Exam 3 Flashcards
(111 cards)
1
Q
Multiple Sclerosis
A
Secondary disorder
2
Q
Glial cells of the brain: Oligodendrocytes
A
3
Q
Multiple Sclerosis (MS)
A
-Blocks messages being sent to CNS
4
Q
Epidemiology
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- Most common inflammatory neurological disease
- 600,000 live with MS
- no direct genetic link
- More woman have MS than men
- immune disorder,
- If a women becomes pregnant with MS it will lessen the symptoms of MS
5
Q
MS more common in the northern hemisphere
A
- More north you move from equator, increased risk of MS
- Possible Vitamin D deficiency
- In the first 15 years, location of living is correlated with MS
6
Q
MS presentation
A
- Characterized by lesions in the white matter, can spread to dark matter
- can use MRI to accurately diagnose MS, have to be at least 5mm
- can get lesions in a lot of different places, site of lesions affect symptoms
7
Q
MS presentation symptoms (video)
A
big three
-Dysarthria (plaques on brain stem)
difficulty speaking, movements,
-Nystagmus (plaques on nerve of eyes)
Intention Tremor- smaller, limited to one area
8
Q
Other plague locations and symptoms
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-plaques in Sensory Pathways from Skin
9
Q
Patterns of MS
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-Typically progresses in one of four patterns
1- Relapsing-remitting MS (RRMS)
–Symptom flare-ups (relapse) separated by periods of remission where most symptoms resolve spontaneously
10
Q
SPMS
2- Secondary progressive MS
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symptoms worse gradually overtime without remission periods in between
11
Q
Typical MRI and clinical progression of MS
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Relapsing-remitting phase- have symptoms that spike and plateua, lossing ability to repair oligodentrocytes
-secondary progressive phase- brain volume decreases greatly, no more remission, can’t repair oligodentrocytes
12
Q
MS most likely caused by a mix of genetic and environmental factors
genetics
A
-Some evidence for genetic cause due to familial MS risk, identical twins (one have MS, 33% other might
might be slight but definitely not
13
Q
Genetics of MS
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- HLA-DRB1*1501 allele increases disease risk up to threefold
- links the disease to T-cell functionality
- adaptive immune system
- strongest genetic risk
14
Q
Environmental links to MS
A
-Smoking increases risk of MS twofold in women and threefold in men
-decrease in men’s smoking rate sufficient to explain the increase in female to male ratio of MS
- Vitamin D deficiency- humans can synthesize vitamin D in the skin (requires light)
Lower level of vitamin D correlate with increased risk of MS
-Fish can provide vitamin D
15
Q
Myelination
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oligodendrocytes in CNS wrap around dendrocytes, donating lipids,
16
Q
Myelin organization
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flatten sheets that wrap around axon, there is cytoplasmic reigon but as it flattens some cytoplasm is squeezed out so it’s mostly lipids.
MBP holds membranes together
PLP is transmembrane and spanes the membrane,
membrane aids in electrcal signaling
17
Q
Myelination
A
-everytime there is an action potential, you change the membrane potential, this changes the charge of the membrane which triggers membrane voltage gated channels
- the nodes: helps to ancor the voltage gated channels in that region
if you lose myelin sheet, you lose the localization at those channels, you’d have to keep it going instead of it having little breaks(or skipping)
18
Q
Demyelination is a hallmark of MS
A
Overall losing myelination
19
Q
Cellular hallmarks of MS
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-Inflammation, glial activation and axonal damage are also histopathological makers of the disease
20
Q
What causes demyelination?
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-The bodies immune system attacks the myelin proteins leading to their degradation
21
Q
Immune system review
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-Adaptive immunity
22
Q
Adaptive immunity is dependent on lymphocytes
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different B cell to recognize one specific antigen
same with T cells
23
Q
Lymphocytes are activated by helper T cells
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CD4+
24
Q
Activated B cells become antibody secreting plasma cells
A
25
Cytotoxic T cells: Cell-mediated response
recognize infection inside of cell, causes cell's to lyse
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What causes demyelination?
