathway altered in schizophrenia? (1)

A

Remains unaltered

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46
Q

Give three pieces of evidence for dopamine involvement in schizophrenia. (3)

A
  • Amphetamine (which increases dopamine) causes psychosis (similar to positive schizophrenia symptoms)
  • Effects of amphetamine are resolved by antipsychotic drugs
  • Antipsychotic drugs are dopamine D2 receptor antagonists
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47
Q

11C raclopride binds to D2 receptors in PET studies.

How would you expect the PET signal to change if amphetamine was administered? (1)

A

Signal would reduce

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48
Q

a-MPT inhibits dopamine synthesis.

What would you expect to see in terms of change in D2 receptor availability in the presence of a-MPT in people with and without schizophrenia? (1)

How could this increase in receptor availability be measured? (1)

A

People with schizophrenia show a bigger increase in receptor availability.

PET ligand (11C raclopride) which binds to D2 receptors and look for increase in signal

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49
Q

a-MPT inhibits dopamine synthesis.

In the presence of a-MPT, people with schizophrenia show a larger increase in D2 receptor availability?

Suggest two reasons why this may happen. (2)

A
  • More DA in schizophrenic patients so when DA is taken out there is a bigger difference
  • More D2 receptors altogether in schizophrenia so larger receptor availability overall
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50
Q

Complete the sentence regarding dopamine binding in schizophrenia. (2)

A theory regarding dopaminergic hyperactivity in schizophrenia suggests that the …………….. receptors may be altered to bind to DA with …………. affinity.

A

D2

higher

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51
Q

Describe the general mechanism of antipsychotic drugs. (1)

Which symptom group benefits from this mechanism? (1)

A

D2 receptor antagonism

Benefits positive symptoms

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52
Q

Why are D2 receptors particularly targeted in the treatment of schizophrenia? (1)

A

They are found in high levels in striatum (mesolimbic pathway)

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53
Q

D2 receptor number is increased in schizophrenia.

Does this contribute to the pathophysiology of the disease or is it a result of treatment? (1)

A

Unknown - it could be either

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54
Q

Clinical dose of antipsychotic drugs is dependent on …………………………………… (1)

A

the drug’s affinity for the D2 receptor.

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55
Q

How does the clinical dose of an antipsychotic drug relate to it’s IC50? (2)

A

Lower IC50 = higher affinity = lower dose needed for therapeutic benefit

IC50 relates to concentration needed to block a certain amount of D2 receptors

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56
Q

What is the main mechanism by which side effects are caused by antipsychotic drugs? (1)

A

Drugs blocking DA receptors in pathways other than the target mesolimbic pathway.

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57
Q

Briefly describe the mechanism by which extrapyramidal side effects are caused by antipsychotic drugs. (1)

A

Blockade of nigrostriatal D2 receptors

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58
Q

Give four extrapyramidal side effects which may be experienced with antipsychotic drugs. (4)

Give these side effects in the order with which they are likely to occur with treatment (earliest to latest).

A

Acute dystonia

Pseudo-parkinsonism

Akathisia

Tardive dyskinesia

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59
Q

Acute dystonia can be a side effect of antipsychotic drugs.

Describe what is seen in acute dystonia. (1)

A

Neck or spine spasms or rigidity

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60
Q

Pseudo-parkinsonism can be a side effect of antipsychotic drugs.

Describe what is seen in pseudo-parkinsonism. (3)

A

Rigidity

Tremor

Bradykinesia

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61
Q

Akathisia can be a side effect of antipsychotic drugs.

Describe what is seen in akathisia. (3)

A

Inability to sit still

Restlessness

Agitation

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62
Q

Tardive dyskinesia can be a side effect of antipsychotic drugs.

Describe what is seen in tardive dyskinesia. (5)

A

Abnormal involuntary movement of the face, mouth, or jaw.

