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TMS > Neuroinflammation > Flashcards

Neuroinflammation Flashcards

1
Q

What are the likely symptoms of a brain injury in each of the following areas?

  • Frontal Cortex
  • Parietal Cortex
  • Occipital Lobe
  • Temporal Lobe
  • Cerebellum
  • Brainstem
A
  • Trouble concentrating, problem solving, language difficulty, irritability
  • Difficulty reading, spatial misperception
  • Blind spots and blurred vision
  • Problems with short term and long term memory
  • Difficulty walking, slurred speech
  • Changes in breathing, difficulty swallowing
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2
Q

What are the two main types of head injury and the common features of each?

A

Closed head injury - caused by blunt trauma such as falling over. Can lead to concussion. Point of impact is the coup, can also have a contra-coup which will often result in a subdural haemotoma

Open head injury - penetrative injury, resulting in an open wound, such as a stab wound. Usually fatal if the damage involves both hemispheres, ventricles, brainstem or multiple lobes

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3
Q

What are the common features of a traumatic brain injury?

A

Rotational acceleration
Subdural haematoma (bleeding beneath the dura mater)
Shear injury/white matter injury (tearing of the axons)
Secondary damage (neurotoxic cascade)

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4
Q

What occurs during secondary damage/neurotoxic cascade following TBI?

A

Leakage of neurotransmitters and ions
Inflammation and pressure build up
BBB disruption and oedema
Lack of oxygen supply leading to ischaemia and excitotoxicity

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5
Q

What is second impact syndrome?

A

A second concussion occuring after the brain has had time to recover from the first
Leads to vascular engorgement (swelling), increased intracranial pressure and rapid brain stem failure.
Loss of autoregulation of blood supply to the brain - vessels cannot dilate and constrict properly

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6
Q

What is chronic traumatic encephalopathy?

A

A long term, progressive, degenerative brain disease linked to repeated head trauma
Patients have difficulty concentration, memory problems, depression, trouble walking/speaking, aggressive behaviour

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7
Q

What is the pathology of chronic traumatic encephalopathy?

A

Repeated TBI leads to deposition of Tau protein in the hippocampus and temporal lobe, eventually spreading to cover the whole brain

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8
Q

Who is at increased risk of chronic traumatic encephalopathy?

A

People with certain apolipoprotein E genotypes
Contact sports players
Victims of domestic abuse
Headbangers

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9
Q

What are some of the physiological changes observed in the brain of someone following severe TBI?

A

Enlarged ventricles
Loss of grey matter
Deeper sulci and more prominent gyri
Overall shrinkage

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10
Q

How does TBI affect the rate of cognitive decline?

A

Immediate drop in cognitive reserve then recovery
TBI and ageing have a synergistic effect on cognitive decline
Faster to reach the threshold for dementia

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11
Q

What are the 5 types of glial cell in the CNS?

A 
Astrocytes
Microglia
Oligodendrocytes
Ependymal Cells
Pericytes
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12
Q

What is the function of ependymal cells?

A

Line the ventricles and spinal cord canal
Are ciliated to encourage CSF flow
Act as neural stem cells
Produce small amounts of CSF

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13
Q

What is the function of pericytes?

A

Surround capillary epithelial cells
Regulate cerebral blood flow
Maintain the BBB
Phagocytose cellular debris

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14
Q

Give an overview of the steps involved in the response to TBI

A
  1. CNS damage
  2. BBB disruption and leakage
  3. Activation of neutrophils
  4. Microglia activation to M1/M2
  5. Cytokine/chemokine storm and inflammation
  6. Monocyte and T cell infiltration of brain
  7. Angiogenesis
  8. Formation of astrocytic glial scar
  9. Structural reorganisation by oligodendrocytes, and neurogenesis
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15
Q

Describe the process of astrogliosis

A

Oxidative stress, ROS, IL-1beta and TNFalpha activate astrocytes
They proliferate and migrate to the site of injury
They secrete cytokines and cytotoxins
They contain AEG-1 in the cytoplasm and nucleus
They form a glial scar at the site of injury

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16
Q

Describe the state of resting microglia

A

Microglia in the cortex are ramified microglia. Have limited migration but survey for foreign objects using long filopodia like growths

There are also rod shaped (bipolar) microglia in the corpus callosum

17
Q

What happens to microglia following TBI?

A

Injured neurons release DAMPs which activate microglia
Ramified microglia protrusions contract and it forms an amoeboid shape. Can phagocytose damaged neurons and use autophagy to destroy them.
Rod shaped microglia become more elongated and express MHC II. They migrate into the hippocampus and align along neuronal axons. Involved in phagocytosis and neuronal circuit reorganisation

18
Q

Describe the structure of the blood brain barrier

A

Endothelial cells of capillary connected by tight junctions (no fenestrations)
Supported by pericytes
Supported by astrocyte end feet

19
Q

What is the gliovascular unit?

A

The gliovascular unit is the complex formed by endothelial cells, astrocytes and pericytes that surrounds capillaries in the brain.
Is surrounded by microglia

20
Q

What is the function of astrocytes?

A

Regulate concentrations of ions, gas, nutrients and neurotransmitter surrounding neurons
Form neuronal scars to repair injuries
Support the BBB

21
Q

What is the function of microglia?

