Neuroinflammation

Question 1

How can a microbe affect CNS function (Direct)?

Answer 1

Direct:
-Invasion of parenchyma of brain
(like Viral encephalitis, Cerebral abscess)

-Invasion of supporting structures of brain (VZV large-vessel vasculopathy)

Question 2

How can a microbe affect CNS function (indirect)?

Answer 2

• Immune-mediated CNS damage
  (Acute disseminated encephalomyelitis, Infection-triggered antibody-associated, Immune reconstitution inflammatory syndrome (IRIS))
• Infection-triggered metabolic catastrophes (Reye’s syndrome or in adults Kapila syndrome, Acute necrotising encephalopathy)
• Toxin-mediated diseases (Tetanus)
• Consequence of systemic sepsis (Septic encephalopathy)

Question 3

Causes of acute viral encephalitis worlwide

Answer 3

Enteroviruses:
Poliovirus
Coxsackie virus
Echovirus
Hepatitis A

Herpesviruses:
HSV types 1 & 2
VZV

Question 4

Diagnosis of Acute Encephalitis:
Lab & Imaging

Answer 4

-Imaging Modalities
-Electroencephalography
-CSF Analysis

Question 5

What is the first line treatment for HSV?

Answer 5

Aciclovir triphosphate is a competitive inhibitor of viral DNA polymerase

Question 6

What is the commonest in the US and 2nd commonest in UK cause of bacterial meningitis

Answer 6

Pneumococcal meningitis

Question 7

What is the first line treatment for Pneumococcal meningitis?

Answer 7

High dose intravenous antibiotics
+ Steroids

Question 8

Emerging Neuroviral Infections

Answer 8

Newly evolved virus e.g. EV 71 (1970s)

Environmental changes e.g. WNV in USA; Tick-borne encephalitis in UK

Virus crossing species barrier e.g. Nipah or bird ‘flu (H5N1)*

Question 9

What are the 3 types of Glia cells in the brain?

Answer 9

1.
Oligodendrocytes

2. Astrocytes
3. Microglia

Question 10

What are microglia?

Answer 10

Resident inflammatory cells of the CNS (Innate Immune System)

Question 11

What do Oligodendrocytes do?

Answer 11

They form myelin sheaths around axons in the CNS for efficient signal conductance

Question 12

What do Astrocytes do?

Answer 12

• Regulation of synaptic connectivity
• Maintenance of ionic/neurotransmitter homeostasis in the extracellular milieu
• wound healing/limiation of inflammation

Question 13

How many clusters of microglia are there in the human brain?

Answer 13

9

Question 14

What does the cell morphology depend on?

Answer 14

location = reflecting function

Question 15

Name 4 functions of microglia:

Answer 15

1. Clearing of apoptotic cells
2. Neuron protection
3. Synaptic pruning
4. Tissue maintenance

Question 16

What signals is microglia sensitive to?

Answer 16

PAMPS & DAMPS (dying, stressed neuronal cell)
PRRs (eat me signal)

Question 17

What does the ramified microglia morphology imply?

Answer 17

High plasticity:
- change in shape
- change of secretion
- change of behaviour

Question 18

Type of microglia reponses:

Answer 18

1. Phagocytosis (engulf)
2. Chemotaxis (move towards areas of damage)
3. Cytokines & Chemokines (release)
4. Complement and coagulation factors (produce and activate for elimination of pathogens)

Question 19

Microglia M1 vs M2 activation

Answer 19

M1: Pro-inflammatory (classically activated)

M2: Anti-inflammatory (alternatively activated)

Question 20

When does Immune activation occur in the brain

Answer 20

• Dementia
  -Depression
• Schizophrenia/Psychosis

Question 21

When does immune activation occur in the periphery?

Answer 21

Obesity/Metabolic
Ageing
Infections
Autoimmune diseases
e.g. arthritis, diabetes

Question 22

Which diseases are oligodendrocytes involved in?

Answer 22

• MS, MSA, Charcot-Marie-Tooth, Leukodystropgies, brain injury

[possibly schizophrenia & bipolar disorder]

Question 23

Which diseases are astrocytes involved in?

Answer 23

AD, epilepsy, ALS, SCA, PD, HD, stroke, focal cerebral ischaemia, hepatic encephalopathy, brain injury

Question 24

Which diseases are Microglia involved in?

Answer 24

AD, CJD, Batten’s disease, PD, ALS, HD, brain injury

Question 25

What happens if microglia are activated in AD?

Answer 25

• Microglia surround plaques, neurofibrilary tangles and damage neurons
• Change morphology from ramified to amoeboid
• Increase in number (proliferation)
• Correlate with disease markers > neuronal cell death and emergence of behavioural symptoms

Question 26

What is Inflammatory risk gene (immune) TREM2

Answer 26

TREM2 stands for Triggering Receptor Expressed on Myeloid Cells 2.

Function: It encodes a protein that is primarily expressed on microglia. TREM2 is involved in regulating the function of microglia, including their response to injury, inflammation, and the clearance of cellular debris.

Mutations in the TREM2 gene have been linked to an increased risk of developing neurodegenerative diseases, such as Alzheimer’s disease.

Question 27

What is TNFα?

Answer 27

Tumor Necrosis Factor-α is a pro-inflammatory cytokine produced by various immune cells in response to infection, inflammation, or injury.

Dysregulation of TNF-alpha has been implicated in the pathogenesis of various inflammatory and autoimmune diseases. Additionally, elevated levels of TNF-alpha have been observed in neurodegenerative disorders, including Alzheimer’s disease.