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PM4 - Neuroscience > Reindl > Flashcards

Reindl Flashcards

1
Q

drug discovery neurological diseases

A

hard
less applied and less approved
more time invested

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2
Q

current neurological drugs

A
  • more symptomatic rather than causative treatment
  • low success of disease modifying drugs
  • worst possible treatment options for neurodegenerative diseases
  • no neuroprotective drugs (e.g. stroke)
  • exception MS (Natalizumab, Ocrelizumab)
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3
Q

neurodegenerative diseases

A

PD
AD
ALS

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4
Q

neuroinflammmation
origin

A
  • infection
  • tissue injury
  • tissue stress and malfunction
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5
Q

neuroinflammation
physiological purpose

A
  • host defence
  • tissue-repair process
  • adaptation to stress and clearence
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6
Q

neuroinfammation
pathological consequence

A
  • autoimmunity, inflammatory tissue damage and sepsis
  • fibrosis, gliosis, metaplasia and tumor growth
  • neurodegeneration and chronic inflammation
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7
Q

neuroinflammation
by infection (purpose and consequence)

A
  • host defence
  • autoimunity, inflammatory tissue damage, sepsis
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8
Q

neuroinflammation
by tissue-damage (purpose and consequence)

A
  • promoting tissue-repair
  • fibrosis, gliosis, metaplasia, tumor growth
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9
Q

neurodegeneration
by tissue-stress and malfunction (purpose and consequence)

A
  • adaptation to stress, clearance
  • neurodegeneration and chronic inflammation
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10
Q

hallmarks innate immunity

A
  • fast (hours)
  • primary response
  • unspecific, no memory
  • outer surfaces (meninges, CSF)
  • tissue barriers (BBB)
  • mediated by microglia, astrocytes, macrophages
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11
Q

cell types mediating innate immunity

A

microglia
astrocytes
macrophages

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12
Q

hallmarks of adaptive immunity

A
  • slow (days)
  • secondary response
  • highly specific, memory
  • regulation of innate response
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13
Q

timeline activation of immune reponse

A
  • pathogen entry or endogenous factor
  • activation of immune cells by PRR
  • innate host defence
  • adaptive immune reposes
  • modulation of innate response
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14
Q

cellular components of neuroinflammation (all)

A

microglia
astrocytes
oligodendrocytes
epithelial cells
neurons
macrophages
T and B cells
NK cells
neutrophil granulocytes

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15
Q

microglia in neuroinflammation

A

responsible for phagocytosis
degradation of pathogens
Ag presentation (MHC I and II)
production of cyto and chemokines
control of BBB

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16
Q

astrocytes in neuroinflammation

A

control BBB
leukocyte recruitment
gliosis
production of cytokines
production of neutropins
Ag presentation (MHC I and II)

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17
Q

neurons in neuroinflammation

A

degenerating neurons express some MHC I

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18
Q

microglial cells
origin

A

yolk sac blood islands
yolk sac stem cell
erythromyeloid progenitor
embyonic microglia
mature microglia

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19
Q

origin of macrophages/DCs

A

fetal liver bone marrow
haematopoietic stem cell
myleoid precursor
monocyte
macrophage/DC

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20
Q

microglial cells
morphology

A
  • resting: ramified
  • intermediate: hyper-ramified
  • reactive: thickened morphology
  • phagocytic: macrophage-like (differentiated)
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21
Q

microglial cells
activation and function

A
  • inflammatory signals (PRR, cyto/chemokines, NT, etc)
  • response via cyto/chemokines, neutropins, NO and ROS
  • leads to inflammation, cell motility and phagocytosis
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22
Q

neuroinfammation
health vs disease

A

HEALTH: tissue surveillance, microenvironment scanning, neuronal plasticity, circuit shaping

DISEASE: autoimmunit, neurodegeneration

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23
Q

BBB
components

A
  • EC with tight junctions
  • Endothelial and parenchymal basement membrane
  • pericytes
  • glia limitans (by astrocyte processes)
  • microglia and other APCs
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24
Q

BBB
pathways across

A
  • water soluble paracellular
  • lipid-soluble transcellular
  • transport proteins
  • receptor-mediated transcytosis
  • adsorptive transcytosis
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25
Q

adhesion molecules and function

A

extravasation of immune cells (tethering, rolling, transmigration)