A

Immune cells of CNS - survey for and phagocytose foreign bodies
Eliminate unnecessary synapses
Release neuronal growth factor

22
Q

What are the 5 ways in which something can pass the BBB? Brief description of each and an example of something that uses this method

A
  1. Paracellular aqueous pathway - water soluble agents (electrolytes) pass through tight junctions
  2. Transcellular lipophilic pathway - lipid soluble agents (steroid hormones) diffuse through endothelial cells
  3. Transport proteins – specific transport proteins move glucose/amino acid across endothelial cell membrane
  4. Receptor-mediated transcytosis – receptors bind the molecule (e.g. insulin), the receptor-molecule complex is endocytosed and then exocytosed the other side
  5. Adsorptive transcytosis – molecule alone is endocytosed and then exocytosed (e.g. albumin)
23
Q

What are the two polarisation states of microglia?

A

M1 - pro-inflammatory. Secretes ROS, iNOS, NADPH oxidase, IL-1beta, TNFalpha etc. Recruits Th1 and Th17 cells. MHC II positive
M2 - anti-inflammatory. Secretes neurotrophic factors, IL-6 and IL-10. Supports tissue remodelling. Recruits Th2 cells.

Some microglia present a mixed M1/M2 phenotype.

24
Q

What is microglial priming?

A

When activated, microglia have greater expression of MHC II and CD68 antigens, meaning they have a lower threshold for reactivation. If another TBI occurs in a short amount of time, they become hyperactivated and secrete a greater amount of cytokines and interleukins.

25
Q

Describe the normal M1/M2 ratio in response to TBI and how this is affected following repeat brain injuries

A

Normally there is an increase in M1 state which resolves within a few weeks and M2 dominates again.
Following repeat injuries, M1 dominates for much longer and pro inflammatory cytokine levels remain raised for longer.

26
Q

Name the 7 methods of diagnosing a TBI

A 
X-ray
Computed tomography (CT) scan
Magnetic Resonance Imaging (MRI)
Electroencephalography (EEG)
Positron Emission Tomography (PET) scan
Diffusion Tensor Imaging (DTI)
Glasgow coma scale
27
Q

What are the pros and cons of diffusion tensor imaging?

A

Can actually show damage to the brain as it isolates the white matter axon tracts. Shows where axon damage has occurred/where they are missing. Can tell you what type of injury it is, where it is located and what part of the brain it might affect.

However it is very expensive and most healthcare centres don’t have the funds to implement it

28
Q

What are the pros and cons of a computed tomography scan?

A

Can show bleeding, fractures, clots and swelling. Most commonly used. Can be done quickly and are not too sensitive to movement.

However can’t show any specific information about the brain damage. Results sometimes don’t correlate with neurological examinations

29
Q

What are the pros and cons of an MRI?

A

Can show build-up of fluid and skull damage. Very detailed – might be able to detect things a CT scan cannot.

However can’t show any specific information about the brain damage. Claustrophobia. Very sensitive to movement. Cannot be done if the patient has any metal in their body.

30
Q

What are the pros and cons of a PET scan?

A

Similarly to MRI, can show build-up of fluid and skull damage. More sensitive than MRIs or CT scans.

Very expensive. Patient has to abstain from food and exercise for 6 hours beforehand.

31
Q

What are some possible treatments for TBI?

A

Craniotomy to relieve pressure
Lowering brain temperature to slow inflammatory processes/neurotransmitter activity
Coma inducement - reduces brain requirement for oxygen
Oxygen therapy
Rehabilitation therapy (physical therapy, speech therapy)
Medications - Anticonvulsants, anticoagulations, muscle relaxants, antidepressants

32
Q

What are the 4 animals models used to investigate TBI?

A

Weight drop injury model
Controlled cortical impact injury model
Forced percussion injury model
Blast injury model

33
Q

Describe the controlled cortical impact injury model of TBI

A

Driven piston penetrates brain. Mimics BBB disruption, concussion and axonal injury. Highly precise and reproducible.

34
Q

Describe the blast injury model of TBI

A

Mouse placed in shock tube and exposed to blast. Mimics military explosions. Results in diffuse, blunt force trauma, no external injury. Injuries can be variable and inconsistent

35
Q

Describe the fluid percussion injury model of TBI

A

Fluid injected with force into brain leading to swelling and intracranial haemorrhage. Mimics subdural haemorrhage. Can observe behavioural effects using water morris maze test. Easy to reproduce however has high mortality rate.

36
Q

Describe the weight drop injury models of TBI

A

A weight of set mass dropped from set height. Cheap and easy but high variability in injury so not reproducible.
Marmarou’s model - used to investigate diffuse injury. Metal disk placed over skull to prevent bone fractures
Shohami’s model - used to investigate focal point injury. Weight drop delivered to one side of skull left unprotected

37
Q

What imaging techniques can be used to look at glia following TBI?

A

Two-photon microscopy - use in vivo surgery to observe live movement of cells following an experimental procedure
Optical coherence tomography - observe microglia through retina. Non invasive and can be used for early detection of abnormalities. Clearer than CTs and x-rays

TMS (12 decks)

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