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scientific foundations > Neurodegenerative Diseases > Flashcards

Neurodegenerative Diseases Flashcards

1
Q

What are neurodegenerative diseases?

A

A range of conditions which primarily affect the neurons of the brain (sometimes spinal cord) resulting in a loss of structure and/or function

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2
Q

What is dementia?

A

▪️Multiple cognitive deficits (including memory)
▪️Decline form previous levels of functioning
▪️Severe enough to impair occupational and/or social functioning.

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3
Q

Do neurodegenerative diseases effect the brain symmetrically?

A

Not always

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4
Q

What functions may show impairment with degeneration in the frontal lobes?

A

▪️Behavioural problems, particularly disinhibition
▪️Judgement
▪️Abstract reasoning and strategic planning
▪️Emotional restraint
▪️Control of appetite and continence

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5
Q

What functions may show impairment with degeneration in the parietal lobes?

A

▪️Visuospatial skills
▪️Integration of sensory inputs ▪️This may lead to sensory agnosia and apraxias

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6
Q

Disorders of memory and hallucinations may suggest degeneration in which brain areas?

A

The medial temporal lobe, hippocampus, amygdala, and limbic system

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7
Q

What impairments may be apparent with degeneration in the temporal neocortex?

A

Receptive dysphasia (understanding language) and automatisms

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8
Q

What problem mignt be seen with occipital lobe degeneration?

A

Failure of visual sensory systems

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9
Q

What is the pathological classification of neurodegenerative diseases typically based on?

A

The accumulation of filamentous proteins

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10
Q

What are the two main categories of protein accumulation?

A

Intraneuronal and extracellular

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11
Q

What are the two main proteins associated with abnormal extracellular accumulation?

A

Amyloid beta and prion protein

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12
Q

What category of disease are associated with prion protein?

A

Human prion diseases such as Creutzfeldt-Jakob disease (CJD) and fatal familial insomnia (FFI)

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13
Q

What conditions are associated with abnormal accumulation of amyloid beta?

A

Alzheimer’s and Down’s syndrome

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14
Q

What are the two main categories of abnormal intraneuronal accumulation?

A

Intranuclear and cytoplasmic/neuritic

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15
Q

What category of disorders is associated with abnormal intranuclear accumulations?

A

Polyglutamine disorders

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16
Q

What are three examples of polyglutamine disorders?

A

Huntington’s disease, spinocerebellar ataxia, and DRPLA

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17
Q

What are the four main proteins associated with abnormal cytoplasmic/neuritic accumulation?

A

▪️Tau
▪️Alpha synuclein
▪️TDP-43
▪️FUS

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18
Q

What is TDP-43?

A

A RNA/DNA-binding protein involved in RNA splicing, trafficking, and stabilisation, and thus regulating gene expression

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19
Q

What diseases are associated with TDP-43opathy?

A

Motor Neurone Disease (ALS-TDP), the FTLD-MND spectrum, and FTLD-TDP

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20
Q

What genetic mutation has been found in association with TDP-43opathy?

A

C9orf72 (a repeat insertion)

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21
Q

Why have C9orf72 mutations been found in individuals with what was thought to be sporadic ALS/FTD?

A

It has very low penetrance

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22
Q

What diseases are associated with FUSopathy?

A

ALS-FUS and FTLD-FUS (almost always familial and very rarely both)

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23
Q

What is alpha-synuclein?

A

A protein involved in the regulation of synaptic vesicles and subsequent neurotransmitter release

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24
Q

What three disease are primarily associated with an alpha-synucleinopathy?

A

Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy

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25
Q

In Parkinson’s, where are abnormal protein accumulations typically seen?

A

In the substantia nigra and parts of the brain stem

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26
Q

In dementia with Lewy bodies, where are abnormal protein accumulations typically seen?

A

In the cortex (may also be seen in the midbrain and brainstem hence parkinsonian features are also common)

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27
Q

Why is the alpha-synucleinopathy in multiple system atrophy unusual?

A

Because it is mainly deposited in oligodendrocytes (Papp-Lantos inclusions)

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28
Q

What are the two main categories of tauopathy?

