Central Nervous System

Question 1

What is Brain Injury?

Answer 1

• Multiple disabilities due to damage of the brain after birth.
• Results in cognitive, behavioral or independent functioning.
• Can be due to accidents, strokes, Alzheimer’s etc.

Question 2

Explain the autoregulation of Cerebral Blood Flow and its importance. ⭐️

Answer 2

• Diameter of blood vessels constrict or dilate due to physiological changes.

Systemic BP –> if raised, arterioles constricts to reduce blood flow and vice-versa.

Blood gases –> increased CO2, arterioles dilate to increase blood flow.

• This meets changing demands for O2 and glucose AND protects the brain by increasing O2 delivery and removing acidic metabolites during hypoxia or ischemia.

Question 3

What is Hypoxia?

Answer 3

• Deprivation of oxygen supply

Question 4

What is Ischemia?

Answer 4

• Restriction of blood supply; leading to immediate neurologic dysfunction as neurons cannot generate ATP for energy-requiring processes.

Question 5

What is a stroke and what are the 2 main types?

Answer 5

• Rapidly developing loss of neurological function due to altered blood supply to the brain.
• Ischemic stroke accounts for 80-86%
• Hemorrhagic stroke accounts for 15- 20% of all cases.

Question 6

What are the risk factors for stroke?

Answer 6

Non-modifiable: Age/ Hereditary/ Sex/ Cardiac Arrest

Modifiable: High BP/ Smoking/ Diabetes Mellitus/ Sedentary lifestyle/ Poor diet

Question 7

What are the 3 main causes for Ischemic Stroke?

Answer 7

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Thrombus: a blood clot that blocks an artery supplying the brain.

Embolism: Lodging of blood borne particle in blood vessel (like cholesterol or fat)

Systemic Hypoperfusion: Low blood flow due to circulatory failure induced by heart failing to pump blood to blood. E.g. cardiac arrest.

Question 8

What is the Ischemic Penumbra?

Answer 8

• Rim of tissue outside the ischemic core.
• Viable for therapeutic intervention so it’s reversible though there’s risk for infarction.

FYI: Ischemic core is the graveyard for dead cells AKA irreversible

Question 9

Describe the 7 mechanisms for Ischemic Brain Cell Death. ❗️

Answer 9

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1. Cellular Energy Failure
2. Excitotoxicity
3. Oxidative Stress
4. Inflammation
5. Reperfusion Injury
6. Apoptosis
7. Peri-infarct Depolarisation

Question 10

Describe Cellular Energy Failure. ⭐️

Answer 10

• Neuronal tissue requires a lot of ATP and have limited anaerobic metabolism so it’s highly sensitive to O2 deprivation.
  1. Decreased O2 = Low ATP, which leads to low Na+ pump function (even they need ATP to work) thus ion gradients are disrupted (influx of Ca2+, H2O and Na+, efflux of K+) ; results in blebs and ER swelling.
  2. Anaerobic Glycolysis –> increased lactic acid –> cellular acidosis = nuclear chromatin clumping
  3. Detachment of Ribosomes –> decrease protein synthesis = lipid deposition

More depletion of ATP results in necrotic cell death.ya

Question 11

Describe Excitotoxicity and its role in cell death. ⭐️

Answer 11

• Excessive stimulation of receptors for L-Glutamate leads to cell death. Reuptake mechanisms (lacks ATP) so fails to remove glutamate.

Disruption of ion homeostasis → sustained depolarization → sustained L-Glutamate neurotransmitter release and action = excitotoxicity

Question 12

What are Glutamate Receptors and identify the 3 types.

Answer 12

• Allows for Na+ and Ca2+ in; K+ out

The 3 receptors are NMDA / AMPA/ Kainate

Question 13

How does disrupted sodium/ potassium gradient influence Excitotoxicity?

Answer 13

• Glutamate transporters reverses glutamate transport.
• Further depolarization increase downstream synaptic release of glutamate.
• Decrease in cystine –> decrease in Glutathione antioxidant = increase in ROS (reactive oxygen species)

Question 14

How does high influx of calcium affect Excitotoxicity?

