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Clinical Neuroscience > Unit 2 > Flashcards

Unit 2 Flashcards

1
Q

Types of somatosensory receptors

A

Specialized endings - mechanical stimulation (sensory afferents!)
- Different modalities of touch

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2
Q

Ascending touch pathway

A

1st - periphery to medulla
2nd - medulla to thalamus (decussates)
3rd - thalamus to SS cortex

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3
Q

Proprioception

A

Unconscious sense from muscle spindles and Golgi Tendon organs that follow the same pathway as touch
- Branch to LMNs
- If one muscle contracts, its opposite must relax

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4
Q

Why are nociceptors different from temperature afferents?

A

Nociceptors only respond to HIGH temperatures (45+), but they respond with temperature afferents. Otherwise, only temperature afferents respond and they reach maximum frequency at 45 degrees

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5
Q

Pain and Temperature Pathway

A

1st - periphery to spinal cord
2nd - spinal cord to thalamus (decussates in SC)
3rd - thalamus to SS cortex

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6
Q

It is always the _____ neuron that crosses/decussates

A

Secondary

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7
Q

Damage to thalamus or internal capsule

A

Contralateral hemianesthesia - loss of pain and touch contralaterally

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8
Q

Damage to spinal cord

A

Contralateral analgesia and ipsilateral touch

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9
Q

Commissural syndrome

A

Bilateral pain and temperature loss - no loss of touch

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10
Q

Neuropathy

A

Loss of neurons

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11
Q

What can cause disorders of peripheral neurons?

A

Mutations in myelin or abs to myelin

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12
Q

Symptoms of peripheral nerve damage

A

Loss of sensations, reduced motor activity, loss of reflexes

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13
Q

Pros and Cons of regeneration of PNS neurons

A

While they can regenerate, they take a long time so when they regenerate, the muscle may atrophy

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14
Q

Role of Myelin

A
  • Increases AP conduction speed
  • 100 m/s vs 1m/s
  • Allows for saltatory conduction; Na+ channels are concentrated around Nodes of Ranvier so APs can “jump” without losing a lot of depolarization
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15
Q

Effects of demyelination

A
  • Leaky membrane = current dissipates = not enough depolarization to reach threshold for an AP to fire = conduction speed is reduced
  • Axonal transport is disrupted by calcium influxes so organelles (mitochondria) aggregate
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16
Q

Multiple Sclerosis (general)

A

Autoimmune disorder due to a chronic progressive neuroinflammatory diseases that damages myelin in the brain and SC (could be sensory or motor!)
- Autoimmune attack on myelin
- Combination of genetic and environmental risk
- Activation of T and B cells
- Overall an IMMUNE disease

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17
Q

Focal Sx of MS

A

Sensory loss
Optic Neuritis
Weakness
Pins and needles
Diplopia
Ataxia
Vertigo

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18
Q

Dx of MS

A
  • Sx must occur at least twice separated by at more than a month
  • MRI shows one or more lesions, but if there are more than 2, 80% chance of developing MS
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19
Q

Prevalence and Risk Factors of MS

A
  • Northern and polar regions (maybe vitamin D)
  • Increased incidence in females (but risk decreases
  • Genetic risk
  • Viral - EBV (Epstein Barr Virus) and MS link!
  • Winter months
  • Smoking
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20
Q

What is the relationship between EBV and MS?

A

MS = immune system attacks myelin
EBV = thymus gets lesioned; normally thymus gets rid of self-killing immune cells!

