Stroke

Question 1

Hemiparesis

Answer 1

Hemiparesis is weakness or the inability to move on one side of the body

Question 2

Hemiplegia

Answer 2

Hemiplegia is a condition caused by brain damage or spinal cord injury that leads to paralysis on one side of the body

Question 3

Ischemic vs. hemorrhagic stroke

Answer 3

No symtom differences but vessel occlusion = ischemic stroke (80-90% of all strokes) and Intracranial bleeding = hemorrhagic stroke (10-20 % of all strokes)

Question 4

Best therapy for strokes?

Answer 4

Prevention: no smoking, diabetes, low blood pressure etc.

Question 5

Symptoms of stroke

Answer 5

Hemiparesis and Hemiplegia

Question 6

Pathophysiology of stroke

Answer 6

Very complex. core components are vascular occlusions, glutamate relates, increase in intercellular Ca2+, free radical production and so on

Question 7

Current therapies for stroke

Answer 7

Mechanical recanalization up to 24 hours later (destruction/removal or cloth) or Thrombolysis with recombinant t-PA (4.5-6 hours after, disolves cloth)

Question 8

Limitations of current therapies for stroke

Answer 8

Suitable only for minority of patients
Narrow time window
High intracranial bleeding risk

Question 9

3R Principle

Answer 9

1) Avoid animal experiments altogether (Replacement)
2) To limit the number of animals (Reduction)
3) their suffering (Refinement) in tests to an absolute minimum.

Question 10

Craniotomy

Answer 10

A craniotomy is the surgical removal of part of the bone from the skull to expose the brain

Question 11

Photocoagulation

Answer 11

Photocoagulation takes place by using the laser to create a microscopic burn in the target tissue

Question 12

Vasogenic edema

Answer 12

Vasogenic edema is defined as extracellular accumulation of fluid resulting from disruption of the blood-brain barrier (BBB) and extravasations of serum proteins

Question 13

Vasoconstriction

Answer 13

Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels

Question 14

Microsphere

Answer 14

A Microsphere is a small spherical microparticle, with diameters typically ranging from 1 μm to 1000 μm (1 mm)

Question 15

What types of stroke models exists

Answer 15

In-silico, in-vitro, ex-vivo and (most importantly) in-vitro (Genetically engineered/ mutated animals, Invasive methods in animals, Non-invasive methods for investigations of humans)

Question 16

An ideal stroke models should:

Answer 16

… mimic the clinical situation
… be highly reproducible, controllable and standardized
… be easily to perform
… not produce side-effects within the brain
… allow physiological monitoring
… allow for analysis before (!) symptoms become visible (first minutes)
… allow for fast and direct access to brain tissue
… be cost effective
…and should be of limited ethical concern!

Question 17

Intraluminal suture MCAO model

Answer 17

Use filament that is inserted in the CCA until it comes to the middle cerebral artery. One can do it in 5-7 min.
By occluding the middle cerebral artery, the have a highly comparable model for stroke. Advantage: fast to perform, easy access to tissue, we can use CCT stain to see the ischemic tissue.
You can see what mechanical recanalizing can do to the tissue, as it would be re-oxygenized
Pros: Mimics human ischemic stroke; penumbra; reproducible; reperfusion controllable; no craniectomy
Cons: Increased hemorrhage; not for thrombolysis studies

Question 18

Bederson Score

Answer 18

from 0- 5 on global neurological ability. Test for severe motor deficits in the acute phase. Circling and spinning is considered bad (4), but not as bad a no movement (5)

Question 19

Craniectomy model

Answer 19

Permanent Distal Middle Cerebral Artery Occlusion (including occlusion of both CCAs). Reduces collateral blood flow and thus consolidates the ischemic damage.
Pros: Long-term survival; visual conformation of success
Cons: Highly invasive; surgical skills needed; affects intracranial pressure

Question 20

Photothrombosis model

Answer 20

Using Photoactive dye to and using the laser to create a microscopic burn in the target tissue.
Pros: Long-term survival; defined location; reproducible; low invasiveness
Cons: Early Vasogenic edema formation; not good for research in neuroprotective agents

Question 21

Endothelin-1(ET-1) Model

Answer 21

Injecting a Vasoconstrictive peptide to decrease the circumference of the blood vessel. Leads to a dose dependent ischemic lesion and rapid cerebral blood flow reduction. Reperfusion will occur over hours
Pros: Low mortality; low invasiveness; lesions in cortical/subcortical regions
Cons: Duration of ischemia is not controllable; induction of axonal sprouting and astrocytosis, which can lead to biases

