Blood Brain Barrier

Question 1

Describe the blood flow to the brain

Answer 1

Blood flow to the brain: high at approx. 55ml/100g tissue/min
(~15% of cardiac output, while only ~2% of body weight and 20% O2 consumption)

Question 2

Compare the oxygen consumption of the brain to that of other tissues

Answer 2

Brain- 3mlO2/min per 100g
Kidney- 5 
Skin- 0.2
Resting Muscle- 1
Contracting muscle- 50

Question 3

Describe the consequences of reduced blood flow to the brain

Answer 3

Whenever blood flow to the brain reduced by more than 50% 
insufficient oxygen delivery
function becomes significantly impaired

If total CBF is interrupted for as little as 4 seconds, unconsciousness will result

After a few minutes irreversible damage occurs to brain

Question 4

Summarise syncope (fainting)

Answer 4

Syncope (= fainting) is a common manifestation of reduced blood supply to the brain.
Bleeding and loss of blood is a cause
Has many causes including low blood pressure, postural changes, vaso-vagal attack, sudden pain, emotional shock etc.

All result in a temporary interruption or reduction of blood flow to the brain.

Question 5

Describe a vaso-vagal attack

Answer 5

Vasovagal syncope (vay-zoh-VAY-gul SING-kuh-pee) occurs when you faint because your body overreacts to certain triggers, such as the sight of blood or extreme emotional distress. It may also be called neurocardiogenic syncope. The vasovagal syncope trigger causes your heart rate and blood pressure to drop suddenly.
Blood pools in the legs and extremities whilst going to the brain

Question 6

Summarise the glucose supply to the brain

Answer 6

Normally, vast surplus provision of glucose (the principal energy source) to the brain via the blood.

Some estimates suggest that the brain uses 50-60% of the body’s glucose!

This supply of glucose vital because the brain cannot store, synthesize or utilise any other source of energy (although, in starvation, ketones can be metabolised to a limited extent – adaptation possible in chronic undernutrition?)

Question 7

2. Why is there a vast surplus of glucose delivery to the brain?

Answer 7

Because the brain can only metabolise glucose

Ketone bodies can be metabolized if there is a shortage of glucose but glucose is the main nutrient

Question 8

Describe the consequences of hypoglycaemia on brain function

Answer 8

Many of us might have witnessed or experienced the effects of reduced glucose delivery to the brain in insulin-dependent diabetic individuals, where blood sugar levels drop- administering too much insulin- or not eating enough glucose

An individual appears disoriented, slurred speech, impaired motor function.

Doesn’t just happen to diabetics- anyone with hypoglycaemia will start to feel wobbly and lethargic

If the glucose concentration falls below 2mM it can result in unconsciousness, coma and ultimately death. (Normal fasting levels 4-6 mM)

Question 9

What is the brain

Answer 9

One of the most metabolically demanding and vascularised tissues

Question 10

Describe the importance of the maintenance of cerebral blood flow

Answer 10

Because of the constant need by the brain for oxygen and glucose

it is vital that the cerebral blood flow be maintained

which means that an efficient regulatory system must be operational.

The brain is vulnerable to interruptions in its blood supply because it can store neither oxygen nor glucose, and cannot normally undergo anaerobic metabolism.

Cranial blood vessels are controlled by autoregulation to maintain a constant blood supply.

Question 11

Describe the metabolic adaptations of the CNS to starvation

Answer 11

Under conditions of starvation for several days, the central nervous system can adapt to use ketones (fat derivatives acetoacetate and hydroxybutyrate) as its main energy source. These compounds normally make up approximately 30% of the fuel for the brain in adults but, after fasting for 40 days, this can rise to 70%.

Question 12

4. On what levels do you get regulation of cerebral blood flow?

Answer 12

mechanisms affecting total cerebral blood flow- concerning the cerebral arteries supplying the brain tissue

mechanisms which relate activity to the requirement in specific brain regions by altered localised blood flow

Question 13

5. Between what range in mean arterial blood pressure can autoregulation maintain a constant cerebral blood flow?

Answer 13

Total cerebral blood flow IS AUTOREGULATED

between mean arterial blood pressures (MABP) of approximately 60 and 160 mm Hg

Question 14

Explain how this auto regulation is achieved

Answer 14

Over a wide range of arterial pressures, the arteries and arterioles dilate or contract to maintain blood flow.

