Neuro Section 3 Flashcards
(128 cards)
1
Q
what did the 1st AD patient present with
A
dementia, extracellular and intracellular lesions, neurodegeneration
2
Q
what gene mutation is associated with early onset AD?
A
presenilin 2
3
Q
dementia vs AD
A
dementia - broad, symptom of AD
AD - disease itself, can have AD but not dementia
4
Q
define dementia
A
loss of intellectual functions associated with neurodegeneration not neurodevelopment
5
Q
FAD v SAD AD
A
FAD - genetic, rare
SAD - most AD cases, de novo mutations
6
Q
early vs late onset AD
A
early - before 65, correlated with FAD
late - most AD cases
7
Q
how is vascular disease related to sporadic AD
A
cant get blood/O2/food to the brain –> trigger cell death mechanisms –> neurodegeneration
8
Q
major brain area affected by AD
A
basal forebrain (cholinergic neuron path)
9
Q
is AD a cause of death
A
no, death in AD cases mostly due to infection or stroke
10
Q
severity level of most AD cases
A
moderate, 2 year development
11
Q
MRI AD brain
A
smaller structure (less white area)
less activity
12
Q
extracellular lesions in AD
A
result of AB plaques
13
Q
intracellular lesions in AD
A
tau (neurofibrillary) tangles
14
Q
what is the normal function of tau
A
microtubule binding protein to increase cell structure stabilization
15
Q
why are tau tangles problematic
A
tangles prevent microtubule (tau) formation –> prevent cell stability
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
17
Q
TAUist AD hypothesis
A
abnormal phosphorylation of tau makes them “sticky” —> tangles form and cause cell death
18
Q
how are AB peptides generated
A
cleavage of APP by secretases
19
Q
what AB fragments is prone to aggregation
A
AB 1-42, cleaved by B-secretase
20
Q
are AB plaques a cause or consequence of AD
A
unknown
21
Q
how are tau tangles formed in AD
A
hyper-phosphorylation at specific epitopes
22
Q
all possible genetic mutations of AD are — —-
A
autosomal dominant
23
Q
APP mutations account of 15-20% of —-
A
early onset FAD
24
Q
what other disease mutation causes elevated APP
A
C21 trisomy of DS
25
PSEN mutations account for 30-70% of ---
early onset AD
26
possible PSEN genetic mutations
PSEN1 (c14) and PSEN2 (c1)
27
normal PSEN function
form catalytic part of gamma secretase
28
PSEN mutation and AD relation
mutated catalytic site of gamma secretase --> cleavage of APP at position 42 instead of 40
29
ApoE polymorphisms are associated with ---
late-onset AD
30
define polymorphism
same gene with different sequence of length in each individual
31
e2 allele and AD
protection (7% population)
32
e3 allele and AD
most common, neutral risk/protection
33
e4 allele and AD
risk (14%)
highest in african-american populations
34
3 functions of ApoE
transport cholesterol to neurons
low density lipoprotein receptor gene
facilitate AB clearance via lysosomal pathway
35
what is PIB
PET scan compound that binds AB
36
support for BAPtist hypothesis of AD
AB peptide is primary component of necrotic AD patients, all mutations in early-onset AD are associated with AB
37
limitations of BAPtist hypothesis of AD
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
38
why don't AB plaques alone cause cell death
AB plaques decrease ROS in brain
39
excitotoxicity hypothesis of AD
excess excitation causes overactive Ca2+ transporters and Ca2+ influx --> polarizes membrane and activates cell death pathway
40
all hypothesis of AD end with ----, indicating the ----- organelle is involved
apoptosis, mitochondria (release of cytochrome c)
41
what causes cytotoxicity
imbalance between byproducts and antioxidants
42
3 steps for clinical diagnosis of AD
Neuropsychologic evaluation (behavior, easiest)
Imaging (structure damage, X-ray or MRI)
Functional imaging (low metabolic function, fMRI or PET scan)
43
do the levels of AB 1-42 correlate with disease severity? what does that mean about AB42 being used as a biomarker for AD?
