Pathophysiology Exam 3

Describe the primary functions and distinguishing characteristics of neurons

Nonproliferative, electrically conduct impulses, shape based on: location, shape/morphology, NT, synaptic connections, functional tasks

Describe the primary functions and distinguishing characteristics of oligodendrocytes

Non-proliferative, myelinates neurons in CNS, one oligo can myelinate many axons, target cell for many diseases, myelinated axonal conduction is very fast

Describe the primary functions and distinguishing characteristics of Astrocytes

most abundant cell, supportive cell for neurons, can take up NT from synapses controlling intensity/duration, primary dysfunction in several neurodegenerative disorders

Describe the primary functions and distinguishing characteristics of Microglia

Macrophages of brain (M1 and M2), rapidly respond to nearby injury, secrete cytokines destroying infected neurons, viruses, bacteria, can cause collateral dmg

What is ionotropic neurotranmission?

Ion channels that open when a NT binds

What is metabotropic neurotransmission?

Non-channels causing signaling cascades that open other channels

If you see specific dendrites or neurons get larger, what can you conclude regarding the activity of the pre-synaptic neuron?

The pre-synaptic neuron released a prolonged amount of excitatory neurotransmitter which in turn causes the dendrite that receives it to enlarge.

What ion imbalance is most critical for excitotoxicity and why?

Calcium. Excitotoxicity is caused by prolonged exposure to excitatory neurotransmitters (Glutamate). Excitatory NTs cause a sustained influx of Ca2+ into the neuron which can lead to cytotoxicity and activation of caspases. The mitochondria can absorb too much of this Ca2+ and can release pro-apoptotic proteins.

Would amplifying GABA signaling attenuate excitotoxicity?

Yes, amplified GABA signaling would increase the amount of Chloride shifting into the neuron which would cause the voltage gated calcium channels to close, leading to a reduction to the amount of calcium in the neuron

What effects would a breach in the BBB have on CNS cells?

Glutamate/other substances in blood act as uncontrolled sources of NT, cytokines/complement from plasma enter CSN altering cell f(x) (can cause neurons more likely to fire and can cause cell death), peripheral immune cells enter CNS, fluids enter CNS lymph cant effectively compensate -> edema

Why is edema so bad in the CNS & what stresses cells out?

Swelling of ventricles/CSF compresses brain tissue -> ischemia/anoxia, causing dysfunction/death of CNS cells outright/after perfusion, cells stressed by inflammatory damage and high osmotic pressure.

What is a glial scar composed of and what important function could it serve?

Composed of reactive astrocytes, microglia, vasculature, scar ECM. Serves to help reestablish barrier function.

How would loss of pre-synaptic neurons affect synpatic plasticity?

The lack of a pre-synaptic neuron means that the receiving dendrite will not be receiving either inhibitory or excitatory NTs therefore causing the dendrite to undergo apoptosis

How would loss of inhibitory neurons affect synaptic plasticity

Lack of Inhibitory NT would cause the receiving dendrite to grow since only excitatory input is being received

How would loss of excitatory neurons affect synaptic plasticity

Lack of an excitatory NT would cause the receiving dendrite to shrink resulting in less activity in the post-synaptic neuron

How would disorder of trafficking receptors to synaptic membrane affect synaptic plasticity.

Impaired transport of these NTs can cause many affects to synaptic plasticity, the receiving dendrite could apoptosis, grow or shrink it all depends on how the body handles these out of control NTs

How would hypercalcemia affect synaptic plasticity

decreased neuronal excitability leading to the receiving dendrite to shrink

How does hypocalcemia affect synaptic plasticity.

not enough calcium to induce an action potential -> less excitability -> less NT being released -> shrink

How does astrocyte dysfunction affect synaptic plasticity?

Astrocytes are able to take up NT from the synaptic gap, if there is dysfunction more NT can stay in the synapse which means that the receiving dendrite will grow

How does oligodendroycte loss affect synaptic plasticity?

Less myelination -> less transmission -> shrinkage in dendrites

If an individual presents with ataxia caused by too little activity in the cerebellum, does this mean that the cerebellum will necessarily be the area of the brain with the primary defect?

Not necessarily, as regions of the brain can be influences by neurons in other brain regions, so although the ataxia is caused by little neuronal activity in the cerebellum, that is not necessarily the place with the primary defect.

Explain how mutations cause protein aggregation.

affects AA order -> changes interactions -> aggregation

How do changes in pH cause protein aggregation?

change in charge of protein -> changes interaction -> aggregation

How does ROS cause protein aggregation?

oxidation of AA side chains -> changes interactions -> aggregation

What is a prion-like domain?