1) An autoreactive (attacking something from body) CD4+ cell is reactive to myelin (oligodendrocyte)
-might occur becomes of trauma, or an antigen that is very similar. Another theory is that during the formation of the CD4+ cell, something went wrong
2) Activation of CD4+ and CD8+ (lyse bad cells) cells which move into the brain (very difficult for them to do, why there might be trauma) , also reactive to myelin. CD4+ cells activate microglia which release cytokines(inflammatory signals which further damage oligodendrocytes)
Both cells start to act to destroy oligodendrocytes
T cells are thought to be the biggest part of this
B cells come in later to target and cause phagocytosis
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Remyelination
Periods of remission can be accounted for by phases or remyelination
Oligodendrocyte precursor cells
precursor cells move to areas where
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Regenerated myelin is thinner but effective
- fully allows for saltatory conduction to occur once more
- provides tropic factors to the axon to promote survival (growth factors that are pro survival, more they have, stronger they become) if you lose these factors, causes degeneration and makes it harder to remyelinate
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Repair mechanisms diminish as the disease progresses
decline of time between symptoms
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loss of myelin can result in axonal damage
Axons themselves start to break, macorphages take apart axons, and you lose brain volume, gray matter
The myelin provides tropic factors promoting axonal health
-Toxic signals released from activated microglia and macrophages (cytokines, NO, glutamate) can also damage axons
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Current treatment options
supportive care- just making life easier
disease modifying drugs-
experimental therapeutics- drugs that have made it too drug trails
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Supportive care
Different for all patients
-depends on where dyemylination has occurred
Glucocorticoids
- steroids that dampen immune response
- Anti-inflammatory
- Decrease cytokines production (less overall inflammation)
- inhibits T cell activation(some early response is dampened so less early on)
- Cannot be taken long term
Spasticity
- GABA agonist (Baciofen)
- Inhibits acetylcholine release to decrease muscle contraction
- muscle spasms, increase GABA to decrease acetylcholine
Depression (decrease in serotonin)
- SSRI-serotonin reuptake inhibitors
- Keeps serotonin in the synapse longer
- doesnt let it go back in the cell to be reused
Sexual Dysfunction
-viagra
-acts as vasodilator
-
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Disease-modifying drugs
-Chronic treatments that attempt to change the course of the disease
Interferons
- IFNB is a naturally occurring cytokine which down-regulates immune response
- is an anti-inflammatory (dampens the immune system)
- can decrease T-cell activation
- Helps prevent passage into the Blood Brain Barrier
- decreases B cell response
- Are essential just small polypeptides (should be cheap bc they are easy to make
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Disease modifying drugs
Glatiramer acetate (GA)
- it competes for the binding site, so it will prevent but not lead to activation
- Suppresses T-cell activation
- Competitvely binds
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Natalizumab
- Blocks a4b1 integrin on T-cell that is required for entry into the brain
- inhibits movement of t-cells into the cns
- lymphocytes have receptor (a4b1 integrin
- it prevents protein-protein interaction, prevents T-cells from being able to move outside the PNS
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Experiemental approaches: Na+ blockers
-dosage is finicky
-can't stop all Na+ channels as that can be very deadly
There is a persistent Na+ influx
(if you can selectively inhibit the Na+ channels on affected oligodendroyctes you could decrease excitotoxitity
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Vitamin D (experiemental)
Semi-mature DC make naive CD4+ cells that have anti-inflammatory, this is what vitamin D helps to do
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Stem Cells (Experimental approaches
research in general is very difficult to do
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Experimental approaches: HSCT
-Stem cells present in spine or bone marrow?
Lymphoid progenitor
-Hematopoietic stem cells
used through transplantation, you have autoactivated T cells(which have memory), so if you get rid of them you get rid of that memory
So what they do it do low doses of chemotherapy that causes stem cells to leave bone marrow and enter blood stream, separate stem cells from blood then wreck the immune system and put stem cells back in body
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Experimental approaches: NPC transplantation
- Introduction of induced neuroprogenitor cells
- can differentiate into oligodendrocytes, neurons and astrocytes
- Replace damaged cells in brain to relieve symptoms
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Metastatic (secondary) brain tumors
-Lung and breast cancer most likely to metastasis
Don't tend to metastasis further in the brain as a secondary tumor
If you have multiple secondary tumors, they are all independent from primary tumor
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Primary CNS tumors
-Cancers originating and typically remaining in the brain
Named based on cell type of tissue they are affecting
Medulloblastoma- most common in childern
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Distribution of primary brain tumors
Glioblastoma
Astrocytoma
Oligodendroglioma
make up 1/3 of all brain tumors
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Gliomas (focus of our lectures)
-caused by multiple gene mutations
| not inherited
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Common symptoms of brain cancer
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Headaches
nausea or vomiting
seizure
confusion and issues with self-identity
sleep-wake distrubances
hearing loss/ issues and issues with balance
issues with the vision
differential symptoms depending on where tissue is
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Pathological hallmarks for cancer staging
- Atypical cellular appearance
- nuclear atypical
- mitotic activity
- newly formed blood vessels (tumors do this late stages)
- evidence of dead tissue
tumors do need oxygen,
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Patient survival for gliomas
not good
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Cells of origin for brain cancers
cancers are going to a rise from
Neural stem cell population, also want to maintain stem cell niche
However if you have mistakes (mutations) creation of glioma,
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Cancer stem cells
-tumors are heterogeneous in nature
CD133+= going to refer to as cancer stem cell, can also form blood vessles
+ cells cause cancer
- cells dont
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What controls cell proliferation?