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21
Q

Four progressions of MS

A
  1. RRMS (most common - peaks that go to baseline - could progress to SPMS)
  2. SPMS (peaks that then go down to a baseline that keeps increasing)
  3. PPMS (peaks that go down to a baseline that increases - peaks are flat)
  4. PRMS (just really bad - peaks that increase a LOT from start)
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22
Q

MRI of a patient with MS

A
  • Lesioning of white matter in MS
  • Lesions needs to be large
  • 3+ lesions = highly predictive of MS
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23
Q

Cellular Scx of MS

A

Typically an abundance of immune cells (T, B, and plasma cells) and innate microglia and reactive astrocytes

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24
Q

T Cells Overall

A
  • Two types that impact MS
    1. T Helper (C4+) - recruit microglia and macrophages via cytokine release that kill oligodendrocytes
    2. T Killer (C8+) - also kill oligodendrocytes with the help of microglia and macrophages
  • Myelin debris is then cleaned up so axons are demyelinated
  • ROS release = loss of energy = excitotoxicity
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25
Q

B Cells Overall

A
  • Produced in bone marrow
  • Produce Abs which bind to myelin and help destroy it
  • Depletion of B cells ameliorate sx
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26
Q

Inflammation means

A

More damage

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27
Q

Overall effects of demyelination in MS

A
  • Axons attempt to remyelinate, but this takes a lot of time
  • As MS progresses, remyelination declines so axonal loss occurs that eventually can cause the neuron to die
  • Leaky axon = lack of energy for pumping the gradient = decrease in energy = excitotoxicity
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28
Q

Drug treatments for MS

A
  • Interferon beta - attempts to restore the ratio between T-helper and T-regulatory cells (targets immunomodulation and adhesion and transmigration)
  • Rituximab - destroys B-cells that make antibodies that bind to the myelin
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29
Q

Experimental treatments

A
  • Temperature (hypothermia)
  • Vitamin D
  • Estrogen
  • Diet
  • Cannabis
  • Autologous stem cells
  • K and Na blockers
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30
Q

How do K+ blockers help with MS symptoms?

A

Broadens APs = allows them to jump across demyelinated segments

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31
Q

How do Na+ blockers help with MS symptoms?

A

Blocking the sodium channels prevents leakiness of the membrane, therefore, less energy needs to go into maintaining a gradient and more into APs

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32
Q

UMN travel from _____ to ______

A

Brain; SC/brainstem

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33
Q

LMN travel from _____ to ______

A

SC/brainstem; muscle

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34
Q

What does the basal ganglia act on?

A

UMN (motor, cortex, initiating movements)

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35
Q

What type of movement doesn’t use UMN?

A

Reflexes

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36
Q

UMN Pathways

A
  1. Corticobulbar neurons - premotor cortex to brain stem (most caudal goes to medulla) - innervate cranial nerves
  2. Corticospinal neurons - go from cortex to spinal cord - innervate LMN in SC via interneurons - innervate muscles CONTRALATERALLY (cross in medulla!!)
    - Lateral muscles descend like this
    - Medial muscles are innervated bilaterally and cross in the SC, not in the medulla
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37
Q

Overall Corticospinal Pathway

A
  1. Internal Capsule
  2. Midbrain (cerebral peduncles)
  3. Pons (lots of bundles and colors)
  4. Medulla (pyramids)
  5. Caudal medulla (decussate)
  6. Lateral corticospinal tract
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38
Q

What does the corticobulbar tract innervate?

A

Cranial nerve nuclei, reticular formation, red nucleus, and pontine nuclei

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39
Q

Axial and proximal muscles

A

Ventromedial pathway (bilateral innervation)

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40
Q

Distal muscles

A

Lateral corticospinal tract

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41
Q

Descending motor pathways

A
  1. Rubrospinal (red nucleus)
  2. Reticulospinal (reticular formation - important for necessary processes)
  3. Vestibulospinal (vestibular nuclei - balance)
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42
Q

Myotactic reflex

A
  • Knee jerk response
  • LMN and interneurons
  • Proprioception!
  • Flexor muscle is inhibited, extensor is not
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43
Q

UMN vs LMN Syndrome

A

UMN - spastic paralysis - rigidity, spasticity, tense and toned muscles, Babinksi’s sign
LMN - flaccid paralysis - weakness or paralysis, twitching, muscle atrophy, muscles are loose and relaxed

