Exam 1 Flashcards
What is the definition of a stroke?
Physiological condition which occurs when the blood supply to part of
the brain is interrupted leading to insufficient supply of oxygen and
nutrients to the area
How do strokes first present?
Alteration in consciousness ■ Headache ■ Aphasia ■ Facial weakness or asymmetry ■ Incoordination ■ Ataxia ■ Visual loss, vertigo, double vision, unilateral hearing loss, nausea, vomiting, photophobia, phonophobia
What does the FAST mean?
F- face dropping
A- arm weakness
S- speech difficulty
T- time to call 911
What are the different types of strokes?
Focal Ischemic
Global Ischemic
Hemorrhagic
What is a Focal Ischemic stroke?
Is the result from vessel occlusion which causes a focal defect
Ct scan shows Edema presents with reduced density
(darker region)
How is acetylcholine affected with AD?
Changes neurotransmission. ■Decreases in acetylcholine in AD patients – Choline acetyltransferase synthesis decreases – Loss of neurons in the basal nucleus of Meynert decreases projections – Common treatment in AD are acetyl cholinesterase inhibitors, drugs keep it around longer in neuron so that you end up with same amount, works early on
What is a Global Ischemic stroke?
It is the Global reduction in blood flow (for example through cardiac
insufficiency
What is a Hemorrhagic stroke?
It is the Rupture of a blood vessel
A CT scan shows Iron in blood absorbs Xrays- creates hyperdense
white region
Why is lack of blood flow so detrimental?
■ Brain consumes massive amount of energy to maintain ion gradients! – But only stores a 120 second ATP supply – And neurons have no glycogen storage – Evolutionary trade off: increased neuronal number but constant need for nutrient perfusion
What generates the most ATP?
Oxidative phosphorylation generates the most
ATP, requires both glucose and oxygen which is delivered through the circulatory system.
ATP usage is in neurons
What provides the brain with oxygen and glucose?
Cerebral vascular provides the brain with
glucose and oxygen
Diffusion requires vessel to be within 50um of
neurons - Lots of capillaries!!
What is the typical clotting cascade?
bleeding happens- clotting factors- Prothrombin- Thrombin- Fibrinogen (soluble)- Fibrin(insoluble)
What is the typical cascade of clot degradation?
- TPA (a clot buster and FDA approved treatment of stroke)
- Plasminogen- plasmin
3.Fibrin- degraded
clot breaks up
What are the two types of blood clots?
■ Intrinsic
– Triggered by internal damage to the blood vessel
■ Extrinsic
– Triggered by trauma
– Of interest for stroke because of atherosclerosis
What is Atherosclerosis?
Build up of fatty deposits in large
and medium-sized arteries leading
to the formation of plaques
■ Severe build-up blocks blood flow
What is the Pathogenesis of plaque formation?
■ Foam cells weaken the arterial wall
■ Smooth muscle cells invade the plaque and form a fibrous cap
■ If the cap ruptures, an embolus is released, travels through the blood stream
– If it gets stuck- ischemic stroke
What is the Ischemic Cascade?
Theres a flow disturbance Rapid: O2 depletion energy failure terminal depolarization ion homeostasis failure
Secondary:
excitotoxicity
SD-like depolarizations
disturbance of ion homeostasis
Delayed:
inflammation
apoptosis
The Ischemic Cascade leads to what?
O2 and glucose
depletion lead to energy failure
■ ATP cannot be synthesized in adequate amounts
Loss of resting
membrane potential
■ Na+/K+ stops functioning
– Resting membrane potential slowly lost
What is Terminal depolarization in the ischemic cascade?
■ Neurons hit depolarization threshold within minutes ■ Unregulated action potentials begin
What is the Calcium influx in the Ischemic Cascade?
■ Action potential initiates the opening of the voltage-gated Ca2+ channel at the axon terminal – Further depolarization of the neuron Look at slide
What causes Neuronal death?
