10_Blood Brain Barrier_Q and A_Jonathan

Question 1

What is Autoregulation?

Answer 1

• Mechanism by which blood flow is maintained at a constant rate despite changes in arterial blood pressure.

Question 2

What is the Blood-brain barrier?

Answer 2

• mechanism for selective control of movement from blood into interstitial space of brain.
• Consists of non-fenestrated, continuous capillaries with few pinocytotic vesicles.
• Endothelial cells are induced to take this form by interaction with processes of astrocytes.

Question 3

What is the Blood-CSF barrier?

Answer 3

• mechanism for selective control of movement from blood into CSF.
• It is formed by tight junctions between the choroid epithelial cells that surround fenestrated capillaries.

Question 4

What are examples of blood viscosity affects cerebral blood flow?

Answer 4

• dehydration and hemocrit
• RBC aggregation and cell flexibility (sickle cell)
• Plasma protein concentrations

Question 5

What is the normal range of blood flow for grey matter?

At what level do neurons start to malfunction? Die?

Answer 5

• 50cc/100grams and 100cc/100grams of tissue/minute in gray matter.
• At baseline, the flow in gray matter is about twice that in white matter.
• 20cc/100gm/min ==> neurons will begin to malfunction
• levels lower than 15cc/100gm/min result in death (the lower the quicker the death).

Question 6

What is the order of death of nervous system cells?

Answer 6

• Neurons will die more quickly (~5 minutes of no flow) than axons, which will die more quickly than glial cells.

Question 7

Ischemic injury to neurons results from what series of steps?

Answer 7

• There will be an accumulation of free radicals
• release of intracellular enzymes
• entry of calcium into the neuron.
• The calcium will, in turn, poison the mitochondria.
• This process will be hastened by release of some neurotransmitters from excitatory neurons (particularly glutamate), which opens channels that permit calcium entry (NMDA channels).
• Excess calcium will damage mitochrondria.
• Neurons do not normally have the capacity for anaerobic metabolism, so hypoxia is a primary cause of damage and cell death.

Question 8

Note:
the locus ceruleus is affected by norepi
raphe is affected by serotonin
nucleus basalis is affected by acetylcholine

Answer 8

Note:
the locus ceruleus is affected by norepi
raphe is affected by serotonin
nucleus basalis is affected by acetylcholine

Question 9

How is cerebral blood flow regulated?

Answer 9

• activity-dependent
• There are myoepithelial cells in brain precapillaries that contract when stretched (both smooth muscle endothelial cells and contractile pericytes)
• This is an intrinsic property of these cells and does not require innervation.
• Therefore, when blood pressure rises, the precapillaries constrict, preventing much rise in blood flow in the brain.
• Pericytes and glial cells also influence

Question 10

Through what ranges of blood pressure does cerebral blood flow remain constant?

Answer 10

• Through all normal ranges of mean arterial blood pressure, blood flow will remain constant.
• This autoregulation can be exceeded by malignant hypertension and can result in damage to the endothelium and the blood-brain barrier.

Question 11

What are the dangers of longstanding hypertension on autoregulation?

Answer 11

• Longstanding hypertension results in a shifting of this autoregulatory curve such that low-normal pressures can result in tissue ischemia.

Question 12

What is Hypertensive Encephalopathy?

Answer 12

• Often occurs with stimulants
• Blood pressure exceeds upper limit of autoregulation
• Passive increases in CBF occur with resulting cerebral edema and/or hemorrhage
• Clinical picture involves headache, altered level of consciousness, seizures and potentially death
• Blood brain barrier can be compromised

Question 13

What is Hyperperfusion Syndrome?

Answer 13

• Sudden return of normal flow in a cerebral vascular bed which has had chronically low perfusion (due to occlusion)
• May also result in cerebral edema, seizures, and/or hemorrhage

Question 14

What happens in Lowering pressure too fast in a hypertensive patient? What condition in particular requires great care?

Answer 14

• May result in drop in flow
• May result in hypoperfusion
• May worsen stroke in progress – BE CAREFUL

Question 15

What are the “activity” dependent methods that brain cells can increase cerebral blood flow?

Answer 15

• substances released from neurons and glia that dilate cerebral blood vessels.
• CO2, low pH (which can occur because of increased CO2), adenosine, and nitric oxide, prostaglandins (arachadonic acid metabolyte), glutamate
• These latter compounds are often released in regions of increased neuronal activity and result in increased blood flow (beyond that needed for the increased metabolism) in active areas of the brain.
• Note: grey matter is more active than white matter, therefore has 2x more blood flow
• Note: migraines are cause by vasoactive compounds released in the brain.

Question 16

What is the the proportion of arterial PCO2 and to change in CBF?

