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Chika- SF2 > Neuroinflamation-Manaye > Flashcards

Neuroinflamation-Manaye Flashcards

1
Q

What is the importance of inflammation?

A
  • body’s response against trauma, toxic environment, infection, injury
  • end goal is to restore tissue homeostasis whether it is repairing injured tissues, promoting wound healing, or neutralizing invading pathogens
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2
Q

Does the brain have leukocytes?

A

-the brain does NOT have leukocytes but we have our own immune system

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3
Q

What is the difference between the body inflammation system and the neuronal inflammation system?

A

when you have infection in your systemic organ you have rapid response from leukocytes, T-cells

in the brain you have moderate or slow activation of glial cells (mainly microglia and astrocytes)

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4
Q

Inflammation can have an acute phase that consists of what?

A

acute: hour to a couple of days in the brain

  • inflammatory molecules
  • endothelial cell activation: endothelial around BVs that create the tight junctions
  • platelet deposition
  • tissue edema: inflammation of the meninges or obstruction of the CSF leading to hydrocephalus

-composed largely activation of glial cells without blood brain barrier breakdown

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5
Q

Inflammation can have a chronic phase that consists of?

A
  • typically associated with neurodegenerative diseases
  • neuronal cell death
  • causative factor to the pathogenesis of neurological diseases and disorders

?????

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6
Q

Why do we need a blood-brain barrier important?

A

as a physician need to know if medication will pass BBB

  • it is our protection for the CNS
  • tight junctions present in the ventricles
  • astrocytes are supportive in the development of brain cells

-BBB maintains the chemical composition of the neuronal milleu which is required for proper functioning of
-synaptic transmission
-synaptic remodeling
-angiogenesis
neuronal circuits
-neurogenesis

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7
Q

What centers in the body does not have a brain barrier?

A

vomiting center

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8
Q

What happens if there is disruption of the tight junction during blood brain barrier breakdown?

A
  • altered transport of molecules between blood and brain and brain and blood
  • aberrant angiogenesis
  • vessel regression
  • brain hypoperfusion
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9
Q

What is the role of plasticity of our brains?

A

when you have infection, astrocytes will be activates and will release cytokines which activate resting microglia that will then activate proinflammatory elements

if this persists then neuronal cell death occurs

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10
Q

Although our brain doesn’t have leukocytes, when there is severe inflammation of the CNS, T cells, B cells, and macrophages are recruited by what?

A

vagal nervous stimulation

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11
Q

Is neuroinflammation beneficial or deleterious?

A
  • it depends mainly on the duration of the inflammatory response
  • if a stimulus is persistent and inflammatory condition continues it could lead to neuronal degeneration (such as the breakdown of BBB)
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12
Q

Glial cells are composed of what percentage of our gray matter?

A

13%

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13
Q

What is the role of neuroglia in neuroinflammation?

A

both neuroglia have different morphological changes like glial cells during inflammation which is based on:

  • where the inflammation is
  • how far the cells are from the affected area
  • what is in the integrity of the brain (is there already a comorbidity of the brain (neuroplasm, epilepsy, HIV/AIDS)
  • how active the microglias are

glia respond to stimulus by undergoing activation which is normally beneficial

chronic, unregulated glia activation can be detrimental and lead to neuroinflammation

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14
Q

What are the two forms of astrocytes?

NEED TO KNOW

A

protoplasmic: in your gray matter and cerebral cortex;
short processes because they are abandoned in the CNS; have high packing density

fibrous: in white matter; have long unbranched processes; like pyramidal cells need long axons to travel through the 6 layers of the cortex; fibrous astrocytes cannot communicate with neighboring cells very easily so they have to have extensive roots to travel

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15
Q

Why is the microglial system the most important system we have to protect us from immune disorder?

A

they have 3 functional morphology:

  • resting (brain is okay, no problem)
  • mild activation (we have active inflammation going on)
  • activated, supercharged (in toxic areas)

when there is a frontal lobe lesion (ie. in Broca’s area), microglial cells will be recruited from their resting state and become more round (mild activation) and fully activated and supercharged when they’ve reached the site of insult or toxic region

when activated they will release:

  • cytokines
  • chemokines
  • proteases
  • amyloid precursor protein (PK, Alzheimer’s)
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16
Q

How can a resting microglial cell undergo pathogenesis (bad) or repair (good)?

A

Pathogenesis (neurotoxic):
-can release IFN-gamma and LPS which activates the M1 phenotype leading to proinflammatory molecules like IL-4, IL-Ibeta, TNF-alpha and production of free radicals
-
-loss of myelin then cell death

Repairs (neuroprotection):
-can release IL-4, IL-10, IL-13 activating the M2 phenotype and thus releasing anti-inflammatory molecules like BMP-7, IL-10, growth factors

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17
Q

What are cytokines and chemokines and what is their functions?