A

Triplet and doublet band

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29
Q

Why is the proteinopathy seen in Alzheimer’s disease unusual?

A

It involves both intra and extracellular components

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30
Q

What gene is typically associated with tauopathy?

A

MAPT

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31
Q

What conditions are associated with triplet band 3 and 4 repeat tauopathy?

A

Alzheimer’s, Down’s syndrome and ALS-PDC

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32
Q

What diseases are associated with doublet band tauopathy with predominantly 4 repeats?

A

Parkinsonian disorders such as PSP, CBD, and GGT

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33
Q

What disease is associated with doublet band tauopathy with predominantly 3 repeats?

A

Pick’s disease (FTLD-Tau)

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34
Q

What is the most common dementing illness, particularly in the West?

A

Alzheimer’s disease

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35
Q

What is the average duratuion of Alzheimer’s from symptom onset to death?

A

9-12 years

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36
Q

What are the main symptoms of Alzheimer’s disease?

A

▪️Cognitive decline, particularly memory
▪️Decline in visuo-spatial skills
▪️Delusions and hallucinations
▪️Irritability
▪️Can be associated with movement disorders such as myoclonus
(Consciousness is not disturbed)

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37
Q

What are the two main pathologies associated with Alzheimer’s disease?

A

Abnormal amyloid beta deposition forming plaques, and hyperphosphorylated tau forming neurofibrillary tangles

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38
Q

What is myoclonus?

A

‘Jerking’ disodder

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39
Q

What are the four genetic mutations most commonly associated with familiar AD?

A

APOE e4 allele, APP, Presenilin 1 and Presenilin 2

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40
Q

What is the APP gene

A

The amyloid precursor protein gene - plays a role in the formation of amyloid beta

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41
Q

Why is there an association between familial AD and Down’s syndrome?

A

Because APP is located on chromosome 21

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42
Q

Heritable forms of AD present primarily as which type of AD?

A

Early onset

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43
Q

What are the main pathological brain changes seen in AD?

A

▪️Loss of cortical white matter
▪️Widened sulci
▪️Compensatory dilatoom of ventricles (enlarged)

44
Q

What type of stain used to be used to make a histological diagnosis of AD?

A

Silver stain

45
Q

What is now used to make a histological diagnosis of AD?

A

Antibodies

46
Q

What is the main issue with using antibodies to diagnose AD?

A

Masses of hyperphosphorylated tau can make interpretation difficult

47
Q

Which proteinopathy correlates best with cognitive decline in AD?

A

Tau and neurofibrillary tangles

48
Q

Where are NFTs and NTs typically originally observed in Braak stages 1 and 2 of AD?

A

The transentorhinal cortex with small number in the CA1 region of the hippocampus

49
Q

How does someone in AD Braak stages I and II typically present clinically?

A

Asymptomatic

50
Q

Where do NFTs and NTs typically spread to in Braak stages III and IV of AD?

A

The limbic system - hippocampus, subiculum, fusiform gyrus, amygdala

51
Q

Where do NFTs and NTs typically spread to in Braak stages V and VI of AD?

A

The cortex as well as the anterior cingulate cortex, thalamus, hypothalamus, claustrum, and substantia nigra

52
Q

At what point during the Braak stages of AD do you see occipital lobe involvement?

A

At the highest stage (IV)

53
Q

Which brain areas are relatively spared in AD?

A

The primary sensory and motor cortices

54
Q

What staging is used to measure the progressive accumulation of amyloid plaques in AD?

A

Thal phase: phase 1-2 (A1), phase 3 (A2), phase 4-5 (A3)

55
Q

What staging is used to measure the progressive accumulation of tau and NFTs in AD?

A

Braak staging: stage I-II (B1), stage III-IV (B2), stage V-VI (B3)

56
Q

What structure is associated with the highest thal phase?

A

The cerebellum (although typically because it isn’t involved at all)

57
Q

What is CERAD?

A

Another method of scoring neuritic plaque accumulation, rated mild (C1) moderate (C2) or severe (C3) (although not very meaningful)

58
Q

What is an NIA/AA combined score?

