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markers xxx > Week 9 part 1 > Flashcards

Week 9 part 1 Flashcards

1
Q

What are neurodegenerative disorder characterised by?

A

Progressive loss of neuronal structure and function

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2
Q

What are neurodegenerative disorders?

A

Diverse in their pathophysiology

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3
Q

What is an example of pathophysiology?

A

Heterogenous clinical and pathological expression affect specific subset of neurons in specific-functional anatomic systems

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4
Q

What are parkinson’s disease characterised by?

A
  1. Resting Tremor
  2. Slowness of movement (bradykinesia)
  3. Muscular rigidity
  4. Postural instability
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5
Q

What are defects in motor function due to?

A

loss of dopaminergic neurons in the substantia nigra pars compacta

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6
Q

What is substantia nigra?

A

Strips of cells which contain neuromelanin

Very dark pigment

dopaminergic cells

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7
Q

What do neurodegenerative disorder rise dramatically with?

A

Age

Numbers are expected to increase due to increasing life expectancy

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8
Q

What are Huntington disease characterised by?

A
  1. Involuntary movements
  2. Mood alterations e.g. depression
  3. Personality alterations e.g. irritability, impulsive or eccentric behavioyr
  4. Defect in memory and attention
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9
Q

What is the pathology of Huntington disease?

A
  1. striatal atrophy: loss of medium spiny neurons

2. Cortical atrophy: loss of cortical pyramidal neurons (CPNs) in motor and premotor area

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10
Q

What are defects in motor function of HD pathology?

A
  1. loss of GABAergic neurons in corpus stratium

2. Enlargement of ventricles and shrinkage of basal ganglia

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11
Q

What are limitations to brain bank material?

A
  1. Pathological changes are only revealed post-mortem
  2. Earliest changes in neurodegenerative disorders are missed
  3. End-stage tissue is depleted of neurons
  4. Post-mortem delay affects protein e.g. stability
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12
Q

What can biomarkers reflecting different types of pathophysiology be viewed as?

A
  1. Clinical diagnosis
  2. Predict and monitor disease progression
  3. Monitoring effects of novel drug candidates in clinical trials
  4. Clinical research into the pathogenesis of disease
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13
Q

What are biomarkers that allow for pre-symptomatic detection crucial for

A

Faciliate the development of an efficient and rapid treatment as early as possible

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14
Q

What are Alzheimer’s disease characterised by?

A
  1. Defects in memory
  2. Cognitive decline
  3. Confusion and disorientation
  4. Changes in mood and personality
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15
Q

What are 2 two pathological hallmark of AD?

A
  1. Amyloid plaques

2. Tau - Neurofibril tangles

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16
Q

What do amyloid plaque and Tau have?

A

Specific pattern of deposition

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17
Q

Where are amyloid plaques in?

A

Medial and frontal temporal lobe before the burden increases

Area which amyloid deposits increases in the cortex

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18
Q

Where is Tau located in?

A

Hippocampus

Before spreading to the frontal love and over the cortex

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19
Q

What are Amyloid plaques?

A

Extracellular accumulations prinicipally composed of abnormally folded amylod beta with 40-42 amino acids

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20
Q

What are two by-products of APP metabolism?

A
  1. Ab40

2. Ab42

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21
Q

What is more abundant within plaques?

A

Ab40

Due to higher rate of fibrillisation and insolubility

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22
Q

What is APP cleaved by?

A

beta-gamma secretase which leads to formation of ab peptide

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23
Q

What is Tau?

A
  1. Microtubule-associated protein
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24
Q

What does Tau have a role in?

A
  1. Microtubule stabilisation

2. Axonal transport

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25
Q

What does hyperphosphorylation of Tau result in?

A

Formation of neurofibrillary tangles

which are composed of paired helical filaments (PHF) of Tau

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26
Q

What are the 3 areas where most biomarkers are focused on?

A
  1. Plaques
  2. Tangles of Tau
  3. Neuronal degeneration
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27
Q

When is clinical diagnosis of dementia made?

A

Biomarkers follow this time pattern and when enough change in brain structure happens

28
Q

What is considered in terms of gene base biomarkers?

A

target amyloid and tau progression early on or even better trying to target before

29
Q

What does the cerebrospinal fluid occupy?

A
  1. Ventricular system

2. Cranial and spinal subarachnoid space

30
Q

What does CSF acts as?

A

Liquid cushion providing basic mechanical and immunological protection

31
Q

What is CSF?

A

most informative fluid in biomarker discovery for neurodegenerative disorders.