Stretch-sensitive cerebral vascular smooth muscle contracts at high BP and relaxes at lower BP.

Contracts to reduce blood flow
Relaxes to increase blood flow- to compensate for the reduced BP

Question 15

Compare the consequences of reduced and increased MABP in the brain

Answer 15

Below this autoregulatory pressure range, insufficient supply leads to compromised brain function (as already discussed).- light-headed

Above this autoregulatory pressure range, increased flow can lead to swelling of brain tissue which is not accommodated by the “closed” cranium, therefore intracranial pressure increases – dangerous.

Can’t increase volume as the space is closed- therefore the pressure must increase- putting pressure on structures in the brain.

Question 16

Summarise local auto regulation

Answer 16

The local brain activity determines the local O2 and glucose demands, therefore local changes in blood supply required:
Local autoregulation

Question 17

6. Name one important factor to do with the smooth muscle lining arterioles that allows regulation of blood flow.

Answer 17

Myogenic Mechanism – when the smooth muscle surrounding arterioles is stretched, it will contract to maintain a constant blood flow
This occurs when there is a change in blood pressure in the body

Question 18

What are the two controls of the local regulation of cerebral blood flow

Answer 18

neural control- in response to various stimuli

chemical control- in response to physiology

Question 19

Describe the pattern of vascularisation in CNS tissues

Answer 19

Arteries enter the CNS tissue from as branches of the surface pial vessels. These branches penetrate into the brain parenchyma branching to form capillaries which drain into venules and veins which drain into surface pial veins.
The veins coalesce and return to the surface

Question 20

Describe how densely the CNS is vascularised

Answer 20

No neurone more than 100µm from a capillary.

Inject liquid resin into brain vessels- will form a plastic cast- digesting away the parenchyma- leaving behind only the vessels- which show how densely vascularised the CNS is on a scanning EM

Question 21

What are the four types of neural control of blood flow

Answer 21

Sympathetic innervation of the main cerebral arteries – causes vasoconstriction when arterial blood pressure is high
Parasympathetic (facial nerve) stimulation – can cause a little bit of vasodilation
Central cortical neurons – neurons within the brain itself can release neurotransmitters such as catecholamines that cause vasoconstriction
Dopaminergic neurons – produce vasoconstriction (important in regulating differential blood flow to areas of the brain that are more active)- localised effect relating to brain activity.

Question 22

What is important to remember about the neural control of global blood flow to the brain

Answer 22

The neural control on global brain blood flow is not well defined, and its importance is uncertain.
Chemical control- probably more important

Question 23

Describe the local effect of dopaminergic neurones on CBF

Answer 23

Innervate penetrating arterioles and pericytes around capillaries

Pericytes are cells that wrap around capillaries; have diverse activities (e.g. immune function, transport properties, contractile)

may participate in the diversion of cerebral blood to areas of high activity - by contracting and reducing the blood flow to other areas

Dopamine may cause contraction of pericytes via aminergic and serotoninergic receptors

Question 24

13. Name some chemical factors that increase blood flow to particular tissues.

Answer 24

Carbon dioxide (indirect)
NO
pH (H+, lactic acid, etc, direct)
Anoxia
Adenosine
K+
Other (e.g. kinins, prostaglandins, histamine, endothelins)- both natural and synthetic factors 

All increase blood flow by causing vasodilation

Question 25

What is the normal pCO2 and blood flow to the brain

Answer 25

40kPa 1.0 As the partial pressure of pCO2 increases in the brain- so does the blood flow- see graph

Question 26

What may the contractile cells be

Answer 26

Smooth muscle | Pericytes (in smaller vessels and capillaries)

Question 27

Are H+ and CO2 able to cross the BBB

Answer 27

H+ can't- therefore can't cross from plasma to the vascular smooth muscle CO2 can- therefore can cross from plasma to the vascular smooth muscle

Question 28

15. Describe how carbon dioxide indirectly causes vasodilation in the cerebral vessels.

Answer 28

H+ ions can’t cross the blood-brain barrier but carbon dioxide can Carbon dioxide moves from the blood through the blood-brain barrier into the smooth muscle cells Within the smooth muscle cells, in the presence of carbonic anhydrase, the carbon dioxide reacts with water to form bicarbonate and H+ ions This internally generated H+ ions within the smooth muscle cells cause smooth muscle relaxation (vasodilation)

Question 29

Summarise the cerebral arterial vasodilation by CO2

Answer 29

CO2 from the blood or from local metabolic activity generates H+ using carbonic anhydrase in surrounding neural tissue and in the smooth muscle cells. Elevated H+ means decreased pH. This causes relaxation of the contractile smooth muscle cells, dilation of vessels, resulting in increased blood flow.