Question 22

Embolic Stroke model

Answer 22

Inserting a microsphere or a thromboembolic clot to mimic a blood-clot. Pros: Mimics human pathogenesis best; appropriate to study thrombolysis
Cons: Spontaneous recanalization; High variability of lesion size

Question 23

Analysis of experimental stroke

Answer 23

Functional outcome
    - Behavior tests
Stroke size in the brain (most important)
    - MRI/ Histology
Tissue analysis
    - Molecular biology (PCR, qPCR)
    - Protein analysis (Western blot, ELISA)
    - Histology
    - Flow Cytometry (Cells/Cytokines)
    - Injection of tracers

Question 24

Grip Test

Answer 24

tests motor function, coordination and movement. Scored from 0-5.

Question 25

Infarct volume

Answer 25

Infarct volume is a direct measurement of 1 of the final pathologic steps leading to the clinical deficits caused by an ischemic stroke

Question 26

ischemia-reperfusion injury (IRI)

Answer 26

Reperfusion injury, sometimes called ischemia-reperfusion injury (IRI) or reoxygenation injury, is thetissue damage caused when blood supply returns to tissue (re- + perfusion)after a period of ischemia or lack of oxygen (anoxia or hypoxia)

Question 27

no-reflow

Answer 27

The no-reflow phenomenon refers to the observation that when an organ is made ischemic by occlusion of a large artery supplying it, restoration of patency in that artery does not restore perfusion to the microvasculature supplying the parenchyma of that organ

Question 28

Infarct volume

Answer 28

Infarction is tissue death (necrosis) due to inadequate blood supply to the affected area.

Question 29

Platelets

Answer 29

Platelets, or thrombocytes, are small, colorless cell fragments in our blood that form clots and stop or prevent bleeding. Having them together with T cells can cause increased infarct volume in RAG1 deficient mice

Question 30

Ladder rung walking task

Answer 30

For photosympotic stroke - shows recognition, coordination and motorfunctioning and is good long term, but takes training, more complex than a 1-5 rating

Question 31

Only appoved drug againts strokes?

Answer 31

rt-PA (Alteplase), which is a ”clot-blaster” drug

Question 32

Why don’t we have more drugs for clearing up strokes?

Answer 32

The reproducibility in studies are low
Studies are not comparable (different methods)
The publication bias

Question 33

Possible solutions to getting more drugs for clearing up strokes approved?

Answer 33

To make the clinical trials in mice match the human conditions better - one proposal to that is the STAIR criteria:
Randomization, defining inclucion/exclusion criteria
Power and sample size calculations
Disclosure relevant conflict of interest
Aged animals, animals with comorbidities should be included
Male and female animals
Interaction studies with other medications
Relevant biomarker endpoints (e.g. diffusion/perfusion MRI)

Question 34

What causes neuroinflamation in stroke

Answer 34

T-cells , as shown by the RAG1 defficint mouse-model, however, platelets have a modulatory (increasing effect)

Question 35

Effectiveness in rapid recanalization?

Answer 35

Up to 80%

Question 36

After how long do we see infarction after an induced Middle Cerebral Artery Occlusion stroke model?

Answer 36

8 hours

Question 37

Which part of the platelets should be affected if we want to decrease it’s modulatory effect on T-cells leading to infarction?

Answer 37

The proteins associated with the early phases platelet activation (GPIb and maybe GPVI). Affecting later stage proteins which are responsible fo aggregation and thrombus growth might lead to hemorrhagic stages.

Question 38

Targeting GPIb protects the brain from?

Answer 38

I/R-injury

Question 39

Function of fingolimod (FTY720)

Answer 39

It inhibits the egress of the lymphocytes from the lymponode into the bloodcirculation and thereby redcuces the lymphocyte counts in the blood –> T cells can’t be damaging if they’re not in the blood. In strok it leads to less lession growth and less behavioral damage. This is also seen if the thrombolysis (clot-blaster) was given later

Question 40

When a T cells detrimental and beneficial

Answer 40

For the subacute and chronic stroke: T-cell prevention does not make sense later in the process (in the chronic stage we have immunodepression, so it might be downright problematic to block the T-cells)
As the detrimental effects only occur in the hyper acute and the acute phases, where the T cells increase infarction