Neuronal death in the core results primarily from edema and necrosis ■ As ions enter the cell, osmosis occurs leading to cell swelling (edema) ■ Cellular membranes are ruptured ■ Necrosis ensues
(Mitochondrial damage, cell membrane disruption, production of free radicals, cytoskeletal breakdown, and DNA fragmentation)
What causes Neuronal death?
Neuronal death in the core results primarily from edema and necrosis ■ As ions enter the cell, osmosis occurs leading to cell swelling (edema) ■ Cellular membranes are ruptured ■ Necrosis ensues
What is the Ischemic penumbra?
■ Ischemic penumbra- tissue surrounding the core that is perfused insufficiently by collateral vessels ■ Focus of intervention strategies – Can be saved if perfusion occurs within 6- 24 hours Excitotoxicity leads to cell death in the penumbra
What are treatments for strokes? (tPA)
■ Intravenous administration of tPA protein to
promote clot breakdown
■ Must be administered within the first 4.5
hours
What are treatments for strokes? (Mechanical thrombectomy)
■ Angioplasty
■ Physical removal of the clot
through endovascular surgery
with a stent
What is an experimental stroke treatment?
NMDA blocker
look at slide
What is action potential?
Electrical signals travel down the axon as
ion channels open and close
Every cell has a voltage (difference in electrical charge) across its plasma membrane called a membrane potential
■ The resting potential is the membrane potential of a neuron not sending signals
What is resting membrane potential?
Maintained predominantly by the potassium leak channel
– Aided by sodium leak channel and Na+/K+ pump
Gated ion channels are responsible for electrical signaling
What is hyperpolarization?
The inside of the cell more negative
– For example, K+ exiting the cell or Cl entering the cell
Graded hyperpolarizations produced
by two stimuli that increase
membrane permeability to K+.
What is depolarization?
The inside of the cell becomes more
positive
■ For example, Na+ channels open and
Na+ diffuses into the cell
Graded depolarizations produced
by two stimuli that increase
membrane permeability to Na+.
What is action potential concerning polarization?
An action potential is an extreme depolarization
of the neuron
(c) Action potential triggered by a
depolarization that reaches the
threshold.
What is the first step of an action potential?
Resting state: Voltage gated Na+ and K+ channels are closed; resting potential is maintained by ungated channels (not shown).
What is the second step of an action potential?
Depolarization: A stimulus (ligand) opens some Na+ channels; if threshold is reached, an action potential is triggered.
What is the third step of an action potential?
More Na+ channels (voltage gated) open, K+ channels remain closed; interior of cell becomes more positive. Membrane polarity becomes the reverse of resting state. 3
What is the fourth step of an action potential?
Repolarization: voltage-gated Na+ channels close and inactivate; voltage-gated K+ channels open, and K+ rushes out; interior of cell becomes more negative than outside.
What is the fifth and final step of an action potential before the resting state?
The voltage-gated K+ channels close relatively slowly, causing
a brief undershoot.
Why do action potentials only work in one direction?
-Inactivated Na+ channels behind the zone of depolarization prevent the action potential from traveling backwards -During the refractory period after an action potential, a second action potential cannot be initiated because of the temporary inactivation of the Na+ channels
Why do action potentials only work in one direction?
-Inactivated Na+ channels behind the zone of depolarization prevent the action potential from traveling backwards -During the refractory period after an action potential, a second action potential cannot be initiated because of the temporary inactivation of the Na+ channels
What happens in the nodes of Ranvier during an action potential?
-Voltage-gated channels are restricted to nodes of Ranvier ■ Action potentials in myelinated axons jump between the nodes of Ranvier in a process called saltatory conduction
What happens when an action potential reaches the synaptic terminal?
1- Increased Ca2+ level through voltage-gated Ca2+ channels cause vesicles to release neurotransmitters by exocytosis
2- Neurotransmitters can act as ligands that affect ion channels on the posy-synaptic neuron
How do chemical synapses integrate information?