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44
Q

Babinski’s sign

A

Normal: toes flex down
Abnormal: toes extend up

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45
Q

Motor disorders can affect…

A
  1. The neuron itself (ALS)
  2. Neuromuscular junction (MG and LEMS)
  3. Axon of neuron (MS)
  4. Muscle fibers (MD)
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46
Q

NMJ symptoms

A

Muscle weakness, especially in cranial nerves

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47
Q

Myasthenia Gravis

A
  • MG
  • Sx: eye muscle movements and eye movement abnormal, cranial nerves, muscles that control breathing could be affected
  • Abs block nACh receptor postsynaptically
  • Treatments: AChE inhibitors, things to remove Abs
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48
Q

Difference between LEMs and MG

A

MG APs decrease in amplitude over time (affect post-synaptically), LEMs increase over time (less calcium, affect pre-synaptically)

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49
Q

True or False: ALS affects only UMN

A

False, it affects both UMN and LMN

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50
Q

ALS (general)

A
  • Death/degeneration of UMN and LMN that prevents innervation of muscles
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51
Q

Early Sx of ALS

A
  • Flaccid paralysis (LMN)
  • Spastic paralysis (UMN)
  • Tongue atrophy (bulbar ALS)
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52
Q

Late Sx of ALS

A

Loss of strength, ability to speak, move, eat, and breath

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53
Q

Environmental risks of ALS

A

Chemicals, smoking, and soccer

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54
Q

General pathology of ALS

A

Death of UMN and LMN, especially in the lateral corticospinal tract (distal muscles)
- some LMNs die -> sprouting and aberrant activity in other LMNs (twitching)
- All LMNs die -> muscle atrophy and paralysis

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55
Q

Overall cellular pathology of ALS

A

Some aggregates of SOD1 and TDP-43

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56
Q

Four main genetic mutations in ALS

A
  • SOD1
  • TDP-43
  • FUS
  • C9orf72
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57
Q

SOD1’s role in ALS

A
  • SOD1 needs to be mutated
  • Normal fx: detoxify free radicals
  • Sx are present if SOD1 is mutated only in motor neurons, but sx are accelerated if SOD1 mutations are present in astrocytes and microglia (cell non-autonomous effect)
  • Aggregated SOD1 binds to mitochondria and causes apoptosis
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58
Q

Cell Autonomous vs Cell Non-Autonomous

A

CA: a genotype in cell A changes cell A’s phenotype
CNA: a genotype in cell A causes a change in cell B’s phenotype (i.e. glia : neuron)

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59
Q

FUS and TDP-43 Role in ALS

A
  • Normally do like everything (mostly things to do with transcription!) and remain in nucleus
  • In ALS, TDP-43 leaves nucleus and accumulates in cytoplasmic granules (aggregates!)
  • These aggregates can lead to less SOD1 (more ROS, less energy, and defective mito), less EAAT2 (excitotoxicity), and membrane-less organelles
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60
Q

C9orf72’s role in ALS

A
  • Located in an intron
  • Can affect splicing (making protein long or short)
  • Three major effects
    1. Less protein expression
    2. Toxic RNA (RNA accumulations)
    3. Dipeptide repeats which can be found in inclusions
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61
Q

Major theories of ALS

A
  1. Dying forward (UMN deaths cause LMN deaths via excitotoxicity)
  2. Dying back (LMN deaths cause UMN deaths by diffusible factors, inflammation, etc.)
  3. Independent deaths of LMN and UMN
  4. Aggregates are toxic because they block up proteasome systems
  5. Prion like spread of SOD1
  6. MN die by apoptosis (caspases - mitochondria involved)
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62
Q

Cells involved in ALS

A

UMN, LMN, microglia, and astrocytes

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63
Q

Current treatments of ALS

A
  1. Riluzole (blocks Na+, limites glu release - different types of intake)
  2. Radicava (antioxidant)
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64
Q

