Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Applied Neuroanatomy > ALS > Flashcards

ALS Flashcards

1
Q

What is ALS?

A

a rapidly progressive and fatal neurodegenerative disease

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the average age of onset of ALS?

A

55

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the types of ALS?

A

Sporadic - 90-95%
Familial - 5%
Guamanian - Guam territories around pacific - due to diet?

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are clinical symptoms of ALS onset?

A

Limbs - weakness of grip, decreased dexterity, foot drop, leg stiffness, tripping
Throat - slurred speech, difficulty chewing or swallowing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the clinical limb symptoms of ALS onset?

A

weakness of grip, decreased dexterity, foot drop, leg stiffness, tripping

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the clinical throat symptoms of ALS onset?

A

slurred speech, difficulty chewing or swallowing

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What are the clinical symptoms of ALS progression?

A

Limbs - unable to hold objects, write, feed or toilet, walk or stand or turnover in bed
Throat - unable to speak, swallow food or saliva
Breathing - breathless with exertion or lying flat
Cognition - dementia is rare but subtle deficits are common

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What are the clinical limb symptoms of ALS progression?

A

unable to hold objects, write, feed or toilet, walk or stand or turnover in bed

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

What are the clinical throat symptoms of ALS progression?

A

unable to speak, swallow food or saliva

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are the clinical breathing symptoms of ALS progression?

A

breathless with exertion or lying flat

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the clinical cognitive symptoms of ALS progression?

A

dementia is rare but subtle deficits are common

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What symptoms may occur as the disease progresses?

A

difficulty breathing
difficulty swallowing
paralysis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the cause of death in ALS?

A

usually respiratory failure around 22m from diagnosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Where are UMN located?

A

motor cortex and travel down to the spinal cord

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Where are LMN located?

A

Travel out of the spinal cord to the relative muscles

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What are the premotor clinical signs of ALS?

A

planning and initiation of movements are difficult

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

What are the UMN clinical signs of ALS?

A

modest weakness, stiffness, spasticity, hyperreflexia, extensor plantar response

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

What are the LMN clinical signs of ALS?

A

major weakness, muscle wasting, fasiculation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

WHat are the cognitive clinical signs of ALS?

A

subtle deficits in around 30% patients affecting verbal fluency and executive functions

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

What are the spare clinical signs of ALS?

A

sensation, eye movement, bladder and bowel function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

How is ALS diagnosed?

A

it is a diagnosis of exclusion which normally occurs around 12 months after symptom onset

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What causes the muscle wasting in ALS?

A

due to lack of use because of de-innervation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

What is thought to contribute to the degeneration process of ALS?

A

build up of unwanted proteins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What contributes to the development of paralysis?

A

pyramidal MNs in the frontal lobe degenerate and die causing severe spasticity and mild weakness of the muscle groups

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What are the gene mutations associated with familial ALS?

A

c9orf71, SOD1, FUS, TDP43

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

What are the gene mutations associated with sporadic ALS?

A

c9orf72

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

What role does TDP-43 play in MN degeneration?

A

accumulates in the cell body of MNs in 95% of MND cases

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

Where does TDP-43 normally reside?

A

in the nucleus where is processes gene transcripts

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

What does TDP-43stand for?

A

Transactivation response DNA-binding protein of 43kDa

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What can be seen in chick spinal neurons that express TDP-43 mutant?

A
  • a reduction of axonal length
  • increased cell toxicity
  • developmental delay
  • apoptotic cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Why are zebrafish useful to explore neurodegeneration?

A

zebrafish have a short life span

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What are 20% of familial ALS cases caused by?

A

mutations in the protein Cu/Zn Superoxide dismutase

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What is the most common mutation in SOD1?

A

ala->val

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

What is mutant SOD1 a key component of in ALS?

A

protein aggregates

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What does SOD1 do normally?

A

converts superoxide radicals to hydrogen peroxide and oxygen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Where is SOD1 generally found?