Including:

  • Lip smacking
  • Tongue protrusion
  • Grimacing
  • Bodily writhing
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63
Q

Briefly describe the exact neurochemical change that may cause acute dystonia and akathisia in antipsychotic treatment. (1)

A

Circuitry changes in the basal ganglia

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64
Q

Briefly describe the exact neurochemical change that may cause parkinsonism in antipsychotic treatment. (1)

A

Lack of dopamine in striatum (D2 antagonism)

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65
Q

Briefly describe the exact neurochemical change that may cause tardive dyskinesia in antipsychotic treatment. (3)

A
  • Long-term dopamine excess in striatum
  • Caused by blockade of D2 causing compensatory increase in DA receptors
  • And antagonists blocking presynaptic D2 autoreceptors to increase DA release
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66
Q

Give two reasons why antipsychotics blocking D2 receptors may cause a decrease in treatment efficacy over time. (2)

A
  • Compensatory increase in receptors
  • Blockage of autoreceptors causing increased DA release
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67
Q

Of the four extrapyramidal side effects of antipsychotic drugs, which two are thought to be due to changes in basal ganglia circuitry and which two are thought to be due to changes in dopamine signalling pathways? (4)

A

BASAL GANGLIA CIRCUITRY:

  • Dystonia
  • Akathisia

DOPAMINE SIGNALLING:

  • Parkinsonism
  • Tardive dyskinesia
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68
Q

Give two examples of first-generation antipsychotics. (2)

A
  • Flupentixol
  • Chlorpromazine
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69
Q

Flupentixol is a first-generation antipsychotic.

Describe the effects of a-flupentixol and b-flupentixol on D2 receptors and schizophrenia. (2)

A

a-flupentixol selectively blocks D2 receptors and is effective in schizophrenia

b-flupentixol has no effect on D2 receptors and is not clinically active

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70
Q

Chlorpromazine is able to improve the positive symptoms of schizophrenia by acting on what dopaminergic pathway in the brain? (1)

A

Mesolimbic

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71
Q

Complete the sentence relating to the side effects of chlorpromazine. (3)

Chlorpromazine may cause extrapyramidal side effects because it binds to and blocks ………………… receptors, and there are high levels of these receptors in the striatum. Therefore the ……………… dopamine pathway is affected.

A

D2

nigrostriatal

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72
Q

Give a neuroendocrine side effect which could be seen with chlorpromazine. (1)

A

Hyperprolactin

73
Q

Describe the mechanism by which chlorpromazine may have an anti-emetic (side) effect. (2)

A

D2 antagonism

in the chemoreceptor trigger zone (CTZ)

***CTZ also called the area postrema, in the medulla oblongata

74
Q

Briefly describe the mechanism by which chlorpromazine can cause weight gain. (1)

A

5HT2c antagonism

75
Q

Is clozapine a first-generation, or atypical antipsychotic? (1)

A

Atypical

76
Q

When would clozapine be used to treat schizophrenia? (1)

A

If a patient is resistant to benefit from other antipsychotics.

77
Q

Describe the affinities of clozapine for the D2, D3, and D4 receptors. (3)

A

D2 - low

D3 - high

D4 - high

78
Q

Why does clozapine cause less extrapyramidal side effects than other antipsychotics? (2)

A

High affinity for D3/D4 and lower affinity for D2

So doesn’t affect nigrostriatal pathway as much

79
Q

Clozapine can antagonise other receptors apart from dopamine receptors to cause side effects.

What two other receptors may facilitate these effects? (2)

A

Muscarinic

a-adrenoreceptors

80
Q

Apart from dopamine, give four other neurotransmitters which may be involved in schizophrenia. (4)

A
  • Serotonin
  • Glutamate
  • GABA
  • Acetylcholine
81
Q

Acetylcholine is usually associated with what group of symptoms in schizophrenia? (1)

A

Cognitive

82
Q

GABA is usually associated with what group of symptoms in schizophrenia? (1)

A

Negative symptoms

83
Q

Serotonin and glutamate are usually associated with what groups of symptoms in schizophrenia? (2)

A

Negative

Cognitive

84
Q

Neuroinflammation is associated with schizophrenia.