Treatment trials for ALS

A
  1. Glutamate modulation to reduce excitotoxicity
  2. Protein aggregation blocking
  3. Immune modulators
  4. Anti-sense oligos ASO to remove aggregated SOD1
  5. Cell replacement therapy
  6. Brain computer interface (think Steven Hawking)
65
Q

Basal Ganglia are a part of the

A

Telencephalon

66
Q

Caudate + putamen =

A

Striatum

67
Q

Striatum Role in Motor Circuit

A

Receives input from motor cortex and sends it further into basal ganglia

68
Q

Internal Capsule Role in Motor Circuit

A

Sends tertiary axons from thalamus to SS cortex

69
Q

Substantia nigra is located in ______ and makes ______

A

Midbrain; dopamine

70
Q

Direct Pathway of Basal Ganglia Overview

A

Caudate and Putamen –> GABA –> GPi –> GABA –> Thalamus –> glu –> Frontal cortex

71
Q

Direct Pathway of Basal Ganglia in Words

A

When striatum is at rest, GPi tonically inhibits the thalamus, so the cortex doesn’t get any information. When the striatum is activated, it transiently inhibits GPi, which disinhibits the thalamus, so it activates the motor cortex

72
Q

What does dopamine do for the direct pathway of the basal ganglia?

A

Activates the caudate putamen = more inhibition of GPi = more activation of thalamus and motor cortex = more movement

73
Q

Indirect Pathway of Movement Overview

A
  • Overall goal - activate/inhibit movements on a broader scale
  • Caudate –> GABA –> GPe –> GABA –> Subthalamus –> Glu –> GPi –> GABA –> Thalamus –> Motor Cortex
74
Q

Indirect pathway of movement in words

A

A lot of subthalamus activity = less movement overall (due to less caudate/putamen activity)
More movement with D2 activation

75
Q

Parkinson’s is an example of a _____ disorder

A

Hypokinetic - loss of dopamine pathway leads to increased subthalamus activity so there is less movement (more rigidity and harder to move)

76
Q

Where is dopamine synthesized?

A

Substantia Nigra and Ventral Tegmental Area

77
Q

Enzymes required to synthesize DA

A

Tyrosine hydroxylase and DOPA decarboxylase

78
Q

True or False: Dopamine can cross the BBB

A

False, but DOPA (a precursor to dopamine) can

79
Q

D1 vs D2 receptors

A

D1 - activates the striatum which inhibits GPi so thalamus is disinhibitied
D2 - inhibits striatum which activates GPe which inhibits subthalamus which can’t activate GPi so thalamus is disinhibited

80
Q

Huntington’s is an example of a ______ disorder

A

Hyperkinetic - degeneration of caudate/putamen causes decreased activity in indirect pathway so there is a lot more inhibition of subthalamus so a lot more uncontrolled and spontaneous movements

81
Q

Three other things the basal ganglia affect

A
  1. Tourettes
  2. SZ
  3. OCD, Depression, anxiety (dysfunction of limbic loop)
82
Q

Parkinson’s Motor Sx

A

Rigidity, tremor at rest, slowness of movement, minimal facial expressions

83
Q

Parkinson’s Non-Motor Sx

A

Loss of smell, change in executive function

84
Q

Stages of PD

A
  1. Early premotor (constipation, loss of olfaction)
  2. Early PD (motor phase, tremor rigidity)
  3. Moderate PD (treatment of DA doesn’t work, depression)
  4. Advanced PD (very disable, motor and cognitive)
85
Q

Pathology of PD

A

Loss of DA neurons in SN (particularly SNc) and a lot less activity in striatum

86
Q

Aggregates in PD

A

Alpha synuclein aggregates (aka lewy bodies)
- normally alpha synuclein modulates the SNARE complex (vesicle release)
- mutation and overexpression leads to beta sheet conformation and aggregates!
- when aggregated it cannot function
- oligomers are thought to be toxic

87
Q

Environmental Causes of PD

A
  • Age
  • Head injury
  • Living in a rural area and exposure to pesticides
  • MPTP
88
Q

What surprising drug reduces the risk of developing PD?