A

they are soluble mediators (small proteins) of innate and adaptive immunity and the mechanisms by which leukocytes communicate with one another

functions:
- stimulation
- inhibition
- differentiation
- cell death
- chemoattraction

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18
Q

What are the common causes and types of neuroinflammation?

A
  • autoimmunity: the body secretes its own enemy; ie. lupus, arthritis
  • microorganisms (microbes and viruses)
  • aging: when neurons die we have activation of microglia to remove all that debris
  • air pollution and active or passive smoke
  • toxic metabolites
  • traumatic brain injury
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19
Q

What are the most common autoimmune disorders affecting the CNS?

A
  • Gullian-Barre syndrome
  • multiple sclerosis
  • myasthenia gravis
  • prion disease
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20
Q

What is multiple sclerosis?

A
  • chronic inflammatory autoimmune disorder of the CNS
  • myelin sheaths that coat nerves and assist in nerve impulse transmission are destroyed. This process is called demyelination, and it results in damaged nerves that cannot transmit impulses.
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21
Q

What is Guillain Barre syndrome?

A
  • an acute inflammatory demyelinating polyneuropathy (All the spinal nerve system is affected in periphery in addition to the CNS)
  • this is a progressive disorder
  • poor nerve conduction due to myelin breakdown
  • triggered by an acute infectious process

-blood brain barrier is intact, cerebral function is intact so the lesion is in the spinal cord

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22
Q

Does Gullain Barre affect the level of consciousness, pupillary function, or cerebral function?

A

NO

that means the lesion is in the spinal cord so the retinal blood barrier is intact in addition to the blood brain barrier

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23
Q

What is myasthenia gravis?

A

-an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatigability

  • it is slowly progressive????
  • goes from lower to upper nervous system damage

-weakness is caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine

This leads to a decrease in end plate depolarization, which may be insufficient to generate an action potential.
Results in a failure of the muscle to contract

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24
Q

With progression of myasthenia gravis, patient develop problems breathing. Why?

A

smooth muscles for breathing have the inability to contract and there is loss of secretion from the endocrine system for the heart rate–> pt dies

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25
Q

What is multiple sclerosis?

A
  • degeneration of myelin there is less contactability between the neurons and so the somas will eventually die off
  • very deformed dendrites and short axons
  • affects the white matter (lesions are seen and pathways are affected= no connectivity)
26
Q

What population does multiple sclerosis affect more?

A

very common and more common in women (1/200) than men (1/400)

27
Q

What are the most common initial symptoms of multiple sclerosis?

A
  • changes in sensation (33%)
  • optic neuritis (20%): hardening of vasculature in the brain and in the eyes means the the blood brain barrier is affected; there is diplopia and difficulty looking at images
  • weakness (exercise induced) (13%)
  • double vision-internuclear ophthalmoplegia (7%)
  • unsteadiness while walking (5%)
  • balance problems (3%)
28
Q

What is human prion disease and how prevalent is it?

A
  • neuroinflammation due to prion protein mutation
  • can be acquired from feeding and taking care of meat (humans feeding on humans)

-familial:
fetal familial insomnia (FFI): inability of baby to sleep due to underdeveloped hypothalamus (life expectancy is 20-30 years)

  • sporadic
  • you will never see; very rare (1/1,000,000)
29
Q

Chronic inflammation (neuroinflammation) that was originally acute are primarily due to what?

A

bacteria and viruses (toxins entering brain because BBB integrity is broken)

30
Q

What are some brain syndromes that are due to microorganisms (microbes and viruses)?

A
  • meningitis which could lead to dementia
  • stroke
  • seizures
  • degenerative disorders
31
Q

What are some HIV-related neurological syndromes ?

A
  • cerebellar ataxia
  • multisystem degeneration
  • anterior horn cell disease

???

we look at viral load in HIV patients instead of looking at the good microglia as they will be damaged by rapidly dividing virus

32
Q

What are some CNS clinical complications and neuropathology ?

A

vascular myelopathy
-the integrity of all your BBB is affected
-poor transmission of information from cell to cell
-poor secretion of neurotransmitters
-overload of circulation of cytokines (IL-1, NO because of cell stress)
-allows for opportunistic bacteria
HIV-Associated Dementia
Peripheral Neuropathy
Toxoplasmosis Cryptococcal meningitis
Lymphoma PML

neuropathology: 
HIV encephalitis
Reactive astrogliosis
Myelin pallor
Microglial nodules
Activated resident microglia
Multinucleated giant cells
Infiltration of blood-derived monocyte/macrophages
33
Q

In summary, neuroinflammation disorders can be caused by infections of what categories?