  • integrins (on endothelium)
  • selectins (on cell)
  • Ig superfamily (ligand for integrins, VCAM, ICAM)
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26
Q

cerebrovascular recruitment of leukocytes
reason and cell type

A
  • indirect trauma (T and NK)
  • neuronal death (more T and NK)
  • direct injury (macro, neutro, T)
  • infection and autoimmune inflammation (T, B, macros neutros)
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27
Q

neurological autoimmune diseases

A
  • inflammatory demyelinating disease
  • autoimmune encephalitis with Ab against neuronal surface Ag
  • autoimmune encephalitis with Ab against intracellular neuronal Ag
  • neuropsychiatric SLE
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28
Q

demyleinating disorders
causes for demyleination

A
  • autoimunity including epitope mimicry and abnormal immune regulation
  • oligodendrocyte/Schwann cell death (by trauma, viral, apoptosis, necrosis)
  • genetic defects of myelinating cells (incl myelin gene dup, point mutations and lipid storage disorders
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29
Q

demyleinating disease
caused by genetic mutation

A

e.g. Charcot Marie Tooth Disease

30
Q
A
31
Q

multiple sclerosis
genetics

A

familial recurrence 20% vs 0.1% general population
esp. HLA DRB1*1501 associated
genetically more related to other inflammatory diseases (neuronal/glial genes rarely associated)

32
Q

demyleinating disorders
caused by autoimmunity

A

MS (multiple sclerosis)
GBS (Guillan-Barré syndrome)
CIPD (chronic inflammatory demyelinating polyradiculo-neuropathy)

33
Q

multiple sclerosis
disease course

A
  • CIP: clinically isolated syndrome, first flare up with inflammation, demyelination, axonal transsection and remyleination
  • RR: relapse-remitting, continous inflammation and demyleination, reversal to symptome free states
  • SP: no symptom-free intervals
  • or PP: primary progressive, no symptom-free intervas from the beginning
34
Q

multiple sclerosis
autoimmune disease evidence

A

probably T cell mediated -> injection of myelin components in EAE model causes T cell mediated AI disease
certain HLA markers increase MS risk

BUT no specific auto-Ag so far known

35
Q

multiple sclerosis
genetics

A

familial recurrence 20% vs 0.1% general population
esp. HLA DRB1*1501 associated
genetically more related to other inflammatory diseases (neuronal/glial genes rarely associated)

36
Q

multiple sclerosis
clinics

A

CIS - RR - SP
optic neuroitis
brainstem/cerebellum syndrome (intended movement)
brainstem syndrome
spinal cord affected
sensory symptoms

37
Q

multiple sclerosis
diagnosis

A

cerebral MRI
lumbar puncture
oligoclonal bands (IgGs that are in CSF but not in serum)

38
Q

multiple sclerosis
pathophysiology

A

HYPOTHESIS

  • EARLY: BBB leakage, immune cell infilatration -> inflammatory demylination of axons
  • LATE: pathophysiology similar to stroke and AD -> GLIA LIMITANS DAMAGE and astrocyte dysfunction, ROS due to demylination, metabolic stress and energy deficiency -> neuro-axonal and oligodendrocyte damage and death -> neurodegenerative processes promote further damage at distal sites
39
Q

multiple sclerosis
result of demyelination

A
  • re-myelination (thinner) -> symptoms get better and inflammation reduces
  • tranection of the xon -> permanent disability
40
Q

multiple sclerosis
pathophysiology early stages

A

BBB leakage
infilatration of immune cells
inflammatory demylination

41
Q

multiple sclerosis
pathophysiology late stages

A
  • pathophysiology similar to stroke and AD
  • GLIA LIMITANS DAMAGE and astrocyte dysfunction
  • ROS due to demylination
  • metabolic stress and energy deficiency
  • neuro-axonal and oligodendrocyte damage and death
  • neurodegenerative processes promote further damage at distal sites
42
Q

EAE

A

experimental allergic disease
animal model to study MS

43
Q

multiple sclerosis
environmental factors

A

influence of Vitamin D, sun light exposure, latitude, race, smoking, nutrition, movement, viral infections (EBV)

44
Q

EAE
induction

A
  • active immunization with CNS homogenates or myelin components in strong adjuvant
  • passive transfer of in vitro activated AI T cell line
  • spontaneous EAE models where a large prortion of T or B cells are myelin-specific
45
Q

anti-NMDA encephalitis
features

A

autoimmune encephalitis with Ab against cell surface and synaptic proteins -> NMDA

  • paraneoplastisch
  • monophasic
  • psychiatric manifestations, memory and motor deficits, seizures, autonomic instability
46
Q

common factors of autoimune encephalitis

A

associations, triggers and common symptoms are psychiatric disorders, epilepsy, limbic encephalitis, cancer, viral infections, atypical demylination

lead to ALTERATIONS OF SYNAPTIC FUNCTION

47
Q

NMOSD
pathology

A

neuromyelitis spectrum disorder

  • optic neuritis
  • cerebral involvement (nausea, emesis, hiccups, other brainstem syndromes)
  • transverse myelitis (motor and sensory deficits)
  • extra-CNS complications: for AQP4+ only
48
Q

