Reindl Flashcards
(71 cards)
1
Q
drug discovery neurological diseases
A
hard
less applied and less approved
more time invested
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)
3
Q
neurodegenerative diseases
A
PD
AD
ALS
4
Q
neuroinflammmation
origin
A
- infection
- tissue injury
- tissue stress and malfunction
5
Q
neuroinflammation
physiological purpose
A
- host defence
- tissue-repair process
- adaptation to stress and clearence
6
Q
neuroinfammation
pathological consequence
A
- autoimmunity, inflammatory tissue damage and sepsis
- fibrosis, gliosis, metaplasia and tumor growth
- neurodegeneration and chronic inflammation
7
Q
neuroinflammation
by infection (purpose and consequence)
A
- host defence
- autoimunity, inflammatory tissue damage, sepsis
8
Q
neuroinflammation
by tissue-damage (purpose and consequence)
A
- promoting tissue-repair
- fibrosis, gliosis, metaplasia, tumor growth
9
Q
neurodegeneration
by tissue-stress and malfunction (purpose and consequence)
A
- adaptation to stress, clearance
- neurodegeneration and chronic inflammation
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
11
Q
cell types mediating innate immunity
A
microglia
astrocytes
macrophages
12
Q
hallmarks of adaptive immunity
A
- slow (days)
- secondary response
- highly specific, memory
- regulation of innate response
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
14
Q
cellular components of neuroinflammation (all)
A
microglia
astrocytes
oligodendrocytes
epithelial cells
neurons
macrophages
T and B cells
NK cells
neutrophil granulocytes
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
16
Q
astrocytes in neuroinflammation
A
control BBB
leukocyte recruitment
gliosis
production of cytokines
production of neutropins
Ag presentation (MHC I and II)
17
Q
neurons in neuroinflammation
A
degenerating neurons express some MHC I
18
Q
microglial cells
origin
A
yolk sac blood islands
yolk sac stem cell
erythromyeloid progenitor
embyonic microglia
mature microglia
19
Q
origin of macrophages/DCs
A
fetal liver bone marrow
haematopoietic stem cell
myleoid precursor
monocyte
macrophage/DC
20
Q
microglial cells
morphology
A
- resting: ramified
- intermediate: hyper-ramified
- reactive: thickened morphology
- phagocytic: macrophage-like (differentiated)
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
22
Q
neuroinfammation
health vs disease
A
HEALTH: tissue surveillance, microenvironment scanning, neuronal plasticity, circuit shaping
DISEASE: autoimmunit, neurodegeneration
23
Q
BBB
components
A
- EC with tight junctions
- Endothelial and parenchymal basement membrane
- pericytes
- glia limitans (by astrocyte processes)
- microglia and other APCs
24
Q
BBB
pathways across
A
- water soluble paracellular
- lipid-soluble transcellular
- transport proteins
- receptor-mediated transcytosis
- adsorptive transcytosis
25
adhesion molecules and function
extravasation of immune cells (tethering, rolling, transmigration)
- integrins (on endothelium)
- selectins (on cell)
- Ig superfamily (ligand for integrins, VCAM, ICAM)
26
cerebrovascular recruitment of leukocytes
reason and cell type
- indirect trauma (T and NK)
- neuronal death (more T and NK)
- direct injury (macro, neutro, T)
- infection and autoimmune inflammation (T, B, macros neutros)
27
neurological autoimmune diseases
- inflammatory demyelinating disease
- autoimmune encephalitis with Ab against neuronal surface Ag
- autoimmune encephalitis with Ab against intracellular neuronal Ag
- neuropsychiatric SLE
28
demyleinating disorders
causes for demyleination
- 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
29
demyleinating disease
caused by genetic mutation
e.g. Charcot Marie Tooth Disease
30
31
multiple sclerosis
genetics
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
demyleinating disorders
caused by autoimmunity
MS (multiple sclerosis)
GBS (Guillan-Barré syndrome)
CIPD (chronic inflammatory demyelinating polyradiculo-neuropathy)
33
multiple sclerosis
disease course
- 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
multiple sclerosis
autoimmune disease evidence
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
multiple sclerosis
genetics
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
multiple sclerosis
clinics
CIS - RR - SP
optic neuroitis