Question 30

Describe how the local changes to blood flow allow imaging of the brain

Answer 30

Local changes to cerebral blood flow allow imaging and mapping of brain activity using techniques such as PET scanning and functional MRI (fMRI). In the CNS, increased blood flow equates to increased neuronal activity. Can see this on the brain as a result of increased H+ ions

Question 31

16. Describe how nitric oxide (NO) causes vasodilation.

Answer 31

Nitric oxide stimulates guanylyl cyclase Guanylyl cyclase converts GTP  cGMP cGMP causes vasodilation

Question 32

Summarise the fluid compartments of the brain

Answer 32

The brain is essentially “floating” in cerebrospinal fluid produced by regions of choroid plexus in the cerebral ventricles. This is an important protective mechanism. brain also bathed in its own tissue fluid- with fluid moving in and out of the I.C fluid

Question 33

Where is CSF found

Answer 33

In the ventricular system and within the spinal canal

Question 34

Describe the arachnoid granulations

Answer 34

Where CSF can lead the ventricular system Openings between ventricular system and plasma on the outer surface of the brain and vessels in the arachnoid mater Arachnoid granulations (also arachnoid villi, and pacchionian granulations or bodies) are small protrusions of the arachnoid mater (the thin second layer covering the brain) into the outer membrane of the dura mater (the thick outer layer). They protrude into the dural venous sinuses of the brain, and allow cerebrospinal fluid (CSF) to exit the subarachnoid space and enter the blood stream. The largest granulations lie along the superior sagittal sinus, a large venous space running from front to back along the center of the head (on the inside of the skull). They are, however, present along other dural sinuses as well.

Question 35

How do the arachnoid granulations ensure the one-way flow of CSF

Answer 35

The arachnoid granulations act as one-way valves. Normally the pressure of the CSF is higher than that of the venous system, so CSF flows through the villi and granulations into the blood.

Question 36

Summarise the ventricular system of the brain

Answer 36

The ventricles, aqueducts and canals of the brain are lined with ependymal cells (epithelial-like glial cells, often ciliated). In some regions of the ventricles, this lining is modified to form branched villus structures: the choroid plexus.

Question 37

19. Describe the passage of CSF through the ventricular system.

Answer 37

CSF is produced by specialized ependymal cells of the choroid plexus (mainly in the lateral ventricles) From the lateral ventricles it goes through the foramen of Monro (inter ventricular foramen) to the 3rd ventricle From the 3rd ventricles, CSF flows down the cerebral aqueduct to the 4th ventricle From the 4th ventricle it enters the subarachnoid space (via medial and lateral apertures) and eventually drains back into the venous system via arachnoid granulation

Question 38

Describe the different parts of the lateral ventricle

Answer 38

Anterior horn Inferior horn Posterior horn

Question 39

Describe the different parts of the forth ventricle

Answer 39

Median aperture and lateral aperture The fourth ventricle is the most inferiorly located ventricle, draining directly into the central canal of the spinal cord.

Question 40

17. Where is CSF produced?

Answer 40

Choroid plexus – these are specific cells associated with the ventricles (in particular the lateral ventricles)

Question 41

Summarise the formation of CSF by the choroid plexus

Answer 41

ependymal cells line ventricles and aqueducts, and lining modified in some regions to produce branched villi structures called the choroid plexus Capillaries leaky, but local ependymal cells have extensive tight junctions. Capillaries line the connective tissue of pia mater Secrete CSF into ventricles (lateral ventricles, 3rd ventricle via interventricular foramina, down cerebral aqueduct into 4th ventricle and into subarachnoid space via medial and lateral apertures) – circulates.

Question 42

What is the circulating volume of CSF in a normal person

Answer 42

Volume: 80-150ml.

