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Neuropharm > ALS > Flashcards

ALS Flashcards

1
Q

Average age of onset

A

55

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2
Q

Prevalence 5/100,000 per year in Europe

A

Chio et al., 2013

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3
Q

Sporadic %

A

90

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4
Q

Familial %

A

5-10

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5
Q

Sx at onset

A

weak grip, decreased dexterity, foot drop, leg stiffness, slurred speech, difficulty chewing

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6
Q

Sx progressively

A

unable to hold things/walk/toilet/feed/talk/swallow. Cognitive deficits (subtle; overt dementia rare)

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7
Q

Death 3-5 years from onset usually from respiratory failure. However 10% will live 1-+ years from dx

A

National Institute of Neurological Disorders and Stroke, 2018

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8
Q

UMN dysfunction

A

modest weakness, hypertonia, hyperreflexia, extensor plantar response

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9
Q

LMN dysfunction

A

major weakness, hypotonia, hyporeflexia, fasciculations, muscle wasting

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10
Q

Dx?

A

clinical, neuroimaging to rule out other conditions

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11
Q

Familial ALS genes

A

C9orf72 25%
SOD1 20%
TDP43 5%

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12
Q

TDP-43 normally lives in nucleus processing gene transcripts. In ALS accumulates in cytoplasm of MNs

A

Arai et al., 2006, Neumann et al., 2006

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13
Q

accumulation of TDP43 in 95% of MND cases

A

Arai et al., 2006, Neumann et al., 2006

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14
Q

Mutations in TDP43 found in ALS cases

A

Sreedharan et al., 2008

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15
Q

Mutated TDP43 cytoplasmic aggregates caused neuronal apoptosis and developmental delay in chick embryos

A

Sreedharan et al., 2008

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16
Q

transgenic TDP43 Drosophila models

A

Li et al., 2010

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17
Q

TDP43 knock out zebrafish

A

Schmid et al., 2013

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18
Q

SOD1 encodes metalloprotein (Zn/Cu have roles in enzyme’s function) which converts superoxides to h2o2 and o2

A

Rosen et al., 1993

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19
Q

20% familial cases caused by dom mutation in SOD1

A

Rosen et al., 1993

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20
Q

Most common SOD1 mutation

A

A4V (but >140 have been found in ALS)

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21
Q

Reviews various SOD1 animal models

A

Joyce et al., 2001

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22
Q

SOD1 knockout mouse did not cause ALS – GOF mutation???

A

Reaume et al., 1996

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23
Q

Studies have suggested loss of function contributes to SOD1 mutations

A

Shefner et al., 1999

24
Q

Mutations in SOD1 cause an exposed…

A

Cu site

25
Q

Exposed Cu site in SOD1 leads to formation of …

A

hydroxyl radicals from hydrogen peroxide –> oxidative damage

26
Q

ALS has been attributed to SOD1 misfolding

A

Jonsson et al., 2004

27
Q

Mutant SOD1 disrupts mitochondrial function

A

Smith et al., 2017

28
Q

SOD1 aggregates accumulate in mitochondria

A

Smith et al., 2017

29
Q

Elevated glutamate in how many cases of sporadic ALS

A

40%

30
Q

elevated glutamate in 40% cases of sporadic ALS

A

ALS Association 2017

31
Q

First and only approved tx for ALS blocks glutametergic neurotransmission

A

Doble, 1996

32
Q

SOD1 mutations affect glutamate transporters ….

A

EAAT2, GLT1 and AMPARs

33
Q

In study lowered EAAT2 levels resulted in neuronal deat in rats

A

Rothstein et al., 1996

34
Q

Why are MNs particularly susceptible to excitotoxicity?

A

a) receive a strong glutametergic input

b) express Ca2+ permeable AMPARs

35
Q

Deletion of part of VEGF causes ALS path in mice

A

Oosthuyse et al., 2001

36
Q

Onset and progression of MND is delayed in mutant SOD1 mice when VEGF is admin

A

Azzouz et al., 2004

37
Q

Other growth factors eg GDNF have protective effects similar to VEGF and may work synergistically in rats to slow MND progression

A

Krakora et al., 2013

38
Q

Astrocytes expressing mutant SOD1 secrete factors toxic to MNs

A

Fritz 2013

39
Q

Hallmark of ALS accumulation of neurofilaments –> common cytoskeletal proteins in MNs and play role in axonal growth –> defective axonal transport plays role in ALS

A

Julien 1995

40
Q

Lower GluR2 accelerates MN degeneration and shortens lifespan in SOD1 mice - replacement sig increases lifespan

A

Van Damme et a., 2005

41
Q

Riluzole extends survival by 2-3 months. decreases VGSCs, potentiating calcium dependent K currents –> inhibits glutamate release

A

Bellingham 2001

42
Q

Ceftriaxone MoA in ALS

A

Stimulates expression of EAAT2

43
Q

Ceftriaxone prolongs survival in animal models but mixed results in human trials

A

Cudkowicz et al., 2014

44
Q

HSP stimulator arimoclomol extends life in SOD1 transgenic mice

A

Kieran et al., 2004

45
Q

HSPs function

A

Facilitate normal folding and degradation of proteins (abnormalities promote MN degeneration)

46
Q

Creatine improves mitochondrial function but has been disappointing in clinical trials

A

Shefner et al., 2004

47
Q

Olesoxime delays onset and extends survival in SOD1 mutant mice; did not show much benefit in ALS pts

A

Lenglet et al., 2014

48
Q

Dexpramipexole extends survival of SOD1 transgenic mice; no difference from placebo in ALS pts

A

Cudkowicz et al., 2013

49
Q

Human neural progenitor cells were developed to release GDNF in the CNS of SOD1 mutant mice. These cells showed good survival and integration into grey and white matter

A

Klein et al., 2005

50
Q

ACE-031 MoA

A

myostatin inhibitor

51
Q

ACE-031 increased muscle mass in mice

A

Cadena et al., 2010

52
Q

CK2017357 MoA

A

increases troponin –> increases muscle force

53
Q

CK2017357 increased muscle strength in a model of myasthenia gravis

A

Russel et al., 2012

54
Q

Gene therapy slows progression and increases survival in SOD1 mutant mice and rats

A

McCampbell et al., 2018

55
Q

ISIS 333611 silence SOD1 gene; clinical trials underway proved safe in Phase 1 study

A

Miller et al., 2013

Neuropharm (9 decks)

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