When a neurotransmitter makes a neuron less likely to fire, it is
inhibiting its firing: Inhibitory post
-synaptic potential (IPSP)– GABA
■ When a neurotransmitter makes a neuron
more likely to fire, it causes an excitatory
postsynaptic potential (EPSP)–Glutamate
■ The summation of excitation and inhibition determines whether or not it will transmit a nerve signal
Can a single EPSP trigger an action potential?
A single EPSP is usually too small to trigger an
action potential in a postsynaptic neuron
What is temporal summation?
Two ESPS, (time) summation, creates an action potential
What is spatial summation?
Same charge: Adding enough positive charges from different
neurons can be enough
to trigger an action
potential
Opposing charges: Adding together opposing charges can prevent an action potential
What are seizures?
■ Abnormal, highly synchronous electrical activity of a restricted brain
region, or in some cases encompassing the whole brain
■ Having a seizure does not make a person epileptic
Seizures can be detected using an EEG
■ Electroencephalograph (EEG)
What are the different types of seizures?
Seizures ■ Focal (Partial) Seizures – focal seizure without cognitive impairment (simple) – focal seizure with cognitive impairment (complex)
Generalized Seizures – Absence – Tonic-clonic – Atonic – Myoclonic
What is Status Epilepticus?
■ A seizure that lasts longer than 5 minutes, or having more than 1
seizure within a 5 minutes period, without returning to a normal level
of consciousness between episodes
■ Medical emergency that can lead to death
What is Epilepsy?
Spontaneous, repeated unprovoked seizures
■ Genetic/idiopathic epilepsy
– Channelopathies
– Presents in early childhood and adolescence
Symptomatic or acquired epilepsy
– Well defined underlying cause
Seizures are caused by excitation/inhibition imbalance
Why does Epilepsy require network firing?
■ Group of neurons spontaneously develop synchronous firing
– Excitation passed through gap junctions
– Alterations in inhibitory signals from basket cells
– Groups of neurons that are individually hyperexcitable
■ Increase in extracellular K+
– Abnormal interactions between groups of neurons
■ Ion channel mutations
What is Epileptogenesis?
■ Little research done on period of time before seizures begin when rewiring most likely occurs
What reuptake happens by Astrocytes?
Reuptake of Glutamate; Excess glutamate taken in by
astrocytes at the synapse and
converted to glutamine
How do ion channels change with epilepsy?
■ Exome sequencing often reveals mutation in ion channels in
individuals suffering from epilepsy
– De novo
– familial
What are the genetics of Epilepsy?
Monozygotic twins- if one is affected, there is a 50-60% chance the other will be as well ■ Dizygotic Twins- 15% ■ Closely related relative have a 5X higher risk of developing epilepsy than the general population Epilepsy Tends to Have Autosomal Dominant Inheritance
What is Monogenetic Epilepsy?
Single gene mutation seems to explain the development of disease
■ SCN1A- encodes for the alpha subunit of the neuronal voltage gated
channel responsible for the AP
What is the SCNA1 mutations with epilepsy?
■ Missense mutations may or may not cause epilepsy ■ Truncations almost anywhere are causative ■ Different mutations cause different phenotypes SCN2A mutations are seen in familial epilepsy
What are KCNQ2 mutations in epilepsy?
Voltage gated K+ channel ■ Mutations tend to slow the repolarization of the cell ■ Associated with benign familiar neonatal seizures
What are GABA receptor mutations?
Reduced GABA receptor mediated inhibition-> increased excitability of pyramidal neurons
What are multigenetic causes of epilepsy?
■ Combination of small changes leads to a phenotype that may confer
heightened susceptibility to seizure under certain conditions
– Stress
– Hypoxia
– Development linked to a combination of genetic and
environmental factors/triggers
How is Kainic acid used?
Chemical induction through injection of glutamate receptor agonist ■ Focal seizures- often used to mimic frontal lobe seizures
What is the Kindling Model?
Recurrent electrical stimulation ■ Ultimately seizures present without stimulation ■ Examine latent period- time before spontaneous seizure formation
What are Mouse Model advantages?