cell cycle
oncogenes promote cell growth, basically has a bunch of growth factors,
turns on signaling cascade after binding
Tumor suppressor genes negative regulators to cell growth (p53
will stop cell cycle to ensure there are no errors)
Two forces that act at the same time, to regulate the rate of the cell cycle
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What Controls cell proliferation? (2)
Oncogenes enhance proliferation however mutations in brain tumors (gain of function)
-more signaling proteins,
or point mutations, ensures that signal occurs whether or not there is a ligand present of not. Possible mutation that causes dimers?
Rass- numbered one mutated gene for cancers, this decreases hydrolysis ability, meaning they are always active and signaling downstream
point mutations can be present anywhere on the cell cycle
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What causes abnormal cell proliferation?
Tumor suppressors mutations in cancer (loss of function)
-both alleles must be mutated to lose growth control
are regulatory, if theres a stop in the cell cycle, usually bc of tumor suppressor
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Signaling pathways common in cancer
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common pathways that you see mutations in, top box is proteins that are mitogene activated
RB pathway- retnablastoma
RB1 can inhibit cell cycle
senescence-cell can no longer divide
oncogenes are proliferation genes
There is multiple levels of regulation
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54
Tumor Invasion
-spread extracellularly opposed to intravascularly
-Poses unique challenges for invading tumor: aided by matrix metalloproteases
geloma's are the most oppressive
once brain tumors are there, they dont tend to migrate, this might be bc there usually isnt vascular trail, just through the tissue itsself
possible linking of tumor cells, move together
One way tumors get through tough extracellular matrix is that they secreate proteases that
55
Glioma invasion in extracellular space requires changes in cell shape and volume
To squeeze through the extracellular space glioma cells change their cell volume and shape through the use of ion channels
-ion intake and osmosis increases the volume of the leading edge
-ion effiux and osmosis at the trailing edge
change 30% of its volume to squeeze through tight places
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Glioma invasion occurs along four major routes
we're only gonna take about Brain Parenchyma and blood vessels
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Growing tumors require nutrients from the circulation
(called co-option) most tumors start on a blood vessel, brian cells dont store glucose of a lot of ATP
movement away, like making a secondary tumor, gliomos increase angiogenesis which is increasing new blood cells
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Tumors secrete VEGF to enhance vessel proliferation
loss of oxygen starts in tumor, this starts VEGF to increase blood vessels
targeting of VEGF has been attempted in clinical trials but was unsuccessful in increasing patient survival, this is bc instead of making larger masses, it started cell dispersion to create more masses near other blood vessels
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New vessels are required to provide glucose to tumor cells
cancer cells really only need glucose, they dont use oxidative phosphorylation
glucose goes through glycolysis, and with or without oxygen, it always does fermentation, so they only make 2 ATP instead of 34 ATP, this is Warburg effect
This might be bc Warburg effect retains carbon, which is needed to make macromolecules, so for a cell that is constantly making new cells
60
Glutamate role in glioma
Glutamate plays a role in invasion of glioma cells, if you measure glutamate around tumor cells, theres like 100-fold higher
Can act on cells in a disregulated form, it disrupts cell interactions
moves astrocyte away from tumors, which means glutamate cant be removed
which then causes extreme excitotoxity bc of an increase of calcium in cell
this damages the entire cell, so you end up with necrotic cell death
This is another way tumors make room, they just kill other cells
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glioma cells have mechanismas to prevent excitotoxic cell death
Glutamate is toxic to cells but not really the glioma bc they have a transport system that transports glutamate out while transporting cysteine into the cell, which makes glutathione(antioxidants, donates electron), which prevents oxidative damage (acts to neutralize)
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Sulfasalazine inhibits transporter system Xc
Trageting SXC patheay to stop glutamate from being released from glioma cells,
it did show decreased glutamate and decreased glioma growth (in nine patients) it also reduced seizures in these patients
having so much excess glutamate release results in seizures
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Tumor treatments: Surgical resection
Meningiomas are usually benign, also can be removed
| Gliomas are much more difficult to remove, hard to figure out what is tumor and what is brain
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Tumore treatments: Surgical resection
Blood brain barrier becomes weaker, Sodium Fluorescein guidance, tumor creates new blood vessles that are weaker (BBB) so the tumors glow
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Tumor treatments: Radiation
Damages DNA, halts cell division, can lead to apoptosis
anything localized to the location will be affected