Answer 14

1. Influx of high Ca2+ and Na+, accompanied by H2O = swelling.
2. Cascade of cell degradation initiates –> proteases disrupts membrane proteins; phospholipases degrades lipids; ATPase reduces ATP; nitric oxide synthase damage cell structures = membrane and nuclear damage, reduction in ATP.
3. Ca2+ sequestered by mitochondria → opening of mitochondrial permeability transition pore = decrease in ATP; production of ROS; Apoptosis signalled by cytokine C.
4. Activate nitric oxide synthase = produce nitric oxide

Question 15

Describe Oxidative stress in ischemic brain cell death. ⭐️

Answer 15

• Mitochondrial dysfunction leads to Ca2+ (calcium ion) overload –> inflammation and reperfusion injury –> balance of oxidants vs antioxidants disrupted –> increase in ROS

First outcome: Membrane breakdown (lipids) –> increase in proteolysis (proteins) –>Damage to DNA = apoptosis

Second outcome: Feedback loop, damaging mitochondria and mito DNA = produce more ROS

Question 16

Name the oxygen and nitrogen radicals as well as anti-radical enzymes.

Answer 16

Oxygen radicals: superoxide, hydroxyl

Nitrogen radicals: nitric oxide, peroxynitrite, nitrosyl

Enzymes that counteract radicals: superoxide dismutase, catalase, glutathione peroxidase

Question 17

How does inflammation cause Ischemic Brain cell death? ⭐️

Answer 17

1. Rapid activation of microglia —> produces pro-inflammatory cytokines and chemokines
2. induces ICAM-1
3. infiltration of leukocytes
4. Production of ROS and protein matrix is broken down
5. Finally disrupts BBB and cell death

Question 18

Explain Reperfusion Injury. ⭐️

Answer 18

• Restoration of blood flow after blockage can result in secondary injury called reperfusion injury.

1. When O2 re-enters cells, erratic transfer of electrons to oxygen produce ROS
2. Cell membranes undergo lipid peroxidation
3. Excess Intracellular Ca2+ also activates various lipases which break down glycerophospholipids to release arachidonic acid
4. This initiates cascade which leads to more free radicals → ultimately increasing BBB permeability.

Question 19

Describe apoptosis as a mechanism in Ischemic Brain Cell Death. ⭐️

Answer 19

Apoptotic pathways require ATP, hence it is associated with damage in the penumbra.

1. Ca2+ overload & disruption of mitochondria leads to intrinsic pathway AKA (Mitochondrial INTRINSIC pathway cell injury)
2. Ischemia leads to upregulation of death receptors AKA (Death Receptor EXTRINSIC pathway receptor ligand interactions)

Question 20

Explain Peri-infarct depolarization. ⭐️

Answer 20

1. Decrease in ATP and release of K+ and Glutamate → Neurons and glia depolarize.

Ischemic core: Cells undergo ischemic depolarization and never repolarize

Penumbra: Cell repolarize and depolarize again due to increase in release of K+ and Glutamate → repetitive depolarization leads to peri-infarct depolarizations

Question 21

What is a traumatic brain injury and what is the difference between primary and secondary TBI?

Answer 21

• Head injury that disrupts normal function of the brain; leads swelling and bleeding of brain tissue.
• Primary brain injury —> tissue distortion and destruction of brain tissue.
• Secondary brain injury —>cellular changes after initial injury. This changes cell function and degeneration of glia and axons = depolarization; excitotoxicity etc.

Question 22

What are the classifications of TBI?

Answer 22

1. Clinical Severity - Glasgow coma scale

2. Injury type - focal vs diffusion

Question 23

What are focal injuries?

Answer 23

1. Cerebral contusions - usually on surface on brain at frontal and temporal lobes.
2. Lacerations - tearing injury which leads to bleeding which leads to oedema and hematomas.
3. Skull Fractures

Question 24

What is Alzheimer’s Disease and its symptoms? ⭐️

Answer 24

• Affects Amyloid beta and tau proteins
• Affects women more than men
• Caused by loss of dopamine neurons in substantia nigra.

Early symptoms: short-term memory loss; mood swings

Late symptoms: long-term memory loss; loss or reduction of speech

Question 25

Define Parkinson’s Disease and its symptoms

Answer 25

• Affects alpha-synuclein; substantia nigra midbrain.

- Tremors, slowed movement, muscle stiffness

Question 26

Describe Huntington’s Disease and its symptoms.

Answer 26

• inherited autosomal dominant; affects huntingtin gene, cerebral cortex.
• caused by loss of med. sized spiny internucial neurons in striatum.