Portions of a protein that have been misfolded and can act like a prion. Meaning it is able to interact with other normal proteins and cause them to destabilize and deform

Why might the CNS be disproportionately affected by protein aggregation & misfolding?

Astrocytes and Microglia are constantly surveying in the CNS, and are able to get rid of misfolded proteins before they get a chance to aggregate

What is the cause of dyskinesia that occurs in PD pts.?

Dyskinesia is usually caused by an excess of dopamine. A common treatment for Parkinson's disease is Levodopa, a medication that is converted into dopamine in the brain along with the slow deterioration of dopamine neurons causes high levels of dopamine leading to dyskinesia

What is the name and function of the protein implicated in PD?

Alpha-synuclein, found in pre-synaptic vesicles and dissociates when neuron fires. Helps in neurotransmitter release and receptor/transporter trafficking due to its ability to alter its conformation and reversible associate w/ membranes

Why this protein aSyn - What are overall risk factors for why this protein would aggregate?

Age, genetic mutations, inflammation, hypoxia, high conformability, etc

What reasons are known to stimulate aggregation of aSyn?

Increased concentration aSyn, overexpression -> more likely to be in conformation that can induce aggregation

How could you tell the difference between a pt. w/ Parkinson's dementia & vascular dementia?

§ Presence of tremors, presentation of hemiparesis, presence of vascular lesions

What are two major causes of vascular dementia?

Stroke and Hypoxemia (low O2 in arterial blood)

For a hypertensive individual w/ vascular dementia, can you treat them w/o complications w/ meds to reduce HTN?

Probably not, a hemorrhagic stroke is one of the main causes of vascular dementia, meaning that blood has exploded out of the vessels and is leaking into the brain. Normal treatment for HTN includes medication that is aimed to lower blood pressure, and with a hemorrhagic stroke (including microbleeds) may lead to hypotension.

Why are anti-coagulants used to prevent strokes?

Anti-coags are usually only used to prevent ischemic strokes as one cause of ischemic strokes is an embolus formed from platelets and fibrin. Anti-coags target these cells and prevents blood from clotting.

What are the three major sources of thrombi that cause ischemic strokes?

Fatty Deposits, Air Bubble, Thrombus from other parts of body (pooled blood in heart, heart valve, atherosclerotic plaque in carotid/vertebral artery.

Why is pooled blood in heart, heart valves, and atherosclerotic plaque in carotid/vertebral artery important in the thrombi for ischemic strokes?

· Pooled blood - usually clots, can break off travel through arteries and get stuck in the brain

· Heart Valve - tissue is highly thrombogenic, damage can expose this tissue and cause a clot to form

· Fat clot can form on these arteries and grow big enough to cause a blockage.

Where would you expect excitotoxicity to occur - the infarct core or the ischemic penumbra?

Ischemic Penumbra - although it receives less blood supply it is still metabolically active, where excess glutamate is still able to allow too much calcium into these cells leading to apoptosis

Describe all of the pathophysiological mechanisms for stroke.

§ Necrosis within ischemic core. No blood flow = 2-4 hr. neuronal viability

§ Lack of O2/Glucose in ischemic penumbra -> no ATP leading to:

· Failure of electrolyte pumps -> osmosis / cytotoxic edema (BBB intact)

· Excitotoxicity - ATP is negative, less ATP -> increased cations = hyperpolarization -> reach threshold easier -> release NT (glutamate)

· Cell damage / apoptosis: Ca2+ excess = more ROS + activation of Ca2+ sensitive enzymes -> degrade BBB + cause apoptosis

§ Necorsis / BBB Degradation -> neuroinfallmation

§ Reperfusion injury (ROS + excitotoxicity)

§ Ischemia + psi buildup from embolus => activates/compromises vascular endothelium (endothelium splitting)

· Vasogenic edema: compression of brain tissue, major cause of pt. death

§ What kills pts.?

· Vasogenic edema

What are the two malformations that increase the risk for hemorrhagic strokes?

Aneurysms + Arteriovenous malformations

Why are hemorrhagic strokes mostly subarachnoid.

Many blood vessels that are in the brain are located within the subarachnoid space. A subarachnoid hemorrhage occurs when a cerebral aneurisms within these vessels suddenly ruptures, and these vessels so happen to be located in the subarachnoid space

Why are hemorrhagic strokes more deadly than ischemic?

The blood that leaks from the vessels quickly spread through the brain and can cause vasogenic edema

Why do most embolic strokes occur in arterial capillaries?