A

A scoring system to classify neuropathological change in AD that combines Thal, CERAD, and Braak staging. It scores pathology as low, medium, high, or not AD

59
Q

Which criteria for AD pathology is more important?

A

Braak staging (NFTs and tau) - can still be classified as low pathology in the present of high Thal and CERAD if tau is low

60
Q

What is amyloid angiopathy?

A

The accumulatoln of amyloid beta peptide in the walls of blood vessels, making them more likely to leak and increasing risk of haemorrhage

61
Q

What is APP?

A

A large transmembrane glycoprotein that sticks out from the membrane, involved in the production of amyloid-beta

62
Q

What happens to amyloid precursor protein in healthy individuals?

A

It is cut apart at two locations firstly by alpha-secretase and secondly by gamma-secretase, producing extracellularly a P3 peptite from the middle

63
Q

What happens to amyloid precursor protein in the amyloidogenic pathway?

A

Decreased alpha-secretase and increased beta-secretase causes beta-secretase to cut the APP higher up before the gamma-secretase, producing an extracellular longer amyloid-beta peptide/beta pleated sheets

64
Q

Why does amyloid-beta form plaques?

A

Amyloid-beta is more hydrophobic than the peptide usually produced thus is harder for the brain to clear

65
Q

What is the secondary mechanism of disease in the amyloid cascade model of AD?

A

hyperphosphorylation and NFT formation

66
Q

What is the feedback mechanism in the amyloid cascade model of AD?

A

Microglia are activated around the plaques to clear them, which increases inflammation in turn triggering the production of more plaques

67
Q

What are the two main arguments against the amyloid cascade hypothesis?

A
  1. Tau pathology correlates better with symptoms than AB, so why is tau only a secondary effect?
  2. Drug trials using anti-AB treatments are so far u effective
68
Q

Why might drug trials addressing AB pathology not yet be effective?

A
  1. We are administering the drug too late (we need biomarkers!)
  2. Multiple pathologies may be present
69
Q

What is tau?

A

A microtubule associated protein that binds and integrates into the microtubules to help stabilise them and give them structural integrity

70
Q

What happens when tau becomes hyperphosphorylated?

A

Structural abnormalities appear in the microtubules, causing it to dissociate, disrupting transport in the cell

71
Q

What happens to tau in tauopathies?

A

The switching on and off of the protein goes wronf and it becomes hyperphosphorylated in the wrong areas

72
Q

What happens to tau when it detaches from the microtubule?

A

It forms paired helical filament which accumulate and stick to each other to form neurofibrillary tangles

73
Q

What is the seeding and propagation model?

A

The hypothesis that proteinopathy is spread through the brain through the induction of structural changes to adjacent proteins. This is still an ongoing argument

74
Q

What are the two most promising tau biomarkers for AD?

A

Blood p-tau 181 and 217

75
Q

What does blood p-tau 181 predict?

A

AD 8 years prior to death

76
Q

What does blood p-tau 217 predict?

A

AD up to 20 years prior to death

77
Q

What are the three key features of parkinsonism?

A

Bradykinesia, rigidity, and tremor

78
Q

How many of the three key features of parkinsonism are needed for a diagnosis of idiopathic Parkinson’s disease?

A

2

79
Q

What is the mean age of PD onset?

A

61

80
Q

What is the mean duration of PD?

A

13 years

81
Q

What are the two key pathological signs of PD?

A

Neuronal loss in the substantia nigra and the presence of Lewy bodies

82
Q

What proteinopathy is PD associated with?

A

Alpha-synucleinopathy

83
Q

What are the dark patches in the substantia nigra and what do they indicate?

A

Neuromelanin - indicating healthy function

84
Q

Why does someone with PD have less pigment in their substantia nigra?

A

Lewy bodies form and cause neuronal death here, leading to the loss of neuromelanin

85
Q

What percentage of neurons in the substantia nigra are lost before the individual develops motor symptoms?

A

70%

86
Q

What are Lewy bodies?

