NEURO - BBB and CSF

Placenta - therefore early stages of embryonic CNS development are most susceptible to various defects

Prior to the BBB, what protects the developing brain of the fetus from toxins in the mother's blood?

Neurons

This supportive cell of the BBB innervates some larger vessels and may function to help regulated the BBB:

Basal Lamina

This supportive cell of the BBB provides structural integrity to the BBB and is composed of several matrix proteins such as Fibronectin, Laminin, Type IV collagen:

True - it is lipophillic

Oxygen can freely diffuse across the BBB - True or False?

Astrocytes

This supportive cell of the BBB functions to create the inner lining and regulate the permeability of the BBB:

Cerebral ventricles

A series of interconnected fluid-filled spaces that are situated in the forebrain and brainstem that are continuous with the sub-arachnoid space:

True

Fenestrated capillaries represent 1% of the total capillary surface area within the brain - True or False?

Hemorrhage

Bloody or Yellow CSF is indicative of...

True

Brain capillaries are not fenestrated and therefore do not allow for intercellular movement of ANY soluble molecules - True or False?

False - capillaries are fenestrated in certain areas known as the circumventricular organs.

Capillaries (i.e. BBB) are locked and impermeable to solute movement throughout the brain - True or False?

True

Choroid Plexus is present in all ventricles - True or False?

Leukocytes and/or high protein content in the CSF as a result of inflammation

Cloudy CSF is indicative of...

The BBB is an endothelial barrier, comprised of 2 endothelial membranes in series.

Describe the BBB structurally:

Tight Junctions - created via contacts between 2 transmembrane proteins, claudins and occludens

Describe the molecular basis of the BBB - how are the endothelial cells locked in a cylinder?

1. Within the choroid plexus, the fenestrated capillaries transport ions from the blood into the ventricular space, causing water to follow but also creating a small hydrostatic pressure; 2. Since the lateral ventricles are by far the largest, is produces the greatest "push of water" and drives the "CSF" down to the third and fourth ventricle. 3. There is an opening in the roof of the 4th ventricle through which the CSF is able to then travel to encase the entire brain, becoming "extracellular fluid," that washed the tissue of unnecessary metabolites. 4. This fluid then reaches the arachnoid granulations, which are 1 way valves. When the pressure reaches a critical level - 15 mm Hg, the valves open, allowing the fluid to go to the sinuses (officially entering the venous system) - mixing with venous blood.

Describe the path of CSF fluid and explain the concept of positive pressure that drives this direction of flow?

True

Disruptions of the basal lamina promote the breakdown of the BBB - True or False?

True

Germinal matrix hemorrhage is common in premature infants - True or False?

False - they travel across the BBB via specialized transporters.

Glucose, amino acids, and nucleotides freely diffuse across the BBB - True or False?

Adsoprtive Transcytosis

How are albumin and other plasma proteins transported across the BBB?

1. CSF has lower K+ and Ca2+ concetrations - thereby allowing for better control of neuron excitability: 2. pH is more acidic; 3. Lower protein concentration so as to minimize obligated water

How does CSF composition differ from the composition of blood - explain why these differences are significant:

Receptor Mediated Transcytosis

How is insulin transported across the BBB?

Bacterial or Fungal Infection

If the CSF has decreased glucose content, this indicates...

A block in the spinal subarachnoid space by a tumor or compression

If the protein content is >500mg/100mL in the CSF, this indicates...

Sub-Arachnoid Hemorrhage must have occurred

If you performed a spinal tap and found RBCs in the extracted CSF - what conclusion could you draw?

Because, Glucose and other hexoses are transported via the same set of Na+ independent transporters (GLUT1). High Galactose levels in galactosemia - leads to the competition of galactose with glucose for the transporters.

In galactosemia, high levels of galactose compete with glucose leading to glucose starvation in the brain - Explain:

True

In human MS, astrocytic processes express low levels of AGT, a potential cause for the leaky vessels seen in this pathology - True or False?

Fenestrated capillaries

In other regions of the blood, the contents of the blood are at equilibrium with the extracellular medium as a cause of ...

True

Small lipophillic molecules such as alcohols and heroine traverse the BBB via direct diffusion - True or False?

False - the BBB develops early in development - at the end of the first trimester.

The BBB develops late in development - True or False?