32
Q

What does CSF have?

A

more physical contact with brain than any other fluid, as it is not separated from the brain by the blood brain barrier (BBB)

33
Q

What most likely diffuse into CSF than into any other bodily fluid?

A

proteins or peptides that may be directly reflective of brain specific activities as well as disease pathology

34
Q

How can we categorise CSF biomarkers?

A
  1. the core csf biomarkers and theres 3 of them

2. theres more novel biomarkers that need more verification and validation

35
Q

What it is total Tau?

A

Not AD specific

36
Q

What is counter intuitive?

A

♣ ab42 and ab42/40 ratio

37
Q

What us lowered ub CSF?

A

increase in CSF of amyloid ab42 and ab42/40 ratio

38
Q

What is the main test for CSF amyloid 42 and the ratio of 42-40?

A

Elisa

39
Q

What is a problem with Elisa?

A

variation between research groups and organizations

40
Q

What are core CSF biomarkers ?

A

Well-validated for neurodegeneration as well as amyloid plaque and tau tangle pathology

41
Q

What are there no validated biomarkers for?

A

Synaptic dysfunction

42
Q

What is biomarkers for synaptic dysfunction?

A

Best pathoanatomical correlates of cognitive deficit and predicts disease better than amyloid plaque load

43
Q

What would be a valuable addition to Alzheimer’s disease diagnostic biomarker toolbox?

A

reliable biomarkers to monitor synaptic and dendritic function and loss directly

44
Q

What is Neurogranin?

A

dendritic protein expressed in the cortex and hippocampus with an important role in long‐term potentiation.

45
Q

Where is Neurogranin expression markedly reduced?

A
  1. Hippocampus
  2. Frontal cortex in AD

indicating loss of post-synaptic element

in AD

46
Q

What does measurement of neurogranin in CSF serve?

A

Biomarker for dendritic instability and synaptic degeneration

47
Q

What does meta analyses studies look at?

A

various AD cohorts and collate all the data that’s been found correlating the biomarker to AD

48
Q

What are biomarkers with the best performance?

A

Core CSF biomarkers

49
Q

What is strongly associated with AD?

A

Neurofilament light chain (NFL)

50
Q

What was moderately associated with AD?

A
  1. neuron specific enolase (NSE),
  2. visinin-like protein 1 (VLP-1),
  3. heart fatty acid binding protein (HFABP)
  4. glial activation protein YKL-40
51
Q

What should be used in clinical practice and clinical research?

A
  1. T-tau, P-tau, Aβ42 and NFL

2. Due to their consistency

52
Q

What is the most validated of AD?

A

CSF biomarkers

53
Q

What are advantages to CSF?

A
  1. Highly sensitive and specific - Not separated from the brain via BBB
  2. Can correlate with Alzheimer’s disease directly
  3. Can detect Alzheimer’s disease progression
54
Q

What are disadvantage to CSF?

A
  1. Invasive and painful procedure via lumbar puncture

2. Irreproducible diagnosis due to sample storage and transportation

55
Q

What makes an ideal for biomarker investigation?

A

Easier sampling of the blood plasma

56
Q

What has met with little success?

A

Plasma biomarkers

57
Q

What makes plasma biomarkers a much easier biomarker method?

A

Easier collection

58
Q

Whatmight occur due to different analytical methodologies utilised in various laboratories, different choice of anticoagulant and depletion strategy and storage related problems in blood-based biomarker?

A
  1. Irreproducibility
59
Q

What are biomarkers for Blood-based biomarkers for AD?

A
  1. CDH

2. a-2m

60
Q

What is the most popular plasma peptide utilised for biomarker reseacher?

A

AB

the fundamental element of senile plaques in brain of Alzheimer’s disease patients

61
Q

What are Ambiguous results probably explained by?

A

that plasma Aβis derived from peripheral tissues and may not reflect brain Aβproduction

62
Q

What can result in epitope masking?

A

the hydrophobic nature of Aβ makes the peptide bind to plasma proteins

63
Q

What did blood tests find?

A

Toxic Alzheimer’s proteins

64
Q

What did they term ab40, ab42 and APP fragment?

A
  1. app699-711

2. Based on its amino acid composition

65
Q

What are advantages for blood?

A
  1. Non-invasive
  2. Samples are easily accessible
  3. Cost effective and routine
  4. ~500ml of CSF absorbed into blood each day
66
Q

What are disadvantage of Blood?

A
  1. Less sensitive and specific than CSF (e.g. epitope masking)
  2. Less correlation with Alzheimer’s disease than CSF

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