A

cell cytosol, nucleus and mitochondrial membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

How many mutations in SOD1 have been found in ALS?

A

more than 140

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

What suggests that SOD1 mutations in ALS are not due to lack of enzyme activity?

A

SOD1 KO mice do not develop ALS

39
Q

What do mutations in SOD1 potentially do to the enzyme?

A

cause it to gain toxic function

40
Q

What are the potential cellular mechanisms underlying ALS?

A

oxidative damage, accumulation of IC aggregates, mitochondrial dysfunction, glutamate excitotoxicity, growth factor deficiency, glial cell pathology, Ca dysregulation

41
Q

What do mutations in SOD1 do to the Cu binding site?

A

cause Cu binding site to be exposed to aberrant substrates

42
Q

Where have protein aggregates been found in ALS?

A

the MNs and glial cells

43
Q

What have protein aggregates in ALS been shown to have?

A

misfolded SOD1 - mutated SOD1 has increased propensity for aggregation

44
Q

Why may there be a protein build up in ALS?

A

due to mitochondria attempting to remove the protein however the normal function of the mitochondria is interfered with OR UPS getting clogged up with protein

45
Q

What have histological studies of mitochondria shown in ALS?

A

swelling and other mitochondrial abnormalities

46
Q

What has mutant SOD1 been directly associated with in sporadic ALS?

A

cytochrome C association with the inner mitochondrial membrane -> disrupts respiration

47
Q

What has been found in terms of glutamate in sporadic ALS?

A

elevated glutamate levels in the CSF

48
Q

Why is glutamate transport markedly reduced in ALS?

A

due to pronounced loss of glial glutamate transport EAAT2

49
Q

What does mutant SOD1 do to glutamate transport?

A

selectively inactivates EAAT2

50
Q

How can EAAT2 involvement be tested?

A

using anti-sense oligonucleotides to lower EAAT2 levels -> neuronal death

51
Q

What growth factor is deficient in ALS?

A

vascular endothelial growth factor

52
Q

What techniques slowed ALS onset and progression in mutant SOD1 mice?

A

overexpression of VEGF
ICV administration of VEGF
IM delivery of VEGF-expressing lentiviral vectors

53
Q

What other growth factors also delay ALS onset and progression in SOD1 mutant mice?

A

IGF-1 and GDNF

54
Q

Why is there growing evidence of glial cell involvement in ALS?

A

astrocytic inclusions are early indicators of SOD1 mutant toxicity
astrocytes expressing mutant SOD1 secrete factors that are toxic to MNs

55
Q

What are the potential secreted agents from astrocytes in ALS?

A

proinflammatory chemokines and cytokines i.e. TNFa

56
Q

What potential reason is there for selective degeneration of MNs in ALS?

A

MNs are more susceptible to excitotocity

57
Q

Why are MNs more susceptible to excitotoxicity?

A

recieve very strong glutamatergic signalling
express Ca permeable AMPA receptors
have a low Ca buffering capacity

58
Q

lack of what AMPA subunit is associated with MNs?

A

GluR2 - normally regulates Ca permeability

59
Q

What is expected to happen with GluR2 in mutant SOD1?

A

accelerates MN degeneration and shortens life span

60
Q

What were some of the first ALS therapies targeted at?

A

glutamate excitotoxicity

61
Q

What is Riluzole?

A

the only drug for ALS which extends life expectency by 2-3 months

62
Q

What are the acute effects of Riluzole in animal models?

A

decreasing persistant Nav currents
potentiation of a Ca-dependent K current
inhibiting glutamate release

63
Q

What is ceftriaxone?

A

an antibiotic

64
Q

What are the effects of ceftriaxone in ALS animal models?

A

increases expression of EAAT2 prolonging survival and upregulating EAAT2 mRNA

65
Q

What are heat shock proteins?

A

proteins involved in protein folding and degradation

66
Q

What is found in heat shock proteins in ALS?

A

abnormalities that lead to MN degeneration

67
Q

What is Arimoclomol?