Pericytes

This supportive cell of the BBB are cells of microvessels, including the capillaries, venules, and arterioles. They wrap around the endothelial cells, providing structural and trophic support.

True

The choroid plexus can be described as a bulging of epithelial cells in the walls of the ventricles that is rich in blood capillaries - True or False?

True

The endothelial cylinder of the choroid plexus is surrounded by epithelial cells that are locked by tight junctions - True or False?

Negative

The release of glutamate, ATP, endothelin-1, bradykinin, NO, MIP-2, TNF-alpha, IL-Beta represent _______________ regulation of BBB permeability:

True

The total volume of CSF within the human ventricular system and subarachnoid space is 150 mL and it is regenerated 3X a day - True or False?

True

The ventricular system is connected to the spinal canal - True or False?

MS and Alzheimer's

These 2 BBB-related CNS pathologies involves the recruitment of blood immune cells and partial BBB disruption:

Cysterns

These are spaces between the pia and arachnoid:

Brain Tumors

They can increase vascular permeability due to their release of VEGF:

Septic Encephalopathy

This BBB-related CNS pathology, decreases cerebral blood flow and oxygen extraction by the brain, induces cerebral edema, and breakdown of the BBB:

Hypoxia-Ischemia

This BBB-related CNS pathology, disrupts tight junctions and increases BBB permeability:

Cerebral Spinal Fluid - CSF

This fluid fills the ventricles:

Subarachnoid Space

This space is frequently a site for bleeding following hemorrhage:

1. Astrocytes 2. Pericytes 3. Neurons 4. Basal Lamina

What 4 supportive cell types function to regulate the BBB?

Protrusions in the venous sinuses from which CSF is absorbed and returns to venous circulation.

What are arachnoid granulations?

Dura Arachnoid Matter Pia Matter

What are the 3 meningeal layers?

Glutamate and blood proteins leak inside the CSF--- bringing water, thereby increasing intracranial pressure

What are the consequences of pathologies that result in a leakage of the BBB?

1. Remove brain metabolites from the ventricular system into the venous sinuses; 2. Provide a mechanical cushion to protect the brain from impact with the skull when the head moves 3. Provide the brain with buoyancy. 4. Medium through which hypothalamic hormones are secreted;

What are the functions of the CSF?

1. Prevent the passage of molecules and ions through the space between cells - regulate what substances are allowed through; 2. Control of water flux - water movement is restricted 3. Block the movement of integral membrane proteins between the basolateral and apical surfaces -- maintain the special functions of each cell surface

What are the functions of tight junctions?

1. Sense the composition of the blood with the need for specialized transport systems which move those compounds across the BBB; 2. Release signaling substances, such as hypothalamic hormones, to the circulation;

What are the purposes of the circumventricular organs?

Germinal Matrix - thickening medial to the basal ganglia in the subventricular zone, which bulges into the lateral ventricle.

What in the fetal brain is analogous to the choroid plexus of the adult brain?

In the brain, the capillaries lack fenestrations - which are permeable to blood proteins and some ions.

What makes the blood brain barrier different from capillaries located elsewhere in the body?

Astrocytes secreted Angiotensinogen (AGT) that is converted into angiotensin II and stimulates AT1 receptors on endothelial cells. This signaling is what maintains the integrity of the tight junctions.

What positively regulates BBB permeability?

CSF is produced by a specialized vascular structure called the choroid plexus, which is present in all cells.

Where is CSF made?

Interface between the walls of capillaries and surrounding brain tissue

Where is the blood brain barrier localized?

In order to create CSF, they must transport particular ions to create an osmotic gradient - i.e. water moves in. This positive pressure is what makes CSF flow in a unidirectional manner.

Why does it make sense that the capillaries in the choroid plexus of the ventricles are fenestrated?

1. Protects the brain against surging fluctuations in ionic concentrations as its activity is dependent on specific concentrations. 2. Restricts the access of things that do not belong - signaling molecules, growth factors, etc. 3. Isolates the brain from blood glutamate and other toxins; 4. Determines the optimal delivery of structural blocks and nutrients

Why is the BBB necessary?

With ion flow, comes water. Resulting brain edema and expanding tissue would lead to a collapse of critical brain vessels.

Why would you want the BBB to be impermeable to ions?