Arterial capillaries have a much smaller diameter compared to arteries nearer the heart, so an embolus gets unlodged, travels through the blood stream and gets stuck in the smaller arteries.

How would you treat somebody who had a thrombus-induced stroke that then caused a hemorrhage?

Stop any anti-thrombolytic medications, if possible reverse the coagulopathy, treat HTN using medication to reduce bleeding, and reduce intracranial pressure

What is a nociceptor and what is its role in pain?

Receptors that respond to various stimuli (mechanical and thermal), they help the perception of pain by converting tissue damage into electrophysiological activity.

Describe the various ways/mechanisms descending pain modulation could affect the activity of a 2nd order projection neuron in spinal cord?

From the cortex, an inhibitory neuron can inhibit the 2nd order relay neuron, and an excitatory neuron can excite an inhibitory interneuron causing decreased pain, on the other hand, an excitatory neuron can excite the 2nd order relay neuron and an inhibitory neuron can inhibit the inhibitory interneuron causing an increase in pain.

What order of neurons would be causing peripheral neuropathic pain?

First-Order

What order of neurons would be causing spinal cord injury pain?

Second Order

Describe the two ways neurons reorganize after an injury that may result in pain?

§ Reorganization - extend axons and dendrites to areas they weren't in before

§ Sprouting - axon increases number of synapses w/ other neurons

How can sprouting and reorganization cause increased pain?

· Sprouting - can extend to 2nd order relay neuron despite inhibition and cause pain

· Reorganization - newly formed neurons can be sensitive to NTs -> pain

Is neuropathic pain nociceptive pain?

No, nociceptive pain is derived from an external stimuli, whereas neuropathic pain is derived from damage to the nervous system itself.

Compare (+) and (-) symptoms of schizophrenia.

§ (+) - development of symptoms not present in normal individuals; psychosis, delusions, hallucinations

§ (-) - reduction in something that is normal; anhedonia (lack of feeling of pleasure), social withdrawal, lac of motivation

What is the evidence for the dopamine hypothesis for schizophrenia?

Increase synthesis, release, concentration of dopamine in SCZ brains

What are the hypothesized roles of Cdc42 & Cdc42EP3 in schizophrenia?

§ CDC42 - spine formation/enlargement

§ CDC42EP3 -inhibits CDC42, no spine strengthening, higher in SCZ

Are there more or less spines in SCZ?

Less

What do monozygotic and dizygotic concordance rates reveal about schizophrenia and depression?

Strong genetic link to SCZ and depression

Why is more 5-HTR1A implicated in depression, which is not enough serotonin signaling?

5-HTR1A acts as a break for serotonin, preventing its release. So more 5-HTR1A means less serotonin is being released from pre-synaptic neurons.

What is the mechanism by which the l and s alleles of the 5-HTT contribute to depression?

Homozygous ss more likely to see symptoms of depression, short version not as transcribed as l -> less mRNA -> less 5HTT -> more serotonin in synapses -> more sensitive to stress/anxiety since body used to low serotonin

Would an osteocyte sensing mechanical strain that required new bone growth be more likely to secrete RANKL or OPG?

OPG - Secreted to dampen the effects of RANKL reducing bone reabsorption

Why would inflammatory cytokines cause RANKL and OPG production simultaneously in bone?

To speed up the process of bone reformation, RANKL promotes the activation/differentiation of osteoclasts, and OPG ensures that is doesn't do too much.

In a patient w/ osteoporosis, would inhibitors of OPG benefit the pt.?

No as that would mean nothing is stopping RANKL from reabsorbing bone

Name all factors that induce RANKL and OPG and what effect they have on bone resorption and formation

§ RANKL: ILs, TNFa , PTH, Prostaglandins, Glucocorticoids

§ OPG: ILs, TNFa, TGFb/BMP2, Estrogen, Leptin, mechanical strain

Given the effects of inflammation on bone resorption would you give glucocorticoids to individuals w/ chronic inflammation at risk for osteoporosis

It is an option but dosing must be carefully monitored as since glucocorticoids can target the inflammatory cytokines reducing their effectiveness and in turn can help with osteoporosis, glucocorticoids themselves can decrease calcium absorption and induce bone reabsorption which can lead to osteoporosis.

Would a mutation in the estrogen receptor that reduces the affinity for estrogen be good or bad for osteoporosis risk? - why or why not?

Less estrogen -> less OPG -> more RANKL -> osteoporosis

What occurs to joints w/ RA?

Destruction of articular cartilage via inflammation, as cartilage breaks down -> bone touches bone -> injury/inflammation worsens

What is RF and how do they contribute to RA?