A

Nicotine

89
Q

MPTP and PD

A

MPTP - lipophilic drug that crosses the BBB, gets taken up by glia, converted to MPP+ by MAO and released
- MPP+ gets taken up into DA neurons by DAT
- MPP+ inhibits mitochondria’s electron transport chain
- DEATH

90
Q

Main gene mutations in PD

A
  1. alpha synuclein - vesicle transport, Lewy bodies
  2. Parkin - ubiquitin ligase that acts in protein degradation
  3. PINK1 - tags bad mitochondria to be destroyed via autophagy
91
Q

Two mechanisms of getting rid of misfolded proteins

A
  • UPS (ubiquitin proteasome system)
  • Autophagy
92
Q

What protein causes UPS to be affected in PD?

A

Parkin

93
Q

How does autophagy get affected in PD?

A

Parkin and PINK1 work together to tag and removed failing mitochondria - PINK1 detects and binds to mitochondria, recruiting Parkin which labels the mitochondria for autophagy

94
Q

Vulnerability of SNc neurons

A
  • Rhythmic tonic activity in basal ganglia (Require a lot of ATP = need too mitochondria)
    1. Alpha synuclein aggregation affects DA release
    2. Clearance of misfolded proteins/failing mitochondria is impaired so it chokes DA neurons (Parkin/PINK1)
    3. Toxicity via herbicides = very bad due to the pacemaking nature of SNc cells
95
Q

Treatments for PD (drugs)

A
  1. Levadopa + carbidopa (levidopa is L-Dopa and carbidopa is a peripheral DOPA decarboxylase inhibitor, so more DOPA crosses the BBB)
  2. COMT and MAO inhibitors
    Other Sx (not dopamine related)
  3. Anti-cholinesterases (dementia)
  4. Antidepressants
  5. Benxodiazepines
96
Q

Other treatments for PD

A
  1. Deep brain stimulation
  2. Neuroprotection (excitotoxicity prevention, NSAIDs, smoking, Ca2+ blockers)
  3. Prevention of Lewy bodies
  4. Cell therapy - use stem cells to make DA
97
Q

HD Early Sx

A

Chorea, athetosis, mood swings, depression, irritability

98
Q

HD Late Sx

A

Concentration problems, trouble eating and swallowing

99
Q

Cause of HD

A

TNRE - trinucleotide repeat of CAG in the htt gene that encodes Huntingtin (HTT) that causes extra glutamine residues in the mutated protein
- Normally: 3 to 34 CAG repeats
- HD: 40+, anticipation - if gene is inherited from father, there may be more CAG repeats = earlier onset of disease

100
Q

Pathology of HD

A
  • Loss of grey matter
  • Striatal GABA-ergic neurons die, leading to decreased striatal volume AND only affecting MSNs in the indirect pathway
  • Decreased connectivity
101
Q

Cellular pathology of HD

A

Misfolded HTT due to mutation in MSNs in the striatum - leads to more spontaneous movements

102
Q

True or false: longer CAG repeats predict disease duration

A

FALSE, they predict disease onset

103
Q

Cellular effect of HTT

A
  • complete knockout of HTT is lethal, but mHTT can reverse lethality
  • mHTT is deadly once you get older
  • mHTT aggregates contain amyloid fibers with a beta sheet configuration
104
Q

Possible mechanisms of HD

A
  1. BDNF
  2. Excitotoxicity
  3. Glia
  4. Proteostasis pathway
  5. Mitochondria
  6. Putting it all together
105
Q

Role of BDNF in HD

A

NORMAL: HTT binds REST and sequesters in
MUTATED: mHTT cannot bind REST so REST suppresses BDNF transcription in cortex; overall mHTT = decrease in BDNF and axonal transport from cortex to MSNs