What group of symptoms in schizophrenia is usually associated with inflammation? (1)

A

Positive symptoms

85
Q

Describe three pieces of evidence supporting the fact that glutamate is involved in schizophrenia. (3)

A
  • NMDA receptor antagonists induce psychosis, exacerbate schizophrenia, and can cause negative symptoms and cognitive impairments in animal models
  • Several gene mutations associated with schizophrenia involve glutamate transmission
  • In post-mortem studies, schizophrenic patients have reduced D-serine and CSF levels of glutamate
86
Q

Name two NMDA antagonists which induce psychosis and exacerbate schizophrenia. (2)

A

Ketamine

Phencyclidine

87
Q

Give three gene mutations associated with schizophrenia which involve glutamate transmission. (3)

A

D-amino acid oxidase

mGluR3

Neuregulin

88
Q

In post-mortem studies of schizophrenic patients, there is reduced D-serine.

What is the effect of this? (1)

A

NMDA hypofunction

89
Q

Describe a potential mechanism by which hypoglutamatergic and hyperdopaminergic neurotransmission may interact in schizophrenia. (3)

A
  • NMDA hypofunction results in decreased glutamate in cortico-limbic pathway (to VTA)
  • Reduced activation of GABAergic inhibitory output to DA neurones in VTA
  • Less inhibition of DA signalling = too much dopamine
90
Q

What neurological condition best fits the following description? (1)

Progressive, irreversible clinical syndrome with a range of cognitive and behavioural symptoms including memory loss, problems with reasoning and communication, change in personality, and reduction in the person’s ability to carry out daily activities.

A

Dementia

91
Q

When diagnosing dementia, give three criteria that must be met. (3)

A
  • Must have deficits in multiple cognitive domains
  • Cognitive disturbances must be severe enough to cause impairment of functioning and must represent a decline from previous level of functioning
  • Symptoms cannot be explained by delirium or another major psychiatric disorder
92
Q

Give five cognitive domains which may show deficits in dementia. (5)

A

Memory

Language

Behaviour

Visuospatial

Executive function

93
Q

Describe the major memory deficit seen in dementia - remembering old information or learning new information? (1)

A

Learning new information

94
Q

Is dementia considered a natural side effect of aging? (1)

A

No

95
Q

What is the most common cause of dementia? (1)

What percentage of dementia cases does this cause account for? (1)

A

Alzheimer’s disease

Pure AD accounts for 40%, AD with another cause takes it up to 70%

96
Q

What is the second most common cause of dementia? (1)

What percentage of all dementia cases does this cause account for? (1)

A

Vascular disease or multi-infarct dementia

Accounts for 5-20%

97
Q

Apart from AD and vascular dementia, give another 3 common causes of dementia. (3)

A
  • Drugs
  • Depression
  • Ethanol
98
Q

Describe the typical time course of onset and decline in Alzheimer’s disease. (2)

A

Gradual onset

Gradual decline

99
Q

Which type/cause of dementia is likely to show focal neurological signs/symptoms related to cerebrovascular disease? (1)

A

Vascular dementia

100
Q

True or false? Explain your answer if appropriate. (1)

Autopsy is needed to properly confirm a diagnosis of Alzheimer’s disease.

A

False - this was true in the past, but now PET scans and fMRI can aid in this diagnosis

101
Q

Give three tracers which could be used in PET scanning to visualise pathology in Alzheimer’s disease.

State what each of these tracers would indicate/bind to. (3)

A

FDDNP - neurofibrillary tangles

FDG - glucose

PIB - beta amyloid

102
Q

Give a definition of ‘mild cognitive impairment’ and explain how it differs from dementia. (2)

A

Onset and evolution of cognitive impairments beyond those expected based on the age and education of the individual.