■ EEG abnormalities mirror those seen in humans
■ Abnormal network connections in hippocampus and cortex can be observed
■ Manipulation of transmitter systems shown to cause seizures in mice
– Increase Glutamate
– Decreased GABA
■ Changes in ion channels- gene mutation research
■ Structural changes lead to epilepsy (lesion model)
■ Trauma, infection and vascular changes can be studied
What is Astrocytes (emerging targets)?
■ Excess glutamate taken in by astrocytes at the synapse and converted to glutamine ■ Mutation to transporter (EAAT2) linked to seizures ■ Mutation to Kir4.1 K+ channel – extracellular K+ not cleared – Enhances BDNF secretion (high concentrations linked to epilepsy)
How are stem cells connected to epilepsy (emerging targets)?
■ Neurogenesis altered following seizures
■ Newborn cells are not incorporated properly into
the circuitry
■ Leads to more seizures
What is the Mammalian Target of Rapamycin (mTOR)?
Signaling protein associated with growth and proliferation ■ mTOR in the brain is regulated by pathways involved in glutamatergic, excitatory transmissions ■ Rapamycin – drug that can inhibit mTOR
How do Antiepileptic drugs work?
Act to raise the threshold for neuronal network excitability
■ Over 20 drugs available that target different proteins
■ Augmenting GABA response
Reduction in Na+ channel activity
■ Alter neurotransmitter release
What is the goal of epileptic drugs?
■ “Freedom from seizures” for 2/3 of individuals
■ Does not always equate with normal EEG activity- just reduction in
behavioral problems
How does surgery for epilepsy work?
Removal of brain abnormalities that are causing the seizures
■ Surgeon maps areas of the cortex that are essential for language, motor, and
sensory function.
Deep Brain Stimulation
■ Stimulation of the vagus nerve or specific brain structure in focal
seizures can desynchronize the EEG
What diet helps epilepsy and why?
Ketogenic Diet
■ Typically used in children with drug resistant epilepsy
Switches the bodies primary energy source
from glucose to ketones
– Ketones are created by the liver from
fats
■ Possible that ketones are directly
responsible for seizure reduction?
■ Increase mitochondria production?
■ ATP from glycolysis normally inhibits the K+
channel?
How does the nervous system age?
■ Neuroplasticity robust throughout life ■ Lack of brain atrophy ■ Only minor structural changes to neurotransmission ■ “benign forgetfulness of the elderly ■ Neurotransmitter levels do not decrease significantly with age
What is Dementia?
■ Loss of global cognitive ability
■ Syndrome- does not arise from a singular cause
What exam do they have people take to gauge dementia?
Mini-mental status exam ■ Normal: 25 or higher ■ Mild impairment: 21-24 ■ Moderate impairment: 10-20 ■ Severe impairment: <10
What is frontotemporal dementia?
Most common dementia in those under 65 years of age
■ Deterioration of the frontal lobe
Changes in social and personal behavior
– Apathy and social withdraw
– Lack of inhibition (stealing, speeding, disinhibited sexual drive)
– Compulsive behaviors
– Loss of speech fluency- cannot articulate language but can fully
comprehend it
– Loss of executive function- decreased ability to plan and organize
tasks
How are memories strengthened and lost?
Memories are strengthened through long-term
potentiation:
The more times a memory moves through the cortex- MLT
pathway, the stronger it becomes
– Strengthened synapse due to increased AMPA
insertion
Memories are lost through long-term depression:
■ Low stimulation of a neuron leads to decreased AMPA receptors – increased
difficult to trigger the neuron
What is Alzheimer’s disease?
Predominant form of dementia
AD symptomology aligns with deteriorative
progression
How is memory distributed in the brain?
You have declarative (things you have to think about) and non declarative memory(things you dont, reflexes, not hippocampus dependent
What memory does storytelling require and why?
Story telling requires semantic and episodic memories to be brought together Declarative memories thought to be stored in the cortex ■ Semantic memories are associated with the region responsible for the task ■ Information must be brought together to tell a story – Cortical-medial temporal lobe network
What is AD cellular pathology?
■ Amyloid Plaques
– extracellular
■ Neurofibrillary tangles
– intracellular
What are microtubules?
