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Brain PD > week 8 part 1 > Flashcards

week 8 part 1 Flashcards

1
Q

What is multiple sclerosis ?

A

Demyelinating disease of the central nervous system which include the brain and the spinal cord

autoimmune disease

polygenic - over 200 different genes that have been identified that are associated with susceptibility

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2
Q

What is myelin?

A

protective sheath that surrounds the axon of neuron allowing them to quickly send electrical impulses

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3
Q

What is myelin produced by?

A

oligodendrocytes - group of cells that supports the neuron

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4
Q

When does demyelination happen?

A

when the immune system attacks and destroys the myelin which makes communication between neurons break diown

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5
Q

What does demyelination cause?

A

sensory, motor and cognitive problems

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6
Q

What is the most important gene?

A

HLADRB1*1501

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7
Q

What is HLADRB1*1501?

A

a Class II member of the major histocompatibility complex (MHC)

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8
Q

Who is more likely to be affected by MS?

A
  1. females

2. It is around 1-3

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9
Q

What does MS have?

A

Graphical distribution

It is more common further away from the equator

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10
Q

What does MS relate to?

A

Vitamin D responsiveness

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11
Q

What are some of the most common risk factors for multiple sclerosis include?

A
  1. Genetics
  2. Certain Infections
  3. Smoking
  4. Obesity
  5. Environmental factors
  6. Certain autoimmune diseases
  7. Age, sex, race
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12
Q

What do individuals with MS have?

A
  1. Epstein Barr Virus infection
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13
Q

When a disease manifests itself what does it manifest as?

A

Relapsing remitting diseases

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14
Q

What is secondary progressive MS?

A

Many people who are initially diagnosed with relapsing remitting MS find that, over time, their MS changes so that there are fewer or no relapses but disability is increasing.

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15
Q

Why is there different residuals signs and symptoms?

A

As a consequence of losing myelin and axons and neurons and synapses

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16
Q

What does the symptoms you will get depend on?

A

Where in the nervous system the attacks occur

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17
Q

In MS brain, where are the lesions observed?

A

Paraventricular lesions

Lesions around the ventricles

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18
Q

What are lesions associated with?

A
  1. De-myelination

2. Astrocytic scarring

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19
Q

Where are the active lesions located?

A

Perivascular areas

Occur around the blood vessels

Contain lymphocytes and monocytes

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20
Q

What are the features of active lesions?

A
  1. Foamy macrophages
  2. Myelin losses
  3. Hypertrophi astrocytes
  4. Perivascular infiltrates
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21
Q

What are chronic active lesions?

A
  1. Large, grey lesions - inactive centre but show an outer hyperceullar rim - contain foamy macrophages
  2. Myelin remnants are seen in the macrophages
  3. Hypertrophic astrocytes are often present in the rim
  4. Oligodendrocytes numbers are depleted, increased or normal
  5. Perivascular lymphoid infiltrates are present
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22
Q

What are macrophages full off?

A

Lipid

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23
Q

What are shadow plaque?

A

If the inflammatory process is arrested at an early phase, plaques are partially remyelinated

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24
Q

What are consequences of chronic inactive lesions?

A
  1. Complete myelin loss
  2. Loss of oligodendrocytes
  3. Few or no inflammatory cells
  4. Gliotic
  5. Surrounded by ‘normal’ white matter
  6. The lesions are clearly hypocellular
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25
Q

What are repairing lesions?

A
  1. Myelin replacement
  2. Thinner myelin
  3. Smaller internode length
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26
Q

What is pathology of MS?

A
  1. Characterised by multifocal lesions - MS plaque
  2. in the acute phase - activated mononuclear cells - including lymphocytes, microglia and macrophages destroy myelin
  3. Myelin debris are picked up by macrophages and degraded
  4. At early stage - macrophages contain myelin fragments
  5. later stage - they contain proteins and lipids from chemical degradation of myelin
  6. with time gliosis develops
  7. Plaques reach a burned-out stage - demyelinated axons traversing glial scar tissue
  8. Remaining oligodendroyctes attempt to make new myelin
  9. If the inflammatory process is arrested at an early phase, plaques are partially remyelinated (shadow plaque)
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27
Q

In more advanced lesions, why is remyelination ineffective?

A

Gliosis creates a barrier between myelin producing cells and their axonal targets

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28
Q

what is Experimental autoimmune encephalomyelitis?