Different to dementia because they are not significant enough to interfere with ADLs.

103
Q

True or false? Explain your answer if appropriate. (1)

Mild cognitive impairment may be a prodromal phase of dementia for about 10-15% of people.

A

True

104
Q

Give a reason why diagnoses of mild cognitive impairment have risen over time. (1)

A

Due to increasing awareness and testing for dementia

105
Q

True or false? Explain your answer if appropriate. (1)

Usually, symptoms of mild cognitive impairment remain stable, improve, or go away completely.

A

True

106
Q

What proportion of people over 65yrs is thought to have mild cognitive impairment? (1)

A

1/3

107
Q

True or false? Explain your answer if appropriate. (1)

Alzheimer’s always occurs due to an antecedent cause.

A

False - there is no antecedent cause such as stroke or injury

108
Q

What is the average life expectancy after diagnosis of Alzheimer’s? (1)

A

5-8 years

109
Q

What is the prevalence of Alzheimer’s disease in the following populations? (2)

a) 65 year olds

b) 85 years and over

A

a) 11%

b) >50%

110
Q

True or false? Explain your answer if appropriate. (1)

In Alzheimer’s disease, pathological changes in the brain can precede onset of symptoms.

A

True - potentially by decades

111
Q

Why is it such an issue in Alzheimer’s disease that pathological changes in the brain can precede symptom onset? (1)

A

Difficult to treat effectively (especially disease modifying treatments) in early stages.

112
Q

Describe the general progression of Alzheimer’s disease over about 8-9 years, naming the first set of symptoms or deficits to the last. (5)

A
  • Cognitive symptoms appear
  • Loss of ADLs
  • Behavioural problems
  • Nursing home placement (loss of independence)
  • Death
113
Q

Name the method which is usually used to assess deficits in Alzheimer’s disease. (1)

A

Mini mental state examination

114
Q

Very briefly describe the MMSE, as used to assess deficits in Alzheimer’s disease. (5)

A

5-10 minute test

With 30 questions

Testing orientation, attention, recall, language, and commands

Score of 30 is normal

Below 25 is dysfunctional

115
Q

Give two classical neuropathological hallmarks of Alzheimer’s disease. (2)

A
  • Beta-amyloid plaques
  • Neurofibrillary tangles
116
Q

Briefly describe what is meant by a ‘beta-amyloid plaque’ in Alzheimer’s disease. (3)

A

Neurotoxic, insoluble aggregate

Of 42 amino acid amyloid peptide

Which is found extracellularly

117
Q

True or false? Explain your answer if appropriate. (1)

Neurofibrillary tangles are not specific to Alzheimer’s disease, and can also be present in other pathologies.

A

True

118
Q

Briefly describe what is meant by a ‘neurofibrillary tangle’ in Alzheimer’s disease. (3)

A

Disorganised bundle of filaments

in the neuronal cytoplasm

formed from hyperphosphorylated tau

119
Q

Briefly describe the pathway that leads to APP forming beta-amyloid plaques. (4)

A
  • APP cleaved by b-secretase
  • Then cleaved by y-secretase
  • To form ab-42 (42 residue form of the APP)
  • ab-42 misfolds and aggregates
120
Q

Briefly describe how accumulation of beta-amyloid plaques may cause the symptoms of Alzheimer’s disease. (4)

A
  • Plaques activate microglia and astrocytes
  • Which cause inflammatory response and loss of synapses
  • Inflammatory response and disrupted cellular communication leads to loss of calcium homeostasis, excitotoxicity, oxidative stress
  • So loss of synapse and neurones, and memory loss
121
Q

How might excitotoxicity be caused and contribute to neuronal loss in Alzheimer’s disease? (2)