Question 43

What is the volume of CSF formed per day

Answer 43

450 mL/day

Question 44

What are the functions of the CSF

Answer 44

Functions: protection (physical and chemical), nutrition of neurones, transport of molecules.

Question 45

27. State four components that have a lower concentration in the CSF than the plasma.

Answer 45

``` K+ Calcium Amino acids Bicarbonate Na+ (slightly lower) ```

Question 46

28. State two components that have a higher concentration in the CSF than the plasma.

Answer 46

Magnesium | Chloride

Question 47

How does the osmolarity of the CSF and plasma differ

Answer 47

They are identical

Question 48

30. How is the pH different in the CSF compared to the plasma?

Answer 48

CSF is slightly more acidic

Question 49

What is the clinical importance of the CSF having very little protein

Answer 49

if protein in CSF then could indicated infection or damage to choroid plexus

Question 50

Describe the choroid plexus

Answer 50

Choroid plexus: capillaries in villi allow filtrate to pass into CSF and waste/unnecessary solutes to be removed

Question 51

Experimentally, how did we discover the presence of a BBB

Answer 51

In the late 19th and early 20th centuries, it was noted that dyes, and other tracers, injected intravenously, accumulated in most tissues, but were excluded from most areas of the CNS (including the retina). Organs removed from a mouse after intravenous injection with a blue dye. The blue dye did not accumulate in the brain This suggested the existence of a Blood-Brain Barrier.

Question 52

Why does a BBB make sense

Answer 52

A Blood-Brain Barrier makes sense because the activity of neurones is highly sensitive to the composition of local environment, and the CNS must be protected from the fluctuations in the composition of the blood. Homeostasis is key for the brain. It became apparent that the BBB was at the level of the CNS capillaries. The blood–brain barrier exists to maintain the environment of the brain in a steady state, protected from extracellular ion changes, peripheral hormones (such as adrenaline (epinephrine)) and drugs. It also prevents neurotransmitters from the central nervous system entering the peripheral circulation.

Question 53

Summarise capillaries

Answer 53

Most exchange between the blood and the tissues occurs across capillary walls. They are generally thin-walled, and abundant (i.e. provide enormous surface area for exchange). Estimated 400 miles of capillaries in the typical human brain. Form 80% of the vasculature

Question 54

Describe the different types of capillary

Answer 54

Continuous Fenestrated- leaky- endocrine organs- to allow hormones to access the circulation and tissues Sinusoid- very leaky- incomplete BM- liver and bone marrow

Question 55

Describe how fluid is exchanged across capillaries

Answer 55

Pores or clefts between endothelial cells

Question 56

Describe the circulation of plasma

Answer 56

Each day, 8L of plasma leaks out of blood vessels. Since the volume of blood plasma is ~3L, the entire plasma volume must pass into the interstitial space and back into the blood circulation every 9 hours!

Question 57

Describe the capillaries of the BBB

Answer 57

the capillaries of the CNS parenchyma derived from surface pial vessels Vessel BBB properties increased in deeper vessels. BBB capillaries have extensive tight junctions at the endothelial cell-cell contacts, massively reducing solute and fluid leak across the capillary wall.

Question 58

What is the Virchow-robin space

Answer 58

Perivascular spaces, also known as Virchow-Robin spaces, are pial-lined interstitial fluid-filled spaces in the brain that surround perforating vessels. Lined by glia limitans membrane ends at the fusion of the leptomeningeal layers

Question 59

Compare cardiac muscle capillaries to that of the brain

Answer 59

Cardiac muscle capillary (continuous type, with transcellular vesicular transport) ``` Brain capillary (continuous type, little transcellular vesicular transport) ```

Question 60

Describe some other difference between peripheral and BBB capillaries

Answer 60

Pericytes are cells closely apposed to capillaries. They have important functions in maintaining capillary integrity and function. Peripheral vessels have sparse pericyte coverage, while BBB capillaries have dense pericyte coverage. In addition, BBB capillaries are covered with “end-feet” from astrocytes. These associations are important for maintaining BBB properties. Brain capillaries -more mitochondria- no intercellular clefts

Question 61

Summarise BBB structure

Answer 61

capillaries have tight junctions and are the continuous type, with little transcellular vesicular transport.

Question 62

Describe the inter endothelial junctions in the BBB

Answer 62