can do whole brain or selective
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Tumor treatments: Chemotherapy
Attacks any cells that are dividing in the body
adminerastered via IV
Theres a lot of different chemotherapy drugs
It could active the immune system that signals for cell death to happen
Microtubules are also a target, spindles important in cell division, some cause proliferation, while somes stop proliferation (them degrading)
Affected DNA replication in S phase
IN mitochondria,
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Chemotherapy: Temazolamide
Currently the best chemotherapeutic for glioma treatment
Extends life like maybe 8 weeks
It causes DNA damages
what is interesting is that on average 8 weeks, some ppl years
in people who survived years, they had weaker DNA repair in general (they had Methylated MGMT promoter)
68
Schizophrenia
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Form of phycosis
Very serious mental disorder
-combination of hallucinations, delusions and extremely disordered thinking
Requires lifelong treatment
for about 50%, the drugs work
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Epidemiology
2.2 million living with disorder in just the US
alot of times they will need life long care
-at anytime however, 300,000 hospitalized
-about 200,000 homeless
Age of onset 18-25
Some famous like painter of scream
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Schizophrenia has been described worldwide
- in 2011, estimates that worldwide 21 million cases
| - Culture has an effect manifestation and stigmatization
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Schizophrenia symptoms
Cognitive- work, trouble thinking, poor memory, difficult to concentrate
Positive- the present of thoughts and perception, Hallucinations and delusions, paranoia (these come and go, compliance with medications)
Negative- Absence of thoughts and perceptions and behaviors in ordinary ppl, lack of emotional expressiveness, speech fluency, experience of pleasure
Everyone with schizophrenia is unique symptom wise
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Schizophrenia brain tissue loss
cant be used for diagnosis, not usually so produced
| -there is some tissue loss, however, postmortum show no glial cells and dendritic processes affect
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Rate of gray matter loss
might be loss of gray matter in schizophrenic subjects but usually only post-mortun
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Schizophrenia brain
anterior cingulate cortex- being able to focus on one individual thing
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Autopsy Markers of schizophrenia
Can not be assessed until person is dead
-affects many neurotranmitters
Decrease of alpha-1 subunti of the GABA receptor
Decrease in synthesis of GABA
Decreased dopaminergic innervation in the prefrontal cortex, this is the reward and pleasure center
Decrease NMDA receptors (glutatmate)
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Schizophrenia genetics
Not mendelian trait
-So twin has 40% of developing schrizophrenia
Think there might be some genes that lead it is but they think there might be a trigger bc it is not 100% genetic
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Schizophrenia-associated Genes
Deleted in schizophrenia complex 1
-help in cell migration of nerves, aids in arborization (synapses), been found in mouse models to aid in memory and gray matter(to not be reduced)
Neuregulin and ERBB4
both aid in synaspe formation,
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DiGeorge Syndrome linked to Schizophrenia
-3.3megabase deletion of chromosome deletion chromosome 22
| 1 in 4000 newborns -of those 1.4 will develop schizophrenia
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Deleted Genes in DiGeorge Syndrome
Homozygous deletion of Genes on chromosme 22
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Schizophrenia-associated genes
Catechol-O-methyltransferase (COMT)
-Enzyme that degrades catecholamines (dopamine, epinephrine and norepinephrine)
-degrads cluster of neurotransmitters
-
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disease of neurotransmitters
Disease involving multiple neurotransmitters,
| no clear mechanism for the development of schizephrenia
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Dopamine Hypothesis
-enhanced dopamine functioning is responsible for most of cardinal symptoms (positive symptoms)
-Anything that is added to individual
increase dopamine
-reduced reuptake
-decrease GABA
-inhibit enzymatic degradation
-increase the amount of dopamine receptors
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Psychosis can be caused by increased dopamine
-anything that activated dopamine signaling can cause psychosis
-patients that are treated with high-levels of levodopa can cause psychosis
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Antipsychotics act as D@ receptor antagonists
Dopamine does play a role in the development of psychosis
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Heightened dopamine synthesis
Associated with schizophrenia, red/orange sections show increased dopamine synthesis
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Dopamine pathways-VTA
-Start in Substantia Nigra,
helps to give emotions to experiance
the more times the nucleus accumbens gives emotion to a sceneria, the more reinforced
in schizophrenia- you have incorrect assignments for different narratives (getting pizza and being scared)
unable to distinguish between internal and external stimulus
