Neuroinflammation in Alcohol Dependence

Question 1

Define inflammation

Answer 1

A reaction to an injury involving the recruitment of cells, heat, redness, and swelling, and accompanied by loss of function and pain

Question 2

Describe the difference between neuroinflammation and inflammation

Answer 2

Neuroinflammation doesn’t involve pain (no CNS pain receptors) or redness, and rarely involves heat - although it does involve broader temperature dysregulation.

Question 3

Name the 2 cells which play the greatest role in neuroinflammation

Answer 3

Astrocytes and microglia

Question 4

What are microglia?

Answer 4

CNS macrophages which orchestrate the immune response and release toxic factors, including ROS, prostaglandins, and cytokines (TNF-alpha and IL-1)

Question 5

Name some classic triggers of neuroinflammation

Answer 5

Infectious microbes, autoimmunity, environmental toxins, disease proteins

Question 6

Name some neurogenic triggers of neuroinflamamtion

Answer 6

Enhanced neural activity - noxious stimuli, psychological stress, epileptic seizures

Question 7

Describe some positive responses to neuroinflammation

Answer 7

Homeostatic responses (release of gliotransmitters, neurotrophic factors, and cytokines, vasodilation, phagocytosis) and anti-inflammatory responses (release of anti-inflammatory molecules, vasodilation)

Question 8

Describe some negative responses to neuroinflammation

Answer 8

Maladaptive responses (release of pro-inflammatory factors, plasma extravasation) and neurotoxic responses (release of pro-inflammatory factors, excitotoxicity, apoptosis, BBB breakdown)

Question 9

State the consequences of homeostatic responses to neuroinflammation

Answer 9

Adaptation: microbe elimination, synaptic plasticity, enhanced perfusion, neuroprotection, repair, and regeneration

Question 10

State the consequences of anti-inflammatory responses to neuroinflammation

Answer 10

Termination of the inflammatory response

Question 11

State the consequences of maladaptive responses to neuroinflammation

Answer 11

Dysfunction: hyperexcitability, impaired inhibition, reduced computational power

Question 12

State the consequences of neurotoxic responses to neuroinflammation

Answer 12

Degeneration: progressive loss of CNS function and chronic disease

Question 13

Based on NICE’s 2011 figures, what percentage of the UK’s population consumes alcohol in a harmful way, and what percentage are dependent?

Answer 13

Harmful use: 25%

Dependent: 5%

Question 14

What percentage of all deaths globally are directly attributable to alcohol? (WHO, 2014)

Answer 14

6%

Question 15

As of 2016, what are the UK guidelines on alcohol consumption?

Answer 15

Weekly limit of 14 units with at least 2 alcohol free days

Question 16

Define hazardous drinking

Answer 16

Drinking resulting in raised physiological observations (e.g. BP) increasing the likelihood of a problem occurring

Question 17

Define problem drinking

Answer 17

Evidence of harmful consequences from alcohol consumption, either physical, psychological, or social

Question 18

Define dependent drinking

Answer 18

3 or more of the following in the last 12 months:

• Craving or compulsion to drink
• Withdrawal symptoms
• Continuing in spite of harm
• Tolerance
• Neglect of other interests
• Difficulty controlling use

Question 19

Describe the effects of alcohol on the brain

Answer 19

General brain atrophy, enlargement of the ventricles, narrow gyri, widened sulci

Question 20

What percentage of the UK population has subtle cognitive dysfunction due to alcohol consumption?

Answer 20

1.5%

Question 21

State at least 4 factors involved in alcohol-related brain damage

Answer 21

Thiamine deficiency, direct neurotoxicity, alcoholic liver disease, multiple withdrawal episodes, TBI, microvascular disease

Question 22

How does alcoholic liver disease contribute to brain damage?