in peripheral capillaries, limited overlap, but with BBB capillaries, the boundary is tortuous and with more tight junctions.

Question 63

Describe the importance of astrocytes for maintenance of the BBB

Answer 63

Astrocytes: produce growth factors to allow maintenance of BBB

Question 64

Describe the key factors of the BBB that allow the control of the balance between the CSF and the plasma

Answer 64

The endothelial cells of the cerebral capillaries have very high resistance tight junctions between them. As a result, even small ions will not permeate between endothelial cells in brain capillaries. Brain capillary endothelial cells also lack the methods of transcellular transport which are present in peripheral capillaries (fluid-phase and carrier-mediated endocytosis). • Astrocytes have foot processes which adhere to the capillary endothelial cells such that they are entirely enclosed. Astrocytic foot processes also secrete factors that help to maintain the tight junctions between endothelial cells.

Question 65

23. Describe the structure of the blood-brain barrier. Which cells are involved?

Answer 65

The capillaries in the brain have endothelial cells with very tight junctions so there is tight control of what can pass through the wall of the capillary The capillaries are also surrounded by pericytes with end-feet running along the capillary wall When the pericytes contract they make it more likely for the molecules to leave the capillary

Question 66

Which type of molecules can cross the BBB easily

Answer 66

Lipophilic molecules, such as diamorphine (an opioid analgesic)

Question 67

Describe exchange across the BBB

Answer 67

Because of the “tightness” of the BBB capillaries, solutes that can exchange across peripheral capillaries cannot cross the BBB. This applies mainly to hydrophilic solutes such as glucose, amino acids, many antibiotics, some toxins and many others. This allows the BBB to control the exchange of these substances using specific membrane transporters to transport into and out of the CNS. (influx and efflux transporters)

Question 68

Where are CNS infections more likely to occur and why

Answer 68

Blood-borne infectious agents may have reduced entry into CNS tissue. (CNS infections more commonly affect the meninges, whose vessels are not BBB). (Some evidence that loss of BBB can help with clearing some infections by allowing immune cells access.)- astrocytes contact the BBB

Question 69

Describe the exchange of lipophilic molecules across the BBB

Answer 69

Lipophilic molecules (e.g. O2, CO2, alcohol, anaesthetics?) cross the BBB so access to, or removal from, CNS directly via diffusion down concentration gradients.

Question 70

How do hydrophilic substances cross the BBB

Answer 70

Many hydrophilic substances to enter the CSF and brain ECF by means of specific transport mechanisms, examples being: a) water, via aquaporin (AQP1, AQP4) channels b) glucose, via GLUT1 transporter proteins c) amino acids, via 3 different transporters d) electrolytes, via specific transporter systems

Question 71

Describe how glucose crosses the BBB

Answer 71

D-glucose, for example, has a stereospecific membrane transporter that facilitates diffusion from the circulation to the CSF at high rates because the brain relies heavily on glucose for energy. However, in situations where there is a dramatic fall in plasma glucose levels (e.g. in diabetic hypoglycaemic states), glucose may diffuse back out of the CSF into the plasma. This is a medical emergency as the neurons needs glucose to survive.

Question 72

Describe how amino acids cross the BBB

Answer 72

Other transport systems include those for amino acids – one each for basic (e.g. arginine), neutral (e.g. phenylalanine) and acidic (e.g. glutamate) amino acids. Clinically, the neutral transporter is important as it will transport L-dopa (used to replace dopamine lost from the substantia nigra in Parkinson’s disease). However, dopamine cannot be given as a treatment because it does not have a transporter.

Question 73

What is meant by the circumventricular organs

Answer 73

In some areas of the brain, it is necessary that the capillaries lack BBB properties. These areas are found close to the ventricles, and are known collectively as the circumventricular organs (CVOs).

Question 74

Describe the features of the circumventricular organs

Answer 74

Their capillaries are fenestrated (therefore leaky). The ventricular ependymal lining close to these areas can be much tighter than in other areas, limiting the exchange between them and the CSF.

Question 75

What are the roles of the circumventricular organs

Answer 75

These regions of the brain (marked as red spots in the diagram on the left) are generally involved in secreting into the circulation, or need to sample the plasma.

Question 76

List some of the circumventricular organs and their roles