106
Q

Glutamate and Excitotoxicity in HD

A

Extrasynaptic NMDARs = more LTD because a lot more glu causes influx of Ca2+

107
Q

Role of glia in HD

A
  • Inclusion bodies are found in neurons ONLY
  • mHTT causes a decrease in EAAT2 transcription
  • neuronal mHTT drives disease but neuronal death is attenuated by wild type astrocytes = cell non-autonomous effect
108
Q

Proteostasis network in HD

A

UPS and Autophagy!
- Maybe UPS is overwhelmed with the number of HTT aggregates

109
Q

Mitochondrial function in HD

A

Swollen mitochondrial can be found in cell throughout the body = loss of energy due to constant twitching = rip mitochondria!

110
Q

Cellular pathogenesis in HD

A
  1. Impaired BDNF transcription due to mHTT no longer binding REST
  2. Extrasynaptic NMDARs get a lot of spillover glu leading to LTD and excitoxicity
  3. Aggregates of mHTT choke up the proteasome system
111
Q

Drugs for HD

A
  1. Tetrabenazine: inhibits amount of DA packed into vesicles in order to inhibit movements
  2. Coenzyme Q10: help with ATP production/decreasing ROS synthesis
  3. Cephalosporin: increases EAAT2 transcription
  4. Memantine: acts on extra synaptic glutamate receptors
  5. RNAi = attempts to turn the production of mHTT off; virus binds to neurons and inserts transgene encoding an miRNA against mHTT RNA
112
Q

Plasticity definition

A

Changing the strength of a synapse in either direction: strengthening or weakening
- Time scale of plasticity can range from milliseconds to hours and years

113
Q

Mechanisms of plasticity (general)

A

Presynaptically (changing the number of vesicles of NT released)
Postsynaptically (receptor/signaling pathways are activated or attenuated)

114
Q

LTP in Hippocampus

A

LTP is usually modelled at the shaffer collateral and CA1 synapse
- LTP only occurs in pathways that have received a high frequency stimulus previously (i.e. are primed) = allows for specificity

115
Q

Hippocampus pathways

A
  1. Entorhinal cortex synapses with dendate gyrus granule cells via perforant path
  2. Granule cells synapses with CA3 pyramidal cells via mossy fibers
  3. CA3 pyramidal cells synapse with CA1 pyramidal cells via Schaffer collaterals
116
Q

Short term LTP Pathway

A
  1. AMPA receptor opens
  2. Membrane depolarizes
  3. NMDAR lets Ca2+ in, which activates Calmodulin kinase and PKC
  4. Leads to additional AMPA receptors being added, so more depolarization can occur
117
Q

Long term LTP Pathway

A
  1. AMPA receptor opens
  2. Membrane depolarizes
  3. NMDAR lets Ca2+ in, which activates protein kinases that not only increase AMPA receptors, but also activate cAMP pathways, activating CREB and increasing transcription of growth factors
  4. Growth factors lead to bigger spines
    - High frequency stimulation for a short amount of time = LTP
118
Q

Long Term LTD Pathway

A

Too much Ca2+ leads to phosphatase activation, which internalizes AMPA receptors
- Low frequency stimulation for a long time = LTD

119
Q

Memory depends on

A

Motivation, past experience, context and perceived importance

120
Q

Types of memory

A
  1. Short term (working memory = coordinated by PFC)
  2. Long term
    a) declarative (episodic and semantic) = hippocampus dependent
    b) non-declarative = basal ganglia, cerebellum, amygdala, and cortical areas
121
Q

Brain Areas that Support Declarative Memory

A
  • Hippocampus
  • Entorhinal cortex
  • Amygdala (affects inputs into the hippocampus so memories have a strong emotional aspect)
122
Q

Theories behind how memories are stored

A
  1. Semon: memory engram (physical alteration)
  2. Lashley: More cortex lesioned = more errors in a maze
  3. Tonegawa: found a subpopulation of cells that are activated by memory formation and whose activation can cause memory recall
123
Q

True or False: spatial learning and memory in rodents depend on the hippocampus

A

True!