A

animal model of brain inflammation

It is an inflammatory demyelinating disease of the central nervous system (CNS)

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29
Q

What is MS?

A

Immune mediated

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30
Q

How does EAE work?

A

immunization with myelin proteins or peptides induces the migration of activated autoreactive T cells across the blood-brain barrier and into the CNS;

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31
Q

What are killing oligodendrocytes which is causing the demyelination?

A

perivascular lesion around blood vessels, these are secreting toxin factors

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32
Q

What was the first drug to affect progressive MS?

A

Ocrelizumab

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33
Q

When do we get an accumulated risk of opportunity infections?

A

When the drugs are not specific and is targeting large parts of immune response

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34
Q

When do you have a risk of malignancy?

A

constantly depressing your immune system

Cannot take live vaccines

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35
Q

What is pulsed immunotherapies?

A

Non-continuous administration

Get treatment over a week or month

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36
Q

What are non-selective Immunotherapy?

A

Gets rid of adaptive and innate immune system

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37
Q

What are semi-selective Immunotherapy?

A

Doesn’t target immune system so much

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38
Q

What is the escalation approach?

A

• You can take low efficacy drugs with low side effects and if the disease breaks through you switch to a higher efficacy drug which higher side effects

39
Q

What is Glatiramer acetate

A

Modulates TH1 and TH2

Preventing and suppressing experimental autoimmune encephalomyelitis (animal model of MS)

Diverts TH1 cells to TH2 cells that suppress inflammatory responses and activate Tregs in the periphery

40
Q

What does Di-methyl furmarate target?

A

NRF2
modulates anti-oxidative respinse

Exert a neuroprotective effect in patients with multiple sclerosis by activating the Nrf2 transcriptional pathway

41
Q

What does Teriflunomide inhibit

A
  1. pyramadine
  2. stop DNA replication - stop proliferation of cells
  3. Inhibits the proliferation of B and T cells
  4. Exerts anti-inflammatory properties by inhibiting IFN-gamma producing T cells
  5. Oral administration - reduce relapse rate, MS lesions and decreased disability progression D
42
Q

How does Fingolimod work?

A

Attaches to surface of certain white blood cells

Retain within the body’s immune system

less lymphocytes get into blood stream and fewer reach the central nervous system

potential for immune attack on cells of brain and spinal cord is reduced

43
Q

What is Natalizumab associated with?

A

increased risk of opportunistic infection and progressive multifocal leucoencephalopathy (PML) caused by JC virus

  1. Humanised monoclonal antibody against the cellular adhesion molecule alpha-4 integrin
  2. Administered intravenously once a month which reduces activated T cells within the CNS, resulting in anti-inflammatory responses and hence neuroprotective effect
  3. Approved by FDA in 2004 but was withdrawn due to 3 cases of rare brain Infection
44
Q

Mechanism of Natalizumab?

A

– it blocks to cells binding to the vascular cell adhesion molecule 1 on the inflamed brain endothelia and therefore the cells cannot get into the brain and therefore cannot get disease

45
Q

How does Cladribine work?

A

kills certain types of blood cells made by your immune system. These white blood cells (or lymphocytes) are called T and B cells.

it phosphorylates the adenosine cytokinase – integrates into the DNA and causes strand breaks and also goes into mitochondria and affects RNA

46
Q

What does Daclizumab block?

A

Interleukin 2

  1. Humanised monoclonal antibody against CD25, the IL-2 receptor expressed not he surface of T cells
  2. Blocks IL-2 receptor on T cells, preventing the activation of T cells
47
Q

What is Interleukin 2?

A

T cell growth factor

Anti-proliferative

48
Q

What is percentage that CD4 T cells are depleted by?

A

80% throughout 2 years

49
Q

What is MS?

A

T cell mediated disease

50
Q

What does transgenic mice have?

A

CD52

51
Q

What are immature B cells?

A

potentially auto-reactive

Re-populating in the absence of any CD8 regulation and CD4 T regulation

52
Q

What is an effective treatment for relapsing MS?

A

Hematopoietic stem cell therapy

53
Q

How does Hematopoietic stem cell therapy work?

A
  1. Deplete the immune system
  2. Liable to infection
  3. Transplant CD34 positive stem cells
  4. within 29-30 days create neutrophil which protect you against infection
54
Q

What happens between 0.5 and 2% of people?