Answer 76

For example: the posterior pituitary and median eminence secrete hormones the area postrema (brainstem) samples the plasma for toxins and will induce vomiting others are involved in sensing electrolytes and regulate water intake. subcommisural and subfornical organs, organum vasculosm lamina terminalis (OVLT) Pineal body CVOs need leaky, fenestrated vessels to carry out these functions.

Question 77

Summarise the circumventricular organs

Answer 77

In certain regions of the brain (including the posterior pituitary and choroid plexus) the capillaries are fenestrated and so there is no blood–brain barrier. Specialized ependymal cells (tanycytes) isolate these areas from the rest of the brain. The absence of the blood–brain barrier at the posterior pituitary allows oxytocin and vasopressin to be secreted directly into the systemic circulation. At other sites, it enables the brain to analyse the concentrations of water and ions for homeostatic functions.

Question 78

When can the BBB break down

Answer 78

The BBB breaks down in many pathological states: inflammation, infection, trauma, stroke, which obviously can have profound effects on CNS function. Trauma to the CNS will result in loss of BBB. Localised trauma, and the resulting local loss of BBB is illustrated the image on the left. The intravenous dye leaks into the brain tissue at the site of damage and surrounding areas.

Question 79

Describe the importance of the BBB in pharmacology

Answer 79

A major issue is in relation to pharmacology: Do you want a particular drug to get into the brain, or not? Many therapeutic drugs cannot access the brain. Others may access the brain too readily causing adverse effects.

Question 80

Describe anti-histamines and the BBB

Answer 80

In the treatment of allergy, the “old-fashioned” H1 blockers are hydrophobic and can cross the BBB by diffusion. Since histamine is important in wakefulness and alertness, these antihistamines made people drowsy. Today, used as sleep aids (often over-the-counter, e.g. Nytol (Diphenhydramine Hydrochloride)). Second-generation antihistamines are polar (i.e. have hydrophilic attachment), therefore do not readily cross the BBB, so do not cause drowsiness.

Question 81

Describe how BBB affects the treatment of Parkinson's

Answer 81

A key therapy in Parkinson’s disease is pharmacologically raising the levels of dopamine in the brain. Peripheral administration of dopamine not the answer, as dopamine cannot cross the BBB. L-DOPA can cross the BBB via an amino acid transporter, and is converted to dopamine in the brain.

Question 82

What is the key issue with L-dopa as a treatment and how can we circumnavigate this

Answer 82

Most of the circulating L-DOPA is converted to Dopamine peripherally (outside of the CNS), so less is available to access the brain. So, need to inhibit this conversion outside of the brain, without affecting it inside. Co-administration with the DOPA decarboxylase inhibitor, Carbidopa, does the job. Carbidopa cannot cross the BBB, so does not affect conversion of L-DOPA in the brain.

Question 83

Describe the consequences of abrupt changes in ionic changes on neurones

Answer 83

Abrupt changes in the ionic concentration can be damaging to neurons. The blood–brain barrier not only helps to protect the brain from such changes in plasma levels, but also helps to remove excess ions from the CSF. For example, intense neuronal activity can increase the CSF potassium concentration. A high concentration of K+ channels on endothelial cells clears the excess.

Question 84

Describe some infections that can disrupt the BBB

Answer 84

Brain ischaemia, brain tumours, haemorrhage, systemic acidosis or infections such as bacterial meningitis can break down the blood–brain barrier.

Question 85

what happens in cerebral ischaemia

Answer 85

In cerebral ischaemia the blood–brain barrier opens, resulting in cytotoxic cerebral oedema: paucity of oxygen causes a decline in endothelial cell ATP which secondarily disrupts the function of the NA+/K+ATPase pump. As a result Na+ accumulates in the cell, water follows osmotically and the cell swells. This swelling compromises the integrity of the tight functions, allowing an influx of ions and water into the brain extracellular space.

Question 86

What happens in diabetic ketoacidosis

Answer 86

In diabetic ketoacidosis (where plasma glucose concentration becomes excessively high), pH of the plasma may fall below 7, at which point the blood–brain barrier is compromised and neuronal death occurs.

Question 87

How is CSF calculates

Answer 87

Cerebral blood flow (CBF) is determined by the difference in systemic blood pressure (SBP) and intracranial pressure (ICP): CBF = SBP – ICP. Therefore, patients with raised intracranial pressure will be hypertensive.