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Glutamate hypothesis
- a reduced function of NMDA receptors, shows both positive and negative symptoms
- postmortem analysis shows loss of NMDA subunits
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Silencing NMDA receptor induces schizophrenia symptoms
prevents Ca from entering cell, which stops glutamate form entering cell
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Glutamate hypothesis pro and cons
- Glutamate signaling complex
- con 90% of glutamate signaling
- pro- explains both positive and negative symptoms
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The GABA hypothesis
Has been correlated with 23-30% decrease in GABAergic interneurons
-an overall decrease in GABA
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Gamma oscillations
Kinda like pace maker of brain, you can disregulate them to cause seizure
have consant flux of excitation and inhibition
rhythmic oscillations
Important for binding information together
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Decreased gamma oscillations
- potentially less binding of narrative coming together
- harder to make coherent thoughts on a situation
- important for cognition, so decreases can cause cognitive defect
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All three hypotheses could act together
-its possible to need changes in all three pathways, neurotransmitter pathways are all connected
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synaptic changes in schizophrenia
structural change happens, synaptic pruning,
| rate at which spines are diminished is increased
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Pruning of spines occurs through early adulthood
Explain graph
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Schizophrenia Treatment
anti-psychosis drugs- made to decrease dopamine
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Addiction
didnt take notes from last class except for a little in studybook
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Plasticity drives drug tolerance
Take drug you become dependent on, so you don't get as much pleasure as before so you increase the dost, which again changes your brain chemistry, so its a cycle,
Your brain plasticity is what allows your brain to change
This is how overdoeses happen, the dose for pleasure increases but the lethal does does not
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Withdrawal
Physiological response to cessation of drug exposure
- varies from drug to drug
- can drive a pathological craving to eliminate negative withdrawal symptoms
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memories of the reward can result in relapse
Going through withdrawal and then some type of life stressor happens or you go to places that remind you of the drug
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Drug addiction: Alcohol and LSD
One legal, one illegal
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Alcohol
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-Produced by the fermentation of sugar
Evolutionarily used in the preservation perishable fruits
-today a common beverage
Prevalence of use in the US
-73% of men
-66% of women
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Its an individual bases, some people have addictive personalities
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Alcohol use disorder
Defined through he DSM-5, but most simply stated:
| -Excessive drinking that interferes with a productive life
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You may have an AUD if you can answer yes to two or more of these questions
A bunch of problems
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COVID effect on Alcohol Consumption
Isolation might have caused an increase in drinking (60.14%)
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Causes of Alcohol-Related Deaths
Takes a while to actually kill you, unless you binge drink it (alcohol poisoning)
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Ethanol
-Depressant
-Effects all tissues because it is able to freely pass through membranes
-Multiple neurotransmitter systems affected
Ethanol by itself is what things are dissolved in, so increase in what it can interact with,
It can also defuse through cell membranes, it is not cell specific
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How alcohols affects the brain, ethanol is solvent
Cerebral Cortex: Affect higher thinking, executive function, decrease in reason, speech, lack of inobition, blurred vision
Hippocampus: Loss of memory, drinking in extremes can mess up longterm ability to learn
Cerebellum: Being wobolly, you can't walk straight,
Medulla: Lower heart rate, could lead to coma
Central Nervous System: Decrease function, acts as a depressent
Hypothalamus: Mess up of homeostatic functions of glands, 4 things-fighting, fleeing, feeding, sex. Decrease of heart rate
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Affects of alcohol on neurotransmissio
hyperpolarizes the cell
NMDA-> acts as an antagonist
One way the body tries to deal with them, your body makes more NMDA receptors in the brain,
withdrawal can cause seizures bc of calcium flooding when theres no ethanol to inhibit glu
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Ethanol Metabolism
Set amount of acetaldehyde dehydrongenase
| Build up of ethanol, so it takes time for enzyme to break down
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Alcohol use disorder treatments
Most effective
-Alcoholics anonymous
Disulfiram
-Compliance issues are common,
causes build-up of acetaldehyde which makes you extremely sick