no, not a good biomarker
44
AD cortical area morphology
cortical thickness decreased, cortical neuron number stays the same --> demyelination/loss of axons/etc
45
3 FDA traditional approved AD drugs (choline esterase inhibitors
galantamine, rivastigimine, donespezil
46
FDA traditional approved excitotoxicity inhibitor
memantine
47
2 FDA accelerated approval drugs for AD
aducanumab, lecanemab
48
how do choline esterase inhibitors work with AD
inhibit the breakdown of Ach from synaptic gap (since cholinergic neurons are lost, there is already a decrease in available Ach)
49
main issues with choline esterase inhibition AD drugs
increased Ach overstimulates PNS
does not address cell death
50
how does memantine (excitotoxicity inhibitor) work with AD?
NMDA antagonist, competitively inhibits glutamatergic system by blocking NMDA receptors
51
what makes memantine effect?
use in combination with choline esterase inhibitors
52
active vaccines
inject a piece of the virus/bacteria/peptide
53
passive vaccine
monoclonal antibody injected (-mab suffix)
54
outcome of treatment trials targeting AB using antibodies
no cognitive benefits
55
current use of lecanemab/aducanumab for AD
passive vaccine
effectively removes AB but mixed reports on efficacy
costly, inconvenient
56
outcome of treatments targeting AB using secretase inhibitors
increases symptoms
57
how can diet be a protective factor from AD
fruits/veggies -> antioxidants to remove ROS
low sat. fats -> avoids vascular disease
58
how can alcohol be protective against AD
small amounts act as a blood thinner and increase circulation in the brain
59
how can statins (lower cholesterol) be protective against AD
reduce risk of clogged blood vessels
60
limitation of AD mouse models
models based on over-expression of human mutant proteins, all associated with early-onset AD
less relevant to disease dynamics
61
is the cause of PD known?
no, don't know why but do know how
62
what type of disorder is PD
motor, progressive (worsens with age/time)
63
how is PD diagnosed
clinically only (no available biomarker test)
must have tremor or bradykinesia (slow movement) AND at least 1 other symptom
64
4 major symptoms of PD (TRAP)
tremors, rigidity, akinesia (loss of movement), postural instability
65
what order do symptoms appear in PD
motor then non-motor (behavioral, sensory, autonomic)
66
PD is a lack of --- in the brain
dopamine
67
why do PD individuals react well to levodopa
levodopa is a dopamine precursor that can enter BBB --> can upregulate dopamine signaling in PD patients
68
2 pathogenesis factors of PD
lewy bodies seen 1st, then dopamine levels checked
69
2 genes associated with PD
alpha-synuclein
Parkin
70
functions associated with gene mutations in PD
lysosomal degradation, mitochondria dysfunction
71
---- mutation and ---- of alpha-syn. gene cause familial PD
missense, triplication
72
mutations to alpha-syn gene cause --- associated with PD
lewy body formation
73
why is rotenone environmental risk factor of PD
it acts as a mitochondrial blocker
74
what is rotenone
insecticide
75
why is paraquat an environmental risk factor of PD
produces superoxides
76
what is paraquat
herbicide
77
how does rotenone act in respect to PD
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
where are motor neurons dying in PD
substantia nigra
79
what are lewy bodies
alpha-syn aggregates
80
how do Parkin mutations contribute to PD
inhibit Ub protease system
81
where does the nigrostriatal pathway innervate to
cortical area - striatum
82
what nt does the nigrostriatal pathway release
dopamine
83
PD patient PET
decreased activity, less dark areas (dopamine activity)
84
mechanism of MPTP
enters cells via DAT--> selectively kills dopamine cells in SN --> inhibits complex 1 of ETC --> prevents ATP synthesis and increase ROS
85
3 most effective treatment ideas for PD
increase dopamine levels (L-dopa)
activate dopamine receptors (receptor agonists)
block dopamine breakdown (MAOI)
86
limitation of dopamine injections for PD