■ Long hollow tubes ■ Composed of alpha and beta tubulin ■ Largest cytoskeletal element ■ Compression resistant ■ Dynamic Provides : Motility of vesicles and organelles
What are Tau proteins?
Microtubules stabilizing protein – Holds together microtubule bundles ■ Function dependent on phosphorylation
What is Tau phosphorylation?
■ 6 isoforms- longest is 441 amino acids in length – Normally phosphorylated at 3 sites – 79 possible phosphorylation sites
How does Tau tangle in AD?
■ Hyperphosphorylation of tau (seen in AD) disrupts microtubule integrity ■ Once microtubules breakdown paired helical fibrils (PHFs) are formed – Insoluble aggregates Tau hyperphosphorylation disrupts axonal transport
What are Amyloid plaques?
■ First described by Rudolf Virchow – Starch like structures – Waxy ■ 1984: the amino acid structure of the plaques was determined – Amyloid beta (Ab) peptides clustered together
What are Amyloid beta (AB) derived from?
Ab derived from processing of APP APP (amyloid precursor protein) – Large transmembrane glycoprotein – Cleaved by three different secretases (alpha, beta, and gamma)
How is APP processing in neurons?
Incorrectly uses alpha-secretase to gamma-secretase (its nonamyloidogenic
What are AB40 and AB42 aggregates?
Ab40 and Ab42 are hydrophobic peptides – Upon cleavage, these peptide form insoluble aggregates – 42 more hydrophobic and more toxic
How is Trisomy 21 associated with AD?
■ Gene for APP found on Did you know… the 21st chromosome – DS patients have heightened accumulation of Ab42 at a younger age
How does AB work in the synapse?
Application of Ab oligomers on hippocampal sections impairs neurotransmission – Decrease LTP – Increase LTD ■ Increase neuronal activity increases the release of Ab ■ Negative feedback loop – Small amounts not as harmful, pathological amounts lead to synaptic death ■ High concentrations of Ab42 leads to inflammation
What is the alternative theory of AB42?
g-secretase plays an important role in Notch signaling – Signaling pathway in development and cell polarity generation ■ Possible Notch was the only intended substrate and Ab is erroneous
What is the Prion hypothesis?
Ab42 acts like a prion and causes further misfolding and aggregation of APP cleavage products – Shown in mouse models of the disease
What are types of Alzheimer’s diseased types?
■ Late-onset
– 80-90% of all cases
– Unclear of there is a genetic component
■ Early-onset
– Before the age of 60
– Most rapid progression
– Most are familial
■ Familial
– <5% of all cases
– Normally affects individuals in early 40s
– Associated genes found on Chromosome 1, 14, and 21
What is Aduhelm?
Received FDA accelerated approval ■ Antibody targeting amyloid plaques – Successfully shown to reduce plaques in patients – Two phase 3 clinical trials- one met the primary endpoint and the other did not ■ Annual price tag set at $56,000
What was The Nun Study?
■ Longitudinal study assessing risk
factors and development of dementia
■ 1- lesions to the brain speed cognitive
impairment
■ 2- greater idea density decreases risk
■ 3- Neurofibrillary tangles most closely
associated with clinical diagnosis of AD
■ 4- “idea density” correlates with disease
What are the 4 major targets of AD treatments?
beta-secretase inhibitors
gamma-secretase inhibitors
AB aggregation inhibitors
immunotherapy
What variant is associated with late-onset of AD?
Apolipoprotein E (ApoE)
■ APOE2- protective against AD
■ APOE3- most frequent in
Caucasians
■ APOE4- risk factor for AD
– 40-60% individuals with
one allele will develop
late-onset AD
APOE binding to its receptor has been associated with increased APP transcription
– APOE4 binds more tightly to the receptor that APOE2
■ Can decreasing the affinity of binding diminish disease progression?
What is a possible explanation for APOE?
■ One possible explanation: – APOE2- strengthens and protects BBB – APOE4- alters tight junctions and make BBB more leaky