RF - Rheumatoid Factor, IgM,IgE,Iga bind to IgG forming complexes, not suficent enough to cause RA, but it can be used as an indicator for RA.

What are ACPAs and how do they contribute to RA?

Anti-citrullinated protein antibodies - auto-antibodies that form against citrullinated proteins. These antibodies attack cintrullinated proteins which drives inflammation which leads to RA

Describe protein citrullination and why this raises the risk for RA

Deaminated arginine -> citrulline, this makes the immune system misidentify them as foreign, leading to an immune attack causing inflammation -> RA

What is the role of HLA-DRB1 in protein citrullination

Increases risk for RA, these genetic variants have higher affinity for citrullinated proteins. These proteins act as auto-antigens leading to thymus dependent B-cell activation.

Why does smoking increase the risk for RA?

Smoking increases amnt of molecules that have high affinity for HLA-DRB1 variants -> display molecules to CD4 -> activation

Describe the trends in the genetic risk factors for developing RA.

Presence of genetic risk factors leads to higher chances of developing RA

What alterations in blood volume and pH might you expect in a patient with a fibrotic kidney?

Impaired kidney function -> impaired Na+/H2O excretion -> increased blood volume + decreased pH (kidney can't excrete H+)

By what mechanism would renal dysfunction contribute to vitamin D imbalances and pH imbalances

The final stage of VitD synthesis happens in the kidney, if the kidney is impaired and cannot metabolize VitD precursor into VitD -> VitD deficiency. An impaired kidney cannot efficiently excrete H+ leading to a decrease of pH in the body

Heart failure increases sympathetic tone, what effect would this have on the kidney?

§ High sympathetic tone -> vasoconstriction of renal arterioles -> lower GFR.

§ Extensive activity of RAAS -> vasoconstriction

§ Improper Na+/H2O excretion -> increased blood volume

Damage to which area of the kidney (and what cells specifically) would cause anemia? Why?

Damage to interstital fibroblasts located around renal tubules. Interstitial fibroblasts create EPO in response to low O2 -> stimulated RBC production in marrow. Damage -> no EPO -> low RBC production -> anemia

What is pre-renal AKI?

Prerenal - assoc. w/ blood entering the kidneys. Decreased blood vol entering kidney -> decreased hydrodstatic psi. of glomerulus -> decreased GFR -> buildup of products usually excreted

What is renal AKI?

Direct damage to kidneys: inflammation, toxins, drugs, infection, reduced blood supply

What is post-renal AKI?

obstruction of urinary outflow, usually no dmg if caught early.

o What is the mechanism and pathophys of contrast induced nephropathy?

§ Dyes used for in vivo imaging toxic to kidney.

§ Ischemia - contrast media injection -> increased renal blood flow -> long term decrease. Vasoconstriction to vessel supplying blood to medulla. Contrast media injection -> thickens blood -> slower O2 delivery to renal medulla -> worsens ischemia

§ ROS

· Medullary hypoxia -> increased ROS in mito

§ Tubular cell toxicity

· Increased oxidative stress -> mito/DNA dmg -> apoptosis/necrosis

What are the effects / molecular mechanisms of NSAIDs affecting renal function

inhibit COX2 -> less PGE2/I2 -> less vasodilation of afferent arteriole -> less blood to glomerulus

What are the effects / molecular mechanisms of ACE-inhibitors / ARBs affecting renal function

Ang II constricts efferent arteriole out of glomerulus compensating for low blood flow. ACE-Inhibitors prevent the creation of Ang II and thus the efferent arteriole relaxes -> reduced blood fow to glomerulus -> decreased GFR -> build-up of should-be excreted materials -> renal damage

What drugs cause acute tubular necrosis (ATN) and by what mechanisms do they do so?

Aminoglycosides by inhibiting bacterial protein synthesis by binding to the 30S ribosomal subunit.

What are the distinguishing mechanisms and characteristics of ATN vs AIN?

§ ATN: Direct damage to tubular cells -> injury / cell death, majority of cases caused by ischemia / exposure to tubule toxins

§ AIN: Severely inflamed interstitium, immune mediated processed attributed to drug, infection auto-immune disorder.

What effects does ATN have on renal cell polarity and what processes would be affected by this?

Na+/K+ ATPase pumps translocated which would cause -> impaired active transport, reduced GFR

What effect does pH have on the solubility of calcium oxalate and how would this impact the development of a kidney stone?

Increased pH would cause calcium oxalate to be less soluble leading to increased risk of renal calculi