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KSU > Neuro Section 3 > Flashcards

Neuro Section 3 Flashcards

1
Q

what did the 1st AD patient present with

A

dementia, extracellular and intracellular lesions, neurodegeneration

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2
Q

what gene mutation is associated with early onset AD?

A

presenilin 2

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3
Q

dementia vs AD

A

dementia - broad, symptom of AD
AD - disease itself, can have AD but not dementia

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4
Q

define dementia

A

loss of intellectual functions associated with neurodegeneration not neurodevelopment

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5
Q

FAD v SAD AD

A

FAD - genetic, rare
SAD - most AD cases, de novo mutations

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6
Q

early vs late onset AD

A

early - before 65, correlated with FAD
late - most AD cases

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7
Q

how is vascular disease related to sporadic AD

A

cant get blood/O2/food to the brain –> trigger cell death mechanisms –> neurodegeneration

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8
Q

major brain area affected by AD

A

basal forebrain (cholinergic neuron path)

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9
Q

is AD a cause of death

A

no, death in AD cases mostly due to infection or stroke

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10
Q

severity level of most AD cases

A

moderate, 2 year development

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11
Q

MRI AD brain

A

smaller structure (less white area)
less activity

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12
Q

extracellular lesions in AD

A

result of AB plaques

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13
Q

intracellular lesions in AD

A

tau (neurofibrillary) tangles

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14
Q

what is the normal function of tau

A

microtubule binding protein to increase cell structure stabilization

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15
Q

why are tau tangles problematic

A

tangles prevent microtubule (tau) formation –> prevent cell stability

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16
Q

BAPtist AD hypothesis

A

AB peptide is the trigger for AD, accumulation of APP leads to plaque formation of AB, which triggers an inflammatory response and neuron death

AB clearance not equal to AB formation

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17
Q

TAUist AD hypothesis

A

abnormal phosphorylation of tau makes them “sticky” —> tangles form and cause cell death

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18
Q

how are AB peptides generated

A

cleavage of APP by secretases

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19
Q

what AB fragments is prone to aggregation

A

AB 1-42, cleaved by B-secretase

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20
Q

are AB plaques a cause or consequence of AD

A

unknown

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21
Q

how are tau tangles formed in AD

A

hyper-phosphorylation at specific epitopes

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22
Q

all possible genetic mutations of AD are — —-

A

autosomal dominant

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23
Q

APP mutations account of 15-20% of —-

A

early onset FAD

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24
Q

what other disease mutation causes elevated APP

A

C21 trisomy of DS

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25
Q

PSEN mutations account for 30-70% of —

A

early onset AD

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26
Q

possible PSEN genetic mutations

A

PSEN1 (c14) and PSEN2 (c1)

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27
Q

normal PSEN function

A

form catalytic part of gamma secretase

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28
Q

PSEN mutation and AD relation

A

mutated catalytic site of gamma secretase –> cleavage of APP at position 42 instead of 40

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29
Q

ApoE polymorphisms are associated with —

A

late-onset AD

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30
Q

define polymorphism

A

same gene with different sequence of length in each individual

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31
Q

e2 allele and AD

A

protection (7% population)

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32
Q

e3 allele and AD

A

most common, neutral risk/protection

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33
Q

e4 allele and AD

A

risk (14%)
highest in african-american populations

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34
Q

3 functions of ApoE

A

transport cholesterol to neurons
low density lipoprotein receptor gene
facilitate AB clearance via lysosomal pathway

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35
Q

what is PIB

A

PET scan compound that binds AB

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36
Q

support for BAPtist hypothesis of AD

A

AB peptide is primary component of necrotic AD patients, all mutations in early-onset AD are associated with AB

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37
Q

limitations of BAPtist hypothesis of AD

A

some AD cases do not have AB plaques, animal models do not show cell death in presence of high levels of AB plaques, removal of APP in presence of NFT’s does not change cognitive function

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38
Q

why don’t AB plaques alone cause cell death

A

AB plaques decrease ROS in brain

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39
Q

excitotoxicity hypothesis of AD

A

excess excitation causes overactive Ca2+ transporters and Ca2+ influx –> polarizes membrane and activates cell death pathway

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40
Q

all hypothesis of AD end with —-, indicating the —– organelle is involved

A

apoptosis, mitochondria (release of cytochrome c)

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41
Q

what causes cytotoxicity

A

imbalance between byproducts and antioxidants

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42
Q

3 steps for clinical diagnosis of AD

A

Neuropsychologic evaluation (behavior, easiest)
Imaging (structure damage, X-ray or MRI)
Functional imaging (low metabolic function, fMRI or PET scan)

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43
Q

do the levels of AB 1-42 correlate with disease severity? what does that mean about AB42 being used as a biomarker for AD?