A
  • bacterial meningitis
  • brain abscess
  • viral encephalitis
  • viral meningitis
34
Q

How can the brain compensate for the loss of function?

A

DNA is damaged due to several causes like inflammation, cancer, starvation, integrity of cell machinery is destroyed, etc.

This all causes apoptosis or necrosis.

The brain will initiate the recruitment of other nucleotides that can repair mitochondria.

35
Q

Describe DNA damage and repair mechanisms in humans.

A
  • DNA is the macromolecule that is the carrier of genetic instructions used in development, functioning and reproduction of all living organisms
  • alteration in chemical structure of DNA is DNA damage which can be caused by either endogenous or exogenous factors
  • DNA impairment affects the nervous system and causes cancer, aging, and various
36
Q

What is neuronal death and how is it caused?

A

it is when a neuron has the inability to perform its biological function (sending or receiving signals) and it is caused by loss of proper connections which can come from:

  • loss of proper growth factors (e.g. NGF)
  • damage (especially oxidative damage)
  • neuronal dysfunction or damage results and loss of cell bodies
37
Q

Is neuronal death reversible?

A
  • synapsis can be reversible but apoptosis is irreversible
  • the remaining cells will be strengthened to compensate
  • certain brain areas of olfactory, amygdala, dentate gyrus show new cells
  • unsure if these cells fully perform the function of the cells that have died
  • there is no formation of cells
38
Q

What are endogenous and exogenous causes of DNA damage?

A
  • Damage to DNA is nothing but effect on primary structure of double helix.
  • It occurs due to environmental factors and normal metabolic processes inside the cell. It occurs at rate 10,000 to 10,00,000 molecular lesions per cell per day.
  • DNA damage can occur due to two main agents viz. endogenous cellular processes and exogenous agents.
  • The endogenous cellular processes include oxidation of nitrogen bases and generation of DNA strand interruptions from reactive oxygen species, alkylation of bases, hydrolysis such as mismatch of bases due to error in the replication process of DNA.

EXAMPLES:
-excessive hormone glucocorticoids causes stress on my cell and can die

-external drugs that reduce or increase glucocorticoids can also damage my DNA integrity

39
Q

What are the mechanisms of neurodegeneration?

A

oxidative stress

  • highly reactive, unstable chemicals
  • associated with cell injury
  • chemicals/drugs, reperfusion injury, inflammation, irradiation, oxygen toxicity, carcinogenesis

causes of cell injury

  • hypoxia
  • chemical
  • physical
  • infection
  • immune
  • nutritional deficiency (or excess!)
40
Q

All neurodegenerative disease is a result of what?

A

CHRONIC inflammation

41
Q

What is etiology of cell death? What is the difference between apoptosis and necrosis?

A

Necrosis is accidental. It is the sum of the morphological changes that follow cell death in a living tissue or organ

Apoptosis is genetic. It is a physiological process that includes specific suicide signals leading to cell death

42
Q

What are the stages in which cells undergo apoptosis?

A

healthy cell–> death signal (extrinsic or intrinsic) —> commitment to die (reversible) –> execution (irreversible)—> dead cell (condensed, cross-linked )–>engulfment (macrophages, neighboring cells)–>degradation

43
Q

What are the stages in which cells undergo necrosis?

A

Homeostatic ‘steady state’

  • –>Cellular adaptations
  • –>Reversible cell injury
  • –>Irreversible cell injury
  • –>necrosis
44
Q

What are the most common neurodegenerative diseases?

A

Parkinson’s

Alzheimers

45
Q

What is the role of microglia in degenerative neurological diseases like Alzheimers and Parkinsons?

A
  • the inability of microglia to clear β-amyloid (Aβ) is a major contributor to Alzheimer’s disease and amyloid deposition is seen in other neurodegenerative diseases such as, Parkinson’s, and prion diseases in addition to other cytopathology.
  • lewy bodies are present in Parkinson’s disease

-This may be due to a senescence process in microglia & Neuron or an overload of the cell.
It may be because of an altered cell signaling.

46
Q

Why does the brain not have leukocytes?

A

the brain does not have a lymphatic system

47
Q

Describe the characteristics of Alzheimer’s disease.

A
  • age related (60 yr or older)
  • brain shrinks either due to formation of plaques (insoluble, round, thick pigment) within the cortical and subcortical regions; astrocytes surround them; also neurofibrillary tangles located throughout the axons, not in the soma (so they are extracellular)
  • a loss of connectivity field (less and less processes)
  • most common in females
  • COX1: increased in activated microglia
  • COX2: high levels in pyramidal neurons
48
Q

What are the effects of neuronal inflammation in Parkinson’s disease?