124
Q

Patient H.M.

A

Loss of hippocampus = lead to severe amnesia

125
Q

AD general overview

A

Progressive neurological disease of the brain with irreversible loss of neurons
- Plaques and tangles develop in the brain, and there is a diffuse loss of neurons in the temporal lobe

126
Q

Types of dementia

A
  1. AD - loss of episodic memories
    2.FTD - loss of executive and frontal functions (SOD1 and TDP-43 aggregates)
  2. DLW - loss of executive and frontal functions allong with PD-like motor sx (alpha synuclein aggregates)
  3. CJD - Prion disease
  4. Vascular dementia - due to stroke (sudden onset)
127
Q

Memory decline, dementia, and AD

A
  • Memory decline occurs in many elderly people
  • However, dementia is a serious loss of global cognitive ability in a previously unimpaired individual and beyond what would be expected from normal aging, including personality changes, fatigue, restlessness and irritability
128
Q

Risk factors for dementia

A
  • Age
  • Sex (2x more common in women)
  • Hypertension, obesity, diabetes, inactivity
  • Family history of dementa
129
Q

Progression of AD

A

Preclinical phase: minimal behavioral sx, some pathological changes in cells
Mild cognitive impairment: neurological sx present, imaging and biomarkers can be seen, plaques become more aparent
Dementia: profound neurological sx, rapid decline, not associate with pronounces increase of plaque, but a lot larger increase in tangles

130
Q

In what order to plaques, tangles, atrophy, and cognitive impairment occur?

A
  1. Plaques
  2. Tangles
  3. Atrophy
  4. Cognitive impairment
131
Q

Atrophy in AD

A

Can include all areas of the cortex, but particularly the temporal lobe (particularly hippocampus)
- can also see reduced blood flow, breaches of the BBB, neuronal death, and gliolisis

132
Q

FTD affects _____

A

Frontal lobe; loss of executive function, most common form of dementia in those under 65, SOD1 and TDP-43 aggregates

133
Q

True or false: you can use Pittsburg compound to treat AD

A

FALSE, Pittsburg compound is used to diagnose AD

134
Q

Pittsburgh Compound

A
  • Finds beta sheet structures
  • Radioactive binding to the beta sheet structures
  • PET scan to see where the beta sheets are
135
Q

Plaques in AD

A
  • Beta amyloid plaques
  • Extracellular deposits of abnormal protein
  • Not known if amyloid plaques are a cause or consequence of AD
136
Q

Formation of BA plaques in AD

A
  • Normally, APP gets cleaved by alpha and gamma secretase into non-toxic APPalpha
  • Abnormally, APP gets cleaved by beta and gamma secretases
137
Q

Oligomers vs Aggregates of AB peptide

A

Oligomers may be more toxic, plaques and aggregates may be a stress response to protect the cell against oligomers

138
Q

Tangles in AD

A
  • Neurofibrillary tangles are abnormally folded tau protein, which normally interacted with tubulin to stabilize microtubules and help with axonal transport
  • AD: tau gets hyperphosphorylated
139
Q

Genetic mutations that lead to early onset AD

A
  • APP
  • Pre-senilin-1 and pre-senilin-2 (gamma secretase components)
140
Q

Genetic mutations that lead to late onset AD

A

APOE e4 - normally binds APP so could involve in the clearance of plaques; not fully penetrating but it does increase risk

141
Q

Inflammation in ADD

A
  • Plaques can activate astrocytes and microglia, which can release ROS that activate apoptosis
  • NSAIDs can reduce the likelihood of AD!
142
Q

Prion-like spread in AD

A

Plaques and tangles tend to spread through the cortex in a predictable pattern beginning in the temporal lobe in a prion like fashion