inconvenient, dopamine does not pass BBB
87
levodopa works best when ---
co-administered with inhibitor of L-amino acid decarboxylase to suppress L-DOPA conversion to dopamine before crossing BBB
88
limitation of using L-dopa for PD
inconsistent long-term
89
how do monoamine oxidase inhibitors (MAOI) work against PD
inhibit enzymes that catalyzes destruction of primary amines (like dopamine) by providing "fake dopamine" to be broken down instead
90
why are MAOI's mot effective in early stage PD
not effective in later stages b/c dopamine levels too low
91
3 limitations of using stem cell transplantation to treat PD
differentiation guidance, axon growth guidance to SN specifically, no guarantee of synapse formation
92
how does HD compare to PD
HD --> more exaggerated uncontrollable movements, earlier onset, cells in dorsal striatum dying
93
what type of disease is HD
degenerative genetic movement disorder
94
what order do symptoms develop with HD
cognitive then motor
95
HD affects the ---- (brain area)
basal ganglia
96
HD is strongly linked to ---
genetic repeat expansion
97
what is hyperkinesia
wild movements
98
how do you test for preliminary HD
cognitive and neuropsych. tests
99
death of HD patients generally happens after --- and by ----
10-20 years, suicide
100
HD gene mutation
autosomal dominant mutation of huntingtin gene (HTT) on C4
101
HTT repeat in HD
CAG repeat, more than 36 repeats (normally <20)
102
HD is often called ---- b/c CAG encodes for ---
polyglutamine disease, glutamine
103
CAG repeats and onset age of HD relationship
the more repeats, the earlier onset
104
how to test genetically for HD
PCR (quicker) or sequencing
105
HD patient CT/MRI scans
small striatum (less white)
106
HD is caused by selective ------ neurons in ---- and lead to ---
degeneration of GABAnergic neurons in the striatum --> lead to loss of inhibitory pathways and loss of motor control
107
function of normal HTT gene
suppress apoptosis by hiding pro-apoptosis enzyme HIP-1
108
how does mutant HTT cause cell death
mutant HTT does not hide HIP-1 which allows uncontrolled apoptosis
109
HTT mutations and BDNF expresssion
suppressed (decrease amount of BDNF neurotropic factor needed for neural survival)
110
mutant HTT and CREB
mutant HTT sticks to CREB binding protein and prevents transcriptional activity
111
what type of inclusion bodies are seen in HD
intracellular HTT aggregates on the nucleus of neurons in the striatum
112
2 major limitations of HD animal models
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
common HD animal model
overexpression of HTT gene
114
why won't Levodopa work against HD
HD affects GABAnergic neurons not dopaminergic
115
only current prescribed HD treatment
tetrabenazine
116
function of tetrabenazine vs HD
VMAT inhibitor--> degrades monoamines (like dopamine)
deplete excess excitatory stimulus since inhibitory neurons are lost and causing an imbalance
117
what type of disease is ALS
progressive neurodegenerative, motor (no decline in cognitive function)
118
lateral and ventral tract status in ALS
ventral (anterior) - intact and functional
lateral (posterior) - hardened
119
normal function of lateral tracts
limb movement
120
what neuron type is degraded in ALS
pyramidal motor neurons (excitatory)
121
most ALS cases are ---
sporadic
122
common cause of death of ALS patients
3-5 years after diagnosis from pulmonary infection
123
morphologic characteristics of lateral tract in ALS
decreased thickness and fiber branching
124
SOD1 aggregation and ALS
overexpression of SOD1 --> not all functional --> aggregation --> ROS not broken down --> motor neuron death
125
ALS shows degeneration and loss of --- and ---
cortical motor neurons and astrocytic gliosis
126
2 intracellular inclusions of ALS
bunina bodies
Ub inclusions
127
diagnosis of ALS
physical symptom evaluations (knee jerk rxn test) first then MRI/CT/EMG to confirm
128
ALS MRI scan
dark outer areas, brighter inside -> degeneration of lateral tract axons