brainstem/cerebellum syndrome (intended movement)
brainstem syndrome
spinal cord affected
sensory symptoms
37
multiple sclerosis
diagnosis
cerebral MRI
lumbar puncture
oligoclonal bands (IgGs that are in CSF but not in serum)
38
multiple sclerosis
pathophysiology
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
multiple sclerosis
result of demyelination
- re-myelination (thinner) -> symptoms get better and inflammation reduces
- tranection of the xon -> permanent disability
40
multiple sclerosis
pathophysiology early stages
BBB leakage
infilatration of immune cells
inflammatory demylination
41
multiple sclerosis
pathophysiology late stages
- 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
EAE
experimental allergic disease
animal model to study MS
43
multiple sclerosis
environmental factors
influence of Vitamin D, sun light exposure, latitude, race, smoking, nutrition, movement, viral infections (EBV)
44
EAE
induction
- 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
anti-NMDA encephalitis
features
autoimmune encephalitis with Ab against cell surface and synaptic proteins -> NMDA
- paraneoplastisch
- monophasic
- psychiatric manifestations, memory and motor deficits, seizures, autonomic instability
46
common factors of autoimune encephalitis
associations, triggers and common symptoms are psychiatric disorders, epilepsy, limbic encephalitis, cancer, viral infections, atypical demylination
lead to ALTERATIONS OF SYNAPTIC FUNCTION
47
NMOSD
pathology
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
NMOSD
neuropathology
- 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
NMOSD
pathophysiology
- 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
NMOSD
treatments
many targets possible
- ECULIZUMAB: against C5
- INEBILIZUMAB: against CD19+ B cells
- SATRALIZUMAB: against IL-6R
51
Eculizumab
treatment of NMOSD
against C5
lead to 80% relapse reduction in AQP4+
52
Inebilizumab
treatment of NMOSD
against CD19+ B cells
lead to 80% relapse reduction in AQP4+
53
Satralizumab
treatment of NMOSD
against IL-6R
lead to 80% relapse reduction in AQP4+
54
multiple sclerosis
treatment
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
natalizumab
treament of MS
against VCAM (prevents extravasation)
side effect: PML if JC-virus positive
56
anti-NMDA encephalitis
pathophysiology
reversible internalization of NMDA via auto-Ab
-> impairment of memory and behavior
57
anti-NMDA encephalitis
disease course
- viral prodrome (fever, etc)
- psychosis (hallucinations, delusions)
- neurological complications (to coma!)
- prolonged deficits
58
anti-NMDA encephalitis
treatment
corticosteroids
intraveneous Ig
plasma exchange
59
PD
diagnosis
cinical symptoms
SPECT only if no clear diagnosis can be given
- response to dopaminergic therapy
- resting tremor
60
PD
clinics
bradykinesia
resting tremor
61
PD
pathophysiology
loss of dompainergic neurons in SNc
first symptoms wehn loss >50%
HYPOTHESIS: due to alpha.synuclein deposits
62
PD treatment
L-DOPA as best therapy but Levodopa-induced dyskinesia
L-DOPA as last resort (before DBS)
other medications before -> e.g. Pramipexole
63
ischemic stroke
caused by hypoxemia due to infarction of CNS
BEFAST as symptoms
64
ischemic stroke
pathophysiology
- 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
ischemic stroke
Ca cytoxicity
- Neurons: ROS and radical production, apoptotic cell eath
- Astrocytes and oligodendrocytes: trophic factor release
- Microglia: inflammatory response (BBB dysfunction)
66
ischemic stroke
acute treatment
intravenous thrombolysis (via rtPA)
mechnical thromboectomy
67
ischemic penumbra
area surrounding ischemic event with suboptimal oxygen and nutrient supply
becomes necrotic over time if blood supply is not restored
68
AD
age of onset
early: genetic familiar (<65y)
late: non-genetic (sporadic, but risk genes, >65y)
69
AD
pathophysiology
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
AD
vascular hypothesis
vascular risk factors are rsik factors causing inflammation, oxidative stress and loss of energy in brain
-> risk factors also risk factors for AD
71
AD
therapy
no good therapy available!
AChE blockers (Donepizel)
anti-amyloid beta Ab: new, not really effective
potential NGF, secretase blockers or beta-sheet breaker