A

no, not a good biomarker

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44
Q

AD cortical area morphology

A

cortical thickness decreased, cortical neuron number stays the same –> demyelination/loss of axons/etc

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45
Q

3 FDA traditional approved AD drugs (choline esterase inhibitors

A

galantamine, rivastigimine, donespezil

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46
Q

FDA traditional approved excitotoxicity inhibitor

A

memantine

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47
Q

2 FDA accelerated approval drugs for AD

A

aducanumab, lecanemab

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48
Q

how do choline esterase inhibitors work with AD

A

inhibit the breakdown of Ach from synaptic gap (since cholinergic neurons are lost, there is already a decrease in available Ach)

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49
Q

main issues with choline esterase inhibition AD drugs

A

increased Ach overstimulates PNS
does not address cell death

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50
Q

how does memantine (excitotoxicity inhibitor) work with AD?

A

NMDA antagonist, competitively inhibits glutamatergic system by blocking NMDA receptors

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51
Q

what makes memantine effect?

A

use in combination with choline esterase inhibitors

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52
Q

active vaccines

A

inject a piece of the virus/bacteria/peptide

53
Q

passive vaccine

A

monoclonal antibody injected (-mab suffix)

54
Q

outcome of treatment trials targeting AB using antibodies

A

no cognitive benefits

55
Q

current use of lecanemab/aducanumab for AD

A

passive vaccine
effectively removes AB but mixed reports on efficacy
costly, inconvenient

56
Q

outcome of treatments targeting AB using secretase inhibitors

A

increases symptoms

57
Q

how can diet be a protective factor from AD

A

fruits/veggies -> antioxidants to remove ROS
low sat. fats -> avoids vascular disease

58
Q

how can alcohol be protective against AD

A

small amounts act as a blood thinner and increase circulation in the brain

59
Q

how can statins (lower cholesterol) be protective against AD

A

reduce risk of clogged blood vessels

60
Q

limitation of AD mouse models

A

models based on over-expression of human mutant proteins, all associated with early-onset AD

less relevant to disease dynamics

61
Q

is the cause of PD known?

A

no, don’t know why but do know how

62
Q

what type of disorder is PD

A

motor, progressive (worsens with age/time)

63
Q

how is PD diagnosed

A

clinically only (no available biomarker test)

must have tremor or bradykinesia (slow movement) AND at least 1 other symptom

64
Q

4 major symptoms of PD (TRAP)

A

tremors, rigidity, akinesia (loss of movement), postural instability

65
Q

what order do symptoms appear in PD

A

motor then non-motor (behavioral, sensory, autonomic)

66
Q

PD is a lack of — in the brain

A

dopamine

67
Q

why do PD individuals react well to levodopa

A

levodopa is a dopamine precursor that can enter BBB –> can upregulate dopamine signaling in PD patients

68
Q

2 pathogenesis factors of PD

A

lewy bodies seen 1st, then dopamine levels checked

69
Q

2 genes associated with PD

A

alpha-synuclein
Parkin

70
Q

functions associated with gene mutations in PD

A

lysosomal degradation, mitochondria dysfunction

71
Q

—- mutation and —- of alpha-syn. gene cause familial PD

A

missense, triplication

72
Q

mutations to alpha-syn gene cause — associated with PD

A

lewy body formation

73
Q

why is rotenone environmental risk factor of PD

A

it acts as a mitochondrial blocker

74
Q

what is rotenone

A

insecticide

75
Q

why is paraquat an environmental risk factor of PD

A

produces superoxides

76
Q

what is paraquat

A

herbicide

77
Q

how does rotenone act in respect to PD

A

inhibits complex 1 of ETC in mitochondria, causes backup of e- b/c not binding to Co-Q, backed up e- bind to free O2 and create ROS

78
Q

where are motor neurons dying in PD

A

substantia nigra

79
Q

what are lewy bodies

A

alpha-syn aggregates

80
Q

how do Parkin mutations contribute to PD

A

inhibit Ub protease system

81
Q

where does the nigrostriatal pathway innervate to

A

cortical area - striatum

82
Q

what nt does the nigrostriatal pathway release

A

dopamine

83
Q

PD patient PET

A

decreased activity, less dark areas (dopamine activity)

84
Q

mechanism of MPTP

A

enters cells via DAT–> selectively kills dopamine cells in SN –> inhibits complex 1 of ETC –> prevents ATP synthesis and increase ROS

85
Q

3 most effective treatment ideas for PD

A

increase dopamine levels (L-dopa)
activate dopamine receptors (receptor agonists)
block dopamine breakdown (MAOI)