143
Q

Current drugs for AD

A
  • Memantine: NMDA receptor antagonist (also used in HD!)
  • NSAIDs: reduce inflammation and could have a role in gamma-secretase cuts of APP
  • Cholinesterase inhibitors and nicotine: cholinergic neurons degenerate in AD
144
Q

Drugs removed from clinical trials of AD

A
  1. gamma secretase inhibitors
  2. beta secretase inhibitors
  3. Antibody to AB peptide
  4. Vaccine to AB peptide
145
Q

Future Treatments for AD

A
  1. gamma secretase inhibitors
  2. beta secretase inhibitors
  3. AB aggregation inhibitors
  4. Immunotherapy (abs to AB peptide)
  5. Apoptosis inhibitors
  6. Metal-protein interaction inhibitors
  7. Stem cell therapies
146
Q

Brain Infections in General

A
  • Brain and SC are encased by bone and protected by meninges
  • Most infections cause edema –> increased intracranial pressure –> headaches –> delirium/loss of consciousness –> coma
147
Q

Meningitis

A
  • Inflammation of the brain coverings
  • Can be bacterial, viral, or fungal infections
  • Viral: most common, fungal: worst, viral: enteroviruses
148
Q

Neurosyphilis

A
  • Late presentation of syphilis
  • Bacterial
  • 4 stages
    1. Acute sore
    2. Diffuse rash
    3. Latent secondary syphilis with no sx
    4. Tertiary syphilis - neurosyphilis (loss of sensory afferents)
149
Q

Polio

A
  • Virus
  • Neurotrpic RNA
  • Kills LMN
  • Preventable through vaccine
150
Q

Rabies

A
  • Virus
  • Neurotropic RNA
  • Aggregates of Negri bodies that travel along CNS motor axons
  • Fatal within days
  • Prevention by vaccination of wildlife and pets
151
Q

HIV

A
  • Virus
  • Retrovirus: inserts genome into cell via reverse transcriptase
  • Act on T-helpers and other immune cells in the brain
  • Sx of dementia
  • HAART helps AIDS but isn’t effective for neuroaids
152
Q

Botulism

A
  • Bacterial toxin
  • LMN
  • Flaccid paralysis
  • Blocks ACh release so no contractions can occur
153
Q

Tetanus

A
  • Bacterial toxin
  • UMN
  • Spastic paralysis
  • Inhibits GABA release from interneurons
  • Causes constant contractions
154
Q

How botulism, tetanus, and botox get into cells

A
  • SNARE proteins
  • Toxin binds to Syt inside a vesicle that just released ACh/GABA, vesicle closes, heavy chain of toxin makes a channel in vesicle, light chain exits and inhibits ACh/GABA release by inhibiting SNARE proteins
155
Q

Prion Diseases

A
  • PrPc: Normal PrP, normally tertiary with alpha helix
  • PrPsc: mutated PrP, with beta sheets that are insoluble, forms oligomers and aggregates
  • Sponge like appearance due to extensive neuron death
  • PrPsc acts as a catalyst: converts PrPc to the beta sheet configuration, which causes it to spread
  • species barrier: easier to infect within a species than between species
156
Q

Primary Amoebic Meningoecephalitis (PAM)

A

Brain eating amoeba, up the nose, hard to kill because it is eukaryotic

157
Q

Neurocysticercosis

A
  • Tapeworm cysts
  • Sx; seizures and confusion
  • Treatment: cystica drugs that reduce swelling
158
Q

Neuronal diseases possibly caused by infectious agents

A
  1. MS - EPV
  2. Varicella-zoster virus - herpes simplex viruses!
  3. SZ - Flu
  4. MMR vaccine and link to autism
  5. AD and ALS - prion and infectious proteins
159
Q

Use of viruses and toxins to treat disease

A
  • Botox - helps migraines
  • Lentivirus - used to deliver genes to virus
  • Zika virus - binds to early developing neuronal cells, so could help treat brain cancer

Clinical Neuroscience (4 decks)

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