Answer 22

Inflammatory cells cross the blood-brain barrier

Question 23

Describe the parts of the brain affected in alcoholic neuroinflammation

Answer 23

Caudate, putamen, thalamus, amygdala, hippocampus

Question 24

Describe the effect of alcohol dependence on the brains of rats (Syapin, 1998; Oberniew, 2002)

Answer 24

It activates microglia, with microglia remaining activated for at least 14 days after the last alcohol dose. It also stimulates toll-like receptors - especially toll-like receptors 4 and 2

Question 25

Which mice are protected against alcohol-induced cytokine and chemokine release?

Answer 25

Toll-like receptor 2&4 knockout mice

Question 26

In the post-mortem brains of alcoholics, where is monocyte chemoattractant protein 1 (MCP-1) increased? (He & Crews, 2008)

Answer 26

Ventral tegmental area, substantia nigra, amygdala, hippocampus

Question 27

How is chronic alcohol intake associated with pre-clinical inflammation?

Answer 27

Alcohol activates microglia via toll-like receptor 4. Over time, this produces increases in pro-inflammatory cytokines in the brain which persist

Question 28

Name at least 3 ways in which peripheral circulating cytokines reach the brain

Answer 28

Dedicated transporters, the vagus nerve, stimulation of macrophages, diffusion

Question 29

How do peripheral circulating cytokines cause ‘sickness behaviour’? (Harrison, 2009)

Answer 29

They enter the brain via various mechanisms and increase activity in the subgenual anterior cingulate cortex

Question 30

How could peripheral inflammation cause memory dysfunction in chronic alcoholism, and give a piece of evidence?

Answer 30

By producing a pro-inflammatory environment in the brain. Peripheral inflammation and high TNF-alpha in AD patients is associated with deterioration in cognition

Question 31

Name a cytokine associated with alcohol withdrawal symptoms and depression

Answer 31

IL-6

Question 32

Name a cytokine associated with performance on cognitive tests in alcoholics

Answer 32

CCL-2

Question 33

Describe how a PET image is produced

Answer 33

A positron annihilates an electron and emits 2 perpendicular gamma rays, which are picked up by the scanner. The electrons are produced by unstable radioligands so that binding can be observed and expression of the target the radioligand binds to can be seen

Question 34

Name a ligand used to measure microglial activation in humans

Answer 34

11C-PRB28

Question 35

What does 11C-PRB28 bind to?

Answer 35

The microglial biomarker TSPO

Question 36

Why might 11C-PRB28 binding not produce a signal in 25% of people?

Answer 36

They are low-affinity TSPO binders

Question 37

Describe the difference in 11C-PRB28 binding in healthy individuals and alcoholics

Answer 37

Alcohol-dependent individuals have lower hippocampal binding, suggesting decreased microglial expression in the hippocampus

Question 38

Describe the association between 11C-PRB28 binding and verbal memory

Answer 38

Increased hippocampal microglial binding correlates with a better delayed verbal memory score

Question 39

Describe the effect of AD on the brain

Answer 39

General brain atrophy, especially of the medial and temporal lobes, narrow gyri, widened sulci, ventricular enlargement, hippocampal atrophy

Question 40

According to the 2015 NICE guidelines, what is the safe level of alcohol consumption for frail elderly patients and those with dementia?

Answer 40

There is no safe level

Question 41

State some risk factors for AD (Heneka et al, 2015)

Answer 41

Ageing, genetics (e.g. APOE4), midlife obesity, TBI, infections, systemic inflammation, reduced physical activity

Question 42

Give 2 examples of hypotheses linking AD and alcohol

Answer 42

1) Alcohol binds to TLR4 and causes inflammation (Venkataraman et al, 2016)
2) Ethanol activates microglia (Fernandez-Izarbe et al, 2009)

Question 43

Give 2 pieces of evidence linking AD and alcohol

Answer 43

1) Thiamine deficiency, a consequence of alcoholism, increases amyloid plaques in mice (Karrupagounder et al, 2009)
2) Systemic inflammation superimposed on neurodegenerative disease accelerates disease progression (Cunningham, 2009)

Question 44

Describe the brain changes from early MCI to AD

Answer 44

Amyloid deposition in the cortical regions increases and cortical thickness decreases (atrophy)