NMOSD
neuropathology

A
  • large destructuve lesions mainly affecting central portion of the cord
  • loss of myelin, glial fibrillary acidic protein, AQP1 and 4 possible
  • leisons contain T, macros, granulo, eosino and active complement
  • AUTO-AB AGAINST AQP4
49
Q

NMOSD
pathophysiology

A
  • autoreactive Ab against AQP4
  • activation of T cells
  • infiltration of immune cells (T, B, eosino, neuro, active microglia)
  • PRIMARY DAMAGE of auto-Ag with complement targeting astrocytes -> necrotic
  • SECONDARY DAMAGE is loss of oligodendrocytes
50
Q

NMOSD
treatments

A

many targets possible

  • ECULIZUMAB: against C5
  • INEBILIZUMAB: against CD19+ B cells
  • SATRALIZUMAB: against IL-6R
51
Q

Eculizumab

A

treatment of NMOSD
against C5

lead to 80% relapse reduction in AQP4+

52
Q

Inebilizumab

A

treatment of NMOSD
against CD19+ B cells

lead to 80% relapse reduction in AQP4+

53
Q

Satralizumab

A

treatment of NMOSD
against IL-6R

lead to 80% relapse reduction in AQP4+

54
Q

multiple sclerosis
treatment

A

therapeutic targets in periphery, circulation, BBB and CNS

therapeutic Ab lead to inhibition, depeletion, prevention of extravasation or promote regeneration

NATALIZUMAB against VCAM (no extravasation)

55
Q

natalizumab

A

treament of MS
against VCAM (prevents extravasation)

side effect: PML if JC-virus positive

56
Q

anti-NMDA encephalitis
pathophysiology

A

reversible internalization of NMDA via auto-Ab
-> impairment of memory and behavior

57
Q

anti-NMDA encephalitis
disease course

A
  • viral prodrome (fever, etc)
  • psychosis (hallucinations, delusions)
  • neurological complications (to coma!)
  • prolonged deficits
58
Q

anti-NMDA encephalitis
treatment

A

corticosteroids
intraveneous Ig
plasma exchange

59
Q

PD
diagnosis

A

cinical symptoms
SPECT only if no clear diagnosis can be given

  • response to dopaminergic therapy
  • resting tremor
60
Q

PD
clinics

A

bradykinesia
resting tremor

61
Q

PD
pathophysiology

A

loss of dompainergic neurons in SNc
first symptoms wehn loss >50%
HYPOTHESIS: due to alpha.synuclein deposits

62
Q

PD treatment

A

L-DOPA as best therapy but Levodopa-induced dyskinesia
L-DOPA as last resort (before DBS)
other medications before -> e.g. Pramipexole

63
Q

ischemic stroke

A

caused by hypoxemia due to infarction of CNS

BEFAST as symptoms

64
Q

ischemic stroke
pathophysiology

A
  • clot reduces cerebral blood flow
  • hypoxia and too little glucose
  • missmatch between energy requirements and availability
  • excess excitatory amines
  • mGluR and NMDA activation
  • excess Ca (CA-CYTOXICITY)
65
Q

ischemic stroke
Ca cytoxicity

A
  • Neurons: ROS and radical production, apoptotic cell eath
  • Astrocytes and oligodendrocytes: trophic factor release
  • Microglia: inflammatory response (BBB dysfunction)
66
Q

ischemic stroke
acute treatment

A

intravenous thrombolysis (via rtPA)
mechnical thromboectomy

67
Q

ischemic penumbra

A

area surrounding ischemic event with suboptimal oxygen and nutrient supply
becomes necrotic over time if blood supply is not restored

68
Q

AD
age of onset

A

early: genetic familiar (<65y)
late: non-genetic (sporadic, but risk genes, >65y)

69
Q

AD
pathophysiology

A

BETA-AMYLOID: forms aggregates over years and extracellular deposits in brain (cell death)
- APP cut by alpha-secretase in good fragments, by b-secretase in bad ones
- aggregation maybe by znc, copper, ApoE4 and low pH (inflammation)

TAU: hyperphosphorylation and aggregation IN neurons (neurofibrillary tangles)
- dysfunction of Tau-transport protein

loss of cholinergic neurons (?)

70
Q

AD
vascular hypothesis

A

vascular risk factors are rsik factors causing inflammation, oxidative stress and loss of energy in brain
-> risk factors also risk factors for AD

71
Q

AD
therapy

A

no good therapy available!
AChE blockers (Donepizel)
anti-amyloid beta Ab: new, not really effective

potential NGF, secretase blockers or beta-sheet breaker

PM4 - Neuroscience (3 decks)

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