Answer 16

• 1mmHg change in pCO2 = 2ml/100gm/min change in CBF

Question 17

In terms of vasodilation vs constriction, how does PCO2 affect CBF? How is this mediated?

Answer 17

• Increased pCO2 causes vasodilation
• Decreased pCO2 causes vasoconstriction (ex: hypoventilation)
• probably pH mediated
o H2O + CO2 H2CO3 H+ + HCO3-

Question 18

How is PCO2 related to intracranial blood volume?

Answer 18

• We used to hyperventilate patients with head injury
• Lower CO2 ==> constriction ==> lowers CBF ==> This lowers intracranial pressure
• But outcomes are worse ==> head injury causes increased pressure ==> lower blood flow ==> if you lower blood flow more, you cause more problems (decreased neuronal nutrients.
• This practice is no longer used.

Question 19

What is the Monro-Kellie doctrine?

Answer 19

• intracranial volume is fixed and is equal to brain volume + CSF + blood volume
o if any of these increase ICP increases

Question 20

What are some examples of causes of increased cranial pressure?

Answer 20

• Tumors ==> take up space ==> squeeze fluid out and compromise circulation
• Brain swelling (edema)

Question 21

How does increased intracranial pressure affect CBF?

Answer 21

• Perfusion pressure = MAP – ICP
• Hyperventilation ↓ blood volume and ICP by vasoconstriction (also increases resistance to flow)
• Increased MAP improves flow
o This is now the treatment ie, if ICP ↑ then we ↑ MAP in order to maintain perfusion pressure

Question 22

What is the Cushing Reflex?

Answer 22

• if pressure inside head ↑ a lot (ex: hematoma), blood pressure increases (via sympa) and heart rate goes down (vagal reflex)

Question 23

What are the cellular features of the blood-brain barrier?

Answer 23

• specialized endothelium
• tight junctions between endothelial cells
• few pinocytotic vesicles
• no fenestra
• high amounts of metabolic activity involved in active transport
o High mitochondria
• Presense of enzymes specific to CNS vessels
• Increased electrical resistance across the cell membrane

Question 24

How do these specializations develop?

Answer 24

• under the influence of footplates of astrocytes, which basically cover the abluminal aspect of the endothelium.

Question 25

What molecules pass through the blood brain barrier?

Answer 25

• Highly lipophilic substances cross the endothelial membranes.
• Water will also cross by simple diffusion.
• Very small molecules are also somewhat more likely to cross, although even these are usually tightly regulated and transport of ions is via active pumps.
• Most nutrients cross the barrier via facilitated diffusion, usually by mechanisms that couple the movement of the nutrient with movement of an ion that is moving down its concentration gradient.

Question 26

What are the general permeability factors affecting permeability of all compounds?

Answer 26

• Lipid solubility – more lipid soluble pass more easily
• Size – smaller pass more easily
• Serum protein binding – protein binding decreases ability to pass
• Polarity – the more polar the less likely to pass

Question 27

What are the qualities of facilitated transport systems?

Answer 27

• important for getting insoluble metabolic substrates back and forth.
• Systems are stereospecific
• They have a finite carrying capacity
• They are subject to competitive inhibition

Question 28

Ion Cotransport Systems- Na+/Cl-, Na+/H+, Na+/K+ ATPase, etc.

Answer 28

Ion Cotransport Systems- Na+/Cl-, Na+/H+, Na+/K+ ATPase, etc.

Question 29

Note: ions are very tightly regulated at the blood brain barrier. Huge increases in plasma ions results in negligible changes in ion concentrations in CSF.

Answer 29

Note: ions are very tightly regulated at the blood brain barrier. Huge increases in plasma ions results in negligible changes in ion concentrations in CSF.

Question 30

What do the regions of the brain that lack a blood-brain barrier do?

Answer 30

• sense the internal milieu of the body
• serum osmolarity
• sense hormone levels
• RELEASE hormonal factors into the blood stream

Question 31

What clinical considerations may compromise the blood brain barrier?

Answer 31

• tumors, stroke, infections, malignant hypertension, head trauma, radiation

Question 32

How do compromised blood brain barrier affect radiographic contrast?

Answer 32

• if the BBB is compromised, contrast may pass through and demonstrates a leaky BBB

Question 33

What are ways to bypass the blood brain barrier?

Answer 33

• take advantage of pathological disruption
o ex: may give penicillin in meningitis because BBB is permeable
• intra-arterial osmotic agents or other vasoactive substances temporarily open the BBB
o mannitol
o adensosine, leukotrienes
o interstitial radiation
• direct administration into CSF
o lumbar punctures
o ventricular catheters

Question 34

What are areas in the brain that sense osmolarity?

What about sense or release hormones?