A

Cell damage causes excessive receptor activation/response

Impairment of glutamate recycling and reuptake mechanisms

122
Q

Describe how beta-amyloid plaques in Alzheimer’s may lead to neurofibrillary tangles forming. (4)

A

Inflammatory response caused by beta-amyloid plaques

Leads to altered neuronal homeostasis and oxidative injury

Which may alter kinase/phosphatase activity

Leading to hyperphosphorylated tau and tangles

123
Q

What is the normal physiological function of tau proteins in neurones? (1)

A

Stabilises microtubules to aid in axonal transport

124
Q

Describe how hyperphosphorylated tau can cause tangles, as seen in Alzheimer’s disease. (2)

A
  • Dissociates from microtubules and moves from axon to cell body
  • Proteins misfold to adopt an abnormal shape, and aggregate
125
Q

Describe two theories of how neurofibrillary tangles may kill neurones. (2)

A
  • Activate microglia for immune response
  • Disruption (potentially precipitation) of cytoskeleton
126
Q

True or false? Explain your answer if appropriate. (1)

In Alzheimer’s disease, misfolded tau can spread between cells to kill healthy neurones. This spreading may be reflected in the progression of the disease.

A

True

127
Q

Give a subset of neurones in the brain which are particularly vulnerable to death due to beta-amyloid plaques and neurofibrillary tangles. (1)

A

Cholinergic neurones

128
Q

Describe a change in neurotransmission seen in Alzheimer’s disease. (1)

Why does this particular change occur? (1)

A

Reduced cholinergic neurotransmission

Because cholinergic neurones are particularly susceptible to b-amyloid and tau tangles.

129
Q

Which neurotransmitter is particularly involved in cognitive deficits in Alzheimer’s disease? (1)

A

Acetylcholine

130
Q

In which cells is amyloid precursor protein expressed? (1)

A

All cells (ubiquitous expression)

131
Q

How is APP associated with plasma membranes? (1)

A

Single transmembrane domain protein

132
Q

What is the normal role of APP in cells? (1)

A

Required for growth and repair

133
Q

Describe the short-life and metabolism of APP. (2)

A

Short half life

Rapidly metabolised

134
Q

Give three enzymes that are involved in the cleavage/processing of amyloid precursor protein. (3)

A

a-secretase

b-secretase

y-secretase

134
Q

Describe the difference between cleavage of APP by a-secretase and b-secretase. (1)

A

a-secretase cleaves so that a smaller portion of the protein is left attached to the membrane and a larger portion is detached.

135
Q

Briefly describe the non-amyloidogenic processing pathway of APP. (5)

A
  • APP cleaved by a-secretase
  • To form APPsa which leaves membrane
  • And C83 which stays associated with membrane
  • C83 cleaved by y-secretase
  • To form amyloid intracellular domain (AICD) and P3 (extracellular)
136
Q

Briefly describe the amyloidogenic processing pathway of APP. (5)

A
  • APP cleaved by b-secretase
  • To form APPsb which leaves membrane
  • And C99 which stays associated with membrane
  • C99 cleaved by y-secretase
  • To form amyloid intracellular domain (AICD) and Ab-42 (extracellular)
137
Q

At which cellular membrane does the non-amyloidogenic processing pathway of APP take place? (1)

A

Plasma membrane

138
Q

At which cellular membrane does the amyloidogenic processing pathway of APP take place? (1)

A

Endosome membrane

139
Q

Name some functions of the secreted APPsb protein. (7)

A
  • Regulates proteases
  • Involved in cell adhesion
  • Promotes neuronal survival
  • Protects against neurotoxic or ischaemic insult
  • Modulates glutamate responses
  • Regulates intracellular Ca2+
  • Regulates cytokine release (anti-inflammatory)
140
Q

Give four ways in which the amyloid-beta peptide affects neurones. (4)

A
  • Renders neurones vulnerable to excitotoxicity
  • Disrupts neuronal calcium homeostasis
  • Aggregates to cause toxicity
  • Promotes inflammatory cytokine release
141
Q