A

Die because of complications related to removing immune system

55
Q

How long does it take for memory B cells to populate?

A

18 months - 4 years

56
Q

What is diagnostic features of MS?

A

Memory B cell pool give rise to plasma blasts - plasma cells that could make oligo clonal bands

57
Q

What is consistent with many autoimmune diseases?

A

B cell follicles

58
Q

Where do you get extra B cell follicles within?

A

Arithritic joints

59
Q

What are B cells that are accumulating in the CSF during active MS?

A
  1. CD27+ memory B cells

2. Plasmablasts

60
Q

What are B cells accumulating in the CNS parenchyma?

A
  1. CD27+ memory B cells

2. Plasmablasts/plasma

61
Q

What may B cell structures be associated with?

A

Disability

62
Q

What does EBV proteins activate?

A

Immune risk gene

63
Q

What induces memory B cells?

A

EBNA3

64
Q

How does the Espar Bar viruses infect B cell?

A
  1. CD21

2. HLA-DR

65
Q

When do you get a higher viral load?

A

Autoimmune risk genes

66
Q

What do Memory B cell up-regulate?

A

CD8 T cell

Becomes APC

67
Q

What does lesion show?

A

Higher prevalence of EBV reactivity

68
Q

What do T cells provide?

A

Trophic support for pathogenic B cells to mediate MS

69
Q

What do memory B cells present?

A

antigen to pathogenic T cells to mediate MS

70
Q

What may cause B cell autoimmunity?

A

Repopulation of Immature B cells in the absence of effective CD4 and CD8 T regulation

71
Q

What is progressive MS not responsive to?

A

Immunotherapy

72
Q

What is MS?

A

Length dependent axonopathy

73
Q

How is MS assessed?

A

Mobility scale

74
Q

What has an effect on progressive MS?

A
  1. Ocrelizumab

2. Slowed the rate of loss down by 24%

75
Q

What happens as a consequence of de-myelination?

A

You get re-distribution of ion channels that maintain the neurological function

76
Q

What does too much glutamate cause?

A

Excessive calcium release

cause nerve death

77
Q

What are some consequences of de-myelination?

A
  1. Mitochondrial problem (energy deficit)
  2. Neuro-excitotoxicity
  3. Problem with mitochdonrial movement
78
Q

What happens in the presence of inflammation from glia?

A
  1. Nitric oxide - causes problems for mitochondria
79
Q

What does lactate influence?

A

Redox potential of the nerve and that can get blocked

80
Q

What is the central driver for the progressive MS?

A

activated glia

produce cytokine e.g. IL=1, TNF

81
Q

What do B cell follicles produce?

A

Antibodies

82
Q

What is inflammation associated with?

A
  1. Length-dependent nerve loss

2. Irreversible disability

83
Q

What is Multiple Sclerosis?

A

Inflammatory and neurodegenerative from beginning to the end

84
Q

What are symptoms of Multiple Sclerosis?

A
  1. Blindness
  2. Nystagmus
  3. Fatigue
  4. Pain
  5. Tremor
  6. Spasms and Spasticity
  7. Bladder problems
  8. Incontinence
  9. Sexual problems
  10. Cognitive deficit
  11. Motor deficits
85
Q

What do nature of the symptoms depend on?

A

Location of lesions within the neural circuitry

86
Q

What is spasticity?

A

Velocity dependent stretch response

Based on the reflex arc

87
Q

Spasticity

A

Muscle stiffness (Exaggerated stretch reflec)

88
Q

What are used for Epileptic Seizures?

A

Standard anti-convulsant (1-8%)

89
Q

What are used for neuropathic pain?

A
  1. Voltage-gated sodium channel blockers
  2. Carbazepine
  3. Phenytoin
  4. Gabapentin
  5. Iamotrigine
  6. Topiramate
90
Q

What are used for depression?

A
  1. Tricyclics (amitriptyline, desipramine)
  2. SSRI (fluoxetine, paroxetine, sertraline)
  3. SNARI (Venlafaxine), NARI (reboxitine)
91
Q

What are used for ataxia and tremor?

A
  1. Clonazepam (GABA A)
  2. Propanolol (beta-blocker)
  3. Gabapentin
  4. Valproate
  5. Physiotherapy-Gait modification walking aids
92
Q

What causes nerve loss?

A

Adaptive inflammation

Demyelination

93
Q

What promotes nerve loss?

A

Glial inflammation

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