Brain vasculature and Neurodegenerative diseases

Question 1

What increases the risk for neurodegenerative disorders?

Answer 1

Cardiovascular factors (high blood pressure), type-2 diabetes, obesity, smoking, high alcohol consumption, diet (saturated fat), brain injury, etc.

Question 2

How does the clearance of the blood happen in the brain?

Answer 2

1. Trans-vascular transport (capillaries): across the BBB
2. Perivascular transport: brain’s interstitial fluid travels in reverse direction of blood flow (drains in deep cervical meningeal lymph nodes)
3. Glymphatic system: para vascular transport of solutes from subarachnoid space through perivascular space (same direction as blood flow)

Question 3

What are the 3 key transport properties across the BBB?

Answer 3

1. Transmembrane diffusion: small molecules (oxygen, CO2, etc.)
2. Carrier-mediated transport: hormones, fatty acids, vitamins, etc.
3. Receptor-mediated transport: transendothelial transport of proteins and peptides in both directions

Question 4

How is the flow of the cerebrospinal fluid?

Answer 4

Convective flow => pressure to flow towards the venous

Question 5

How is the glymphatic system regulated?

Answer 5

Regulation by the sleep-wake cycle

Clearance of metabolic waste also regulated by sleep-wake cycle

Question 6

What can be said about glucose when talking about Alzheimer’s disease?

Answer 6

Cerebral blood flow regulates glucose uptake through Glut1 receptor – reduced blood flow and Glut1 R expression in AD and less glucose to the brain

Question 7

What is the function of the ABC-transporter and what happens in Alzheimer’s disease (AD)?

Answer 7

• Mediates active efflux of drugs and xenobiotic compounds from brain to blood (prevent accumulation in brain)
• Clears Aß across the BBB
• AD have reduced ABC-transporter function

Question 8

What are the evidences for BBB disruption in neurodegenerative disorders?

Answer 8

• Capillary leakage
• Pericyte degeneration
• Endothelial degeneration (disrupted tight junctions)
• Cellular infiltrations (invasion of red blood cells )
• Aberrant angiogenesis (increased cell density)
• Molecular changes (reduced GLUT1, increase of pro-inflammatory pathways, etc.)

Question 9

What are the evidences for BBB disruption in neurodegenerative disorders regarding the cerebrospinal fluid (CSF) levels?

Answer 9

• Increase of CSF albumin over blood albumin
• Increase of blood derived plasminogen and fibrinogen in CSF
• Increase CSF IgG over serum IgG

Question 10

What are the causes of vasculature and neurodegenerative disease?

Answer 10

• Vascular dysfunction
• Hypertension
• Hypercholesterolemia
• Chronic inflammation
• Increased metabolic turnover
• Oxidative stress
• Ischemic stroke
• Aging

Question 11

What does stroke and small vessel diseases cause?

Answer 11

Damage to cerebral white and deep gray matter, enlarged perivascular spaces, cerebral microbleeds and lacunes

Question 12

What is CADASIL?

Answer 12

• Most common form of inherited stroke and vascular dementia
• Lethal disorder: deaths are the result of several strokes, cognitive and motor dysfunctions
• No treatment available that halt or cure the disease

Question 13

What is the pathology of CADASIL?

Answer 13

• Morphological changes in small and middle sized arteries and capillaries: thickened vessel, walls, fibrosis and narrow of lumen
• Degenerating vascular smooth muscle cells
• White matter lesions

Question 14

What is Notch3, what is its function and why is it important for treatment?

Answer 14

• Transmembrane receptor
• Control multiple cell differentiation processes during embryonic and adult life (neurogenesis, angiogenesis, cardiac homeostasis, pancreas development, hematopoesis, T-cell development and mammary gland development)
  => treatment: vaccinate against Notch3 to prevent disease like CADASIL