Answer 34

• Called circumventricular organs because they are areas of low BBB
• Subfornical organ or the area postrema of the brain stem.
• The infundibulum of the hypothalamus and the pituitary gland
o Releasing factors enter the capillaries of the infundibulum and travel to the anterior pituitary gland where they influence the release of the trophic hormones.
o This circulation from the hypothalamus to the pituitary gland is called the hypothalmo-hypophyseal portal system and contains fenestrated capillaries.

Question 35

What are tanicytes?

Why are tanicytes necessary?

Answer 35

• specialized glial cells called tanicytes that separate those areas of the brain with and without blood-brain barriers.
• necessary in order to prevent substances from moving between these brain regions through the interstitial spaces of the brain, circumventing the blood-brain barrier.

Question 36

Is there a CSF-Brain barrier?

Answer 36

• There is no barrier between the cerebrospinal fluid and the brain, i.e., the pia does not provide any significant barrier.

Question 37

Explain the blood-CSF barrier.

Answer 37

• The capillaries of the choroid plexus are fenestrated and have no barrier to passage of macromolecules.
• However, these capillaries are surrounded by choroid plexus epithelium, which forms a barrier.
• tight junctions between the choroid plexus epithelial cells, as well as specific transport mechanisms for nutrient passage and electrolyte regulation.

Question 38

Explain the blood-CSF barrier with regard to intravenous contrast.

Answer 38

• The choroid plexus, itself, enhances with intravenous contrast.
• However, this contrast does not get into the CSF because of the tight junction and barriers to transport that are similar to those mechanisms present in brain capillaries.
• This CSF has similar composition to the interstitial fluids of the brain because there is no barrier between the CSF and the brain substance.

Question 39

How is CSF produced?

Answer 39

• choroid plexus epithelial cells.
• These modified ependymal cells have tight junctions and transport mechanisms that create CSF from blood.

CSF is produced by the choroid plexus
• Capillaries have fenestrations
• The barrier between the blood (choroid plexus) and CSF is at the epithelial lining of the choroid plexus.
• Choroid epithelial cells have tight junctions and few vesicles (like brain capillaries)
• There are similar transport mechanisms in place to those seen in brain capillary enodothelial cells (CSF composition is very similar to brain interstitial fluid)

Question 40

Cerebrospinal fluid (CSF) is created in the choroid plexus. These highly vascular structures are located within the ventricles. This fluid, amounting to about 75cc, has few cells and a low concentration of protein. It does contain 1/2 to 3/4 the concentration of blood glucose (see above table). CSF circulates, and turns over several times per day (depending on the level of hydration).

Answer 40

Cerebrospinal fluid (CSF) is created in the choroid plexus. These highly vascular structures are located within the ventricles. This fluid, amounting to about 75cc, has few cells and a low concentration of protein. It does contain 1/2 to 3/4 the concentration of blood glucose (see above table). CSF circulates, and turns over several times per day (depending on the level of hydration).

Question 41

Where does fluid from the lateral ventricles enter the third ventricle?
The third to the fourth?
The fourth to the spinal column?
The fourth to the subarachnoid space?

Answer 41

• foramen of Monroe.
• the narrow cerebral aqueduct, which is located in the core of the midbrain.
• The fourth ventricle ==> central canal of the caudal medulla at the obex. This canal continues through the caudal medulla and spinal cord to end blindly in the sacral spinal cord.
• The fourth ventricle also connects with the subarachnoid space via the midline foramen of Magendi and the two lateral foramina of Lushka.

Question 42

What does the subarachnoid space do for the brain?

Answer 42

• provides buoyancy and some nourishment for the brain.

Question 43

What are cisterns?

Answer 43

• There are several subarachnoid collections of CSF called cisterns.

Question 44

Where is the larges cistern located?

Answer 44

• The largest is the lumbar cistern located between the end of the spinal cord (around the L1 disc) and the end of the thecal sac, around S2.

Question 45

Where are these found?
Cisterna magna?
Quadrageminal cistern?
Basal Cistern?

Answer 45

• cisterna magna ==> between the dorsal medulla and the posterior part of the cerebellum
• quadrageminal cistern ==> dorsal to the midbrain and containing the pineal gland
• basal cistern ==> ventral to the hypothalamus and containing the beginning of the great vessels.

Question 46

Explain the resorption of cerebral spinal fluid. Where does this occur most?

Answer 46

• resorbed into the venous system at the arachnoid granulations that are associated with the venous dural sinuses, especially the superior sagittal sinus.

Question 47

What is bulk transport?

Answer 47

• This occurs via a process of “bulk transport” vacuole-based exocytosis.

Question 48

What happens when cerebral spinal fluid circulation is impared?

Answer 48

• Any condition that impairs this circulation of CSF is likely to result in increase in pressure inside the head and may result in herniation or other neurologic catastrophes.