86
Q

limitation of dopamine injections for PD

A

inconvenient, dopamine does not pass BBB

87
Q

levodopa works best when —

A

co-administered with inhibitor of L-amino acid decarboxylase to suppress L-DOPA conversion to dopamine before crossing BBB

88
Q

limitation of using L-dopa for PD

A

inconsistent long-term

89
Q

how do monoamine oxidase inhibitors (MAOI) work against PD

A

inhibit enzymes that catalyzes destruction of primary amines (like dopamine) by providing “fake dopamine” to be broken down instead

90
Q

why are MAOI’s mot effective in early stage PD

A

not effective in later stages b/c dopamine levels too low

91
Q

3 limitations of using stem cell transplantation to treat PD

A

differentiation guidance, axon growth guidance to SN specifically, no guarantee of synapse formation

92
Q

how does HD compare to PD

A

HD –> more exaggerated uncontrollable movements, earlier onset, cells in dorsal striatum dying

93
Q

what type of disease is HD

A

degenerative genetic movement disorder

94
Q

what order do symptoms develop with HD

A

cognitive then motor

95
Q

HD affects the —- (brain area)

A

basal ganglia

96
Q

HD is strongly linked to —

A

genetic repeat expansion

97
Q

what is hyperkinesia

A

wild movements

98
Q

how do you test for preliminary HD

A

cognitive and neuropsych. tests

99
Q

death of HD patients generally happens after — and by —-

A

10-20 years, suicide

100
Q

HD gene mutation

A

autosomal dominant mutation of huntingtin gene (HTT) on C4

101
Q

HTT repeat in HD

A

CAG repeat, more than 36 repeats (normally <20)

102
Q

HD is often called —- b/c CAG encodes for —

A

polyglutamine disease, glutamine

103
Q

CAG repeats and onset age of HD relationship

A

the more repeats, the earlier onset

104
Q

how to test genetically for HD

A

PCR (quicker) or sequencing

105
Q

HD patient CT/MRI scans

A

small striatum (less white)

106
Q

HD is caused by selective —— neurons in —- and lead to —

A

degeneration of GABAnergic neurons in the striatum –> lead to loss of inhibitory pathways and loss of motor control

107
Q

function of normal HTT gene

A

suppress apoptosis by hiding pro-apoptosis enzyme HIP-1

108
Q

how does mutant HTT cause cell death

A

mutant HTT does not hide HIP-1 which allows uncontrolled apoptosis

109
Q

HTT mutations and BDNF expresssion

A

suppressed (decrease amount of BDNF neurotropic factor needed for neural survival)

110
Q

mutant HTT and CREB

A

mutant HTT sticks to CREB binding protein and prevents transcriptional activity

111
Q

what type of inclusion bodies are seen in HD

A

intracellular HTT aggregates on the nucleus of neurons in the striatum

112
Q

2 major limitations of HD animal models

A

HD is a genetic disorder –> not useful to use chemical induction in animal models

models show some behavioral changes associated with HD but not HTT cellular changed (like HTT aggregates)

113
Q

common HD animal model

A

overexpression of HTT gene

114
Q

why won’t Levodopa work against HD

A

HD affects GABAnergic neurons not dopaminergic

115
Q

only current prescribed HD treatment

A

tetrabenazine

116
Q

function of tetrabenazine vs HD

A

VMAT inhibitor–> degrades monoamines (like dopamine)

deplete excess excitatory stimulus since inhibitory neurons are lost and causing an imbalance

117
Q

what type of disease is ALS

A

progressive neurodegenerative, motor (no decline in cognitive function)

118
Q

lateral and ventral tract status in ALS

A

ventral (anterior) - intact and functional
lateral (posterior) - hardened

119
Q

normal function of lateral tracts

A

limb movement

120
Q

what neuron type is degraded in ALS

A

pyramidal motor neurons (excitatory)

121
Q

most ALS cases are —

A

sporadic

122
Q

common cause of death of ALS patients

A

3-5 years after diagnosis from pulmonary infection

123
Q

morphologic characteristics of lateral tract in ALS

A

decreased thickness and fiber branching

124
Q

SOD1 aggregation and ALS

A

overexpression of SOD1 –> not all functional –> aggregation –> ROS not broken down –> motor neuron death

125
Q

ALS shows degeneration and loss of — and —

A

cortical motor neurons and astrocytic gliosis

126
Q

2 intracellular inclusions of ALS

A

bunina bodies

Ub inclusions

127
Q

diagnosis of ALS

A

physical symptom evaluations (knee jerk rxn test) first then MRI/CT/EMG to confirm

128
Q

ALS MRI scan

A

dark outer areas, brighter inside -> degeneration of lateral tract axons

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