Neuroinflammation in Alcoholism

Question 1

Simplified mechanism of inflammation?

Answer 1

Tissue damage -> foreign pathogens -> cytokine release -> increase permeability -> immune cell invasion -> inflammation

Question 2

Key clinical features of inflammation

Answer 2

• rubor (redness)
• calor (heat)
• dolor (pain)
• loss of function

Question 3

Triggers of neuroinflammation?

Answer 3

Classical

• infection
• autoimmunity
• toxins

Neurogenic
- due to increased neuronal activity (e.g. substance abuse)

Question 4

Different pathways of neuroinflammation

Answer 4

Physiological
Homeostatic -> adaptation
Anti-inflammatory -> resolution

Pathological
Maladaptive -> dysfunction
Neurotoxic -> degeneration

Question 5

Key cells in neuroinflammation

Answer 5

Microglia: release toxic factors to exacerbate damage

• -> ROS
• -> prostaglandins (COX2)
• -> cytokines: TNFa, IL-1

Question 6

How to calcluate alcohol units?

Answer 6

Units = % x volume (L)

Question 7

Daily limit of alcohol?

Answer 7

Daily limit = 2 units (>2 alcohol free days per week)

Question 8

Define “binge”?

Answer 8

Twice the daily limit

Question 9

Types of problems with alcoholism?

Answer 9

• Hazardous drinking (numbers e.g. BP too high)
• Problem drinking: evidence of harmful consequences- physical/psychological/social
• Dependent drinking: 3 or more of following in last 12 months
• –> craving, withdrawal, tolerance, neglect of other interests, continuing in spite of harm, difficulty controlling use

Question 10

Pathological features of abstinent alcoholics on MRI?

Answer 10

Atrophy (widened sulci, narrow gyri)]- ICAM study

Question 11

Types of alcohol-related brain damage?

Answer 11

Thiamine deficiency: Wernicke-Korsakoff Syndrome

Direct neurotoxicity

Alcoholic liver disease: peripheral inflammation can cross BBB -> neuroinflammation

Head injury: drunk -> high falls risk-> fall-> neuroinflamm -> cog dysfunc

Increased CVD risk: and stroke risk

Question 12

Specific damage sites of alcohol on the brain

Answer 12

Neuroinflammation, particularly in:

• caudate
• putamen
• hippocampus
• medulla

Question 13

Overview of mechanisms how alcohol causes neuroinflammation?

Answer 13

Alcohol activates microglia via TLR4 (Toll) -> inflammation

Alcohol causes gut flora changes -> increas perm to LPS -> Kuffer cell activation -> periph inflam -> neuroinflam
]—–periph cytokines enter brain; vagus nerve; activated macrophates; diffusion AND periph inflam may affect cognition through neuroinflam

Withdrawal -> sympathetic activation -> neuroinflammation

Question 14

Experimental evidence of alcohol’s activation of microglia

Answer 14

(E): activated microglia present 14days after last alcohol dose] - in rat model of dependence

(E): TLR4 KO mice protected against alcohol-induced inflammation

(E): post mortem alcohol-dependent brains show increased microglia and increased inflam cytokines

(E): microglia activation seen during alcohol intake and withdrawal

Question 15

Mechanism of PET imaging?

Answer 15

11C-PBR28 PET ligand binds to TSPO to detect microglia

TSPO polymorphism affects human binding affinities of TSPO: so we must know binding status of subject in advance for good analysis

Question 16

Alcohol-dependent pts PET scan findings?

Answer 16

• alcohol-dependent have reduced hippocampus binding for PBR28 (microglia tracer)]- microglia loss/dysfunction?
• reduced hippocampal TSPO expression assoc w/ reduced memory function

Question 17

Relation between alcohol and AD?

Answer 17

DIRECTLY
- alcohol binds to TLR4 on microglia -> microglia activation -> cytokine release -> neuroinflammation

INDIRECT

• thiamine def -> increase Aβ
• –> thiamine def rats have increased Aβ compared to thiamine rich
• –> alc dependence is most common cause of thiamine def
• fibrillar Aβ binds to TLR4, activating microglia -> neuroinflam -> neuronal death -> AD symptoms -> cycle
• systemic inflammation superimposed on neurodegen disease accelerates disease progression
• TBI
• withdrawal effects

Question 18

Experimental evidence of role of cytokines in alcohol withdrawal?

Answer 18

(E):

Decrease in pro-inflam cytokines whilst Th1 cytokines increased during withdrawal

Pro-inflam cytokines assoc w/ withdrawal severity/depressive symp/cognition: IL-6 (`related to withdrawal and depression) and CCL-2 (positively assoc w/ cognition)

Question 19

TLR signalling specifically?

Answer 19

TLR4 binding -> MyD88 dependent OR independent (via p50,p65,NFkB)

MyD88-dependent:
inflam cytokines

MyD88-independent:
IFN-b, IFN-inducible gene products