Neuroinflammation in Alcohol Dependence Flashcards
Describe the process of neuroinflammation Understand the problems with alcohol and alcohol dependence Describe the relationship between alcohol and neuroinflammation Describe the relationship between alcohol and Alzheimer's disease
Define inflammation
A reaction to an injury involving the recruitment of cells, heat, redness, and swelling, and accompanied by loss of function and pain
Describe the difference between neuroinflammation and inflammation
Neuroinflammation doesn’t involve pain (no CNS pain receptors) or redness, and rarely involves heat - although it does involve broader temperature dysregulation.
Name the 2 cells which play the greatest role in neuroinflammation
Astrocytes and microglia
What are microglia?
CNS macrophages which orchestrate the immune response and release toxic factors, including ROS, prostaglandins, and cytokines (TNF-alpha and IL-1)
Name some classic triggers of neuroinflammation
Infectious microbes, autoimmunity, environmental toxins, disease proteins
Name some neurogenic triggers of neuroinflamamtion
Enhanced neural activity - noxious stimuli, psychological stress, epileptic seizures
Describe some positive responses to neuroinflammation
Homeostatic responses (release of gliotransmitters, neurotrophic factors, and cytokines, vasodilation, phagocytosis) and anti-inflammatory responses (release of anti-inflammatory molecules, vasodilation)
Describe some negative responses to neuroinflammation
Maladaptive responses (release of pro-inflammatory factors, plasma extravasation) and neurotoxic responses (release of pro-inflammatory factors, excitotoxicity, apoptosis, BBB breakdown)
State the consequences of homeostatic responses to neuroinflammation
Adaptation: microbe elimination, synaptic plasticity, enhanced perfusion, neuroprotection, repair, and regeneration
State the consequences of anti-inflammatory responses to neuroinflammation
Termination of the inflammatory response
State the consequences of maladaptive responses to neuroinflammation
Dysfunction: hyperexcitability, impaired inhibition, reduced computational power
State the consequences of neurotoxic responses to neuroinflammation
Degeneration: progressive loss of CNS function and chronic disease
Based on NICE’s 2011 figures, what percentage of the UK’s population consumes alcohol in a harmful way, and what percentage are dependent?
Harmful use: 25%
Dependent: 5%
What percentage of all deaths globally are directly attributable to alcohol? (WHO, 2014)
6%
As of 2016, what are the UK guidelines on alcohol consumption?
Weekly limit of 14 units with at least 2 alcohol free days
Define hazardous drinking
Drinking resulting in raised physiological observations (e.g. BP) increasing the likelihood of a problem occurring
Define problem drinking
Evidence of harmful consequences from alcohol consumption, either physical, psychological, or social
Define dependent drinking
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
Describe the effects of alcohol on the brain
General brain atrophy, enlargement of the ventricles, narrow gyri, widened sulci
What percentage of the UK population has subtle cognitive dysfunction due to alcohol consumption?
1.5%
State at least 4 factors involved in alcohol-related brain damage
Thiamine deficiency, direct neurotoxicity, alcoholic liver disease, multiple withdrawal episodes, TBI, microvascular disease
How does alcoholic liver disease contribute to brain damage?
Inflammatory cells cross the blood-brain barrier
Describe the parts of the brain affected in alcoholic neuroinflammation
Caudate, putamen, thalamus, amygdala, hippocampus
Describe the effect of alcohol dependence on the brains of rats (Syapin, 1998; Oberniew, 2002)
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
Which mice are protected against alcohol-induced cytokine and chemokine release?
Toll-like receptor 2&4 knockout mice
In the post-mortem brains of alcoholics, where is monocyte chemoattractant protein 1 (MCP-1) increased? (He & Crews, 2008)
Ventral tegmental area, substantia nigra, amygdala, hippocampus
How is chronic alcohol intake associated with pre-clinical inflammation?
Alcohol activates microglia via toll-like receptor 4. Over time, this produces increases in pro-inflammatory cytokines in the brain which persist
Name at least 3 ways in which peripheral circulating cytokines reach the brain
Dedicated transporters, the vagus nerve, stimulation of macrophages, diffusion
How do peripheral circulating cytokines cause ‘sickness behaviour’? (Harrison, 2009)
They enter the brain via various mechanisms and increase activity in the subgenual anterior cingulate cortex
How could peripheral inflammation cause memory dysfunction in chronic alcoholism, and give a piece of evidence?
By producing a pro-inflammatory environment in the brain. Peripheral inflammation and high TNF-alpha in AD patients is associated with deterioration in cognition
Name a cytokine associated with alcohol withdrawal symptoms and depression
IL-6
Name a cytokine associated with performance on cognitive tests in alcoholics
CCL-2
Describe how a PET image is produced
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
Name a ligand used to measure microglial activation in humans
11C-PRB28
What does 11C-PRB28 bind to?
The microglial biomarker TSPO
Why might 11C-PRB28 binding not produce a signal in 25% of people?
They are low-affinity TSPO binders
Describe the difference in 11C-PRB28 binding in healthy individuals and alcoholics
Alcohol-dependent individuals have lower hippocampal binding, suggesting decreased microglial expression in the hippocampus
Describe the association between 11C-PRB28 binding and verbal memory
Increased hippocampal microglial binding correlates with a better delayed verbal memory score
Describe the effect of AD on the brain
General brain atrophy, especially of the medial and temporal lobes, narrow gyri, widened sulci, ventricular enlargement, hippocampal atrophy
According to the 2015 NICE guidelines, what is the safe level of alcohol consumption for frail elderly patients and those with dementia?
There is no safe level
State some risk factors for AD (Heneka et al, 2015)
Ageing, genetics (e.g. APOE4), midlife obesity, TBI, infections, systemic inflammation, reduced physical activity
Give 2 examples of hypotheses linking AD and alcohol
1) Alcohol binds to TLR4 and causes inflammation (Venkataraman et al, 2016)
2) Ethanol activates microglia (Fernandez-Izarbe et al, 2009)
Give 2 pieces of evidence linking AD and alcohol
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)
Describe the brain changes from early MCI to AD
Amyloid deposition in the cortical regions increases and cortical thickness decreases (atrophy)