A

Abnormal deposits of alpha-synulcein in the cytoplasm, forming spherical inclusions (have halos under microscope)

87
Q

Why might it be argued that vascular dementia is not a true dementia?

A

Due to its step-wise progression, as oppose to gradual

88
Q

What are the main neuropathological signs of vascular dementia?

A
  1. Multiple infarcts - step-wise progression
  2. Diffuse white matter changes (degeneration) due to ischaemia/hypertension
  3. Strategic infarct - relatively small area wiped out (e.g., thalamus)
89
Q

What symptoms might occur with vascular dementia affecting the subthalamic nucleus or basal ganglia?

A

Movement disturbances (e.g., throwing movements/jerks, parkisonism)

90
Q

What macroscopic pathological changes can you see in Huntington’s disease?

A

Shrinkage of caudate nucleus and putamen

(loss of white matter and thinner cortex?)

91
Q

What microscopic pathological changes can you see in Huntington’s disease?

A

▪️ Neuronal loss
▪️ Astrocytosis (increase)
▪️ Ubiquitin inclusions (intranuclear)

92
Q

What are the two main pathologies typically seen with FTD?

A

▪️ Frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) (more common)
▪️ Pick’s disease (FTLD-Tau) - behavioural!

93
Q

What are the three types of ALS initiation?

A

▪️ Atrophy/weakness of muscles
▪️ Bulbar onset - tongue problems, dysphagia
▪️ Upper motor neurone signs - hyperreflexia

94
Q

What are the main contributors to familial ALS?

A

▪️ C9orf72 repeat expansion - most common
▪️ SOD1 - very rare
▪️ TARDP (TDP-43)
▪️ FUS - very rare

95
Q

Where is pathology most commonly seen in ALS?

A

▪️ Motor cortex
▪️ Brain stem (internal capsule, medulla)
▪️ Corticospinal tracts
▪️ Spinal cord - thinning of anterior nerve roots

96
Q

What inclusions are typically seen in the spinal cord, medulla, and motor cortex of someone with ALS?

A

▪️ TDP-43
▪️ FUS (less commonly)

97
Q

What is TDP-43?

A

▪️ RNA binding protein
▪️ Allows for translation of correct protein (stop translation of unwanted code)

98
Q

What happens when something goes wrong with TDP-43?

A

▪️ Does not bind to unwanted sections
▪️ Protein does not get formed/defective protein made instead
▪️ TDP-43 accumulates in the cytoplasm
▪️ Binds instead to other proteins such as ubiquitin, clogging up the neuron

99
Q

What cellular processes might be impaired with ALS-related genetic mutations, giving rise to disease?

A

▪️ RNA-processing abnormalities
▪️ ER dysfunction and stress
▪️ Mitochondrial dysfunction
▪️ Abnormal axonal transport and microtubule organisation
▪️ Endosomal dynamic dysfunctions

100
Q

What is the most common pathological inclusion in ALS?

A

TDP-43 (97%)

(SOD1 = 2%, FUS <1%)

101
Q

What are the most common pathological inclusions seen in FTD?

A

▪️ TDP-43 (45%) - spectrum with ALS?
▪️ Tau (45%)

(FUS = 9%, UPS = 1%)

102
Q

What are the main types of Human Prion Disease?

A

▪️ Creutzfeldt-Jakob Disease (CJD)
▪️ Variant CJD
▪️ Familial Prion Diseases (e.g., fatal familial insomnia)
▪️ Iatrogenic CJD (e.g., historic treatment with growth hormone)

103
Q

What is the protein only hypothesis?

A

Theory explaining how prion proteins replicate without nucleic acid
▪️ Prion propagates by inducing conformational changes in its normal counterpart - misfolded into beta pleated sheets
▪️ Positive feedback mechanism
▪️ Resulting in structural abnormalities in the brain

104
Q

What are the four components of the prion disease cycle?

A

▪️ Inoculation
▪️ Interaction
▪️ Conversion
▪️ Accumulation

105
Q

What two major histological changes do you see in CJD?

A

▪️ Prion protein deposition
▪️ Spongiform change (holes)

106
Q

What pathology might you see in variant-CJD?

A

Florid plaques

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