Why might large ventricles be seen on brain scans of Alzheimer’s patients? (1)

A

Due to neuronal loss

142
Q

Why, on a PET scan, might a higher signal of FDG be seen in patients with Alzheimer’s disease? (2)

A

FDG represents glucose metabolism

More glucose metabolism may be seen due to neuroinflammation

143
Q

In Alzheimer’s, does neurotoxicity begin with the loss of cells or the loss of synapses? (1)

A

Loss of synapses

144
Q

Which brain area is normally the first to degenerate in Alzheimer’s, and what symptom might this lead to? (2)

A
  • Hippocampus
  • Memory issues
145
Q

Which brain area is normally the second to degenerate in Alzheimer’s? (1)

What symptoms/signs might this lead to? (5)

A

Cerebral cortex

  • Enlarged ventricles
  • Decline in reading, judgement, and language
  • Emotional outbursts
  • Forgetting how to do simple tasks
  • Inability to think clearly
146
Q

In Alzheimer’s, atrophy of which part of the cerebral cortex leads to reading and language impairment? (1)

A

Temporal lobe

147
Q

In Alzheimer’s, atrophy of which part of the cerebral cortex leads to emotional outbursts? (1)

A

Amygdala

148
Q

Give four specific symptoms that may be experienced in very advanced / late stage Alzheimer’s disease. (4)

A
  • Agitation
  • Wandering
  • Inability to recognise faces
  • Inability to communicate
149
Q

Name the main three neurotransmitter pathways that are affected in Alzheimer’s disease. (3)

A
  • Cholinergic
  • Noradrenergic
  • Serotonin
150
Q

In Alzheimer’s disease there is often a loss of noradrenaline and serotonin.

What deficits may be seen due to this? (2)

A
  • Emotional deficits
  • Loss of emotional context to memories
151
Q

Describe how levels of glutamatergic neurotransmission are altered throughout the course of Alzheimer’s disease. (2)

A

Early stages (before amyloid plaques) shows a reduction in glutamate levels

Later stages show too much glutamate

152
Q

How are GABAergic cortical interneurones altered in Alzheimer’s disease?

What effect might this have? (2)

A

Loss of GABAergic cortical interneurones

which may amplify the neurotoxicity already seen.

153
Q

In Alzheimer’s disease, there is loss of cholinergic neurones from which specific basal forebrain nucleus? (1)

A

Nucleus of Meynert

154
Q

Give three specific changes seen to cholinergic activity in Alzheimer’s disease. (3)

A
  • Loss of cholinergic neurones from the nucleus of Meynert
  • Reduced ChAT activity so reduced ACh synthesis
  • Selective loss of nicotinic receptor subtypes (nAChRa7) in hippocampus and cortex
155
Q

In Alzheimer’s disease, which specific subtype of ACh receptor is lost in the hippocampus and cortex? (1)

A

nAChRa7

156
Q

True or false? Explain your answer if appropriate. (1)

Familial Alzheimer’s disease is usually due to genes involved in reduced amyloid-beta clearance, and sporadic AD is usually due to increased APP production or processing.

A

False - familial AD is usually due to altered production and processing, and sporadic AD is usually due to altered clearance

157
Q

Give three genes/mutations which are associated with familial, early onset Alzheimer’s disease. (3)

Give the chromosomes that these genes are found on. (3)

A

Mutations in APP (chromosome 21)

Presenilin 1 (chromosome 14)

Presenilin 2 (chromosome 1)

158
Q

In AD, mutations in the presenilin 1 and presenilin 2 genes can lead to familial AD.