A

-causes the activation of alpha-synuclein which causes intracellular occlusions known as lewy bodies

when we age there is accumulation of ions that give us
melanin pigment that paralyzes the normal function of cells and those cells will die and be phagocytosed by macrophages or microglial cells
-it is motor deficit involving the striatum (loss of dopamine producing cells in the midbrain)

-most common in males

common symptoms include:

  • resting tremor
  • bradykinesia
  • muscle rigidity
49
Q

Why do African Americans (AA) suffer more than caucasians and hispanics suffer more than both AA and caucasians in both Alzheimers and Parkinsons?

A
  • due to metabolic disorders due to the foods we eat, lifestyle, obesity causing neuroinflammation causing release of cytokines in the body
  • epigenetic!
50
Q

Neuroinflammation appears to occur as a consequence of a series of damage signals, including what?

A

trauma, infection, oxidative agents, redox iron, oligomers of τ and β-amyloid, etc

51
Q

What is the major characteristics of of Alzheimer’s (AD) and Parkinson’s disease (PD)?

A

Chronic inflammation

52
Q

Studies in PD patients show evidence of augmented levels of potent pro-inflammatory molecules such as?

A

TNF-α, iNOS, IL-1β

53
Q

Experimental Parkinsonism has been consistently demonstrated that these are particularly vulnerable to activated glia releasing these toxic factors.

A

dopaminergic neurons

54
Q

Microglia, astrocytes and infiltrating T cells are known to mediate what?

A

chronic inflammation

  • the roles of other immune-competent cells are less well understood
  • Inflammation is a tightly controlled process
55
Q

What is neuroplasticity?

A

the more you do something over and over again you get better with it

  • refers to the moldable structure of the brain and nerves that results from changes in neural pathways and synapses
  • These changes stem from changes in behavior, environment, neural processes as well as changes from bodily injury
  • Age-dependent factor (Young dev. brains more plastic).
  • Occurs under two conditions (Normal development & In response to damage or disease.
56
Q

It has only been recently appreciated that the adult brain is capable of considerable plasticity.

Neurogenesis has been demonstrated in what areas of the brain?

A

plasticity can occur at organic or structural level, in muscular or in cellular level.

You can modify your behavior and stimulate your brain to produce more nerve growth factor to facilitate your learning. then with practice you will be more focused.

You can strengthen your weak neuronal connections

Neurogenesis occurs in hippocampus, olfactory bulb, and association cortex

57
Q

What is neurogenesis?

A
  • when you strengthen your synaptic connectivity by inducing the cell to fire several times, or the cell can form new processes increasing the activity of the neuron
  • Synaptic Plasticity is achieved through enhancing communication at the synaptic site between existing neurons, neurogenesis refers to the birth and proliferation of new neurons in thebrain.
  • Neurogenesis has become scientifically established and we know that it occurs when stem cells, (the dentate gyrus, the hippocampus and pre-frontal cortex), divide into two cells
  • Those new neurons will then migrate to distant areas of the brain where they are needed, and thus have the potential to allow the brain to replenish its supply of neurons.
58
Q

What is the neuroplasticity?

A
  • to learn new skills
  • to be efficient in communication
  • this is why we have speech therapy after stroke (increasing the plasticity of the area of brain that is damaged or the muscle)
59
Q

What are the positive outcomes of neuroplasticity?

A
  • New skills
  • Better cognition
  • More efficient communication between sensory and motor pathways
  • Improved function of the aging brain
  • Slowing down pathological processes
  • Promoting recovery of sensory losses
  • Improved motor control
  • Improved memory
60
Q

What are the negative outcomes of neuroplasticity?

A

-you have to train the patient in one specific function and you forget about the other functions of the patient (asking whether PD pts have pain)

  • Decline in brain function
  • Altered motor control
  • Impaired performance of activities of daily living
  • Amplified perception of pain
  • Neuronal cell death
61
Q

What are the structural changes and neuroplastic responses?

A

Change in neurons: (neuronal migration Neurogenesis)

  • Increased no. of neurons (hippocampus)
  • Increased dendritic branching
  • Increased efficiency in NTF production

Changes in Synapses: (Synaptogenesis/synaptic plasticity)

-Increased in no. of synapses between neurons

62
Q

T/F. Environmental contamination such as smoking will cause Neuronal inflammation, Cell Death and prevent neuronal plasticity!

A

TRUE!!

Chika- SF2 (63 decks)

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