Early symptoms: Fidgetiness

Late symptoms: cognitive impairment, depression, behavioural disturbances

Question 27

Explain what is Motor neuron disease or Amyotrophic lateral sclerosis and their symptoms. ⭐️

Answer 27

• Affects Superoxide Dismutase (SOD1); affects brainstem.
• caused by death of upper and lower motor neurons.
• Genes involved familial ALS is SOD-1, TDP-43, FUS-TLS.
• Muscle weakness in hands, arms, legs; progressive paralysis, voluntary movement is eventually lost

Question 28

Describe the pathway common to all neurodegenerative diseases. ❗️

Answer 28

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1. Held by molecular chaperones
2. Degraded through ubiquitin-proteosome system.
3. Degraded by fusion of autophagosomes and lysomes - autolysomes
4. Chaperone-mediated autophagy - selectively degraded misfolded proteins with KFERQ motif
5. Formation of oligomers —> arranged to fibrils, forming intracellular inclusions or extracellular aggregates.
6. Mitophagy initiated by damaged mitochondria - PINK-1 Parkinson’s pathway
7. Ultimately if protein aggregates cannot be degraded through UPS or autophagy is over saturated = unfolded protein commits to apoptosis.

Question 29

How do protein aggregates cause disease? ⭐️

Answer 29

1. Loss of function - PINK1 mutation causes mitochondrial damage results in Parkinson’s
2. Gain of toxic function —> mutation that confers new activity. (Alpha-synuclein mutation has high likelihood to aggregate which renders hsp70 inactive)

Question 30

Explain the 4 mechanisms of Neuronal Death.

Answer 30

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1. ER stress and the unfolded protein response (UPR)
2. Ubiquitin-Proteosome System (UPS)
3. Autophagy
4. Apoptosis

Question 31

Describe the process of Unfolded Protein Response. ⭐️

Answer 31

1. Misfolded proteins leads to ER stress to trigger UPR.
2. Initial response is pro-survival aimed at relieving stress and restoring homeostasis.
3. BiP chaperon binds PERK, IRE1 and ATF6.
4. ER stress recruits BiP to bind to misfolded proteins instead of having them go through PERK, IRE1 and ATF6 pathway.
5. If ER stress is severe, apoptotic cell death occurs.

FYI:

PERK pathway - stops protein translation by interfering with 80S ribosome. Activates ATF4 to trigger cell death if ER stress is chronic.

IRE1 pathway - triggers ER Associated Proteins to degrade misfolded proteins by splicing Xbp1 which activates its binding to ERSE and UPRE.

ATF6 pathway - increase BiP expression which is key to protein folding by translocating to golgi to be cleaved by proteases.

Question 32

What is the Ubiquitin- Proteosome System? ⭐️

Answer 32

• Ubiquitin chains are added to lysine resides by Ub ligase and chaperoned to proteosome to be degraded.

In neurodegenerative disorders, misfolded proteins:

1. Cannot be ubiquinated; inaccessible to lysine residues because it’s misfolded(duh)
2. Cannot enter pore of proteosome —> inhibits proteosome activity
   - This leads to large aggregates accumulating in the cytosol
   - reduced UPS directly impinges on Autophagy

Question 33

What is Autophagy?⭐️

Answer 33

• Disassembly of dysfunctional cellular components or proteins with long half life.
• Defective mitochondria (produces a lot of ROS) is degraded by Autophagy.
• Fusion of Lysosome + Autophagosome = autolysosome

E.g. in Parkinson’s, alpha-synuclein sequesters hsp70 and binds irreversibly to LAMP-2A, blocking lysosome action

Question 34

What is Apoptosis in the context of neuronal cell death? ⭐️

Answer 34

• Cell deaths in neurodegenerative conditions are mediated by apoptosis.

1. Via intrinsic mitochondrial pathway:
   - mitochondrial damage leads to outer membrane permeability.
   - release of cytokine C
   - apoptosis
2. Via extrinsic (death receptor) pathway:
   - death receptor activates
   - assembly of Death Inducing Signalling Complex
   - activates caspase 8
   - triggers cytokine c release from mitochondria
   - apoptosis

In neurodegenerative diseases, mitochondria can trigger intrinsic apoptotic pathway when they are dysfunctional in Alzheimer’s/ Huntington/ Parkinson’s etc.

• this is catastrophic for neurons as they need ATP to survive. Decreased activity in Complex I and IV reduces ATP production.
• dysfunctional calcium ion signaling