Describe the general role of the presenilin proteins in the context of AD. (1)

A

Interact with gamma-secretase

159
Q

Give two genes/mutations which increase risk of developing sporadic Alzheimer’s disease. (2)

A
  • ApoE4
  • TREM2
160
Q

Describe how an altered ApoE4 gene may increase risk of developing Alzheimer’s disease. (1)

A

Mutations result in reduced beta-amyloid clearance

161
Q

Describe how an altered TREM2 gene may increase risk of developing Alzheimer’s disease. (1)

A

Mutations alter beta-amyloid phagocytosis by microglia

162
Q

What percentage of sporadic AD may have involvement from the ApoE4 gene? (1)

A

25%

163
Q

Give 5 biochemical factors in the brain which may increase risk of developing Alzheimer’s disease. (5)

A
  • Inflammation
  • High levels of free radicals
  • Low levels of nerve growth factor
  • Altered transport of lipoprotein/cholesterol
  • Altered synaptic function
164
Q

Give five general lifestyle/characteristic risk factors for Alzheimer’s disease. (5)

A
  • Age
  • Gender (more prevalent in females)
  • Increased head size
  • Lower educational level
  • Stress
165
Q

What percentage of Alzheimer’s disease cases are true familial Alzheimer’s? (1)

A

Less than 5%

166
Q

True or false? Explain your answer if appropriate. (1)

The genes that are known to play a role in sporadic, late-onset AD are neither necessary or sufficient to cause the disease on their own.

A

True - they increase change of getting AD by interacting with other risk factors

167
Q

Briefly describe three general approaches to treat Alzheimer’s disease. (3)

A
  • Boost cholinergic transmission
  • Alter glutamatergic function
  • Anti-amyloid immunisation
168
Q

Give a class of drug, and give four examples of drugs that can be used to boost cholinergic transmission in Alzheimer’s disease. (5)

(This class of drugs is approved for use in humans)

A

AChE Inhibitors:

  • donepezil
  • galantamine
  • tacrine
  • rivastigmine
168
Q

Describe the effects of AChE inhibitors on progression and cognitive deficits in Alzheimer’s disease. (2)

A

Slow progression by about 12-18 months

Boost cognition by about 25-30%

169
Q

Are AChE inhibitors more effective at treating Alzheimer’s disease when they are administered early or late in the disease? (1)

A

Early

170
Q

Give three issues with treating Alzheimer’s disease with AChE inhibitors. (3)

A
  • Only see improvements in 2/3 patients
  • Improvement in function/ADLs is very variable
  • Little evidence for improvement in behaviour
171
Q

True or false? Explain your answer if appropriate. (1)

Treating Alzheimer’s disease with AChE inhibitors has shown no effect in delaying nursing home placements.

A

False - may delay nursing home placement by about 20 weeks

172
Q

Give a class of drug and two examples of a drug which may be able to boost cholinergic transmission in Alzheimer’s disease, but has not yet been approved in humans. (3)

A

Muscarinic agonists

  • Arecoline
  • Pilocarpine
173
Q

Give two possible classes of drugs (each with an example) which may treat Alzheimer’s disease by altering glutamatergic function. (4)

Why aren’t these drugs commonly used? (1)

A
  • Nootropic agents (piracetam)
  • NMDA antagonists (memantine)

Mechanisms are controversial or unproven

174
Q

Describe what is meant by ‘anti-amyloid immunisation’ when talking about treating Alzheimer’s disease. (1)

A

Monoclonal antibodies against amyloid-beta plaques or targeting amyloid deposition.

175
Q

Describe a piece of evidence calling into question the amyloid hypothesis of Alzheimer’s disease. (1)

A

When using anti-amyloid antibodies to reduce amyloid-beta load, effect sizes are only moderate.

176
Q

Give six potential future therapeutic strategies for treating Alzheimer’s disease. (6)

A
  • b and y secretase inhibitors
  • a-secretase stimulators
  • Anti-amyloid immunisation
  • Anti-inflammatory drugs
  • Tau kinase inhibitors
  • Tau aggregation inhibitors (eg. antibodies)

Neuroscience Y2S2 (15 decks)

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