A

an oral agent that increases expression of HSPs involved in neuroprotective mechanisms

68
Q

Which agent was disappointing in clinical trials targetting mitochondrial function?

A

creatine

69
Q

What does creatine do?

A

stimulates mitochondrial respiration and phosphocreatine synthesis

70
Q

why is simple stem cell therapy not enough in ALS?

A

cells around the MNs are damaged too

71
Q

How would stem cell therapy be approached in ALS?

A

directing stem cells to the damaged area and providing growth factors for the MNs and other ells

72
Q

What experimental protocol showed mouse embryonic stem cells to be successfully transplanted into a chick embryo?

A
  • mouse embryonic stem cells treated with a chemical cocktail (retinoic acid and sonic hedgehog)
  • after 2 week take form of MNs and dependent on same growth factos
  • when transplanted to chick spinal cord migrated to anterior horn where MNs reside
  • transplanted axons make functional contact with muscle cells
73
Q

What is required for stem cell therapy to be effective?

A

the new cells must differentiate into MNs and make the connections to the denervated muscle

74
Q

What is a current drawback in stem cell therapy?

A

Thus far they can improve limb function but limited evidence to suggest that they can connect with all desired targets - in humans this is up to 3M away

75
Q

What is a potential drawback in stem cell therapy?

A

immunogenicity

76
Q

What more specific cells may be used in stem cell therapy?

A

neural progenitor cells

77
Q

What is a specific gene that needs to be expressed in order to regenerate damaged MNs?

A

glial cell line derived neurotrophic factor (GDNF)

78
Q

Where have rat models particularly thrived with stem cell therapy?

A

when there has been two injection points
- the MNs
- the muscle
slower disease progression and increased survival

79
Q

What is the suggested result of stem cell therapy?

A

provides protection rather than replacing MNs by differentiating into different cells that produce growth factors that reduce toxic damage

80
Q

What is the main cause of death in ALS?

A

respiratory failure

81
Q

Why is the main cause of death in ALS important for considering new therapies?

A

if diaphragm function can be improved, death might be delayed

82
Q

What is ACE-031?

A

a protein that inhibits negative regulators of muscle growth i.e. myostatin

83
Q

What does CK-2017357 do?

A

activates fast skeletal muscle troponin complex by increasing sensitivity to Ca - increases muscle force

84
Q

What results have been found with ACE-031 in clinical trials thus far?

A

subcutaneous treatment is well-tolerated and increases muscle mass and volume

85
Q

What results have been found with CK-2017357 in clinical trials so far?

A

well tolerated and muscle strength and pulmonary function have increased

86
Q

How might RNA be targeted in treating ALS?

A

use of anti-sense oligonucleotides and siRNAs to lower mutant mRNA

87
Q

What is the purpose of using anti-sense oligonucleotides and siRNAs to target ALS?

A

slows disease progress and increases survival in SOD1 mutant mice
helps patients with familial SOD1 mutations

88
Q

What is ISIS666311?

A

a RNA targeting treatment that silences SOD1 gene expression and has been successful in phase 1 clinical trial

89
Q

What do mutations in VEGF correlate to in ALS?

A

lower levels of VEGF protein expression and thus 2x risk of ALS developing

90
Q

What has been found with regards to VEGF in ALS patients?

A

lower levels of VEGF in the CSF

91
Q

What normally occurs with VEGF mRNA in healthy patients?

A

binds with HuR which results in VEGF protein production for neuroprotection and O2 supply to MNs

92
Q

What occurs with VEGF mRNA in ALS patients?

A

mutant SOD1 competes with HuR to binding mRNA and thus reduces VEGF and compromising neuroprotection and perfusion - MN degeneration

93
Q

How might VEGF be targeted in therapy?

A

delivering recombinant VEGF intracerebroventricularly to provide degenerating MNs with increased neuroprotective survival - improved o2 supply

Applied Neuroanatomy (11 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions